Clinical Focus


  • Cancer > Radiation Oncology
  • Cancer > Thoracic Oncology
  • Radiation Oncology
  • Radiation Therapy

Administrative Appointments


  • Cancer Biology Graduate Program Admissions Committee, Stanford University (2012 - Present)
  • Stem Cell Biology & Regenerative Medicine Graduate Program Admissions Committee, Stanford University (2013 - Present)
  • Medical Scientist Training Program (MSTP) Admissions Committee, Stanford University (2011 - Present)

Honors & Awards


  • Thomas Temple Hoopes Prize for outstanding senior thesis, Harvard University (1997)
  • Medical Scientist Training Program, Stanford University (1997-2004)
  • Franklin G. Ebaugh, Jr. Award for Research, Department of Medicine, Stanford University (2005)
  • Annual Meeting Basic Science Travel Grant Award, American Society for Therapeutic Radiology and Oncology (ASTRO) (2006)
  • ASTRO Residents in Radiation Oncology Research Seed Grant, American Society for Therapeutic Radiology and Oncology (ASTRO) (2006-2008)
  • Holman Research Pathway, American Board of Radiology (ABR) (2006-2009)
  • RSNA Research Resident/Fellow Grant, Radiological Society of North America (RSNA) (2007-2009)
  • Roentgen Resident/Fellow Research Award, Radiological Society of North America (RSNA) (2008)
  • Malcolm A. Bagshaw Award, Stanford University (2009)
  • Sidney Kimmel Scholar Award, Sidney Kimmel Foundation (2010-2013)
  • Doris Duke Clinical Scientist Development Award, Doris Duke Charitable Foundation (2010-2014)
  • Edward Mallinckrodt, Jr. Foundation Grant, Edward Mallinckrodt, Jr. Foundation (2010-2014)
  • Donald E. and Delia B. Baxter Foundation Faculty Scholar Award, Donald E. and Delia B. Baxter Foundation (2011-2012)
  • Henry S. Kaplan Memorial Prize for Teaching, Stanford University (2012)
  • Lung Cancer Research Program Promising Clinician Research Award, Department of Defense (2012-2014)
  • CRK Faculty Scholar, CRK (2012-present)
  • Walter H. Coulter Translational Research Grant, Walter H. Coulter Foundation (2013-2014)
  • V Foundation Scholar Grant, V Foundation (2013-2015)
  • NIH Director's New Innovator Award, National Institute of Health (NIH) (2013-2018)
  • American Red Cross Blood Services Hero Award, American Red Cross (2016)
  • Election to American Society for Clinical Investigation, American Society for Clinical Investigation (ASCI) (2017)
  • ASCO Leadership Development Program, American Society of Clinical Oncology (ASCO) (2017-2018)
  • Elected to the National Academy of Medicine, National Academy of Medicine (NAM) (2021)

Boards, Advisory Committees, Professional Organizations


  • Member, American Society for Therapeutic Radiology and Oncology (ASTRO) (2004 - Present)
  • Member, Radiological Society of North America (RSNA) (2004 - Present)
  • Member, International Society for Stem Cell Research (ISSCR) (2010 - Present)
  • Member, International Association for the Study of Lung Cancer (IASLC) (2011 - Present)

Professional Education


  • Residency: Stanford University Dept of Radiation Oncology (2009) CA
  • Medical Education: Stanford University School of Medicine (2004) CA
  • Internship: Stanford University Internal Medicine Residency (2005) CA
  • Board Certification: American Board of Radiology, Radiation Oncology (2010)
  • MD, Stanford University (2004)
  • PhD, Stanford University, Biophysics (2004)
  • AB, Harvard College, Biochemical Sciences (1997)

Current Research and Scholarly Interests


My laboratory focuses on two main areas: 1) cancer stem cell biology and its implications for therapy and 2) development of genomics-based biomarkers for identifying the presence of malignant cells (diagnostic), predicting outcome (prognostic), and predicting response to therapy (predictive). Areas of study include cancers of the lung, breast, and gastrointestinal system. We are also interested in developing a deeper molecular understanding of normal and cancer stem cells, including identifying pathways and genes important for survival and self-renewal. Additionally, we are developing methods for overcoming resistance mechanisms to radiotherapy and chemotherapy in cancer stem cells. We employ the tools of cancer genomics, including high throughput sequencing for detecting cancer mutations and quantifying gene expression. Clinically I specialize in the treatment of lung cancer and applications of stereotactic ablative radiotherapy and perform both prospective and retrospective clinical studies.

Clinical Trials


  • Novel Serum Markers for Monitoring Response to Anti-Cancer Therapy Recruiting

    The purpose of this study is to measure the levels of serum proteins and other biomarkers in cancer patients and in patients suspected of having cancer. We believe that some of these markers may be useful for confirming the diagnosis or for selecting patients for specific types of cancer therapies. These markers may also help to predict response to therapy, relapse after therapy, and survival after therapy.

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  • Personalized Escalation of Consolidation Treatment Following Chemoradiotherapy and Immunotherapy in Stage III NSCLC in Stage III NSCLC Recruiting

    The purpose of this study is to test whether or not number of circulating cancer cells detected in the blood can be decreased the by combining the standard treatment (durvalumab) with Tremelimumab and additional chemotherapy

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  • Biopsy of Human Tumors for Cancer Stem Cell Characterization: a Feasibility Study Not Recruiting

    To see if a limited sampling of tumor tissue from human subjects is a feasible way to gather adequate tissue for cancer stem cell quantification.

    Stanford is currently not accepting patients for this trial. For more information, please contact Ruth Lira, 650-723-1367.

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  • BLP25 Liposome Vaccine and Bevacizumab After Chemotherapy and Radiation Therapy in Treating Patients With Newly Diagnosed Stage IIIA or Stage IIIB Non-Small Cell Lung Cancer That Cannot Be Removed by Surgery Not Recruiting

    RATIONALE: Vaccines may help the body build an effective immune response to kill tumor cells. Monoclonal antibodies, such as bevacizumab, can block tumor growth in different ways. Some block the ability of tumor cells to grow and spread. Others find tumor cells and help kill them or carry tumor-killing substances to them. Drugs used in chemotherapy work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Radiation therapy uses high-energy x-rays to kill tumor cells. Giving vaccine therapy together with bevacizumab after chemotherapy and radiation therapy may kill more tumor cells. PURPOSE: This phase II trial is studying the side effects of giving BLP25 liposome vaccine together with bevacizumab after chemotherapy and radiation therapy in treating patients with newly diagnosed stage IIIA or stage IIIB non-small cell lung cancer that cannot be removed by surgery.

    Stanford is currently not accepting patients for this trial. For more information, please contact Maria Pitsiouni, 650-721-6977.

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  • Breath Analysis for Evaluation of Radiation Exposure in Lung Cancer Patients Treated With Radiation Not Recruiting

    Patients treated with radiation therapy for lung tumors can experience inflammation after treatment. This study hopes to evaluate the use of breath analysis to evaluate changes in the composition of exhaled breath in patients undergoing radiotherapy. If changes can be detected, this may ultimately serve as biomarkers for identifying patients at highest risk for radiation-induced lung injury (radiation pneumonitis).

    Stanford is currently not accepting patients for this trial. For more information, please contact Laura Gable, (650) 736 - 0798.

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  • Cisplatin and Etoposide Plus Radiation Followed By Nivolumab/Placebo For Locally Advanced NSCLC Not Recruiting

    Patients with Stage III unresectable non-small cell lung cancer will receive thoracic radiation, cisplatin and etoposide followed by nivolumab or placebo given every 2 weeks for a year.

    Stanford is currently not accepting patients for this trial. For more information, please contact Madelyn Kissel, 650-497-8966.

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  • CT Perfusion Imaging in Predicting Treatment Response in Patients With Non-small Cell Lung Cancer or Lung Metastases Treated With Stereotactic Ablative Radiation Therapy Not Recruiting

    This study assesses computed tomography (CT) perfusion imaging in predicting treatment response in patients with non-small cell lung cancer or tumors that have spread from the primary site (place where it started) to the lungs (metastases) treated with stereotactic ablative radiation therapy. CT perfusion imaging is a special type of CT that uses an injected dye in order to see how blood flow through tissues, including lung tissue. CT perfusion imaging of the lungs may help doctors learn whether perfusion characteristics of lung tumors may be predictive of response to treatment and whether lung perfusion characteristics can be used to follow response to treatment.

    Stanford is currently not accepting patients for this trial. For more information, please contact Samantha Wong, 650-498-8495.

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  • CyberKnife Radiosurgical Treatment of Inoperable Early Stage Non-Small Cell Lung Cancer Not Recruiting

    The purpose of this study is to assess the short and long-term outcomes after CyberKnife stereotactic radiosurgery for early stage non-small cell lung cancer (NSCLC) in patients who are medically inoperable.

    Stanford is currently not accepting patients for this trial. For more information, please contact Lisa Zhou, (650) 736 - 4112.

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  • Erlotinib Hydrochloride or Crizotinib and Chemoradiation Therapy in Treating Patients With Stage III Non-small Cell Lung Cancer Not Recruiting

    This randomized phase II trial studies how well erlotinib hydrochloride or crizotinib with chemoradiation therapy works in treating patients with stage III non-small cell lung cancer. Radiation therapy uses high energy x rays to kill tumor cells. Specialized radiation therapy that delivers a high dose of radiation directly to the tumor may kill more tumor cells and cause less damage to normal tissue. Drugs used in chemotherapy, such as cisplatin, etoposide, paclitaxel, and carboplatin, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. It is not yet known whether giving erlotinib hydrochloride is more effective than crizotinib with chemoradiation therapy in treating patients with non-small cell lung cancer.

    Stanford is currently not accepting patients for this trial. For more information, please contact Katie Brown, 650-723-1423.

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  • Imaging and Biomarkers of Hypoxia in Solid Tumors Not Recruiting

    Hypoxia, meaning a lack of oxygen, has been associated strongly with a wide range of human cancers. Hypoxia occurs when tumor growth exceeds the ability of blood vessels to supply the tumor with oxygenated blood. It is currently understood that hypoxic tumors are more aggressive. Current methods for measuring hypoxia include invasive procedures such as tissue biopsy, or insertion of an electrode into the tumor. EF5-PET may be a non-invasive way to measure tumor hypoxia.

    Stanford is currently not accepting patients for this trial. For more information, please contact Justin Carter, 650-725-4796.

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  • Individualized Lung Tumor Stereotactic Ablative Radiotherapy (iSABR) Not Recruiting

    A research study of a procedure to treating lung cancer with focused radiation called Stereotactic Ablative Radiotherapy (SABR). The purpose of this study is to evaluate the effectiveness of individualizing the dose of radiation used to treat lung tumors with SABR based on tumor-specific factors. While recent research has identified SABR as a promising method to increase local control (LC) of lung cancer, further research has indicated that tumor volume is a prognostic factor, with increased size/volume of tumor being associated with poorer outcomes. This study explores if a volume-adapted strategy for the radiologic exposure (dose) will improve efficacy in larger tumors (ie, \> 10 cc). This is a study of the procedure stereotactic ablative radiotherapy (SABR). It is not a study of a specific drug or device.

    Stanford is currently not accepting patients for this trial. For more information, please contact Samantha Wong, 650-498-8495.

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  • Lapatinib Ditosylate and Radiation Therapy in Treating Patients With Locally Advanced or Locally Recurrent Breast Cancer Not Recruiting

    This phase II trial studies how well lapatinib ditosylate and radiation therapy work in treating patients with locally advanced or locally recurrent breast cancer. Lapatinib ditosylate may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Radiation therapy uses high energy x rays to kill tumor cells. Giving lapatinib ditosylate together with radiation therapy may be an effective treatment for breast cancer.

    Stanford is currently not accepting patients for this trial. For more information, please contact Amanda Simmons, 650-724-4606.

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  • Manuka Honey in Preventing Esophagitis-Related Pain in Patients Receiving Chemotherapy and Radiation Therapy For Lung Cancer Not Recruiting

    RATIONALE: Manuka honey may prevent or reduce esophagitis-related pain caused by chemotherapy and radiation therapy. It is not yet known whether Manuka honey is more effective than standard care in preventing pain. PURPOSE: This randomized phase II clinical trial is studying Manuka honey to see how well it works in preventing esophagitis-related pain in patients receiving chemotherapy and radiation therapy for lung cancer.

    Stanford is currently not accepting patients for this trial. For more information, please contact Laura Gable, (650) 736 - 0798.

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  • Molecular Analysis of Thoracic Malignancies Not Recruiting

    A research study to learn about the biologic features of cancer development, growth, and spread. We are studying components of blood, tumor tissue, normal tissue, and other fluids, such as urine, cerebrospinal fluid, abdominal or chest fluid in patients with cancer. Our analyses of blood, tissue, and/or fluids may lead to improved diagnosis and treatment of cancer by the identification of markers that predict clinical outcome, markers that predict response to specific therapies, and the identification of targets for new therapies.

    Stanford is currently not accepting patients for this trial. For more information, please contact Jordan Preiss, 650-723-1002.

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  • Molecular and Cellular Analysis of Breast Cancer Not Recruiting

    The purpose of the study is to investigate the different types and subtypes of cells found in breast tumors. The investigators will do this using a variety of molecular analysis tools that may allow for improved tests. The different types of cells in breast cancer impacts the way individuals respond to various treatments.

    Stanford is currently not accepting patients for this trial. For more information, please contact Michelle Aboytes, 650-498-9071.

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  • Pulmonary Interstitial Lymphography in Early Stage Lung Cancer Not Recruiting

    The stereotactic body radiation therapy (SBRT) procedure is an emerging alternative to the standard treatment for early stage non-small cell lung cancer (NSCLC), typically lobectomy with lymphadenectomy. This procedure (lobectomy) does not fulfill the medical need as many patients are poor operative candidates or decline surgery. This study assesses the feasibility of stereotactic body radiation therapy (SBRT) as a tool to produce therapeutically useful computed tomography (CT) scans, using standard water-soluble iodinated compounds as the contrast agents.

    Stanford is currently not accepting patients for this trial. For more information, please contact Laura Gable, (650) 736 - 0798.

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  • Radiation Therapy in Treating Patients With Extensive Stage Small Cell Lung Cancer Not Recruiting

    RATIONALE: Radiation therapy uses high energy x-rays to kill tumor cells. This may be an effective treatment for extensive stage small cell lung cancer. PURPOSE: This randomized phase II trial is comparing how well radiation therapy to the brain works when given with or without radiation therapy to other areas of the body in treating patients with extensive stage small cell lung cancer.

    Stanford is currently not accepting patients for this trial. For more information, please contact Laura Gable, (650) 736 - 0798.

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  • Radiation Therapy in Treating Patients With Stage I Non-Small Cell Lung Cancer Not Recruiting

    RATIONALE: Radiation therapy uses high-energy x-rays to kill tumor cells. Specialized radiation therapy that delivers a high dose of radiation directly to the tumor may kill more tumor cells and cause less damage to normal tissue. It is not yet known which regimen of stereotactic body radiation therapy is more effective in treating patients with non-small cell lung cancer. PURPOSE: This randomized phase II trial is studying the side effects of two radiation therapy regimens and to see how well they work in treating patients with stage I non-small cell lung cancer.

    Stanford is currently not accepting patients for this trial. For more information, please contact laura gable, (650) 736 - 0798.

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  • Radical-Dose Image Guided Radiation Therapy in Treating Patients With Metastatic Non-small Cell Lung Cancer Undergoing Immunotherapy Not Recruiting

    This phase II trial studies how well radical-dose image guided radiation therapy works in treating patients with non-small cell lung cancer that has spread to other places in the body who are undergoing immunotherapy. Radiation therapy uses high energy x-rays to kill tumor cells and shrink tumors. Giving radical-dose image guided radiation therapy to patients with non-small cell lung cancer may help to improve response to immunotherapy anti-cancer treatment.

    Stanford is currently not accepting patients for this trial. For more information, please contact Kim Nguyen, 650-497-8966.

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  • Randomized Study to Compare CyberKnife to Surgical Resection In Stage I Non-small Cell Lung Cancer Not Recruiting

    Lung cancer remains the most frequent cause of cancer death in both men and women in the world. Surgical resection using lobectomy with mediastinal lymph node dissection or sampling has been a standard of care for operable early stage NSCLC. Several studies have reported high local control and survival using SBRT in stage I NSCLC patients. SBRT is now an accepted treatment for medically inoperable patients with stage I NSCLC and patients with operable stage I lung cancer are entered on clinical protocols. The purpose of this study is to conduct a phase III randomized study to compare CyberKnife SBRT with surgery, the current standard of care for stage I operable NSCLC.

    Stanford is currently not accepting patients for this trial. For more information, please contact Lisa Zhou, (650) 736 - 4112.

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  • SABR-ATAC: A Trial of TGF-beta Inhibition and Stereotactic Ablative Radiotherapy for Early Stage Non-small Cell Lung Cancer Not Recruiting

    The SABR-ATAC trial (Stereotactic Ablative Radiotherapy and anti-TGFB Antibody Combination) is a phase I/II trial that studies the side effects and efficacy of fresolimumab, an anti-transforming growth factor beta (TGFB) antibody, when given with stereotactic ablative radiotherapy in patients with stage IA-IB non-small cell lung cancer. Fresolimumab may inhibit radiation side effects and block tumor growth through multiple mechanisms. Stereotactic ablative radiotherapy (SABR), also known as stereotactic body radiotherapy (SBRT), is a specialized form of radiation therapy that precisely delivers high dose radiation directly to tumors, thus killing tumor cells and minimizing damage to normal tissue. Giving fresolimumab with SABR may work better in treating patients with early stage non-small cell lung cancer than treating with SABR alone.

    Stanford is currently not accepting patients for this trial. For more information, please contact Laura Gable, 650-736-0798.

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  • Study of Positron Emission Tomography and Computed Tomography in Guiding Radiation Therapy in Patients With Stage III Non-small Cell Lung Cancer Not Recruiting

    This randomized phase II trial studies how well positron emission tomography (PET)/computed tomography (CT)-guided radiation therapy works compared to standard radiation therapy in treating patients with stage III non-small cell lung cancer. Radiation therapy uses high-energy x-rays to kill tumor cells. Using imaging procedures, such as PET and CT scans, to guide the radiation therapy, may help doctors deliver higher doses directly to the tumor and cause less damage to healthy tissue.

    Stanford is currently not accepting patients for this trial. For more information, please contact Laura Gable, 650-736-0798.

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  • Surgery With or Without Internal Radiation Therapy Compared With Stereotactic Body Radiation Therapy in Treating Patients With High-Risk Stage I Non-Small Cell Lung Cancer Not Recruiting

    RATIONALE: Surgery with or without internal radiation therapy may be an effective treatment for non-small cell lung cancer. Internal radiation uses radioactive material placed directly into or near a tumor to kill tumor cells. Stereotactic body radiation therapy may be able to send x-rays directly to the tumor and cause less damage to normal tissue. It is not yet known whether stereotactic body radiation therapy is more effective than surgery with or without internal radiation therapy in treating non-small cell lung cancer. PURPOSE: This randomized phase III trial is studying how well surgery with or without internal radiation therapy works compared with stereotactic body radiation therapy in treating patients with high-risk stage IA or stage IB non-small cell lung cancer.

    Stanford is currently not accepting patients for this trial. For more information, please contact Lisa Zhou, (650) 736 - 4112.

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  • Testing the Safety of Adding Either Monalizumab (IPH2201) or Oleclumab (MEDI9447) to Durvalumab (MEDI4736) Plus Standard Radiation Therapy for Locally Advanced Non-small Cell Lung Cancer (NSCLC), ARCHON-1 Trial Not Recruiting

    This phase I trial studies the safety of adding durvalumab to accelerated hypofractionated radiation therapy (ACRT) or conventionally fractionated radiation therapy, as well as the safety of adding either monalizumab or oleclumab to durvalumab plus conventionally fractionated radiation therapy in treating patients with non-small cell lung cancer that has spread to nearby tissue or lymph nodes (locally advanced). Accelerated hypofractionated radiation therapy delivers higher doses of radiation therapy over a shorter period of time and may kill more tumor cells and have fewer side effects. Immunotherapy with monoclonal antibodies, such as durvalumab and monalizumab, may help the body's immune system attack the tumor, and may interfere with the ability of tumor cells to grow and spread. Oleclumab is in a class of medications called monoclonal antibodies. It binds to a protein called CD73, which is found on some types of tumor cells. Oleclumab may block CD73 and help the immune system kill tumor cells. It is not yet known whether adding durvalumab to ACRT or adding monalizumab or oleclumab to durvalumab plus conventionally fractionated radiation therapy will work better in treating patients with non-small cell lung cancer.

    Stanford is currently not accepting patients for this trial. For more information, please contact Cancer Clinical Trials Office (CCTO), 650-498-7061.

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2024-25 Courses


Stanford Advisees


All Publications


  • Integrating genomic features for non-invasive early lung cancer detection NATURE Chabon, J. J., Hamilton, E. G., Kurtz, D. M., Esfahani, M. S., Moding, E. J., Stehr, H., Schroers-Martin, J., Nabet, B. Y., Chen, B., Chaudhuri, A. A., Liu, C., Hui, A. B., Jin, M. C., Azad, T. D., Almanza, D., Jeon, Y., Nesselbush, M. C., Keh, L., Bonilla, R. F., Yoo, C. H., Ko, R. B., Chen, E. L., Merriott, D. J., Massion, P. P., Mansfield, A. S., Jen, J., Ren, H. Z., Lin, S. H., Costantino, C. L., Burr, R., Tibshirani, R., Gambhir, S. S., Berry, G. J., Jensen, K. C., West, R. B., Neal, J. W., Wakelee, H. A., Loo, B. W., Kunder, C. A., Leung, A. N., Lui, N. S., Berry, M. F., Shrager, J. B., Nair, V. S., Haber, D. A., Sequist, L. V., Alizadeh, A. A., Diehn, M. 2020
  • Noninvasive Early Identification of Therapeutic Benefit from Immune Checkpoint Inhibition. Cell Nabet, B. Y., Esfahani, M. S., Moding, E. J., Hamilton, E. G., Chabon, J. J., Rizvi, H. n., Steen, C. B., Chaudhuri, A. A., Liu, C. L., Hui, A. B., Almanza, D. n., Stehr, H. n., Gojenola, L. n., Bonilla, R. F., Jin, M. C., Jeon, Y. J., Tseng, D. n., Liu, C. n., Merghoub, T. n., Neal, J. W., Wakelee, H. A., Padda, S. K., Ramchandran, K. J., Das, M. n., Plodkowski, A. J., Yoo, C. n., Chen, E. L., Ko, R. B., Newman, A. M., Hellmann, M. D., Alizadeh, A. A., Diehn, M. n. 2020

    Abstract

    Although treatment of non-small cell lung cancer (NSCLC) with immune checkpoint inhibitors (ICIs) can produce remarkably durable responses, most patients develop early disease progression. Furthermore, initial response assessment by conventional imaging is often unable to identify which patients will achieve durable clinical benefit (DCB). Here, we demonstrate that pre-treatment circulating tumor DNA (ctDNA) and peripheral CD8 T cell levels are independently associated with DCB. We further show that ctDNA dynamics after a single infusion can aid in identification of patients who will achieve DCB. Integrating these determinants, we developed and validated an entirely noninvasive multiparameter assay (DIREct-On, Durable Immunotherapy Response Estimation by immune profiling and ctDNA-On-treatment) that robustly predicts which patients will achieve DCB with higher accuracy than any individual feature. Taken together, these results demonstrate that integrated ctDNA and circulating immune cell profiling can provide accurate, noninvasive, and early forecasting of ultimate outcomes for NSCLC patients receiving ICIs.

    View details for DOI 10.1016/j.cell.2020.09.001

    View details for PubMedID 33007267

  • KEAP1/NFE2L2 mutations predict lung cancer radiation resistance that can be targeted by glutaminase inhibition. Cancer discovery Binkley, M. S., Jeon, Y. J., Nesselbush, M. n., Moding, E. J., Nabet, B. Y., Almanza, D. n., Kunder, C. n., Stehr, H. n., Yoo, C. H., Rhee, S. n., Xiang, M. n., Chabon, J. J., Hamilton, E. n., Kurtz, D. M., Gojenola, L. n., Owen, S. G., Ko, R. B., Shin, J. H., Maxim, P. G., Lui, N. S., Backhus, L. M., Berry, M. F., Shrager, J. B., Ramchandran, K. J., Padda, S. K., Das, M. n., Neal, J. W., Wakelee, H. A., Alizadeh, A. A., Loo, B. W., Diehn, M. n. 2020

    Abstract

    Tumor genotyping is not routinely performed in localized non-small cell lung cancer (NSCLC) due to lack of associations of mutations with outcome. Here, we analyze 232 consecutive patients with localized NSCLC and demonstrate that KEAP1 and NFE2L2 mutations are predictive of high rates of local recurrence (LR) after radiotherapy but not surgery. Half of LRs occurred in KEAP1/NFE2L2 mutation tumors, indicating they are major molecular drivers of clinical radioresistance. Next, we functionally evaluate KEAP1/NFE2L2 mutations in our radiotherapy cohort and demonstrate that only pathogenic mutations are associated with radioresistance. Furthermore, expression of NFE2L2 target genes does not predict LR, underscoring the utility of tumor genotyping. Finally, we show that glutaminase inhibition preferentially radiosensitizes KEAP1 mutant cells via depletion of glutathione and increased radiation-induced DNA damage. Our findings suggest that genotyping for KEAP1/NFE2L2 mutations could facilitate treatment personalization and provide a potential strategy for overcoming radioresistance conferred by these mutations.

    View details for DOI 10.1158/2159-8290.CD-20-0282

    View details for PubMedID 33071215

  • Circulating tumor DNA dynamics predict benefit from consolidation immunotherapy in locally advanced non-small-cell lung cancer Nature Cancer Moding, E. J., Liu, Y., Nabet, B. Y., Chabon, J. J., Chaudhuri, A. A., Hui, A. B., Bonilla, R. F., Ko, R. B., Yoo, C. H., He, J., Qiao, Y., Xu, T., Heymach, J. V., Tsao, A., Liao, Z., Gomez, D. R., Das, M., Padda, S. K., Ramchandran, K. J., Neal, J. W., Wakelee, H. A., Loo, B. W., Lin, S. H., Alizadeh, A. A., Diehn, M. 2020; 1
  • Detection and Surveillance of Bladder Cancer Using Urine Tumor DNA CANCER DISCOVERY Dudley, J. C., Schroers-Martin, J., Lazzareschi, D., Shi, W., Chen, S. B., Esfahani, M. S., Trivedi, D., Chabon, J. J., Chaudhuri, A. A., Stehr, H., Liu, C., Lim, H., Costa, H. A., Nabet, B. Y., Sin, M. Y., Liao, J. C., Alizadeh, A. A., Diehn, M. 2019; 9 (4): 500–509
  • Early detection of molecular residual disease in localized lung cancer by circulating tumor DNA profiling. Cancer discovery Chaudhuri, A. A., Chabon, J. J., Lovejoy, A. F., Newman, A. M., Stehr, H. n., Azad, T. D., Khodadoust, M. S., Esfahani, M. S., Liu, C. L., Zhou, L. n., Scherer, F. n., Kurtz, D. M., Say, C. n., Carter, J. N., Merriott, D. J., Dudley, J. C., Binkley, M. S., Modlin, L. n., Padda, S. K., Gensheimer, M. F., West, R. B., Shrager, J. B., Neal, J. W., Wakelee, H. A., Loo, B. W., Alizadeh, A. A., Diehn, M. n. 2017

    Abstract

    Identifying molecular residual disease (MRD) after treatment of localized lung cancer could facilitate early intervention and personalization of adjuvant therapies. Here we apply Cancer Personalized Profiling by Deep Sequencing (CAPP-Seq) circulating tumor DNA (ctDNA) analysis to 255 samples from 40 patients treated with curative intent for stage I-III lung cancer and 54 healthy adults. In 94% of evaluable patients experiencing recurrence, ctDNA was detectable in the first post-treatment blood sample, indicating reliable identification of MRD. Post-treatment ctDNA detection preceded radiographic progression in 72% of patients by a median of 5.2 months and 53% of patients harbored ctDNA mutation profiles associated with favorable responses to tyrosine kinase inhibitors or immune checkpoint blockade. Collectively, these results indicate that ctDNA MRD in lung cancer patients can be accurately detected using CAPP-Seq and may allow personalized adjuvant treatment while disease burden is lowest.

    View details for PubMedID 28899864

  • Role of KEAP1/NRF2 and TP53 Mutations in Lung Squamous Cell Carcinoma Development and Radiation Resistance. Cancer discovery Jeong, Y., Hoang, N. T., Lovejoy, A., Stehr, H., Newman, A. M., Gentles, A. J., Kong, W., Truong, D., Martin, S., Chaudhuri, A., Heiser, D., Zhou, L., Say, C., Carter, J. N., Hiniker, S. M., Loo, B. W., West, R. B., Beachy, P., Alizadeh, A. A., Diehn, M. 2016

    Abstract

    Lung squamous cell carcinoma (LSCC) pathogenesis remains incompletely understood, and biomarkers predicting treatment response remain lacking. Here, we describe novel murine LSCC models driven by loss of Trp53 and Keap1, both of which are frequently mutated in human LSCCs. Homozygous inactivation of Keap1 or Trp53 promoted airway basal stem cell (ABSC) self-renewal, suggesting that mutations in these genes lead to expansion of mutant stem cell clones. Deletion of Trp53 and Keap1 in ABSCs, but not more differentiated tracheal cells, produced tumors recapitulating histologic and molecular features of human LSCCs, indicating that they represent the likely cell of origin in this model. Deletion of Keap1 promoted tumor aggressiveness, metastasis, and resistance to oxidative stress and radiotherapy (RT). KEAP1/NRF2 mutation status predicted risk of local recurrence after RT in patients with non-small lung cancer (NSCLC) and could be noninvasively identified in circulating tumor DNA. Thus, KEAP1/NRF2 mutations could serve as predictive biomarkers for personalization of therapeutic strategies for NSCLCs.We developed an LSCC mouse model involving Trp53 and Keap1, which are frequently mutated in human LSCCs. In this model, ABSCs are the cell of origin of these tumors. KEAP1/NRF2 mutations increase radioresistance and predict local tumor recurrence in radiotherapy patients. Our findings are of potential clinical relevance and could lead to personalized treatment strategies for tumors with KEAP1/NRF2 mutations. Cancer Discov; 7(1); 86-101. ©2016 AACR.This article is highlighted in the In This Issue feature, p. 1.

    View details for PubMedID 27663899

  • Circulating tumour DNA profiling reveals heterogeneity of EGFR inhibitor resistance mechanisms in lung cancer patients NATURE COMMUNICATIONS Chabon, J. J., Simmons, A. D., Lovejoy, A. F., Esfahani, M. S., Newman, A. M., Haringsma, H. J., Kurtz, D. M., Stehr, H., Scherer, F., Karlovich, C. A., Harding, T. C., Durkin, K. A., Otterson, G. A., Purcell, W. T., Camidge, D. R., Goldman, J. W., Sequist, L. V., Piotrowska, Z., Wakelee, H. A., Neal, J. W., Alizadeh, A. A., Diehn, M. 2016; 7

    Abstract

    Circulating tumour DNA (ctDNA) analysis facilitates studies of tumour heterogeneity. Here we employ CAPP-Seq ctDNA analysis to study resistance mechanisms in 43 non-small cell lung cancer (NSCLC) patients treated with the third-generation epidermal growth factor receptor (EGFR) inhibitor rociletinib. We observe multiple resistance mechanisms in 46% of patients after treatment with first-line inhibitors, indicating frequent intra-patient heterogeneity. Rociletinib resistance recurrently involves MET, EGFR, PIK3CA, ERRB2, KRAS and RB1. We describe a novel EGFR L798I mutation and find that EGFR C797S, which arises in ∼33% of patients after osimertinib treatment, occurs in <3% after rociletinib. Increased MET copy number is the most frequent rociletinib resistance mechanism in this cohort and patients with multiple pre-existing mechanisms (T790M and MET) experience inferior responses. Similarly, rociletinib-resistant xenografts develop MET amplification that can be overcome with the MET inhibitor crizotinib. These results underscore the importance of tumour heterogeneity in NSCLC and the utility of ctDNA-based resistance mechanism assessment.

    View details for DOI 10.1038/ncomms11815

    View details for PubMedID 27283993

  • An ultrasensitive method for quantitating circulating tumor DNA with broad patient coverage NATURE MEDICINE Newman, A. M., Bratman, S. V., To, J., Wynne, J. F., Eclov, N. C., Modlin, L. A., Liu, C. L., Neal, J. W., Wakelee, H. A., Merritt, R. E., Shrager, J. B., Loo, B. W., Alizadeh, A. A., Diehn, M. 2014; 20 (5): 552-558

    Abstract

    Circulating tumor DNA (ctDNA) is a promising biomarker for noninvasive assessment of cancer burden, but existing ctDNA detection methods have insufficient sensitivity or patient coverage for broad clinical applicability. Here we introduce cancer personalized profiling by deep sequencing (CAPP-Seq), an economical and ultrasensitive method for quantifying ctDNA. We implemented CAPP-Seq for non-small-cell lung cancer (NSCLC) with a design covering multiple classes of somatic alterations that identified mutations in >95% of tumors. We detected ctDNA in 100% of patients with stage II-IV NSCLC and in 50% of patients with stage I, with 96% specificity for mutant allele fractions down to ∼0.02%. Levels of ctDNA were highly correlated with tumor volume and distinguished between residual disease and treatment-related imaging changes, and measurement of ctDNA levels allowed for earlier response assessment than radiographic approaches. Finally, we evaluated biopsy-free tumor screening and genotyping with CAPP-Seq. We envision that CAPP-Seq could be routinely applied clinically to detect and monitor diverse malignancies, thus facilitating personalized cancer therapy.

    View details for DOI 10.1038/nm.3519

    View details for Web of Science ID 000335710700028

  • Analysis of Circulating Tumor DNA Predicts Outcomes of Short Course Consolidation Immunotherapy in Unresectable Stage III Non-Small Cell Lung Cancer. Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer Jun, S., Shukla, N. A., Durm, G., Hui, A. B., Cao, S., Ganti, A. K., Jabbour, S. K., Kunder, C., Alizadeh, A. A., Hanna, N. H., Diehn, M. 2024

    Abstract

    The current standard of care for patients with inoperable stage III non-small cell lung cancer (NSCLC) includes chemoradiotherapy (CRT) followed by one year of checkpoint inhibitor (CPI) therapy. However, the optimal duration of consolidation CPI remains unknown. Here, we characterized the relationship between circulating tumor DNA (ctDNA) minimal residual disease (MRD) and clinical outcomes of unresectable locally advanced NSCLC patients treated on a phase 2 trial of short course consolidation immunotherapy after CRT, with the goal of testing if ctDNA may be able to identify patients who do not require a full year of treatment.Plasma samples for ctDNA analysis were collected from patients on the BTCRC LUN 16-081 trial after completion of CRT, prior to C2D1 of CPI (i.e. 1 month after treatment start), and at the end of up to 6 months of treatment. Tumor-informed ctDNA MRD analysis was performed using CAPP-Seq. Levels of ctDNA at each time point were correlated with clinical outcomes.Detection of ctDNA predicted significantly inferior progression-free survival (PFS) after completion of CRT (24-month 29% vs 65%, P = 0.0048), prior to C2D1 of CPI (24-month 0% vs 72%, P < 0.0001) and at the end of CPI (24-month 15% vs 67%, P = 0.0011). Additionally, patients with decreasing or undetectable ctDNA levels after one cycle of CPI had improved outcomes compared to patients with increasing ctDNA levels (24-month PFS 72% vs 0%, P < 0.0001). Progression of disease occurred within <12 months of starting CPI in all patients with increasing ctDNA levels at C2D1.Detection of ctDNA before, during, or after 6 months of consolidation CPI is strongly associated with inferior outcomes. Our findings suggest that analysis of ctDNA MRD may enable personalizing the duration of consolidation immunotherapy treatment.

    View details for DOI 10.1016/j.jtho.2024.06.024

    View details for PubMedID 38971369

  • Assessing the Evidence for Circulating Tumor HPV DNA in Patients With Oropharyngeal Cancer. JAMA oncology Lee, N. Y., Morris, L. G., Diehn, M. 2024

    View details for DOI 10.1001/jamaoncol.2024.1821

    View details for PubMedID 38935364

  • Combined JAK inhibition and PD-1 immunotherapy for non-small cell lung cancer patients. Science (New York, N.Y.) Mathew, D., Marmarelis, M. E., Foley, C., Bauml, J. M., Ye, D., Ghinnagow, R., Ngiow, S. F., Klapholz, M., Jun, S., Zhang, Z., Zorc, R., Davis, C. W., Diehn, M., Giles, J. R., Huang, A. C., Hwang, W. T., Zhang, N. R., Schoenfeld, A. J., Carpenter, E. L., Langer, C. J., Wherry, E. J., Minn, A. J. 2024; 384 (6702): eadf1329

    Abstract

    Persistent inflammation driven by cytokines such as type-one interferon (IFN-I) can cause immunosuppression. We show that administration of the Janus kinase 1 (JAK1) inhibitor itacitinib after anti-PD-1 (programmed cell death protein 1) immunotherapy improves immune function and antitumor responses in mice and results in high response rates (67%) in a phase 2 clinical trial for metastatic non-small cell lung cancer. Patients who failed to respond to initial anti-PD-1 immunotherapy but responded after addition of itacitinib had multiple features of poor immune function to anti-PD-1 alone that improved after JAK inhibition. Itacitinib promoted CD8 T cell plasticity and therapeutic responses of exhausted and effector memory-like T cell clonotypes. Patients with persistent inflammation refractory to itacitinib showed progressive CD8 T cell terminal differentiation and progressive disease. Thus, JAK inhibition may improve the efficacy of anti-PD-1 immunotherapy by pivoting T cell differentiation dynamics.

    View details for DOI 10.1126/science.adf1329

    View details for PubMedID 38900877

  • Risk of Second Tumors and T-Cell Lymphoma after CAR T-Cell Therapy. The New England journal of medicine Hamilton, M. P., Sugio, T., Noordenbos, T., Shi, S., Bulterys, P. L., Liu, C. L., Kang, X., Olsen, M. N., Good, Z., Dahiya, S., Frank, M. J., Sahaf, B., Mackall, C. L., Gratzinger, D., Diehn, M., Alizadeh, A. A., Miklos, D. B. 2024; 390 (22): 2047-2060

    Abstract

    The risk of second tumors after chimeric antigen receptor (CAR) T-cell therapy, especially the risk of T-cell neoplasms related to viral vector integration, is an emerging concern.We reviewed our clinical experience with adoptive cellular CAR T-cell therapy at our institution since 2016 and ascertained the occurrence of second tumors. In one case of secondary T-cell lymphoma, a broad array of molecular, genetic, and cellular techniques were used to interrogate the tumor, the CAR T cells, and the normal hematopoietic cells in the patient.A total of 724 patients who had received T-cell therapies at our center were included in the study. A lethal T-cell lymphoma was identified in a patient who had received axicabtagene ciloleucel therapy for diffuse large B-cell lymphoma, and both lymphomas were deeply profiled. Each lymphoma had molecularly distinct immunophenotypes and genomic profiles, but both were positive for Epstein-Barr virus and were associated with DNMT3A and TET2 mutant clonal hematopoiesis. No evidence of oncogenic retroviral integration was found with the use of multiple techniques.Our results highlight the rarity of second tumors and provide a framework for defining clonal relationships and viral vector monitoring. (Funded by the National Cancer Institute and others.).

    View details for DOI 10.1056/NEJMoa2401361

    View details for PubMedID 38865660

  • Quantification of cerebrospinal fluid tumor DNA in lung cancer patients with suspected leptomeningeal carcinomatosis. NPJ precision oncology Azad, T. D., Nanjo, S., Jin, M. C., Chabon, J. J., Kurtz, D. M., Chaudhuri, A. A., Connolly, I. D., Hui, A. B., Liu, C. L., Merriott, D., Ko, R., Yoo, C., Carter, J., Chen, E., Bonilla, R., Hata, A., Katakami, N., Irie, K., Yano, S., Okimoto, R., Bivona, T. G., Newman, A. M., Iv, M., Nagpal, S., Gephart, M. H., Alizadeh, A. A., Diehn, M. 2024; 8 (1): 121

    Abstract

    Cerebrospinal fluid tumor-derived DNA (CSF-tDNA) analysis is a promising approach for monitoring the neoplastic processes of the central nervous system. We applied a lung cancer-specific sequencing panel (CAPP-Seq) to 81 CSF, blood, and tissue samples from 24 lung cancer patients who underwent lumbar puncture (LP) for suspected leptomeningeal disease (LMD). A subset of the cohort (N = 12) participated in a prospective trial of osimertinib for refractory LMD in which serial LPs were performed before and during treatment. CSF-tDNA variant allele fractions (VAFs) were significantly higher than plasma circulating tumor DNA (ctDNA) VAFs (median CSF-tDNA, 32.7%; median plasma ctDNA, 1.8%; P < 0.0001). Concentrations of tumor DNA in CSF and plasma were positively correlated (Spearman's ρ, 0.45; P = 0.03). For LMD diagnosis, cytology was 81.8% sensitive and CSF-tDNA was 91.7% sensitive. CSF-tDNA was also strongly prognostic for overall survival (HR = 7.1; P = 0.02). Among patients with progression on targeted therapy, resistance mutations, such as EGFR T790M and MET amplification, were common in peripheral blood but were rare in time-matched CSF, indicating differences in resistance mechanisms based on the anatomic compartment. In the osimertinib cohort, patients with CNS progression had increased CSF-tDNA VAFs at follow-up LP. Post-osimertinib CSF-tDNA VAF was strongly prognostic for CNS progression (HR = 6.2, P = 0.009). Detection of CSF-tDNA in lung cancer patients with suspected LMD is feasible and may have clinical utility. CSF-tDNA improves the sensitivity of LMD diagnosis, enables improved prognostication, and drives therapeutic strategies that account for spatial heterogeneity in resistance mechanisms.

    View details for DOI 10.1038/s41698-024-00582-1

    View details for PubMedID 38806586

    View details for PubMedCentralID 5641214

  • Chest wall pain after single-fraction thoracic stereotactic ablative Radiotherapy: Dosimetric analysis from the iSABR trial. Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology Lau, B., Wu, Y. F., Cui, S., Fu, J., Jackson, S., Pham, D., Dubrowski, P., Eswarappa, S., Skinner, L., Shirato, H., Taguchi, H., Gensheimer, M. F., Gee, H., Chin, A. L., Diehn, M., Loo, B. W., Moiseenko, V., Vitzthum, L. K. 2024: 110317

    Abstract

    Concerns over chest wall toxicity has led to debates on treating tumors adjacent to the chest wall with single-fraction stereotactic ablative radiotherapy (SABR). We performed a secondary analysis of patients treated on the prospective iSABR trial to determine the incidence and grade of chest wall pain and modeled dose-response to guide radiation planning and estimate risk.This analysis included 99 tumors in 92 patients that were treated with 25 Gy in one fraction on the iSABR trial which individualized dose by tumor size and location. Toxicity events were prospectively collected and graded based on the CTCAE version 4. Dose-response modeling was performed using a logistic model with maximum likelihood method utilized for parameter fitting.There were 22 grade 1 or higher chest wall pain events, including five grade 2 events and zero grade 3 or higher events. The volume receiving at least 11 Gy (V11Gy) and the minimum dose to the hottest 2 cc (D2cc) were most highly correlated with toxicity. When dichotomized by an estimated incidence of ≥ 20 % toxicity, the D2cc > 17 Gy (36.6 % vs. 3.7 %, p < 0.01) and V11Gy > 28 cc (40.0 % vs. 8.1 %, p < 0.01) constraints were predictive of chest wall pain, including among a subset of patients with tumors abutting or adjacent to the chest wall.For small, peripheral tumors, single-fraction SABR is associated with modest rates of low-grade chest wall pain. Proximity to the chest wall may not contraindicate single fractionation when using highly conformal, image-guided techniques with sharp dose gradients.

    View details for DOI 10.1016/j.radonc.2024.110317

    View details for PubMedID 38679202

  • First in human Phase I Clinical Trial of Stereotactic Irradiation to Achieve Lung Volume Reduction (SILVR) in Severe Emphysema. International journal of radiation oncology, biology, physics Kamtam, D. N., Binkley, M. S., Kapula, N., Sadeghi, C., Nesbit, S., Md, H. H., Chang, J., Maxim, P. G., Diehn, M., Loo, B. W., Shrager, J. B. 2024

    Abstract

    Only a subset of patients with severe emphysema qualify for lung volume reduction surgery or endobronchial valves. We previously demonstrated that Stereotactic Ablative Radiotherapy (SABR) of lung tumors reduces lung volume in treated lobes by creating localized lung fibrosis. We aimed to determine the safety and, secondarily, explore the efficacy of Stereotactic Irradiation for Lung Volume Reduction (SILVR) over 18 months following intervention in patients with severe emphysema.We conducted a single-arm prospective clinical trial in eligible patients with severe emphysema treated with unilateral SABR (45 Gy in three fractions) to a target within the most emphysematous region. Primary outcome was safety i.e., incidence of grade≥3 adverse events. Secondary outcomes of efficacy were also explored.Eight subjects received the intervention. Median (range) baseline characteristics were age 73 years (63-78), FEV1% 28.5% (19.0-42.0), DLCO% 40% (24.0-67.0), and BODE index 5.5 (5-9). The incidence of grade≥3 adverse events was 3/8 (37.5%). The relative Δtarget lobe volume was -23.1% (-1.6,-41.5) and -26.5% (-20.6,-40.8) at six and 18 months, respectively. Absolute ΔFEV1% was greater in subjects with BODE index ≤5 vs. ≥6 (+12.0% vs. -2.0%). The mean baseline lung density (in Hounsfield units, reflecting the amount of preserved parenchyma) within the intermediate dose volume (V60BED3) correlated with the absolute Δtarget lobe volume at 18 months.Stereotactic Irradiation for Lung Volume Reduction appears to be safe, with a signal for efficacy as a novel therapeutic alternative for patients with severe emphysema. SILVR may be most safe/effective in patients with lower BODE index and/or less parenchymal destruction.

    View details for DOI 10.1016/j.ijrobp.2024.03.049

    View details for PubMedID 38615887

  • Cancer biomarkers: Emerging trends and clinical implications for personalized treatment. Cell Passaro, A., Al Bakir, M., Hamilton, E. G., Diehn, M., André, F., Roy-Chowdhuri, S., Mountzios, G., Wistuba, I. I., Swanton, C., Peters, S. 2024; 187 (7): 1617-1635

    Abstract

    The integration of cancer biomarkers into oncology has revolutionized cancer treatment, yielding remarkable advancements in cancer therapeutics and the prognosis of cancer patients. The development of personalized medicine represents a turning point and a new paradigm in cancer management, as biomarkers enable oncologists to tailor treatments based on the unique molecular profile of each patient's tumor. In this review, we discuss the scientific milestones of cancer biomarkers and explore future possibilities to improve the management of patients with solid tumors. This progress is primarily attributed to the biological characterization of cancers, advancements in testing methodologies, elucidation of the immune microenvironment, and the ability to profile circulating tumor fractions. Integrating these insights promises to continually advance the precision oncology field, fostering better patient outcomes.

    View details for DOI 10.1016/j.cell.2024.02.041

    View details for PubMedID 38552610

  • A human lymphoma organoid model for evaluating and targeting the follicular lymphoma tumor immune microenvironment. Cell stem cell Kastenschmidt, J. M., Schroers-Martin, J. G., Sworder, B. J., Sureshchandra, S., Khodadoust, M. S., Liu, C. L., Olsen, M., Kurtz, D. M., Diehn, M., Wagar, L. E., Alizadeh, A. A. 2024

    Abstract

    Heterogeneity in the tumor microenvironment (TME) of follicular lymphomas (FLs) can affect clinical outcomes. Current immunotherapeutic strategies, including antibody- and cell-based therapies, variably overcome pro-tumorigenic mechanisms for sustained disease control. Modeling the intact FL TME, with its native, syngeneic tumor-infiltrating leukocytes, is a major challenge. Here, we describe an organoid culture method for cultivating patient-derived lymphoma organoids (PDLOs), which include cells from the native FL TME. We define the robustness of this method by successfully culturing cryopreserved FL specimens from diverse patients and demonstrate the stability of TME cellular composition, tumor somatic mutations, gene expression profiles, and B/T cell receptor dynamics over 3 weeks. PDLOs treated with CD3:CD19 and CD3:CD20 therapeutic bispecific antibodies showed B cell killing and T cell activation. This stable system offers a robust platform for advancing precision medicine efforts in FL through patient-specific modeling, high-throughput screening, TME signature identification, and treatment response evaluation.

    View details for DOI 10.1016/j.stem.2024.01.012

    View details for PubMedID 38402619

  • Pulmonary interstitial lymphography: A prospective trial with potential impact on stereotactic ablative radiotherapy planning for early-stage lung cancer. Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology Ko, R. B., Abelson, J. A., Fleischmann, D., Louie, J. D., Hwang, G. L., Sze, D. Y., Schuler, E., Kielar, K. N., Maxim, P. G., Le, Q., Hara, W. H., Diehn, M., Kothary, N., Loo, B. W. 2023: 110079

    Abstract

    This prospective feasibility trial investigated pulmonary interstitial lymphography to identify thoracic primary nodal drainage (PND). A post-hoc analysis of nodal recurrences was compared with PND for patients with early-stage lung cancer; larger studies are needed to establish correlation. Exploratory PND-inclusive stereotactic ablative radiotherapy plans were assessed for dosimetric feasibility.

    View details for DOI 10.1016/j.radonc.2023.110079

    View details for PubMedID 38163486

  • Specificity of Immunoglobulin High-Throughput Sequencing Minimal Residual Disease Monitoring in Non-Hodgkin Lymphomas. Blood advances Shukla, N., Schroers-Martin, J., Sworder, B., Kathuria, K. R., Alig, S., Frank, M. J., Miklos, D. B., Coutre, S. E., Diehn, M., Khodadoust, M. S., Roschewski, M. J., Kurtz, D. M., Alizadeh, A. A. 2023

    View details for DOI 10.1182/bloodadvances.2023011997

    View details for PubMedID 38147627

  • Distinct Hodgkin lymphoma subtypes defined by noninvasive genomic profiling. Nature Alig, S. K., Esfahani, M. S., Garofalo, A., Li, M. Y., Rossi, C., Flerlage, T., Flerlage, J. E., Adams, R., Binkley, M. S., Shukla, N., Jin, M. C., Olsen, M., Telenius, A., Mutter, J. A., Schroers-Martin, J. G., Sworder, B. J., Rai, S., King, D. A., Schultz, A., Bögeholz, J., Su, S., Kathuria, K. R., Liu, C. L., Kang, X., Strohband, M. J., Langfitt, D., Pobre-Piza, K. F., Surman, S., Tian, F., Spina, V., Tousseyn, T., Buedts, L., Hoppe, R., Natkunam, Y., Fornecker, L. M., Castellino, S. M., Advani, R., Rossi, D., Lynch, R., Ghesquières, H., Casasnovas, O., Kurtz, D. M., Marks, L. J., Link, M. P., André, M., Vandenberghe, P., Steidl, C., Diehn, M., Alizadeh, A. A. 2023

    Abstract

    The scarcity of malignant Hodgkin and Reed-Sternberg (HRS) cells hamper tissue-based comprehensive genomic profiling of classic Hodgkin lymphoma (cHL). Liquid biopsies, in contrast, show promise for molecular profiling of cHL due to relatively high circulating tumor DNA (ctDNA) levels1-4. Here, we show that the plasma representation of mutations exceeds the bulk tumor representation in most cases, making cHL particularly amenable to noninvasive profiling. Leveraging single-cell transcriptional profiles of cHL tumors, we demonstrate HRS ctDNA shedding to be shaped by DNASE1L3, whose increased tumor microenvironment-derived expression drives high ctDNA concentrations. Using this insight, we comprehensively profile 366 patients, revealing two distinct cHL genomic subtypes with characteristic clinical and prognostic correlates, as well as distinct transcriptional and immunological profiles. Furthermore, we identify a novel class of truncating IL4R-mutations that are dependent on IL13 signaling and therapeutically targetable with IL4R blocking antibodies. Finally, using PhasED-Seq5 we demonstrate the clinical value of pre- and on-treatment ctDNA levels for longitudinally refining cHL risk prediction, and for detection of radiographically occult minimal residual disease. Collectively, these results support the utility of noninvasive strategies for genotyping and dynamic monitoring of cHL as well as capturing molecularly distinct subtypes with diagnostic, prognostic, and therapeutic potential.

    View details for DOI 10.1038/s41586-023-06903-x

    View details for PubMedID 38081297

  • Predicting Adverse Cardiac Events After Radiotherapy for Locally Advanced Non-Small Cell Lung Cancer. JACC. CardioOncology No, H. J., Guo, F. B., Park, N. J., Kastelowitz, N., Rhee, J. W., Clark, D. E., Chin, A. L., Vitzthum, L. K., Horst, K. C., Moding, E. J., Loo, B. W., Diehn, M., Binkley, M. S. 2023; 5 (6): 775-787

    Abstract

    Radiotherapy may cause grade ≥3 cardiac events, necessitating a better understanding of risk factors. The potential predictive role of imaging biomarkers with radiotherapy doses for cardiac event occurrence has not been studied.The aim of this study was to establish the associations between cardiac substructure dose and coronary artery calcium (CAC) scores and cardiac event occurrence.A retrospective cohort analysis included patients with locally advanced non-small cell lung cancer treated with radiotherapy (2006-2018). Cardiac substructures, including the left anterior descending coronary artery, left main coronary artery, left circumflex coronary artery, right coronary artery, and TotalLeft (left anterior descending, left main, and left circumflex coronary arteries), were contoured. Doses were measured in 2-Gy equivalent units, and visual CAC scoring was compared with automated scoring. Grade ≥3 adverse cardiac events were recorded. Time-dependent receiver-operating characteristic modeling, the log-rank statistic, and competing-risk models were used to measure prediction performance, threshold modeling, and the cumulative incidence of cardiac events, respectively.Of the 233 eligible patients, 61.4% were men, with a median age of 68.1 years (range: 34.9-90.7 years). The median follow-up period was 73.7 months (range: 1.6-153.9 months). Following radiotherapy, 22.3% experienced cardiac events, within a median time of 21.5 months (range: 1.7-118.9 months). Visual CAC scoring showed significant correlation with automated scoring (r = 0.72; P < 0.001). In a competing-risk multivariable model, TotalLeft volume receiving 15 Gy (per 1 cc; HR: 1.38; 95% CI: 1.11-1.72; P = 0.004) and CAC score >5 (HR: 2.51; 95% CI: 1.08-5.86; P = 0.033) were independently associated with cardiac events. A model incorporating age, TotalLeft CAC (score >5), and volume receiving 15 Gy demonstrated a higher incidence of cardiac events for a high-risk group (28.9%) compared with a low-risk group (6.9%) (P < 0.001).Adverse cardiac events associated with radiation occur in more than 20% of patients undergoing thoracic radiotherapy within a median time of <2 years. The present findings provide further evidence to support significant associations between TotalLeft radiotherapy dose and cardiac events and define CAC as a predictive risk factor.

    View details for DOI 10.1016/j.jaccao.2023.08.007

    View details for PubMedID 38205000

    View details for PubMedCentralID PMC10774791

  • Patient Selection and Outcomes for Hypofractionated Accelerated Radiation and Concurrent Chemotherapy for Non-Small-Cell Lung Cancer. Clinical lung cancer Hui, C., Marquez, C., Lau, B., Das, M., Myall, N. J., Roy, M., Wakelee, H. A., Neal, J. W., Kovalchuk, N., Chin, A., Diehn, M., Loo, B. W., Xiang, M., Vitzthum, L. K. 2023

    Abstract

    Adoption of hypofractionated accelerated radiation therapy (HART) with concurrent chemotherapy has been limited by toxicity concerns. We aimed to describe outcomes of patients treated with HART and concurrent chemotherapy and to evaluate dosimetry to organs at risk to guide patient selection.We evaluated a retrospective cohort of NSCLC patients treated with concurrent chemotherapy with HART (>2.2 Gy per fraction) or standard fractionated radiation therapy (SFRT; 2-2.2 Gy fractions). Dosimetric parameters to key organs at risk were compared, and toxicity, patterns of recurrence and survival were calculated for the cohorts.Fifty-three patients treated with HART were compared with 100 patients treated with SFRT. Median dose per fraction for the HART cohort was 2.75 Gy (range 2.4-3 Gy). HART patients had significantly lower doses to the lung, heart, and esophagus due to patient selection. The HART group and had rates of grade 2+ pneumonitis (9.4 vs. 19%, P = .16) and grade 2+ esophagitis (20.8 vs. 45%, P < .01) that compared favorably to SFRT. Cumulative incidence of in-field recurrence trended lower in the HART cohort (7.6% vs. 23.1%, P = .058). Among the HART group, 88.7% (47/53) met the newly proposed lung constraints based on the degree of hypofractionation CONCLUSION: In select patients with favorable dosimetry to organs at risk, definitive HART with concurrent chemotherapy achieved excellent local control with low toxicity. These results are being used to inform a prospective study on the safety and efficacy of HART with concurrent chemotherapy for select NSCLC patients.

    View details for DOI 10.1016/j.cllc.2023.11.008

    View details for PubMedID 38065707

  • Personalized Accelerated ChEmoRadiation (PACER) for Lung Cancer: Protocol for a Bayesian Optimal Phase I/II Trial. Clinical lung cancer Hui, C., Brown, E., Wong, S., Das, M., Wakelee, H., Neal, J., Ramchandran, K., Myall, N. J., Pham, D., Xing, L., Yang, Y., Kovalchuk, N., Yuan, Y., Lu, Y., Xiang, M., Chin, A., Diehn, M., Loo, B. W., Vitzthum, L. K. 2023

    Abstract

    Prior attempts to escalate radiation dose for non-small cell lung cancer (NSCLC) have not improved survival. Given the high risk for cardiopulmonary toxicity with treatment and heterogenous presentation of locally advanced NSCLC, it is unlikely that a single dose regimen is optimal for all patients. This phase I/II trial aims to evaluate a novel treatment approach where the level of accelerated hypofractionation is determined by the predicted toxicity from dose to organs at risk (OARs).Patients ≥ 18 years old with lung cancer planned for fractionated radiotherapy to the lung with concurrent chemotherapy will be eligible. Radiation therapy (RT) will be delivered to a total dose of 60 to 66 Gy in 30, 25, or 20 fractions depending on the ability to meet constraints to key organs at risk including the lungs, heart, and esophagus. The primary endpoint is high grade pulmonary, esophageal, or cardiac toxicity. A Bayesian optimized design is used to determine stopping boundaries and evaluate the primary endpoint.PACER will evaluate the safety and feasibility of personalized accelerated chemoradiotherapy for lung cancer.

    View details for DOI 10.1016/j.cllc.2023.11.004

    View details for PubMedID 38040540

  • CAR19 Therapy Drives Expansion of Clonal Hematopoiesis and Associated Cytopenias Hamilton, M. P., Sworder, B. J., Alig, S. K., Good, Z., Boegeholz, J., Schroers-Martin, J., Tamaresis, J., Esfahani, M., Lu, Y., Olsen, M., Liu, C., Ehlinger, Z., Desai, M., Liu-Fei, F., Muffly, L. S., Negrin, R. S., Arai, S., Johnston, L., Lowsky, R., Meyer, E. H., Rezvani, A. R., Shizuru, J., Weng, W., Shiraz, P., Sidana, S., Bharadwaj, S., Smith, M., Dahiya, S., Sahaf, B., Diehn, M., Frank, M. J., Mackall, C. L., Kurtz, D. M., Miklos, D. B., Alizadeh, A. A. AMER SOC HEMATOLOGY. 2023
  • Longitudinal Noninvasive Surveillance & Fragmentomic Characterization of Follicular Lymphoma Schroers-Martin, J., Mutter, J. A., Esfahani, M., Scherer, F., Soo, J., Alig, S. K., Kurtz, D. M., Sugio, T., Rossi, C., Tessoulin, B., Olsen, M., Liu, C., Diehn, M., Alizadeh, A. A. AMER SOC HEMATOLOGY. 2023
  • Optimizing Circulating Tumor DNA Limits of Detection for DLBCL during First Line Therapy Goldstein, J., Kim, W., Yoon, S., Kim, S., Roschewski, M., Westin, J., Lynch, R. C., Alig, S. K., Close, S., Chabon, J. J., Rossi, D., Wilson, W. H., Diehn, M., Alizadeh, A. A., Kurtz, D. M. AMER SOC HEMATOLOGY. 2023
  • Prognostic Utility of Minimal Residual Disease (MRD) after Curative Intent Induction Therapy for DLBCL: A Prospective Real-World Ctdna Study Sworder, B. J., Yoon, S., Kim, S., Schultz, A., Hogan, G., Close, S., Chabon, J. J., Diehn, M., Kurtz, D. M., Alizadeh, A. A., Kim, W. AMER SOC HEMATOLOGY. 2023
  • Distinct Circulating Genomic Features of Classical Hodgkin Lymphoma of Older Adults Rossi, C., Boegeholz, J., Alig, S. K., Garofalo, A., Esfahani, M., Schroers-Martin, J., Olsen, M., Kang, X., Kurtz, D. M., Sugio, T., Hamilton, M. P., Andre, M., Casasnovas, R., Fornecker, L., Diehn, M., Ghesquieres, H., Alizadeh, A. A. AMER SOC HEMATOLOGY. 2023
  • Inferred Gene Expression By Cell-Free DNA Profiling Allows Noninvasive Lymphoma Classification Mutter, J. A., Esfahani, M., Schroers-Martin, J., Alig, S. K., Hamilton, M. P., Sworder, B. J., Tessoulin, B., Boegeholz, J., Flerlage, T., Flerlage, J. E., Binkley, M. S., Sugio, T., Rossi, C., Olsen, M., Liu, C., Le Gouill, S., Kurtz, D. M., Diehn, M., Alizadeh, A. A. AMER SOC HEMATOLOGY. 2023
  • End-of-Treatment Response Assessment after Frontline Therapy for Aggressive B-Cell Lymphoma: Landmark Comparison of a Singular PET/CT Scan Versus Ultrasensitive Circulating Tumor DNA Roschewski, M., Lindenberg, L., Mena, E., Lakhotia, R., Melani, C., Steinberg, S. M., Schultz, A., Hogan, G., Chabon, J. J., Close, S., Diehn, M., Sworder, B. J., Kurtz, D. M., Alizadeh, A. A., Wilson, W. H. AMER SOC HEMATOLOGY. 2023
  • An Integrated Multimodal Framework for Noninvasive TCL Disease Detection and Monitoring Sugio, T., Shukla, N., Khodadoust, M. S., Nesselbush, M., Kato, K., Alig, S. K., Boegeholz, J., Schroers-Martin, J., Esfahani, M., Mutter, J. A., Garofalo, A., Jun, S., Hamilton, M. P., Rossi, C., Olsen, M., Liu, C., Akashi, K., Diehn, M., Alizadeh, A. A. AMER SOC HEMATOLOGY. 2023
  • Phased Variants Allow Robust Profiling of Circulating Tumor DNA in Untreated Follicular Lymphomas Nagy, A., Batai, B., Hogan, G., Chabon, J. J., Troke, M., Riley, L., Schultz, A., Close, S., Diehn, M., Alpar, D., Timar, B., Alizadeh, A. A., Kurtz, D. M., Bodor, C. AMER SOC HEMATOLOGY. 2023
  • Genomic, Transcriptional, and Immunological Validation of Distinct Molecular Subtypes of Classic Hodgkin Lymphoma through Tissue-Based and Noninvasive Methods Alig, S. K., Esfahani, M., Garofalo, A., Li, M., Rossi, C., Flerlage, T., Flerlage, J. E., Adams, R., Binkley, M. S., Shukla, N., Jin, M., Olsen, M., Telenius, A., Mutter, J. A., Schroers-Martin, J., Sworder, B. J., Rai, S., King, D., Schultz, A., Bogeholz, J., Su, S., Kathuria, K. R., Liu, C., Kang, X., Langfitt, D. M., Pobre-Piza, K., Tian, F., Strohband, M. J., Spina, V., Tousseyn, T., Buedts, L., Fornecker, L., Castellino, S. M., Advani, R. H., Rossi, D., Lynch, R. C., Ghesquieres, H., Casasnovas, O., Kurtz, D. M., Marks, L. J., Link, M. P., Andre, M., Vandenberghe, P., Steidl, C., Diehn, M., Alizadeh, A. A. AMER SOC HEMATOLOGY. 2023
  • Investigating Dosimetry and Imaging Biomarkers for Prediction of Major Adverse Cardiac Events Following Locally Advanced Non-Small Cell Lung Cancer Radiotherapy. International journal of radiation oncology, biology, physics No, H. J., Park, N. J., Guo, F. B., Kastelowitz, N., Snyder, J. M., Rhee, J. W., Clark, D. E., Chin, A. L., Vitzthum, L., Horst, K. C., Moding, E. J., Loo, B. W., Diehn, M., Binkley, M. S. 2023; 117 (2S): S170

    Abstract

    PURPOSE/OBJECTIVE(S): Thoracic radiotherapy (RT) may confer major adverse cardiac events (MACE) following treatment. Mean heart dose positively associates with MACE and recent studies show cardiac substructure dosimetry improves MACE prediction. Use of imaging biomarkers with cardiac substructure dose has not been studied for prediction of MACE. We sought to develop an integrated model for cardiac substructure dose and baseline coronary artery calcium (CAC) scoring and establish its relationship to MACE.MATERIALS/METHODS: A retrospective cohort analysis was performed of consecutive patients with locally advanced non-small cell lung cancer (NSCLC) treated with definitive RT from 2006-2018 at a single institution. Demographics, medical history, cardiac events, and treatments received were recorded. Cardiac substructures were contoured, including the left descending artery (LAD), left main coronary artery (LMCA), left circumflex (LCX), right coronary artery (RCA), TotalLeft (LAD+LMCA+LCX), and TotalCor (TotalLeft+RCA). Doses were measured in 2 Gy equivalent dose. CAC was scored by visual assessment and compared to established automated Agatston scoring. Primary endpoint was MACE incidence. Receiver operating characteristic (ROC) curves assessed dose and CAC metric model performance. Threshold modeling was conducted using the log rank statistic with 95% confidence intervals measured using bootstrap resampling with 1000 iterations. Competing risk models adjusted for death were used to measure cumulative incidence of MACE as well as in univariable and multivariable risk regression modeling. Pearson correlations were used to validate CAC scoring. P-values were two tailed and considered significant at P≤0.05.RESULTS: Of 233 eligible patients, 61.4% were male with a 68.1 years (range 34.9-90.7) median age. Median follow-up was 73.7 months (range 1.6-153.9). Median overall survival was 34.8 months. Following RT, 22.3% experienced at least one cardiac event at a median time of 21.5 months (range 1.7-118.9). Visual CAC scoring showed significant correlation with automated Agatston scoring (r = 0.72, P=1e-5). While left sided coronary arteries (TotalLeft), mean heart dose (MHD) and CAC scores individually predicted for MACE (AUC = 0.56-0.59), a multivariable model of TotalLeft CAC had the highest ROC analysis performance (AUC = 0.69). On univariable and multivariable competing risk regression analyses, TotalLeft V15 Gy >2.53 cc and CAC score >5 independently associated with MACE (P<0.05). A model incorporating age, TotalLeft CAC>5 and V15>2.53cc, showed incrementally higher MACE incidences for low (9.3%), intermediate (18.4%), and high-risk groups (27.7%) (P<0.01).CONCLUSION: RT-induced MACE occurs in >20% of those undergoing thoracic RT in a median time of <2 years. We validate significant associations between TotalLeft RT dose and MACE and establish CAC as a predictive risk factor. These findings may serve to inform personalized RT and future cardiac risk in locally advanced NSCLC.

    View details for DOI 10.1016/j.ijrobp.2023.06.273

    View details for PubMedID 37784425

  • Prospective Trial of Using Imaging to Predict Pathologic Response and Clinical Outcomes in Locally Advanced Esophageal Cancer. International journal of radiation oncology, biology, physics Liu, Y., Hobbs, B. P., Hofstetter, W., Murphy, M. B., Gandhi, S., Nguyen, Q. N., Chang, J. Y., Liao, Z., Diehn, M., Ma, J., Lin, S. H. 2023; 117 (2S): S12-S13

    Abstract

    PURPOSE/OBJECTIVE(S): Trimodality therapy with chemoradiation (CRT) followed by esophagectomy is the standard of care for locally advanced esophageal cancer. An unresolved question is whether pathologic complete response (pCR) can be assessed non-invasively for patients post-CRT. In this study, we assessed whether diffusion-weighted imaging (DWI) with MRI or PET can be used as predictors of pCR and other clinical outcomes after CRT.MATERIALS/METHODS: Patients were enrolled on a single-arm institutional trial (PA13-0380) assessing the role of imaging in predicting outcomes in potentially resectable esophageal patients undergoing trimodality therapy. All patients received neoadjuvant CRT, and 29 patients had subsequent surgery. DWI MRI and PET scans were obtained at baseline, 2 weeks after the start of CRT (interim) and 4 to 6 weeks after completion of CRT (follow up). Apparent diffusion coefficients (ADCs) were calculated based on DWI images. Circulating tumor DNA was obtained for 27 patients post-radiation using CAPP-Seq. Mann-Whitney tests compared imaging changes associated with pCR. Discrimination of pCR by imaging changes was quantified by received operating characteristics. Youden's index was applied to select optimal thresholds. Kaplan-Meier analysis was performed to assess differences in overall survival (OS) and progression-free survival (PFS) by changes in DWI, PET, and ctDNA parameters.RESULTS: Our cohort of 60 patients had a median follow up of 42.7 months, age of 65.4 yrs, and ECOG of 1 at completion of CRT. 90% were male, 58% had a history of smoking, and 85% were white. 83% had adenocarcinoma with the rest squamous cell carcinoma. Stages of the patients ranged from IIA to IIIB. All had moderately (47%) or poorly (53%) differentiated disease. All received 41.4-50.4 Gy in 1.8 Gy fractions with the majority receiving 50.4 Gy (95%). 29 patients underwent surgery after CRT of which 8 (27.6%) had pCR. Mean DeltaADC from baseline to mid-treatment was most associated with pCR (AUC = 0.98, p<0.001) for patients undergoing surgery. Max DeltaADC from baseline to first follow-up was most associated with OS (p = 0.002) and PFS (p<0.001) for the whole cohort. 27 patients had ctDNA analyzed after RT with the presence of ctDNA significantly associated with worse OS (HR = 0.12, p = 0.05) and PFS (HR = 0.10, p = 0.002). Combining ctDNA and max DeltaADC generated a model that was more predictive of OS and PFS than either alone. We found that neither the PET parameters of TLG or SUV max at baseline or changes in these parameters from baseline to mid-treatment or first follow-up were as predictive as DWI.CONCLUSION: We show that changes in DWI is associated with pCR, OS, and PFS in resectable esophageal cancer patients undergoing CRT. DWI was more predictive than PET and a model combining DWI and ctDNA was the most predictive of clinical outcomes. This study shows the significant promise of using DWI in potentially guiding treatment decisions in esophageal cancer patients and will require validation in a larger cohort.

    View details for DOI 10.1016/j.ijrobp.2023.06.227

    View details for PubMedID 37784311

  • Concurrent Radiation and Immunotherapy Augments Local Immunity and Improves Survival in Aneuploid NSCLC. International journal of radiation oncology, biology, physics Spurr, L. F., Martinez, C., Kang, W., Chen, M., Zha, Y., Hseu, R., Gutiontov, S., Turchan, W. T., Lynch, C., Pointer, K. B., Vokes, E. E., Bestvina, C. M., Patel, J. D., Diehn, M., Weichselbaum, R. R., Chmura, S. J., Pitroda, S. P. 2023; 117 (2S): S23

    Abstract

    PURPOSE/OBJECTIVE(S): Over 500 clinical trials combining radiation (RT) and immune checkpoint blockade (ICB) have been initiated based on preclinical evidence that RT can augment local immunity and improve the efficacy of ICB. However, many recent clinical trials have not found a benefit of combining RT and ICB, raising questions about whether a synergy exists. We examined whether RT and ICB interact to beneficially stimulate the immune response in patients and identified biomarkers of response to RT and ICB.MATERIALS/METHODS: We performed a molecular analysis of 1,740 patients from 3 cohorts. The COSINR dataset is a randomized clinical trial of 22 non-small cell lung cancer (NSCLC) patients treated with concurrent or sequential SBRT and ipilimumab/nivolumab. Paired pre- and on-treatment biopsies of an irradiated metastasis underwent whole exome sequencing and RNA-seq. On-treatment biopsies were obtained after SBRT and prior to ICB (sequential) or after SBRT and one cycle of ICB (concurrent). The UC cohort consisted of targeted DNA sequencing of 58 NSCLC patients treated with ICB alone, sequential RT+ICB, or concurrent RT+ICB. The MSKCC dataset is a pan-cancer cohort of targeted DNA sequencing of 1,660 patients treated with ICB. Aneuploidy score (AS) was defined as the fraction of chromosome arms with arm-level copy number alterations. Survival analyses utilized the Kaplan-Meier method and multivariable Cox proportional hazards models.RESULTS: In the COSINR trial, SBRT+ICB increased, whereas SBRT alone decreased, expression of effector T cell IFN-gamma and adaptive immune signatures (P<0.05). Established biomarkers of ICB response, including IFN-gamma signature, tumor mutational burden (TMB), PD-L1 expression, and neoantigen burden were not associated with survival (P>0.05). However, patients whose tumors exhibited high (≥median) but not low, AS had improved survival when treated with concurrent vs. sequential SBRT+ICB (1-year overall survival [OS] 100% vs. 17%, P = 0.025). Our findings were corroborated in the UC cohort: high AS tumors treated with RT + ICB had superior 1-year OS compared to those treated with ICB alone (59% vs. 31%, P = 0.021). Among those who received RT + ICB, concurrent treatment improved OS relative to sequential (1-year OS 76% vs. 38%). RT did not improve OS in patients with low (

    View details for DOI 10.1016/j.ijrobp.2023.06.279

    View details for PubMedID 37784457

  • Hyperfractionated Reirradiation for Locally Recurrent Thoracic Tumors. International journal of radiation oncology, biology, physics Butler, S. S., Raclin, T., Lau, B., Raja, N., Chin, A. L., Skinner, L., Diehn, M., Loo, B. W., Vitzthum, L. 2023; 117 (2S): e9

    Abstract

    PURPOSE/OBJECTIVE(S): For patients with locally recurrent thoracic tumors or second primaries within previously irradiated volumes, hyperfractionated reirradiation (re-RT) may mitigate late toxicity compared to conventional fractionation, but clinical outcomes have not been extensively studied. We herein report our institutional experience with thoracic hyperfractionated reirradiation.MATERIALS/METHODS: We identified 26 cases among 23 patients treated with re-RT to either primary or metastatic thoracic tumors, 60 Gy in 50 fractions, twice daily over 5 weeks using highly conformal image guided RT with motion management. Nineteen patients had dosimetry data available. The primary outcome was Grade (G2) or higher toxicity rates per CTCAEv5.0. Secondary endpoints were 12-month local control (LC), progression free survival (PFS)-determined by treating physician and/or multidisciplinary tumor board-and overall survival (OS).RESULTS: Median follow-up was 13 months. Half had non-small cell lung cancer, 95.8% had ultracentral tumors, 57.7% had single prior thoracic RT course; 38.5%, 11.5% and 11.5% received concurrent chemotherapy, immunotherapy, and targeted agents, respectively. Minimum and median intervals between RT courses were 10 and 39.5 months, respectively; 94.7% of re-irradiation plans had overlapping 80% isodose volumes. Median OS and PFS were 13 and 10 months, respectively. Crude 12-month LC was 73.1%. Of those with a recurrence, the first recurrence occurred locally in 6 (54.6%), regionally in 3 (27.3%), and distantly in 8 (72.7%) patients. ≥G2 and ≥G3 toxicity rates were 30.8% and 7.69%, respectively (one G3 atrial fibrillation; one G5 pneumonitis). Using the American Radium Society guidelines for thoracic reirradiation, only 10.5% met all dose volume constraint recommendations.CONCLUSION: Definitive hyperfractionated thoracic re-RT was well tolerated with promising local control. ≥G3 toxicities were rare. Patients should be counseled on the low but potential risk of life-threatening toxicity. Consensus guidelines for dose constraints may be difficult to meet in reirradiation setting; in this cohort, rates of severe toxicity were low despite exceeding putative constraints in most patients.

    View details for DOI 10.1016/j.ijrobp.2023.06.666

    View details for PubMedID 37786208

  • Predicting Local Control with Dosimetric Parameters in Patients Receiving Individualized Stereotactic Ablative Radiotherapy for Lung Tumors. International journal of radiation oncology, biology, physics Wu, Y. F., Lau, B., Fu, J., Cui, S., Pham, D., Dubrowski, P., Eswarappa, S., Zgrabik, J., Candow, L., Skinner, L., Shirato, H., Taguchi, H., Gensheimer, M. F., Gee, H. E., Diehn, M., Chin, A. L., Loo, B. W., Vitzthum, L. 2023; 117 (2S): e76

    Abstract

    PURPOSE/OBJECTIVE(S): Stereotactic ablative radiotherapy (SABR) is an effective treatment option for lung tumors. The individualized lung tumor SABR (iSABR) trial was a phase II single-arm study that personalized lung tumor SABR dose and fractionation based on tumor size, location, and histology with very low rates of local recurrence (LR). A secondary analysis of this trial was conducted to assess for potential dosimetric predictors of LR, in order to help guide future clinical treatment planning.MATERIALS/METHODS: From 2011 to 2018, local, regional and distant recurrence data were prospectively collected from 204 patients (261 lung SABR treatments) enrolled in a prospective trial. Baseline characteristics and treatment details were evaluated. Dosimetric and treatment plan parameters were evaluated for their potential to predict LR, using logistic regression and chi-squared analyses.RESULTS: The majority of treated tumors were peripheral (71%, vs 29% central), primary lesions (76%, versus 24% metastatic), and of adenocarcinoma histology (67%, versus 13% squamous cell carcinoma and 19% other). The median follow-up was 24 months (range 2-95). Twenty-seven (10.3%) LRs occurred, with a median time to LR of 15 months (range 6-81 months). There were no significant associations between the overall cohort and the dosimetric parameters. However, for the multi-fraction cohort, an increased proportion of the PTV receiving 110% and 115% of the prescription dose were associated with lower LR (p = 0.01 and p = 0.01 respectively). Specifically for the 50 Gy in 4 fraction cohort, an increased D1cc, D0.03cc, as well as the proportion of the PTV receiving 110%, 115%, and 120% of the prescription dose were associated with lower LR (p < 0.001, p = 0.001, p = 0.003, p < 0.001, p = 0.004, respectively). There was no association of LR with prescription dose expressed as biologically effective dose using an alpha/beta of 10 Gy (BED10), D99%, or single- versus multi-fraction regimens.CONCLUSION: SABR for lung tumors using the individualized protocol on this trial showed excellent LR rates. We identified dosimetric parameters that were associated with LR, including V110% and V115% within the multi-fraction cohort, as well as the 50 Gy in 4 fraction cohort the D1cc, D0.03cc, and proportions of the PTV receiving 110%, 115%, and 120% of the prescription dose in the 50 Gy in 4 fraction cohort. Optimal thresholds for these parameters will be identified in further analyses. There did not appear to be an association with LR and BED10, D99%, or comparing single- vs multi-fraction regimens.

    View details for DOI 10.1016/j.ijrobp.2023.06.814

    View details for PubMedID 37786175

  • Improved early outcome prediction by MRI-based 3D tumor volume assessment in patients with CNS lymphomas. Neuro-oncology Lauer, E. M., Riegler, E., Mutter, J. A., Alig, S. K., Bleul, S., Kuehn, J., Ranganathan, L., Klingler, C., Demerath, T., Wurtemberger, U., Rau, A., WeiSS, J., Eisenblaetter, M., Bamberg, F., Prinz, M., Finke, J., Duyster, J., Illerhaus, G., Diehn, M., Alizadeh, A. A., Schorb, E., Reinacher, P. C., Scherer, F. 2023

    Abstract

    BACKGROUND: Central nervous system lymphomas (CNSL) display remarkable clinical heterogeneity, yet accurate prediction of outcomes remains challenging. The IPCG criteria are widely used in routine practice for the assessment of treatment response. However, the value of the IPCG criteria for ultimate outcome prediction is largely unclear, mainly due to the uncertainty in delineating complete from partial responses during and after treatment.METHODS: We explored various MRI features including semi-automated 3D tumor volume measurements at different disease milestones and their association with survival in 93 CNSL patients undergoing curative-intent treatment.RESULTS: At diagnosis, patients with more than three lymphoma lesions, periventricular involvement, and high 3D tumor volumes showed significantly unfavorable PFS and OS. At first interim MRI during treatment, the IPCG criteria failed to discriminate outcomes in responding patients. Therefore, we randomized these patients into training and validation cohorts to investigate whether 3D tumor volumetry could improve outcome prediction. We identified a 3D tumor volume reduction of ≥97% as the optimal threshold for risk stratification (=3D early response, 3D_ER). Applied to the validation cohort, patients achieving 3D_ER had significantly superior outcomes. In multivariate analyses, 3D_ER was independently prognostic of PFS and OS. Finally, we leveraged prognostic information from 3D MRI features and circulating biomarkers to build a composite metric that further improved outcome prediction in CNSL.CONCLUSIONS: We developed semi-automated 3D tumor volume measurements as strong and independent early predictors of clinical outcomes in CNSL patients. These radiologic features could help improve risk stratification and help guide future treatment approaches.

    View details for DOI 10.1093/neuonc/noad177

    View details for PubMedID 37713267

  • Individualized Stereotactic Ablative Radiotherapy for Lung Tumors: The iSABR Phase 2 Nonrandomized Controlled Trial. JAMA oncology Gensheimer, M. F., Gee, H., Shirato, H., Taguchi, H., Snyder, J. M., Chin, A. L., Vitzthum, L. K., Maxim, P. G., Wakelee, H. A., Neal, J., Das, M., Chang, D. T., Kidd, E., Hancock, S. L., Shultz, D. B., Horst, K. C., Le, Q. T., Wong, S., Brown, E., Nguyen, N., Liang, R., Loo, B. W., Diehn, M. 2023

    Abstract

    Stereotactic ablative radiotherapy (SABR) is used for treating lung tumors but can cause toxic effects, including life-threatening damage to central structures. Retrospective data suggested that small tumors up to 10 cm3 in volume can be well controlled with a biologically effective dose less than 100 Gy.To assess whether individualizing lung SABR dose and fractionation by tumor size, location, and histological characteristics may be associated with local tumor control.This nonrandomized controlled trial (the iSABR trial, so named for individualized SABR) was a phase 2 multicenter trial enrolling participants from November 15, 2011, to December 5, 2018, at academic medical centers in the US and Japan. Data were analyzed from December 9, 2020, to May 10, 2023. Patients were enrolled in 3 groups according to cancer type: initial diagnosis of non-small cell lung cancer (NSCLC) with an American Joint Committee on Cancer 7th edition T1-3N0M0 tumor (group 1), a T1-3N0M0 new primary NSCLC with a history of prior NSCLC or multiple NSCLCs (group 2), or lung metastases from NSCLC or another solid tumor (group 3).Up to 4 tumors were treated with once-daily SABR. The dose ranged from 25 Gy in 1 fraction for peripheral tumors with a volume of 0 to 10 cm3 to 60 Gy in 8 fractions for central tumors with a volume greater than 30 cm3.Per-group freedom from local recurrence (same-lobe recurrence) at 1 year, with censoring at time of distant recurrence, death, or loss to follow-up.In total, 217 unique patients (median [IQR] age, 72 [64-80] years; 129 [59%] male; 150 [69%] current or former smokers) were enrolled (some multiple times). There were 240 treatment courses: 79 in group 1, 82 in group 2, and 79 in group 3. A total of 285 tumors (211 [74%] peripheral and 74 [26%] central) were treated. The most common dose was 25 Gy in 1 fraction (158 tumors). The median (range) follow-up period was 33 (2-109) months, and the median overall survival was 59 (95% CI, 49-82) months. Freedom from local recurrence at 1 year was 97% (90% CI, 91%-99%) for group 1, 94% (90% CI, 87%-97%) for group 2, and 96% (90% CI, 89%-98%) for group 3. Freedom from local recurrence at 5 years ranged from 83% to 93% in the 3 groups. The proportion of patients with grade 3 to 5 toxic effects was low, at 5% (including a single patient [1%] with grade 5 toxic effects).The results of this nonrandomized controlled trial suggest that individualized SABR (iSABR) used to treat lung tumors may allow minimization of treatment dose and is associated with excellent local control. Individualized dosing should be considered for use in future trials.ClinicalTrials.gov Identifier: NCT01463423.

    View details for DOI 10.1001/jamaoncol.2023.3495

    View details for PubMedID 37707820

  • Early-Stage Lung Cancer: Using Circulating Tumor DNA to Get Personal. Journal of clinical oncology : official journal of the American Society of Clinical Oncology Bestvina, C. M., Garassino, M. C., Neal, J. W., Wakelee, H. A., Diehn, M., Vokes, E. E. 2023: JCO2300258

    View details for DOI 10.1200/JCO.23.00258

    View details for PubMedID 37352477

  • Association between locoregional failure and NFE2L2/KEAP1/CUL3 pathway mutations in NRG/RTOG 9512: A randomized trial of hyperfractionation vs. conventional fractionation in T2N0 glottic squamous cell carcinoma (SCC). Guan, L., Torres-Saavedra, P. A., Zhao, X., Major, M. B., Holmes, B. J., Nguyen, N., Kumaravelu, P., Hodge, T., Diehn, M., Zevallos, J., Emami, B., Sagar, S. M., Morrison, W. H., Schultz, C. J., Caudell, J. J., Jones, C. U., Yom, S. S., Harris, J., Le, Q., Hayes, D. N. LIPPINCOTT WILLIAMS & WILKINS. 2023
  • 17th International Conference on Malignant Lymphoma, Palazzo dei Congressi, Lugano, Switzerland, 13 - 17 June, 2023. Hematological oncology Rossi, C., Boegeholz, J. L., Alig, S. K., Garofolo, A., Esfahani, M. S., Schroers-Martin, J., Olsen, M., Kang, X., Kurtz, D. M., Sugio, T., Hamilton, M. P., André, M., Casasnovas, O., Diehn, M., Ghesquières, H., Alizadeh, A. A. 2023; 41 Suppl 2: 321-322

    View details for DOI 10.1002/hon.3164_228

    View details for PubMedID 39112166

  • 17th International Conference on Malignant Lymphoma, Palazzo dei Congressi, Lugano, Switzerland, 13 - 17 June, 2023. Hematological oncology Alig, S. K., Esfahani, M. S., Garofalo, A., Li, M. Y., Rossi, C., Adams, R., Binkley, M. S., Jin, M. C., Olsen, M., Telenius, A., Mutter, J., Sworder, B. J., Schroers-Martin, J., King, D. A., Schultz, A., Bögeholz, J., Su, S., Kathuria, K. R., Kang, X., Liu, C. L., Spina, V., Tousseyn, T., Buedts, L., Flerlage, T., Flerlage, J. E., Castellino, S. M., Advani, R., Rossi, D., Lynch, R., Ghesquières, H., Casasnovas, O., Kurtz, D. M., Marks, L. J., Link, M. P., André, M., Vandenberghe, P., Steidl, C., Diehn, M., Alizadeh, A. A. 2023; 41 Suppl 2: 96-98

    View details for DOI 10.1002/hon.3163_60

    View details for PubMedID 39112400

  • Unilateral diaphragmatic paralysis after stereotactic ablative radiotherapy to a lung tumor abutting the course of the phrenic nerve. Practical radiation oncology Eke, I., Guo, H. H., Loo, J. B., Sung, A. W., Diehn, M., Vitzthum, L., Chin, A. L., Gensheimer, M. F. 2023

    Abstract

    We present the case of a woman with metastatic adenoid cystic carcinoma who received stereotactic ablative radiotherapy (SABR) with a total dose of 50 Gy in 4 fractions to two lung metastases and developed symptomatic left phrenic nerve injury 2 years after radiation. The maximum dose to the approximate location of the phrenic nerve was 57.7 Gy which corresponds to a biologically effective dose for late effects (using α/β ratio = 3) of 335.14 Gy. Here, we discuss the case, planning considerations by radiation oncologists and medical physicists, and the multidisciplinary medical management of this patient.

    View details for DOI 10.1016/j.prro.2023.04.010

    View details for PubMedID 37150318

  • Pulmonary Hemorrhage in Patients Treated with Thoracic Stereotactic Ablative Radiotherapy and Anti-Angiogenic Agents. Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer Lau, B., Wu, Y. F., No, H. J., Ko, R. B., Devine, M., Das, M. S., Neal, J. W., Wakelee, H. A., Ramchandran, K., Gensheimer, M. F., Diehn, M., Chin, A. L., Loo, B. W., Vitzthum, L. K. 2023

    Abstract

    Severe pulmonary hemorrhage can occur in patients treated with thoracic stereotactic ablative radiotherapy (SABR) and vascular endothelial growth factor inhibitors (VEGFi). There is limited understanding of which patients are at risk for toxicity with the combination of thoracic SABR and VEGFis or how the risk differs over either therapy alone.We evaluated a prospectively maintained cohort of 690 patients with 818 pulmonary tumors treated with highly conformal SABR. Rates of any grade and grade-three-plus (G3+) pulmonary hemorrhage were compared between patients treated with or without VEGFi therapy across tumor locations. Outcomes were compared between patients treated with SABR + VEGFi and a propensity-matched cohort of those treated with VEGFi therapy alone.Treatment with VEGFi + SABR was associated with higher rates of G3+ pulmonary hemorrhage compared to those treated with SABR alone for the overall cohort (3-year incidence: 7.9% vs 0.6%, p<0.01) and those with central tumors (19.1% vs 3.3%, p=0.04). When further subdivided, there were significantly higher toxicity rates with VEGFi for the ultracentral (9.0% vs 45.0%, p = 0.044), but not central non-abutting tumors (0.0% vs 1.3% p = 0.69). There was an increased incidence of G3+ hemorrhage in patients treated with VEGFi + SABR compared to VEGFi alone (9.6 vs 1.3%, p=0.04).The combination of VEGFi and SABR was associated with an increased risk of high-grade pulmonary hemorrhage over either therapy alone. Low rates of toxicity were observed when excluding patients with SABR to ultracentral tumors and applying highly conformal SABR techniques.

    View details for DOI 10.1016/j.jtho.2023.04.007

    View details for PubMedID 37085030

  • Real-world risk of brain metastases in stage III non-small cell lung cancer in the era of PET and MRI staging. Frontiers in oncology Alhusaini, S., Lanman, T. A., Ko, R. B., Therkelsen, K. E., Eyben, R. V., Diehn, M., Soltys, S. G., Pollom, E. L., Chin, A., Vitzthum, L., Wakelee, H. A., Padda, S. K., Ramchandran, K., Loo, B. W., Neal, J. W., Nagpal, S. 2023; 13: 1139940

    Abstract

    The 2-year incidence of brain metastases (BrMs) in stage III non-small lung cell cancer (NSCLC) has been estimated to be around 30%. However, recent clinical trials have demonstrated considerably lower BrMs rates in this patient population. In this study, we aimed to review the real-world incidence, surveillance, and treatment patterns of BrMs in stage III NSCLC.Using a retrospective single-center study design, we identified patients with stage III NSCLC who received radiation with curative intent over a 10-year period. Outcome variables included BrMs incidence, overall survival (OS), and survival from date of BrMs. Additionally, we assessed patterns of BrMs surveillance in stage III NSCLC and treatment.We identified a total of 279 stage III NSCLC patients, of which 160 with adequate records were included in the final analyses [adenocarcinoma (n = 96), squamous cell carcinoma (n = 53), other histology subtype (n = 11)]. The median OS for the entire cohort was 41 months (95% CI, 28-53), while the median time from BrMs to death was 19 months (95% CI, 9-21). Twenty-three patients (14.4%) received planned surveillance brain MRIs at 6, 12, and 24 months after completion of treatment. The remaining 137 patients (85.6%) received brain MRIs at systemic recurrence (restaging) or when neurologically symptomatic. A total of 37 patients (23%) developed BrMs, with a 2-year cumulative BrMs incidence of 17% (95% CI, 11-23). A higher incidence of BrMs was identified in patients with adenocarcinoma relative to those with squamous cell carcinoma (p < 0.01). Similarly, a higher 2-year BrMs incidence was observed in patients who received planned surveillance brain MRI relative to those who did not, although statistical significance was not reached. Stereotactic radiosurgery (SRS) treated 29 of BrMs patients (78.4%) and was preferred over WBRT, which treated only 3 patients (8.1%).At our center, BrMs incidence in stage III NSCLC patients was lower than historically reported but notably higher than the incidence described in recent clinical trials. Routine BrMs surveillance potentially allows earlier detection of asymptomatic BrMs. However, asymptomatic BrMs were mostly detected on restaging MRI at the time of recurrence.

    View details for DOI 10.3389/fonc.2023.1139940

    View details for PubMedID 37035171

    View details for PubMedCentralID PMC10080021

  • Tracing founder mutations in circulating and tissue-resident follicular lymphoma precursors. Cancer discovery Schroers-Martin, J. G., Soo, J., Brisou, G., Scherer, F., Kurtz, D. M., Sworder, B. J., Khodadoust, M. S., Jin, M. C., Bru, A., Liu, C. L., Stehr, H., Vineis, P., Natkunam, Y., Teras, L. R., Song, J. Y., Nadel, B., Diehn, M., Roulland, S., Alizadeh, A. A. 2023

    Abstract

    Follicular lymphomas (FL) are characterized by BCL2 translocations, often detectable in blood years before FL diagnosis, but also observed in aging healthy individuals suggesting additional lesions are required for lymphomagenesis. We directly characterized early cooperating mutations by ultra-deep sequencing of pre-diagnostic blood and tissue specimens from 48 subjects who ultimately developed FL. Strikingly, CREBBP lysine acetyltransferase (KAT) domain mutations were the most commonly observed precursor lesions, and largely distinguished patients developing FL (14/48, 29%) from healthy adults with or without detected BCL2 rearrangements (0/13, p=0.03 and 0/20, p=0.007, respectively). CREBBP variants were detectable a median of 5.8 years before FL diagnosis, were clonally selected in FL tumors, and appeared restricted to the committed B-cell lineage. These results suggest that mutations affecting the CREBBP KAT domain are common lesions in FL cancer precursor cells (CPC), with potential for discriminating subjects at risk of developing FL or monitoring residual disease.

    View details for DOI 10.1158/2159-8290.CD-23-0111

    View details for PubMedID 36939219

  • NFE2L2 mutations enhance radioresistance in head and neck cancer by modulating intratumoral myeloid cells. Cancer research Guan, L., Nambiar, D. K., Cao, H., Viswanathan, V., Kwok, S., Hui, A. B., Hou, Y., Hildebrand, R., von Eyben, R., Holmes, B. J., Zhao, J., Kong, C. S., Wamsley, N., Zhang, W., Major, M. B., Seol, S. W., Sunwoo, J. B., Hayes, D. N., Diehn, M., Le, Q. T. 2023

    Abstract

    Radiotherapy is one of the primary treatments of head and neck squamous cell carcinoma (HNSCC), which has a high risk of locoregional failure (LRF). Presently, there is no reliable predictive biomarker of radioresistance in HNSCC. Here, we found that mutations in NFE2L2, which encodes Nrf2, are associated with a significantly higher rate of LRF in patients with oral cavity cancer treated with surgery and adjuvant (chemo)radiotherapy but not in those treated with surgery alone. Somatic mutation of NFE2L2 led to Nrf2 activation and radioresistance in HNSCC cells. Tumors harboring mutant Nrf2E79Q were substantially more radioresistant than tumors with wild-type Nrf2 in immunocompetent mice, while the difference was diminished in immunocompromised mice. Nrf2E79Q enhanced radioresistance through increased recruitment of intratumoral polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) and reduction of M1-polarized macrophages. Treatment with the glutaminase inhibitor CB-839 overcame the radioresistance induced by Nrf2E79Q or Nrf2E79K. Radiotherapy increased expression of PMN-MDSC-attracting chemokines, including CXCL1, CXLC3 and CSF3, in Nrf2E79Q-expressing tumors via the TLR4, which could be reversed by CB-839. This study provides insights into the impact of NFE2L2 mutations on radioresistance and suggests that CB-839 can increase radiosensitivity by switching intratumoral myeloid cells to an anti-tumor phenotype, supporting clinical testing of CB-839 with radiation in HNSCC with NFE2L2 mutations.

    View details for DOI 10.1158/0008-5472.CAN-22-1903

    View details for PubMedID 36652552

  • STK11 Inactivation Predicts Rapid Recurrence in Inoperable Early-Stage Non-Small-Cell Lung Cancer. JCO precision oncology Katipally, R. R., Spurr, L. F., Gutiontov, S. I., Turchan, W. T., Connell, P., Juloori, A., Malik, R., Binkley, M. S., Jiang, A. L., Rouhani, S. J., Chervin, C. S., Wanjari, P., Segal, J. P., Ng, V., Loo, B. W., Gomez, D. R., Bestvina, C. M., Vokes, E. E., Ferguson, M. K., Donington, J. S., Diehn, M., Pitroda, S. P. 2023; 7: e2200273

    Abstract

    Molecular factors predicting relapse in early-stage non-small-cell lung cancer (ES-NSCLC) are poorly understood, especially in inoperable patients receiving radiotherapy (RT). In this study, we compared the genomic profiles of inoperable and operable ES-NSCLC.This retrospective study included 53 patients with nonsquamous ES-NSCLC (stage I-II) treated at a single institution (University of Chicago) with surgery (ie, operable; n = 30) or RT (ie, inoperable; n = 23) who underwent tumor genomic profiling. A second cohort of ES-NSCLC treated with RT (Stanford, n = 39) was included to power clinical analyses. Prognostic gene alterations were identified and correlated with clinical variables. The primary clinical end point was the correlation of prognostic genes with the cumulative incidence of relapse, disease-free survival, and overall survival (OS) in a pooled RT cohort from the two institutions (N = 62).Although the surgery cohort exhibited lower rates of relapse, the RT cohort was highly enriched for somatic STK11 mutations (43% v 6.7%). Receiving supplemental oxygen (odds ratio [OR] = 5.5), 20+ pack-years of tobacco smoking (OR = 6.1), and Black race (OR = 4.3) were associated with increased frequency of STK11 mutations. In the pooled RT cohort (N = 62), STK11 mutation was strongly associated with inferior oncologic outcomes: 2-year incidence of relapse was 62% versus 20% and 2-year OS was 52% versus 85%, remaining independently prognostic on multivariable analyses (relapse: subdistribution hazard ratio = 4.0, P = .0041; disease-free survival: hazard ratio, 6.8, P = .0002; OS: hazard ratio, 6.0, P = .022). STK11 mutations were predominantly associated with distant failure, rather than local.In this cohort of ES-NSCLC, STK11 inactivation was associated with poor oncologic outcomes after RT and demonstrated a novel association with clinical hypoxia, which may underlie its correlation with medical inoperability. Further validation in larger cohorts and investigation of effective adjuvant systemic therapies may be warranted.

    View details for DOI 10.1200/PO.22.00273

    View details for PubMedID 36603171

  • Determinants of resistance to engineered T cell therapies targeting CD19 in large B cell lymphomas. Cancer cell Sworder, B. J., Kurtz, D. M., Alig, S. K., Frank, M. J., Shukla, N., Garofalo, A., Macaulay, C. W., Shahrokh Esfahani, M., Olsen, M. N., Hamilton, J., Hosoya, H., Hamilton, M., Spiegel, J. Y., Baird, J. H., Sugio, T., Carleton, M., Craig, A. F., Younes, S. F., Sahaf, B., Sheybani, N. D., Schroers-Martin, J. G., Liu, C. L., Oak, J. S., Jin, M. C., Beygi, S., Hüttmann, A., Hanoun, C., Dührsen, U., Westin, J. R., Khodadoust, M. S., Natkunam, Y., Majzner, R. G., Mackall, C. L., Diehn, M., Miklos, D. B., Alizadeh, A. A. 2022

    Abstract

    Most relapsed/refractory large B cell lymphoma (r/rLBCL) patients receiving anti-CD19 chimeric antigen receptor (CAR19) T cells relapse. To characterize determinants of resistance, we profiled over 700 longitudinal specimens from two independent cohorts (n = 65 and n = 73) of r/rLBCL patients treated with axicabtagene ciloleucel. A method for simultaneous profiling of circulating tumor DNA (ctDNA), cell-free CAR19 (cfCAR19) retroviral fragments, and cell-free T cell receptor rearrangements (cfTCR) enabled integration of tumor and both engineered and non-engineered T cell effector-mediated factors for assessing treatment failure and predicting outcomes. Alterations in multiple classes of genes are associated with resistance, including B cell identity (PAX5 and IRF8), immune checkpoints (CD274), and those affecting the microenvironment (TMEM30A). Somatic tumor alterations affect CAR19 therapy at multiple levels, including CAR19 T cell expansion, persistence, and tumor microenvironment. Further, CAR19 T cells play a reciprocal role in shaping tumor genotype and phenotype. We envision these findings will facilitate improved chimeric antigen receptor (CAR) T cells and personalized therapeutic approaches.

    View details for DOI 10.1016/j.ccell.2022.12.005

    View details for PubMedID 36584673

  • Circulating Tumor DNA Profiling for Detection, Risk Stratification, and Classification of Brain Lymphomas. Journal of clinical oncology : official journal of the American Society of Clinical Oncology Mutter, J. A., Alig, S. K., Esfahani, M. S., Lauer, E. M., Mitschke, J., Kurtz, D. M., Kühn, J., Bleul, S., Olsen, M., Liu, C. L., Jin, M. C., Macaulay, C. W., Neidert, N., Volk, T., Eisenblaetter, M., Rauer, S., Heiland, D. H., Finke, J., Duyster, J., Wehrle, J., Prinz, M., Illerhaus, G., Reinacher, P. C., Schorb, E., Diehn, M., Alizadeh, A. A., Scherer, F. 2022: JCO2200826

    Abstract

    Clinical outcomes of patients with CNS lymphomas (CNSLs) are remarkably heterogeneous, yet identification of patients at high risk for treatment failure is challenging. Furthermore, CNSL diagnosis often remains unconfirmed because of contraindications for invasive stereotactic biopsies. Therefore, improved biomarkers are needed to better stratify patients into risk groups, predict treatment response, and noninvasively identify CNSL.We explored the value of circulating tumor DNA (ctDNA) for early outcome prediction, measurable residual disease monitoring, and surgery-free CNSL identification by applying ultrasensitive targeted next-generation sequencing to a total of 306 tumor, plasma, and CSF specimens from 136 patients with brain cancers, including 92 patients with CNSL.Before therapy, ctDNA was detectable in 78% of plasma and 100% of CSF samples. Patients with positive ctDNA in pretreatment plasma had significantly shorter progression-free survival (PFS, P < .0001, log-rank test) and overall survival (OS, P = .0001, log-rank test). In multivariate analyses including established clinical and radiographic risk factors, pretreatment plasma ctDNA concentrations were independently prognostic of clinical outcomes (PFS HR, 1.4; 95% CI, 1.0 to 1.9; P = .03; OS HR, 1.6; 95% CI, 1.1 to 2.2; P = .006). Moreover, measurable residual disease detection by plasma ctDNA monitoring during treatment identified patients with particularly poor prognosis following curative-intent immunochemotherapy (PFS, P = .0002; OS, P = .004, log-rank test). Finally, we developed a proof-of-principle machine learning approach for biopsy-free CNSL identification from ctDNA, showing sensitivities of 59% (CSF) and 25% (plasma) with high positive predictive value.We demonstrate robust and ultrasensitive detection of ctDNA at various disease milestones in CNSL. Our findings highlight the role of ctDNA as a noninvasive biomarker and its potential value for personalized risk stratification and treatment guidance in patients with CNSL.

    View details for DOI 10.1200/JCO.22.00826

    View details for PubMedID 36542815

  • Highly aneuploid non-small cell lung cancer shows enhanced responsiveness to concurrent radiation and immune checkpoint blockade. Nature cancer Spurr, L. F., Martinez, C. A., Kang, W., Chen, M., Zha, Y., Hseu, R., Gutiontov, S. I., Turchan, W. T., Lynch, C. M., Pointer, K. B., Chang, P., Murgu, S., Husain, A. N., Cody, B., Vokes, E. E., Bestvina, C. M., Patel, J. D., Diehn, M., Gajewski, T. F., Weichselbaum, R. R., Chmura, S. J., Pitroda, S. P. 2022

    Abstract

    Over 500 clinical trials are investigating combination radiotherapy and immune checkpoint blockade (ICB) as cancer treatments; however, the majority of trials have found no positive interaction. Here we perform a comprehensive molecular analysis of a randomized phase I clinical trial of patients with non-small cell lung cancer (NSCLC) treated with concurrent or sequential ablative radiotherapy and ICB. We show that concurrent treatment is superior to sequential treatment in augmenting local and distant tumor responses and in improving overall survival in a subset of patients with immunologically cold, highly aneuploid tumors, but not in those with less aneuploid tumors. In addition, radiotherapy alone decreases intratumoral cytotoxic T cell and adaptive immune signatures, whereas radiotherapy and ICB upregulates key immune pathways. Our findings challenge the prevailing paradigm that local ablative radiotherapy beneficially stimulates the immune response. We propose the use of tumor aneuploidy as a biomarker and therapeutic target in personalizing treatment approaches for patients with NSCLC treated with radiotherapy and ICB.

    View details for DOI 10.1038/s43018-022-00467-x

    View details for PubMedID 36443406

    View details for PubMedCentralID 6085329

  • Radiotherapy in combination with CD47 blockade elicits a macrophage-mediated abscopal effect. Nature cancer Nishiga, Y., Drainas, A. P., Baron, M., Bhattacharya, D., Barkal, A. A., Ahrari, Y., Mancusi, R., Ross, J. B., Takahashi, N., Thomas, A., Diehn, M., Weissman, I. L., Graves, E. E., Sage, J. 2022

    Abstract

    Radiation therapy is a mainstay of cancer treatment but does not always lead to complete tumor regression. Here we combine radiotherapy with blockade of the 'don't-eat-me' cell-surface molecule CD47 in small cell lung cancer (SCLC), a highly metastatic form of lung cancer. CD47 blockade potently enhances the local antitumor effects of radiotherapy in preclinical models of SCLC. Notably, CD47 blockade also stimulates off-target 'abscopal' effects inhibiting non-irradiated SCLC tumors in mice receiving radiation. These abscopal effects are independent of T cells but require macrophages that migrate into non-irradiated tumor sites in response to inflammatory signals produced by radiation and are locally activated by CD47 blockade to phagocytose cancer cells. Similar abscopal antitumor effects were observed in other cancer models treated with radiation and CD47 blockade. The systemic activation of antitumor macrophages following radiotherapy and CD47 blockade may be particularly important in patients with cancer who suffer from metastatic disease.

    View details for DOI 10.1038/s43018-022-00456-0

    View details for PubMedID 36411318

  • Induction EGFR tyrosine kinase inhibitors prior to definitive chemoradiotherapy in unresectable stage III EGFR-mutated non-small cell lung cancer. Cancer treatment and research communications Aredo, J. V., Wakelee, H. A., Hui, A. B., Padda, S. K., Joshi, N. D., Guo, H. H., Chaudhuri, A., Diehn, M., Loo, B. W., Neal, J. W. 2022; 33: 100659

    Abstract

    INTRODUCTION: Increasing evidence suggests that consolidation durvalumab confers limited benefits for patients with stage III EGFR-mutated NSCLC. Induction or maintenance EGFR tyrosine kinase inhibitors (TKIs) added to concurrent chemoradiotherapy (CRT) may optimize definitive treatment, but there are limited data supporting an induction TKI strategy.METHODS: We evaluated the efficacy and safety of induction EGFR TKIs administered before concurrent CRT in a retrospective series of patients with unresectable locally advanced EGFR-mutated NSCLC. Circulating tumor DNA (ctDNA) analysis was performed on a patient subset using CAPP-seq and correlated with outcomes.RESULTS: Of six patients, three received erlotinib and three osimertinib as induction therapy before CRT. Induction TKIs were administered for a median of 2.5 months. The objective response rate after induction TKI was 83%. One patient had a complete response to induction erlotinib and continued erlotinib for 4 years until local progression, which was treated with CRT. Two patients completed maintenance erlotinib after CRT, and another received consolidation durvalumab. After a median follow-up of 20.5 months, only one patient developed disease recurrence, with rising ctDNA coinciding with recurrence. ctDNA remained undetectable in patients without recurrence, or low-level in a patient receiving maintenance erlotinib. Adverse events were mild and expected, and none developed pneumonitis.CONCLUSION: Induction EGFR TKI before CRT may achieve high disease control rates with promising signs of durability in patients with locally advanced EGFR-mutated NSCLC. ctDNA analysis after CRT can correlate well with clinical outcomes. Prospective studies are needed to define the role of induction EGFR TKIs in this setting.

    View details for DOI 10.1016/j.ctarc.2022.100659

    View details for PubMedID 36427429

  • Specificity & Precision of Minimal Residual Disease Monitoring in DLBCL Using Ig-HTS Shukla, N. D., Schroers-Martin, J., Kathuria, K. R., Sworder, B., Alig, S. K., Frank, M. J., Miklos, D. B., Coutre, S., Diehn, M., Khodadoust, M. S., Roschewski, M., Kurtz, D. M., Alizadeh, A. A. AMER SOC HEMATOLOGY. 2022: 6403-6404
  • Higher Rates of Severe Infection and Persistent Cytopenias in Long-Term CAR19 Responders Than after Autologous HCT: A Single Institution Study of 139 Subjects Hamilton, M. P., Liu-Fei, F. C., Alig, S. K., Tamaresis, J., Esfahani, M., Good, Z., Sworder, B., Schroers-Martin, J., Liu, C., Severinsen, F., Hanson, P. J., Lu, Y., Lowsky, R., Negrin, R. S., Meyer, E. H., Smith, M., Bharadwaj, S., Shizuru, J. A., Sidana, S., Shiraz, P., Rezvani, A. R., Johnston, L. J., Weng, W., Arai, S., Muffly, L., Dahiya, S., Diehn, M., Kurtz, D. M., Sahaf, B., Mackall, C. L., Frank, M. J., Miklos, D. B., Alizadeh, A. A. AMER SOC HEMATOLOGY. 2022: 7545-7547
  • Clonal Hematopoiesis Driven By Recurrent Somatic Mutations but Not with Recurrent Copy Number Alterations Is Associated with Inferior Outcomes in DLBCL after Induction Chemotherapy, but Not CAR19 Therapy Boegeholz, J., Alig, S. K., Sworder, B., Schroers-Martin, J., Macaulay, C., Craig, A. M., Duehrsen, U., Huettmann, A., Westin, J., Cherng, H. J., Miklos, D. B., Frank, M. J., Diehn, M., Kurtz, D. M., Alizadeh, A. A. AMER SOC HEMATOLOGY. 2022: 8609-8610
  • Tumor Microenvironment Determinants of Immunotherapy Response Identified By Integrated Host & Viral Analysis of Post-Transplant Lymphoproliferative Disorders Schroers-Martin, J., Garofalo, A., Soo, J., Boegeholz, J., Alig, S. K., Sworder, B., Liu, C., Luikart, H., Gamino, G., Morales, D., Freystaetter, K., Hamilton, J., Kurtz, D. M., Hollander, S., Rosenthal, D., Dhillon, G., Raikhelkar, J., Verleden, S., Nijland, M., Agbor-Enoh, S., Andreas, M., Kfoury, A., Ross, H., Zaffiri, L., Natkunam, Y., Diehn, M., Khush, K., Alizadeh, A. A. AMER SOC HEMATOLOGY. 2022
  • Distinct Molecular Subtypes of Classic Hodgkin Lymphoma Identified By Comprehensive Noninvasive Profiling Alig, S. K., Esfahani, M., Li, M. Y., Adams, R., Garofalo, A., Jin, M. C., Olsen, M., Telenius, A., Sworder, B., Schroers-Martin, J., King, D. A., Rossi, C., Schultz, A., Kathuria, K. R., Liu, C., Spina, V., Buedts, L., Flerlage, J. E., Castellino, S. M., Advani, R. H., Rossi, D., Lynch, R. C., Casasnovas, O., Kurtz, D. M., Marks, L. J., Link, M. P., Andre, M., Vandenberghe, P., Steidl, C., Diehn, M., Alizadeh, A. A. AMER SOC HEMATOLOGY. 2022: 1295-1296
  • Viral cfDNA Profiling Reveals Distinct EBV Subtypes and Stratifies Risk in Hodgkin Lymphomas Garofalo, A., Alig, S. K., Schroers-Martin, J., Shyam, R., Olsen, M., Kurtz, D. M., Rossi, C., Schultz, A., Kathuria, K. R., Liu, C., Spina, V., Flerlage, J. E., Castellino, S. M., Advani, R. H., Rossi, D., Lynch, R. C., Casasnovas, O., Marks, L. J., Link, M. P., Andre, M., Vandenberghe, P., Steidl, C., Diehn, M., Alizadeh, A. A. AMER SOC HEMATOLOGY. 2022: 1318-1319
  • MRD-Negativity As a Potential Surrogate Endpoint after Frontline DLBCL Therapy: Pooled Analysis of Trials & Implications for Clinical Trial Design Roschewski, M., Kurtz, D. M., Westin, J., Lynch, R. C., Macaulay, C., Kuffer, C., Hogan, G. J., Close, S., Chabon, J. J., Rossi, D., Diehn, M., Alizadeh, A. A., Schultz, A. AMER SOC HEMATOLOGY. 2022
  • Ultrasensitive MRD Profiling Predicts Outcomes in DLBCL after Frontline Therapy with Tafasitamab in Combination with Lenalidomide and R-CHOP Kurtz, D. M., Hogan, G. J., Schultz, A., Kopeckova, K., Kuffer, C., Blair, D., Wagner, S., Close, S., Diehn, M., Chabon, J. J., Alizadeh, A. A., Westin, J. AMER SOC HEMATOLOGY. 2022: 3498-3499
  • Determinants of Resistance to Engineered T-Cell Therapies Targeting CD19 in Large B-Cell Lymphomas Sworder, B., Kurtz, D. M., Alig, S. K., Frank, M. J., Shukla, N. D., Garofalo, A., Macaulay, C., Esfahani, M., Olsen, M., Hamilton, J., Hosoya, H., Hamilton, M. P., Spiegel, J. Y., Baird, J. H., Carleton, M., Craig, A. M., Younes, S. F., Sahaf, B., Sheybani, N., Schroers-Martin, J., Liu, C., Oak, J. S., Jin, M. C., Beygi, S., Huttmann, A., Hanoun, C., Duhrsen, U., Westin, J., Khodadoust, M. S., Natkunam, Y., Majzner, R. G., Mackall, C. L., Diehn, M., Miklos, D. B., Alizadeh, A. A. AMER SOC HEMATOLOGY. 2022: 1301-1303
  • A Review of Concurrent Chemo/Radiation, Immunotherapy, Radiation Planning, and Biomarkers for Locally Advanced Non-small Cell Lung Cancer and Their Role in the Development of ECOG-ACRIN EA5181. Clinical lung cancer Varlotto, J. M., Sun, Z., Ky, B., Upshaw, J., Fitzgerald, T. J., Diehn, M., Lovly, C., Belani, C., Oettel, K., Masters, G., Harkenrider, M., Ross, H., Ramalingam, S., Pennell, N. A. 2022; 23 (7): 547-560

    Abstract

    ECOG-ACRIN EA5181 is a current prospective, randomized trial that is investigating whether the addition of concomitant durvalumab to standard chemo/radiation followed by 1 year of consolidative durvalumab results in an overall survival benefit over standard chemo/radiation alone followed by 1 year of consolidative durvalumab in patients with locally advanced, unresectable non-small cell lung cancer (NSCLC). Because multiple phase I/II trials have shown the relative safety of adding immunotherapy to chemo/radiation and due to the known synergism between chemotherapy and immunotherapy, it is hoped that concomitant durvalumab can reduce the relatively high incidence of local failure (38%-46%) as seen in recent prospective, randomized trials of standard chemo/radiation in this patient population. We will review the history of radiation for LA-NSCLC and discuss the role of induction, concurrent and consolidative chemotherapy as well as the concerns for late cardiac and pulmonary toxicities associated with treatment. Furthermore, we will review the potential role of next generation sequencing, PD-L1, ctDNA and tumor mutation burden and their possible impact on this trial.

    View details for DOI 10.1016/j.cllc.2022.06.005

    View details for PubMedID 35882620

  • Characterizing Metastatic Non-Small Cell Lung Cancer Presenting to an Academic Medical Center in an Era of Changing Treatment Paradigms Raja, N., No, H. J., Von Eyben, R., Das, M., Roy, M., Myall, N., Chin, A. L., Diehn, M., Loo, B. W., Chang, D. T., Pollom, E., Vitzthum, L. ELSEVIER SCIENCE INC. 2022: E407
  • Investigating the Impact of Coronary Artery Dosimetry on Major Adverse Cardiac Events after Thoracic Radiation Therapy Guo, F. B., No, H. J., Rhee, J. W., Chin, A. L., Vitzthum, L., Horst, K. C., Moding, E. J., Loo, B. W., Diehn, M., Binkley, M. S. ELSEVIER SCIENCE INC. 2022: E418
  • Early Outcomes and Toxicity with Concurrent Chemotherapy and Hypofractionated Radiation Therapy in Patients with Non-Small Cell Lung Cancer Hui, C., Marquez, C., Lau, B., Von Eyben, R., Das, M., Myall, N., Roy, M., Chin, A., Diehn, M., Loo, B., Vitzthum, L. LIPPINCOTT WILLIAMS & WILKINS. 2022: S44
  • Chest Wall Toxicity after Individualized Stereotactic Ablative Radiotherapy for Lung Tumors Lau, B., Wu, Y. F., Fu, J., Cui, S., Pham, D., Gee, H., Skinner, L., Shirato, H., Taguchi, H., Chin, A., Gensheimer, M., Diehn, M., Loo, B., Vitzthum, L. ELSEVIER SCIENCE INC. 2022: S36-S37
  • Dosimetric Predictors of Local Control after Stereotactic Ablative Radiotherapy (SABR) for Lung Tumors: A Secondary Analysis of a Phase II Prospective Trial of Individualized SABR (iSABR) Wu, Y., Lau, B., Fu, J., Skinner, L., Gensheimer, M., Gee, H., Diehn, M., Loo, B., Chin, A., Vitzthum, L. LIPPINCOTT WILLIAMS & WILKINS. 2022: S16
  • Isolated Nodal Recurrence After Definitive Stereotactic Ablative Radiotherapy for Non-Small Cell Lung Cancer. Practical radiation oncology Devine, M., Merriott, D. J., No, H. J., Lau, B., Say, C., Yoo, C., Yi, E., Ko, R. B., Neal, J. W., Wakelee, H. A., Das, M., Loo, B. W., Diehn, M., Chin, A. L., Vitzthum, L. K. 2022

    Abstract

    Stereotactic ablative radiotherapy (SABR) results in high rates of primary tumor control for early-stage non-small cell lung cancer (NSCLC). For patients with isolated hilar or mediastinal nodal recurrences (INR) after SABR, the optimal salvage treatment strategy is unclear. The purpose of this study is to determine the rate of INR after SABR for early-stage NSCLC and to describe patterns of care and treatment outcomes after salvage therapy.This retrospective cohort study included 342 patients with Stage T1-3N0M0 NSCLC treated with definitive SABR from 2003-2018. We evaluated the incidence of INR and baseline factors between patients who did and did not experience INR. Among patients who experienced INR, we described treatment patterns and outcomes including overall (OS) and progression free survival (PFS) from the time of nodal failure using the Kaplan-Meier method.With a median follow-up of 3.3 years, the 3-year INR rate was 10.6% (6.6% -13.4%). Among the 34 patients experiencing INR, the 3-year rates of OS and PFS were 39.3% (24.4 - 63.3%) and 26.7% (14.1 - 50.3%), respectively. The 34 patients with INR were treated with RT alone (26.7 %), concurrent chemoradiotherapy (CRT) (43.3 %), chemotherapy alone (13.3%), or observation (16.7%). CRT had the best survival outcomes with a 3-year OS and PFS of 81.5% (61.1 - 100.0%) and 63.9% (40.7 - 100.0%), respectively. Of the patients treated with salvage RT or CRT, 14.3% experienced grade 3 toxicity with no patients having grade 4+ toxicity.INR occurred in approximately 10% of patients treated with SABR for early-stage NSCLC. The highest rates of OS an PFS among patients with INR were observed in those treated with salvage chemoradiotherapy.

    View details for DOI 10.1016/j.prro.2022.06.013

    View details for PubMedID 35858658

  • Genomic Profiling of Bronchoalveolar Lavage Fluid in Lung Cancer. Cancer research Nair, V. S., Hui, A. B., Chabon, J. J., Shahrokh Esfahani, M., Stehr, H., Nabet, B. Y., Zhou, L., Chaudhuri, A. A., Benson, J. A., Ayers, K., Bedi, H., Ramsey, M. C., Van Wert, R., Antic, S., Lui, N. S., Backhus, L. M., Berry, M. F., Sung, A. W., Massion, P. P., Shrager, J. B., Alizadeh, A. A., Diehn, M. 2022

    Abstract

    Genomic profiling of Bronchoalveolar Lavage (BAL) samples may be useful for tumor profiling and diagnosis in the clinic. Here, we compared tumor-derived mutations detected in BAL samples from subjects with non-small cell lung cancer (NSCLC) to those detected in matched plasma samples. CAncer Personalized Profiling by deep Sequencing (CAPP-Seq) was used to genotype DNA purified from BAL, plasma and tumor samples from patients with NSCLC. The characteristics of cell-free DNA (cfDNA) isolated from BAL fluid were first characterized to optimize the technical approach. Somatic mutations identified in tumor were then compared to those identified in BAL and plasma, and the potential of BAL cfDNA analysis to distinguish lung cancer patients from risk-matched controls was explored. In total, 200 biofluid and tumor samples from 38 cases and 21 controls undergoing BAL for lung cancer evaluation were profiled. More tumor variants were identified in BAL cfDNA than plasma cfDNA in all stages (p<0.001) and in stage I-II disease only. Four of 21 controls harbored low levels of cancer-associated driver mutations in BAL cfDNA (mean VAF=0.5%), suggesting the presence of somatic mutations in non-malignant airway cells. Finally, using a Random Forest model with leave-one-out cross validation, an exploratory BAL genomic classifier identified lung cancer with 69% sensitivity and 100% specificity in this cohort and detected more cancers than BAL cytology. Detecting tumor-derived mutations by targeted sequencing of BAL cfDNA is technically feasible and appears to be more sensitive than plasma profiling. Further studies are required to define optimal diagnostic applications and clinical utility.

    View details for DOI 10.1158/0008-5472.CAN-22-0554

    View details for PubMedID 35748739

  • ESMO recommendations on the use of circulating tumour DNA assays for patients with cancer: a report from the ESMO Precision Medicine Working Group. Annals of oncology : official journal of the European Society for Medical Oncology Pascual, J., Attard, G., Bidard, F., Curigliano, G., De Mattos-Arruda, L., Diehn, M., Italiano, A., Lindberg, J., Merker, J. D., Montagut, C., Normanno, N., Pantel, K., Pentheroudakis, G., Popat, S., Reis-Filho, J. S., Tie, J., Seoane, J., Tarazona, N., Yoshino, T., Turner, N. C. 2022

    Abstract

    Circulating tumour DNA (ctDNA) assays conducted on plasma are rapidly developing a strong evidence base for use in patients with cancer. The European Society for Medical Oncology convened an expert working group to review the analytical and clinical validity and utility of ctDNA assays. For patients with advanced cancer, validated and adequately sensitive ctDNA assays have utility in identifying actionable mutations to direct targeted therapy, and may be used in routine clinical practice, provided the limitations of the assays are taken into account. Tissue based testing remains the preferred test for many cancer patients, due to limitations of ctDNA assays detecting fusion events and copy number changes, although ctDNA assays may be routinely used when faster results will be clinically important, or when tissue biopsies are not possible or inappropriate. Reflex tumour testing should be considered following a non-informative ctDNA result, due to false negative results with ctDNA testing. In patients treated for early-stage cancers, detection of molecular residual disease (MRD) or molecular relapse (MR), has high evidence of clinical validity in anticipating future relapse in many cancers. MRD/MR detection cannot be recommended in routine clinical practice, as currently there is no evidence for clinical utility in directing treatment. Additional potential applications of ctDNA assays, under research development and not recommended for routine practice, include identifying patients not responding to therapy with early dynamic changes in ctDNA levels, monitoring therapy for the development of resistance mutations prior to clinical progression, and in screening asymptomatic people for cancer. Recommendation for reporting of results, future development of ctDNA assays, and future clinical research are made.

    View details for DOI 10.1016/j.annonc.2022.05.520

    View details for PubMedID 35809752

  • Analysis of circulating tumor DNA in the phase 2 BTCRC LUN 16-081 trial of consolidation nivolumab with or without ipilimumab after chemoradiation in stage III non-small cell lung cancer. Jun, S., Shukla, N., Durm, G., Hui, A. B., Cao, S., Kunder, C., Alizadeh, A. A., Hanna, N. H., Diehn, M. LIPPINCOTT WILLIAMS & WILKINS. 2022
  • Characterization of Metastatic Non-Small Cell Lung Cancer and Oligometastatic Incidence in an Era of Changing Treatment Paradigms. International journal of radiation oncology, biology, physics No, H. J., Raja, N., Von Eyben, R., Das, M., Roy, M., Myall, N., Neal, J., Wakelee, H., Chin, A., Diehn, M., Loo, B. W., Chang, D. T., Pollom, E. L., Vitzthum, L. K. 2022

    Abstract

    Due to the limitations of current staging systems and evolving definitions, there are limited data on oligometastatic non-small cell lung cancer (NSCLC) epidemiology. The purpose of this study is to evaluate metastatic disease burden and the incidence of oligometastatic disease using recent clinical trial edibility criteria.A cohort of patients with metastatic NSCLC, diagnosed from 2016 to 2019, were randomly sampled from a curated tumor registry. Definitions for oligometastatic disease were obtained from relevant clinical trials. The Stanford Cancer Institute Research Database (SCIRDB) was used to identify baseline patient factors, systemic and local therapy, extent and location of metastatic lesions, and survival outcomes.Among 120 patients presenting with metastatic NSCLC, the majority had de novo metastatic disease (75%) with a median of 4 metastatic lesions involving 3 organ systems. 37.5% would have been eligible for at least one oligometastatic trial with 28.3% meeting criteria for MDACC, 20.0% for NRG-LU002, 6.7% for SINDAS and 16.7% for SABR-COMET. By adding malignant pleural effusions (MPE) and early progression as exclusionary criteria, only 54.1% of patients with ≤3 synchronous metastases were eligible for consideration of local therapy. Early progression on systemic therapy was associated with worse survival (10.0 vs. 42.4 months, p < 0.001), whereas presence of MPE was not. Of those tumors identified as oligometastatic, 44.4% received local therapy and 28.9% underwent ablative therapy to all sites. There was a trend towards greater overall survival (44.4 vs 24.9 months, p=0.055) and progression free survival (8.0 vs. 5.4 months, p=0.06) in patients meeting eligibility for at least one oligometastatic trial.Around 48% of patients with metastatic NSCLC had ≤3 metastases at presentation and 28% met clinical trial criteria for oligometastatic disease. Future research is needed to better define the oligometastatic state and identify patients most likely to benefit from local therapy.

    View details for DOI 10.1016/j.ijrobp.2022.04.050

    View details for PubMedID 35654305

  • Early Assessment of Chemotherapy Response in Advanced Non-Small Cell Lung Cancer with Circulating Tumor DNA. Cancers Yaung, S. J., Woestmann, C., Ju, C., Ma, X. M., Gattam, S., Zhou, Y., Xi, L., Pal, S., Balasubramanyam, A., Tikoo, N., Heussel, C. P., Thomas, M., Kriegsmann, M., Meister, M., Schneider, M. A., Herth, F. J., Wehnl, B., Diehn, M., Alizadeh, A. A., Palma, J. F., Muley, T. 2022; 14 (10)

    Abstract

    Monitoring treatment efficacy early during therapy could enable a change in treatment to improve patient outcomes. We report an early assessment of response to treatment in advanced NSCLC using a plasma-only strategy to measure changes in ctDNA levels after one cycle of chemotherapy. Plasma samples were collected from 92 patients with Stage IIIB-IV NSCLC treated with first-line chemo- or chemoradiation therapies in an observational, prospective study. Retrospective ctDNA analysis was performed using next-generation sequencing with a targeted 198-kb panel designed for lung cancer surveillance and monitoring. We assessed whether changes in ctDNA levels after one or two cycles of treatment were associated with clinical outcomes. Subjects with ≤50% decrease in ctDNA level after one cycle of chemotherapy had a lower 6-month progression-free survival rate (33% vs. 58%, HR 2.3, 95% CI 1.2 to 4.2, log-rank p = 0.009) and a lower 12-month overall survival rate (25% vs. 70%, HR 4.3, 95% CI 2.2 to 9.7, log-rank p < 0.001). Subjects with ≤50% decrease in ctDNA level after two cycles of chemotherapy also had shorter survival. Using non-invasive liquid biopsies to measure early changes in ctDNA levels in response to chemotherapy may help identify non-responders before standard-of-care imaging in advanced NSCLC.

    View details for DOI 10.3390/cancers14102479

    View details for PubMedID 35626082

  • Inferring gene expression from cell-free DNA fragmentation profiles. Nature biotechnology Esfahani, M. S., Hamilton, E. G., Mehrmohamadi, M., Nabet, B. Y., Alig, S. K., King, D. A., Steen, C. B., Macaulay, C. W., Schultz, A., Nesselbush, M. C., Soo, J., Schroers-Martin, J. G., Chen, B., Binkley, M. S., Stehr, H., Chabon, J. J., Sworder, B. J., Hui, A. B., Frank, M. J., Moding, E. J., Liu, C. L., Newman, A. M., Isbell, J. M., Rudin, C. M., Li, B. T., Kurtz, D. M., Diehn, M., Alizadeh, A. A. 2022

    Abstract

    Profiling of circulating tumor DNA (ctDNA) in the bloodstream shows promise for noninvasive cancer detection. Chromatin fragmentation features have previously been explored to infer gene expression profiles from cell-free DNA (cfDNA), but current fragmentomic methods require high concentrations of tumor-derived DNA and provide limited resolution. Here we describe promoter fragmentation entropy as an epigenomic cfDNA feature that predicts RNA expression levels at individual genes. We developed 'epigenetic expression inference from cell-free DNA-sequencing' (EPIC-seq), a method that uses targeted sequencing of promoters of genes of interest. Profiling 329 blood samples from 201 patients with cancer and 87 healthy adults, we demonstrate classification of subtypes of lung carcinoma and diffuse large B cell lymphoma. Applying EPIC-seq to serial blood samples from patients treated with PD-(L)1 immune-checkpoint inhibitors, we show that gene expression profiles inferred by EPIC-seq are correlated with clinical response. Our results indicate that EPIC-seq could enable noninvasive, high-throughput tissue-of-origin characterization with diagnostic, prognostic and therapeutic potential.

    View details for DOI 10.1038/s41587-022-01222-4

    View details for PubMedID 35361996

  • Detection of Recurrence After Thoracic Stereotactic Ablative Radiotherapy Using FDG-PET-CT. Clinical lung cancer Sodji, Q. H., Harris, J. P., Quon, A., Modlin, L. A., Lau, B., Jiang, A., Trakul, N., Maxim, P. G., Diehn, M., Loo, B. W., Hiniker, S. M. 2022

    Abstract

    INTRODUCTION/BACKGROUND: Differentiating local recurrence (LR) from post-treatment changes following stereotactic ablative radiotherapy (SABR) for thoracic tumors is challenging. We sought to evaluate the performance of FDG-PET-CT in distinguishing recurrence from post-radiation changes in patients with stage I-II non-small cell lung cancer (NSCLC) treated with SABR.MATERIALS AND METHODS: We performed a retrospective review of patients with stage I-II NSCLC treated with SABR and subsequently followed with surveillance FDG-PET-CT scans from 2004 to 2014. The radiology reports were coded as 0 or 1 if minimally or substantially concerning for LR, respectively, and correlated with outcome. Prognostic factors for false-positive FDG-PET-CT were assessed using logistic regression models.RESULTS: We identified 145 patients meeting inclusion criteria for the retrospective analysis. Amongst the 39 (26.9%) patients with FDG-PET-CT scans concerning for LR 3 to 24 months after treatment, 14 were confirmed to have LR. Thus, the positive predictive value (PPV) of FDG-PET-CT in identifying LR was 36% (14/39). Factors associated with a false-positive scan included concerning FDG-PET-CT at the earliest post-treatment time point (3 months) (odds ratio 0.67, P= .04) and older age (odds ratio 2.3, P= .02).CONCLUSION: Our analysis indicates that the PPV of a concerning FDG-PET-CT after SABR for early-stage NSCLC is relatively low, especially at early post-treatment timepoints, but accuracy is improving over time with institutional experience.

    View details for DOI 10.1016/j.cllc.2022.01.006

    View details for PubMedID 35246393

  • Predictive Radiation Oncology - A New NCI-DOE Scientific Space and Community. Radiation research Buchsbaum, J. C., Jaffray, D. A., Ba, D., Borkon, L. L., Chalk, C., Chung, C., Coleman, M. A., Coleman, C. N., Diehn, M., Droegemeier, K. K., Enderling, H., Espey, M. G., Greenspan, E. J., Hartshorn, C. M., Hoang, T., Hsiao, H. T., Keppel, C., Moore, N. W., Prior, F., Stahlberg, E. A., Tourassi, G., Willcox, K. E. 1800

    Abstract

    With a widely attended virtual kickoff event on January 29, 2021, the National Cancer Institute (NCI) and the Department of Energy (DOE) launched a series of 4 interactive, interdisciplinary workshops-and a final concluding "World Cafe" on March 29, 2021-focused on advancing computational approaches for predictive oncology in the clinical and research domains of radiation oncology. These events reflect 3,870 human hours of virtual engagement with representation from 8 DOE national laboratories and the Frederick National Laboratory for Cancer Research (FNL), 4 research institutes, 5 cancer centers, 17 medical schools and teaching hospitals, 5 companies, 5 federal agencies, 3 research centers, and 27 universities. Here we summarize the workshops by first describing the background for the workshops. Participants identified twelve key questions-and collaborative parallel ideas-as the focus of work going forward to advance the field. These were then used to define short-term and longer-term "Blue Sky" goals. In addition, the group determined key success factors for predictive oncology in the context of radiation oncology, if not the future of all of medicine. These are: cross-discipline collaboration, targeted talent development, development of mechanistic mathematical and computational models and tools, and access to high-quality multiscale data that bridges mechanisms to phenotype. The workshop participants reported feeling energized and highly motivated to pursue next steps together to address the unmet needs in radiation oncology specifically and in cancer research generally and that NCI and DOE project goals align at the convergence of radiation therapy and advanced computing.

    View details for DOI 10.1667/RADE-22-00012.1

    View details for PubMedID 35090025

  • Acute and Late Esophageal Toxicity Following Stereotactic Ablative Radiotherapy to Thoracic Tumors near or Abutting the Esophagus. International journal of radiation oncology, biology, physics Sodji, Q. H., Ko, R., von Eyben, R., Owen, S. G., Capaldi, D. P., Bush, K., Binkley, M. S., Alrowais, F., Pickthorn, B., Maxim, P. G., Gensheimer, M. F., Diehn, M., Loo, B. W. 1800

    Abstract

    PURPOSE: To evaluate the incidence of acute and late esophageal toxicity in patients with thoracic tumors near or abutting the esophagus treated with stereotactic ablative radiotherapy (SABR).METHODS AND MATERIALS: Among patients with thoracic tumors treated with SABR, we identified those with tumors near or abutting the esophagus. Using the linear-quadratic model with an alpha/SS ratio of 10, we determined the correlation between dosimetric parameters and esophageal toxicity graded using the Common Terminology Criteria for Adverse Events (CTCAE), version 5.0.RESULTS: Out of 2200 patients treated with thoracic SABR, 767 patients were analyzable for esophageal dosimetry. We identified 55 patients with tumors near the esophagus (52 evaluable for esophagitis grade), 28 with PTV overlapping the esophagus. Median follow-up and overall survival were 16 and 23 months respectively. Thirteen patients (25%) developed temporary grade 2 acute esophageal toxicity, 11 (85%) of whom had PTV overlapping the esophagus. Symptoms resolved within 1-3 months in 12 patients, and 6 months in all patients. No grade 3-5 toxicity was observed. Only 3 patients (6%) developed late or persistent grade 2 dysphagia or dyspepsia of uncertain relationship to SABR. Cumulative incidence of acute esophagitis was 15% and 25% at 14 days and 60 days respectively. Acute toxicity correlated on univariate analysis with esophageal Dmax, D1cc, D2cc, Dmax/Dprescription and whether the PTV was overlapping the esophagus. Esophageal Dmax (BED10) < 62 Gy, D1cc (BED10) < 48 Gy, D2cc (BED10) < 43 Gy, and Dmax/Dprescription < 85% was associated with <20% risk of grade 2 acute esophagitis. Only 2 local recurrences occurred.CONCLUSIONS: Although 25% of patients with tumors near the esophagus developed acute esophagitis (39% of those with PTV overlapping the esophagus), these toxicities were all grade 2 and all temporary. This suggests the safety and efficacy of thoracic SABR for tumors near or abutting the esophagus when treating with high conformity and sharp dose gradients.

    View details for DOI 10.1016/j.ijrobp.2021.12.008

    View details for PubMedID 34942312

  • Noninvasive Cell-of-Origin Classification of Diffuse Large B-Cell Lymphoma Using Inferred Gene Expression from Cell-Free DNA Sequencing Esfahani, M., Alig, S., Mehrmohamadi, M., Hamilton, E. G., King, D. A., Schultz, A., Steen, C. B., Macaulay, C., Sworder, B., Kurtz, D. M., Diehn, M., Alizadeh, A. A. AMER SOC HEMATOLOGY. 2021
  • Impact of Facility Treatment Volume on Stereotactic Ablative Radiotherapy (SABR) Outcomes in Early-Stage Non-Small Cell Lung Cancer (NSCLC). International journal of radiation oncology, biology, physics Marar, M., Bryant, A. K., Nalawade, V., Das, M., Jr, B. W., Diehn, M., Chin, A. L., Murphy, J. D., Vitzthum, L. 2021; 111 (3S): e447

    Abstract

    PURPOSE/OBJECTIVE(S): Prior research suggests that radiation oncologist provider experience may influence outcomes for radiation treatment modalities requiring greater technical expertise for given disease sites. We investigated whether institution treatment volume (TV) for SABR technique impacted survival outcomes for patients with NSCLC.MATERIALS/METHODS: We conducted a retrospective cohort study using the Veteran's Affairs Informatics and Computing Infrastructure (VINCI) database to identify patients who underwent treatment for NSCLC between 2012 and 2017 at Veteran's Health Administration Medical Centers (VHAMCs). Patients were included in the cohort if they had tumor (T) stage 1 or 2 disease, node negative (N0) disease, and underwent SABR radiation treatment based on associated Current Procedural Terminology codes. We conducted univariate and multivariate analyses for overall survival (OS) and cause-specific survival (CSS) using Cox regression models accounting for age, sex, race, histology, T stage, tobacco history, ECOG status, and VHAMC facility TV. TV was calculated as the total number of SABR treatments performed per facility over the study period and was categorized into high and low volume groups based on a median TV cutoff.RESULTS: The observational cohort included N = 433 patients with early-stage NSCLC who underwent treatment with SABR across 25 VHAMC facilities. Most patients (83.1%) had T stage 1 disease, and nearly equal proportions had SCC (31.2%) and adenocarcinoma (32.5%) histologies, with the remaining having clinical diagnoses of NSCLC. Median facility TV was 29 SABR treatments (interquartile range 19-33). Median follow up was 657 days. Estimated 2-year overall and cause-specific survival rates were 78.4% (95% CI: 73.9% - 82.1%) and 87.0% (95% CI: 83.2% - 90.0%), respectively. On univariate analysis, high versus low facility TV was not significantly associated with OS (hazard ratio (HR) 1.08, 95% CI: 0.74-1.58) or CSS (HR 1.06, 95% CI: 0.65 - 1.73). Similarly, facility volume was not associated with OS or CSS on multivariate analysis. In a sensitivity analysis, facility volume was not associated with survival outcomes when treated as a continuous variable. Covariates associated with decreased OS included male sex (HR 4.5, P < 0.05), age over 65 (HR 1.77, P < 0.05), ECOG status 2 or greater (HR 1.94, P < 0.05), SCC histology (HR 1.66, P < 0.05), and T stage 2 disease (HR 1.68, P < 0.05).CONCLUSION: In this observational cohort of patients treated at VHAMCs, facility TV was not associated with survival outcomes for early-stage NSCLC radiation treatment using SABR technique. Research is ongoing to account for factors including baseline pulmonary function, comorbidities, and variations in institutional treatment patterns such as propensity for treatment with surgery versus radiation.

    View details for DOI 10.1016/j.ijrobp.2021.07.1262

    View details for PubMedID 34701476

  • Impact of Facility Treatment Volume on Stereotactic Ablative Radiotherapy (SABR) Outcomes in Early-Stage Non-Small Cell Lung Cancer (NSCLC) Marar, M., Bryant, A. K., Nalawade, V., Das, M., Loo, B. W., Diehn, M., Chin, A. L., Murphy, J. D., Vitzthum, L. ELSEVIER SCIENCE INC. 2021: E447
  • Deep Learning Based Identification and Segmentation of Lung Tumors on Computed Tomography Images Kashyap, M., Panjwani, N., Hasan, M. A., Huang, C., Bush, K., Dong, P., Zaky, S. S., Chin, A. L., Vitzthum, L., Loo, B. W., Diehn, M., Xing, L., Gensheimer, M. F. ELSEVIER SCIENCE INC. 2021: E92-E93
  • A Phase II Trial of Individualized Stereotactic Ablative Radiotherapy for Lung Tumors (iSABR) Gensheimer, M. F., Gee, H. E., Von Eyben, R., Shirato, H., Taguchi, H., Wong, S., Brown, E., Nguyen, N., Liang, R., Maxim, P. G., Wakelee, H. A., Neal, J. W., Das, M., Loo, B. W., Diehn, M. ELSEVIER SCIENCE INC. 2021: S89-S90
  • Patterns of Care in Patients With Isolated Nodal Recurrence After Definitive Stereotactic Ablative Radiotherapy for Non-Small Cell Lung Cancer Devine, M., Merriott, D. J., Say, C., Yoo, C., Yi, E., Lau, B., Ko, R. B., Shaheen, S., Neal, J. W., Wakelee, H. A., Das, M., Loo, B. W., Diehn, M., Chin, A. L., Vitzthum, L. ELSEVIER SCIENCE INC. 2021: E435
  • Pulmonary Hemorrhage in Patients Treated With Thoracic Stereotactic Ablative Radiotherapy and Anti-Angiogenic Agents Lau, B., No, H. J., Wu, Y. F., Ko, R. B., Devine, M., Das, M., Neal, J. W., Ramchandran, K. J., Wakelee, H. A., Shaheen, S., Diehn, M., Chin, A. L., Loo, B. W., Vitzthum, L. ELSEVIER SCIENCE INC. 2021: E423
  • A Phase II Trial of Individualized Stereotactic Ablative Radiotherapy for Lung Tumors (iSABR). International journal of radiation oncology, biology, physics Gensheimer, M. F., Gee, H. E., Von Eyben, R., Shirato, H., Taguchi, H., Wong, S., Brown, E., Nguyen, N., Liang, R., Maxim, P. G., Wakelee, H. A., Neal, J. W., Das, M., Loo, B. W., Diehn, M. 2021; 111 (3S): S89-S90

    Abstract

    PURPOSE/OBJECTIVE(S): Stereotactic ablative radiotherapy (SABR) is an effective treatment for lung tumors, but can result in toxicity such as chest wall pain and life-threatening damage to central lung structures. We hypothesized that while larger tumors require higher dose, small tumors up to 10cc in volume can be controlled with biologically effective dose < 100Gy. In this phase II single-arm trial, we tested the hypothesis that individualizing lung SABR dose and fractionation to tumor size, location, and histology would result in excellent local control with acceptable toxicity. The trial was conducted at two centers in the United States and Japan (NCT# redacted for blinded review).MATERIALS/METHODS: Patients in three groups were enrolled: initial diagnosis of non-small cell lung cancer (NSCLC), AJCC 7th edition stage T1-3 N0 M0 (group 1); new primary NSCLC with history of NSCLC, or multiple synchronously diagnosed NSCLCs (group 2); and lung metastases from NSCLC or another primary site (group 3). Up to four tumors could be treated with once-daily SABR. There were six dose/fractionation schedules used, depending on gross tumor volume (≤10cc, 10-30cc, > 30cc) and location (peripheral vs. central). Larger tumors received higher dose and central tumors generally received lower dose per fraction. Dose ranged from 25Gy in one fraction for 0-10cc peripheral tumors to 60Gy in 8 fractions for > 30cc central tumors. Colorectal cancer metastases were treated to higher dose, at least 50Gy in 4 fractions. The primary endpoint was per-group cumulative incidence of local recurrence at 1 year (recurrence of treated tumor within same lobe), with distant recurrence and death as competing risks. Treated tumor recurrence (recurrence with epicenter within 1cm of PTV) and toxicity were also analyzed.RESULTS: A total of 217 patients were enrolled from 2011-2018 (some patients were enrolled multiple times). Median age was 72, 59% were male, and 69% were current/former smokers. There were 240 treatment courses and 285 tumors treated (range 1-3 tumors per course). 211 tumors were peripheral and 74 were central. Tumor size distribution was: ≤10cc, 74%; 10-30cc, 19%; > 30cc, 7%. The most common dose was 25Gy in one fraction (158 tumors). Median follow-up was 30 months (range 2-95). Median overall survival was 57 months. Local recurrence data are currently being updated and will be presented at the meeting. The rate of grade 2 or higher pneumonitis was 16/217 (7%) and grade 3 or higher pneumonitis was 3/217 (1%). The rate of grade 2 or higher chest wall pain was 13/217 (6%). One patient had a grade 5 adverse event, developing pulmonary hemorrhage that was possibly related to radiotherapy, 17 months after treatment of a large central NSCLC.CONCLUSION: Individualized SABR to lung cancers resulted in excellent local control and favorable toxicity profile.

    View details for DOI 10.1016/j.ijrobp.2021.07.212

    View details for PubMedID 34700657

  • Patterns of Care in Patients With Isolated Nodal Recurrence After Definitive Stereotactic Ablative Radiotherapy for Non-Small Cell Lung Cancer. International journal of radiation oncology, biology, physics Devine, M., Merriott, D. J., Say, C., Yoo, C., Yi, E., Lau, B., Ko, R. B., Shaheen, S., Neal, J. W., Wakelee, H. A., Das, M., Loo, B. W., Diehn, M., Chin, A. L., Vitzthum, L. 2021; 111 (3S): e435

    Abstract

    PURPOSE/OBJECTIVE(S): Patients treated with stereotactic ablative radiotherapy (SABR) for early-stage non-small cell lung cancer (NSCLC) have high rates of local control but may be at increased risk of nodal recurrence compared to those who undergo surgical resection with more invasive nodal evaluation. The optimal treatment for patients with isolated nodal recurrence (INR) is unclear. The purpose of this study is to determine the rate of INR after SABR for early-stage NSCLC and describe patterns of care and treatment outcomes for patients that experience INR.MATERIALS/METHODS: This retrospective cohort study included 342 patients with stage T1-3N0 NSCLC treated with definitive SABR. We evaluated the estimated rate of INR using the cumulative incidence function with death as a competing risk and compared baseline factors among patients who did or did not experience INR. Among patients that experienced INR, we describe patterns of treatment and outcomes including overall (OS) and progression free survival (PFS) from the time of nodal failure using the Kaplan-Meier method. OS and PFS outcomes were compared between treatment groups using the log-rank test.RESULTS: Of the 342 patients treated with SABR from 2003-2018, 34 developed INR and 19 developed any nodal recurrence. Patients were treated with definitive SABR for T1 (62.6%, n = 214), T2 (25.4%, n = 87) and T3 (12.0%, n = 41) NSCLC with a median BED10 of 87.5. The 3- and 5-year cumulative incidence of INR was 9.3 (95% CI 6.1 - 12.4) and 10.1 (6.8 -13.4) %, respectively. Pathologic nodal staging prior to SBRT was 9.1 and 13.3 % (P = 0.68) for patients who did or did not experience INR, respectively. The median number of involved nodes at the time of recurrence was one with a maximum of four. Among the 30 patients with a known treatment course after INR, patients were treated with RT alone (26.7 %, n = 8), chemotherapy and RT (CRT) (43.3 %, n = 13), chemotherapy alone (13.3%, n = 4) or observation (16.7%, n = 5). RT regimens included standard fractionation (38.0%, n = 8), hypofractionation (52.4%, n = 11) or SABR (9.5%, n = 2). The estimated two-year OS and PFS for patients experiencing INR were 48.0 (32.6 - 70.7) % and 27.6 (14.7 - 52.8) %, respectively. Treatment with CRT was associated with improved OS (2 year est: 91.7 vs 16.7 %, P < 0.01) and PFS (2 year est: 63.9 vs 0 %, P < 0.01) over RT alone. Similarly, CRT was associated with improved OS (91.7 vs 25.0 %, P < 0.01) and PFS (63.9 vs 0%, P < 0.01) over chemotherapy alone. Median follow-up time after INR was 21.7 months.CONCLUSION: INR occurred in approximately 10% of patients treated for early-stage NSCLC with SABR. Treatment paradigms for post-SABR INR varied significantly at our institution and included combined chemotherapy and radiation, chemotherapy alone, SABR and hypofractionated RT. The highest rates of survival in patients with post-SABR INR were observed in those treated with combined chemotherapy and radiation.

    View details for DOI 10.1016/j.ijrobp.2021.07.1235

    View details for PubMedID 34701446

  • Deep Learning Based Identification and Segmentation of Lung Tumors on Computed Tomography Images. International journal of radiation oncology, biology, physics Kashyap, M., Panjwani, N., Hasan, M. A., Huang, C., Bush, K., Dong, P., Zaky, S. S., Chin, A. L., Vitzthum, L., Loo, B. W., Diehn, M., Xing, L., Gensheimer, M. F. 2021; 111 (3S): e92-e93

    Abstract

    PURPOSE/OBJECTIVE(S): Rapid and accurate estimation of tumor burden in biomedical images is essential for precisely monitoring cancer progression and assessing therapeutic response. The ability to detect and segment tumors using an automated approach is a key part of this task. Despite recent advances from deep learning, lung tumor delineation remains challenging, particularly when the tumor bounding box is not provided to the model. We hypothesized that clinical radiation oncology contours could supply a large enough dataset of 3D tumor segmentations to enable more accurate models. We developed and validated a deep learning-based model to identify and segment primary and metastatic lung tumors on computed tomography (CT) images.MATERIALS/METHODS: We curated a dataset consisting of CT images and clinical segmentations of 1,916 lung tumors in 1,504 patients who received radiation treatment for one or more primary or metastatic lung tumors. Segmentation quality was independently verified by a radiation oncologist using a custom web application. This dataset was used to train two 3D U-Net convolutional neural networks with varying model properties: one using high-resolution and small input volumes, and one using low-resolution and large input volumes. Models were ensembled together during validation. Performance was evaluated using an external held-out test set of CT images and segmentations from 59 patients with a single primary or metastatic lung tumor, treated at a separate clinical site. This test set consisted of 50 primary lung cancers and 9 metastases. To benchmark model performance against physicians, the test set was also contoured by two additional radiation oncologists.RESULTS: Median tumor volume in the external test set was 80.48 cubic centimeters (interquartile range [IQR]: 14.40 to 177.65). The segmentations generated by the ensembled model produced a mean Dice coefficient of 0.62 (IQR: 0.47 to 0.85) on the test set. The sensitivity for detecting a tumor, as defined by correctly predicting at least one voxel within a ground truth tumor, was 93.2%, and the Dice coefficient for the scans with correctly identified lesions was 0.67 (IQR: 0.53 to 0.85). In comparison, the mean interobserver Dice coefficient for the three physicians on the test set was 0.76 (IQR: 0.70 to 0.84). We observed strong correlation between physician-determined tumor size and model-predicted tumor size (Pearson correlation, r = 0.69, P < 0.0001).CONCLUSION: An end-to-end deep learning-based model was able to identify and segment lung tumors in a completely automated fashion, with near-expert level performance. Such models could soon be useful for clinical contouring and automatic quantification of tumor burden.

    View details for DOI 10.1016/j.ijrobp.2021.07.476

    View details for PubMedID 34702000

  • Pulmonary Hemorrhage in Patients Treated with Thoracic Stereotactic Ablative Radiotherapy and Anti-Angiogenic Agents Lau, B., No, H., (Fred) Wu, Y., Devine, M., Ko, R., Loo, B., Diehn, M., Chin, A., Vitzthum, L. LIPPINCOTT WILLIAMS & WILKINS. 2021: S105
  • Treatment Patterns for Isolated Nodal Recurrences in Non-Small Cell Lung Cancer After Definitive Stereotactic Ablative Radiotherapy No, H., Devine, M., Lau, B., Loo, B., Diehn, M., Chin, A., Vitzthum, L. LIPPINCOTT WILLIAMS & WILKINS. 2021: S109
  • Local Recurrence Outcomes of Colorectal Cancer Oligometastases Treated With Stereotactic Ablative Radiotherapy. American journal of clinical oncology Benson, K. R., Sandhu, N., Zhang, C., Ko, R., Toesca, D. A., Lee, P. E., Von Eyben, R., Diehn, M., Gensheimer, M., Maxim, P. G., Bush, K., Loo, B. W., Soltys, S. G., Pollom, E. L., Chang, D. T. 2021

    Abstract

    PURPOSE: The aim of this study was to report local failure (LF) outcomes and associated predictors in patients with oligometastatic colorectal cancer (CRC) treated with stereotactic ablative radiotherapy (SABR).MATERIALS AND METHODS: We retrospectively reviewed patients with CRC metastases to the brain, liver, spine, or lung treated with SABR between 2001 and 2016. Time to LF was summarized using cumulative incidence of LF curves with death as a competing risk.RESULTS: The analysis included a total of 130 patients and 256 lesions. Of the metastases treated, 129 (50%) were brain, 50 (20%) liver, 49 (19%) spine, and 28 (11%) lung. Median gross tumor volume was 24 mL for liver metastases, 2 mL for brain metastases, 4 mL for spine metastases, and 1 mL for lung metastases. The overall 1, 2, and 3-year cumulative incidence of LF rates were 21.6% (16.5, 27.1), 28.2% (22.3, 34.4), and 31.5% (25.2, 38.0), respectively. LF was highest among the liver metastases (1 y: 26.0%, 2 y: 38.5%), followed by spine (1 y: 25.1%, 2 y: 31.1%), brain (1 y: 20%, 2 y: 25.2%), and lung (1 y: 13.7%, 2 y: insufficient data). Metastases from right-sided primary CRC were significantly more likely to have LF (P=0.0146, HR=2.23). Biologically effective dose>70 Gy, defined using a standard linear quadratic model using alpha/beta ratio of 10 on the individual lesion level, and pre-SABR chemotherapy were also significant predictors of LF (P= 0.0009 and 0.018, respectively).CONCLUSIONS: CRC metastases treated with SABR had significantly higher rates of LF if they originated from right-sided primary CRC, compared with left-sided. Liver metastases had the highest rates of LF compared with other metastatic sites. Thus, CRC liver metastases and metastases from right-sided CRC may benefit from more aggressive radiotherapy.

    View details for DOI 10.1097/COC.0000000000000864

    View details for PubMedID 34534143

  • Radiological tumor classification across imaging modality and histology. Nature machine intelligence Wu, J., Li, C., Gensheimer, M., Padda, S., Kato, F., Shirato, H., Wei, Y., Schönlieb, C. B., Price, S. J., Jaffray, D., Heymach, J., Neal, J. W., Loo, B. W., Wakelee, H., Diehn, M., Li, R. 2021; 3: 787-798

    Abstract

    Radiomics refers to the high-throughput extraction of quantitative features from radiological scans and is widely used to search for imaging biomarkers for prediction of clinical outcomes. Current radiomic signatures suffer from limited reproducibility and generalizability, because most features are dependent on imaging modality and tumor histology, making them sensitive to variations in scan protocol. Here, we propose novel radiological features that are specially designed to ensure compatibility across diverse tissues and imaging contrast. These features provide systematic characterization of tumor morphology and spatial heterogeneity. In an international multi-institution study of 1,682 patients, we discover and validate four unifying imaging subtypes across three malignancies and two major imaging modalities. These tumor subtypes demonstrate distinct molecular characteristics and prognoses after conventional therapies. In advanced lung cancer treated with immunotherapy, one subtype is associated with improved survival and increased tumor-infiltrating lymphocytes compared with the others. Deep learning enables automatic tumor segmentation and reproducible subtype identification, which can facilitate practical implementation. The unifying radiological tumor classification may inform prognosis and treatment response for precision medicine.

    View details for DOI 10.1038/s42256-021-00377-0

    View details for PubMedID 34841195

    View details for PubMedCentralID PMC8612063

  • Circulating tumor DNA profiling for noninvasive detection, classification, and risk stratification of patients with CNS lymphomas Mutter, J. A., Alig, S., Lauer, E. M., Esfahani, M. S., Mitschke, J., Kurtz, D. M., Olsen, M., Liu, C. L., Jin, M. C., Bleul, S., Macaulay, C. W., Neidert, N. N., Heiland, D. H., Finke, J., Duyster, J., Wehrle, J., Prinz, M., Illerhaus, G., Reinacher, P. C., Schorb, E., Diehn, M., Alizadeh, A. A., Scherer, F. KARGER. 2021: 90
  • Radiological tumour classification across imaging modality and histology NATURE MACHINE INTELLIGENCE Wu, J., Li, C., Gensheimer, M., Padda, S., Kato, F., Shirato, H., Wei, Y., Schonlieb, C., Price, S., Jaffray, D., Heymach, J., Neal, J. W., Loo, B. W., Wakelee, H., Diehn, M., Li, R. 2021
  • A comprehensive circulating tumor DNA assay for detection of translocation and copy number changes in pediatric sarcomas. Molecular cancer therapeutics Shah, A. T., Azad, T. D., Breese, M. R., Chabon, J. J., Hamilton, E. G., Straessler, K., Kurtz, D. M., Leung, S. G., Spillinger, A., Liu, H., Behroozfard, I. H., Wittber, F. M., Hazard, F. K., Cho, S., Daldrup-Link, H. E., Vo, K. T., Rangaswami, A., Pribnow, A., Spunt, S. L., Lacayo, N. J., Diehn, M., Alizadeh, A. A., Sweet-Cordero, E. A. 2021

    Abstract

    Most circulating tumor DNA (ctDNA) assays are designed to detect recurrent mutations. Pediatric sarcomas share few recurrent mutations but rather are characterized by translocations and copy number changes. We applied CAncer Personalized Profiling by deep Sequencing (CAPP-Seq) for detection of translocations found in the most common pediatric sarcomas. We also applied ichorCNA to the combined off-target reads from our hybrid capture to simultaneously detect copy number alterations. We analyzed 64 prospectively collected plasma samples from 17 pediatric sarcoma patients. Translocations were detected in the pre-treatment plasma of 13 patients and were confirmed by tumor sequencing in 12 patients. Two of these patients had evidence of complex chromosomal rearrangements in their ctDNA. We also detected copy number changes in the pre-treatment plasma of 7 patients. We found that ctDNA levels correlated with metastatic status and clinical response. Furthermore, we detected rising ctDNA levels before relapse was clinically apparent, demonstrating the high sensitivity of our assay. This assay can be utilized for simultaneous detection of translocations and copy number alterations in the plasma of pediatric sarcoma patients. While we describe our experience in pediatric sarcomas, this approach can be applied to other tumors that are driven by structural variants.

    View details for DOI 10.1158/1535-7163.MCT-20-0987

    View details for PubMedID 34353895

  • Enhanced detection of minimal residual disease by targeted sequencing of phased variants in circulating tumor DNA. Nature biotechnology Kurtz, D. M., Soo, J., Co Ting Keh, L., Alig, S., Chabon, J. J., Sworder, B. J., Schultz, A., Jin, M. C., Scherer, F., Garofalo, A., Macaulay, C. W., Hamilton, E. G., Chen, B., Olsen, M., Schroers-Martin, J. G., Craig, A. F., Moding, E. J., Esfahani, M. S., Liu, C. L., Duhrsen, U., Huttmann, A., Casasnovas, R., Westin, J. R., Roschewski, M., Wilson, W. H., Gaidano, G., Rossi, D., Diehn, M., Alizadeh, A. A. 2021

    Abstract

    Circulating tumor-derived DNA (ctDNA) is an emerging biomarker for many cancers, but the limited sensitivity of current detection methods reduces its utility for diagnosing minimal residual disease. Here we describe phased variant enrichment and detection sequencing (PhasED-seq), a method that uses multiple somatic mutations in individual DNA fragments to improve the sensitivity of ctDNA detection. Leveraging whole-genome sequences from 2,538 tumors, we identify phased variants and their associations with mutational signatures. We show that even without molecular barcodes, the limits of detection of PhasED-seq outperform prior methods, including duplex barcoding, allowing ctDNA detection in the ppm range in participant samples. We profiled 678 specimens from 213 participants with B cell lymphomas, including serial cell-free DNA samples before and during therapy for diffuse large B cell lymphoma. In participants with undetectable ctDNA after two cycles of therapy using a next-generation sequencing-based approach termed cancer personalized profiling by deep sequencing, an additional 25% have ctDNA detectable by PhasED-seq and have worse outcomes. Finally, we demonstrate the application of PhasED-seq to solid tumors.

    View details for DOI 10.1038/s41587-021-00981-w

    View details for PubMedID 34294911

  • Liquid Biopsy for Advanced Non-Small Cell Lung Cancer: A Consensus Statement from The International Association for the Study of Lung Cancer (IASLC). Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer Rolfo, C., Mack, P., Scagliotti, G. V., Aggarwal, C., Arcila, M. E., Barlesi, F., Bivona, T., Diehn, M., Dive, C., Dziadziuszko, R., Leighl, N., Malapelle, U., Mok, T., Peled, N., Raez, L. E., Sequist, L., Sholl, L., Swanton, C., Abbosh, C., Tan, D., Wakelee, H., Wistuba, I., Bunn, R., Freeman-Daily, J., Wynes, M., Belani, C., Mitsudomi, T., Gandara, D. 2021

    View details for DOI 10.1016/j.jtho.2021.06.017

    View details for PubMedID 34246791

  • Mutational landscape of the bronchial epithelium of individuals at high risk for lung cancer. Rahman, S., Zhao, S., Chu, S., Zou, Y., Hui, A. B., Stricker, T. P., Heidi, C., Diehn, M., Massion, P. P. AMER ASSOC CANCER RESEARCH. 2021
  • Phased variants improve DLBCL minimal residual disease detection at the end of therapy. Kurtz, D., Chabon, J. J., Soo, J., Keh, L., Alig, S., Schultz, A., Jin, M. C., Scherer, F., Craig, A. M., Liu, C., Duehrsen, U., Huettmann, A., Casasnovas, R., Westin, J., Roschewski, M. J., Wilson, W., Gaidano, G., Rossi, D., Diehn, M., Alizadeh, A. A. LIPPINCOTT WILLIAMS & WILKINS. 2021
  • Noninvasive identification of emergent mutations following cytotoxic therapy for lung cancer. Moding, E., Hui, A. B., Murciano-Goroff, Y. R., Nabet, B., Schultz, A., Qiao, Y., Li, B. T., Lin, S. H., Alizadeh, A. A., Diehn, M. LIPPINCOTT WILLIAMS & WILKINS. 2021
  • Relationship between KEAP1/NFE2L2 pathway activation and radiation resistance in oral cavity cancer. Guan, L., Cao, H., Hui, A., Kwok, S., Viswanathan, V., Nambiar, D., Eyben, R. V., Holmes, B., Kong, C., Diehn, M., Quynh-Thu Le AMER ASSOC CANCER RESEARCH. 2021
  • Circulating tumor DNA kinetics to identify genomic predictors of rapid response to chemoradiation in non-small cell lung cancer. Moding, E. J., Liu, Y., Hui, A. B., He, J., Qiao, Y., Xu, T., Yao, L., Gandhi, S., Liao, Z., Das, M., Ramchandran, K. J., Padda, S. K., Neal, J. W., Wakelee, H. A., Loo, B. W., Lin, S. H., Alizadeh, A. A., Diehn, M. AMER ASSOC CANCER RESEARCH. 2021
  • Investigating gene expression profiles associated with clinical radiation resistance in KEAP1/NFE2L2 wildtype lung cancer. Binkley, M. S., Jeon, Y., Nesselbush, M., Moding, E. J., Nabet, B., Almanza, D., Yoo, C., Kurtz, D. M., Owen, S., Backhus, L. M., Berry, M. F., Shrager, J. B., Ramchandran, K. J., Padda, S. K., Das, M., Neal, J. W., Wakelee, H. A., Alizadeh, A. A., Loo, B. W., Diehn, M. AMER ASSOC CANCER RESEARCH. 2021
  • Genetic determinants of EGFR-Driven Lung Cancer Growth and Therapeutic Response In Vivo. Cancer discovery Foggetti, G., Li, C., Cai, H., Hellyer, J. A., Lin, W., Ayeni, D., Hastings, K., Choi, J., Wurtz, A., Andrejka, L., Maghini, D. G., Rashleigh, N., Levy, S., Homer, R., Gettinger, S. N., Diehn, M., Wakelee, H. A., Petrov, D. A., Winslow, M. M., Politi, K. 2021

    Abstract

    In lung adenocarcinoma, oncogenic EGFR mutations co-occur with many tumor suppressor gene alterations, however the extent to which these contribute to tumor growth and response to therapy in vivo remains largely unknown. By quantifying the effects of inactivating ten putative tumor suppressor genes in a mouse model of EGFR-driven Trp53-deficient lung adenocarcinoma, we found that Apc, Rb1, or Rbm10 inactivation strongly promoted tumor growth. Unexpectedly, inactivation of Lkb1 or Setd2 - the strongest drivers of growth in a Kras-driven model - reduced EGFR-driven tumor growth. These results are consistent with mutational frequencies in human EGFR- and KRAS-driven lung adenocarcinomas. Furthermore, Keap1 inactivation reduced the sensitivity of EGFR-driven tumors to the EGFR inhibitor osimertinib and mutations in the KEAP1 pathway were associated with decreased time on tyrosine kinase inhibitor treatment in patients. Our study highlights how the impact of genetic alterations differ across oncogenic contexts and that the fitness landscape shifts upon treatment.

    View details for DOI 10.1158/2159-8290.CD-20-1385

    View details for PubMedID 33707235

  • A review of immunotherapy for stage 3 and metastatic NSCLC & the rationale for the ECOG-ACRIN EA5181 study. The oncologist Varlotto, J. M., Sun, Z., Ky, B., Upshaw, J., Katz, S. I., Fitzgerald, T. J., Wakelee, H., Diehn, M., Mankoff, D. A., Lovly, C., Belani, C., Oettel, K., Masters, G., Ramalingam, S., Pennell, N. A. 2021

    Abstract

    ECOG-ACRIN EA5181 is a phase III prospective, randomized trial that randomizes patients undergoing chemo/radiation for locally advanced non-small cell lung cancer (LA- NSCLC) to concomitant durvalumab or no additional therapy with both arms receiving one year of consolidative durvalumab. Radiation dose-escalation failed to improve overall survival in RTOG 0617. However, conventionally-fractionated radiation to 60Gy with concomitant chemotherapy is associated with a high risk of local failure (38-46%). It is hoped that concomitant immunotherapy during chemo/radiation can help decrease the risk of local failure, thereby improving overall survival and progression-free survival with acceptable toxicity. In this article, we will review conventional chemo/radiation therapy for LA-NSCLC as well as the quickly evolving world of immunotherapy in the treatment of NSCLC and discuss the rationale and study design of EA5181. IMPLICATIONS FOR PRACTICE: Our article provides an up-to-date assessment of how immunotherapy is re-shaping the landscape of metastatic NSCLC and how the impact of this therapy is now rapidly moving into the treatment of patients with locally advanced NSCLC who are presenting for curative treatment. We will review the history of concurrent chemo/radiation, the recent publications of immunotherapy combined with chemotherapy or chemo/radiation, and our strategy for improving the OS of patients with locally advanced NSCLC by using concomitant immunotherapy with standard concurrent chemo/radiation.

    View details for DOI 10.1002/onco.13725

    View details for PubMedID 33594771

  • Global analysis of shared T cell specificities in human non-small cell lung cancer enables HLA inference and antigen discovery. Immunity Chiou, S. H., Tseng, D. n., Reuben, A. n., Mallajosyula, V. n., Molina, I. S., Conley, S. n., Wilhelmy, J. n., McSween, A. M., Yang, X. n., Nishimiya, D. n., Sinha, R. n., Nabet, B. Y., Wang, C. n., Shrager, J. B., Berry, M. F., Backhus, L. n., Lui, N. S., Wakelee, H. A., Neal, J. W., Padda, S. K., Berry, G. J., Delaidelli, A. n., Sorensen, P. H., Sotillo, E. n., Tran, P. n., Benson, J. A., Richards, R. n., Labanieh, L. n., Klysz, D. D., Louis, D. M., Feldman, S. A., Diehn, M. n., Weissman, I. L., Zhang, J. n., Wistuba, I. I., Futreal, P. A., Heymach, J. V., Garcia, K. C., Mackall, C. L., Davis, M. M. 2021; 54 (3): 586–602.e8

    Abstract

    To identify disease-relevant T cell receptors (TCRs) with shared antigen specificity, we analyzed 778,938 TCRβ chain sequences from 178 non-small cell lung cancer patients using the GLIPH2 (grouping of lymphocyte interactions with paratope hotspots 2) algorithm. We identified over 66,000 shared specificity groups, of which 435 were clonally expanded and enriched in tumors compared to adjacent lung. The antigenic epitopes of one such tumor-enriched specificity group were identified using a yeast peptide-HLA A∗02:01 display library. These included a peptide from the epithelial protein TMEM161A, which is overexpressed in tumors and cross-reactive epitopes from Epstein-Barr virus and E. coli. Our findings suggest that this cross-reactivity may underlie the presence of virus-specific T cells in tumor infiltrates and that pathogen cross-reactivity may be a feature of multiple cancers. The approach and analytical pipelines generated in this work, as well as the specificity groups defined here, present a resource for understanding the T cell response in cancer.

    View details for DOI 10.1016/j.immuni.2021.02.014

    View details for PubMedID 33691136

  • The landscape of tumor cell states and ecosystems in diffuse large B cell lymphoma. Cancer cell Steen, C. B., Luca, B. A., Esfahani, M. S., Azizi, A., Sworder, B. J., Nabet, B. Y., Kurtz, D. M., Liu, C. L., Khameneh, F., Advani, R. H., Natkunam, Y., Myklebust, J. H., Diehn, M., Gentles, A. J., Newman, A. M., Alizadeh, A. A. 2021

    Abstract

    Biological heterogeneity in diffuse large B cell lymphoma (DLBCL) is partly driven by cell-of-origin subtypes and associated genomic lesions, but also by diverse cell types and cell states in the tumor microenvironment (TME). However, dissecting these cell states and their clinical relevance at scale remains challenging. Here, we implemented EcoTyper, a machine-learning framework integrating transcriptome deconvolution and single-cell RNA sequencing, to characterize clinically relevant DLBCL cell states and ecosystems. Using this approach, we identified five cell states of malignant B cells that vary in prognostic associations and differentiation status. We also identified striking variation in cell states for 12 other lineages comprising the TME and forming cell state interactions in stereotyped ecosystems. While cell-of-origin subtypes have distinct TME composition, DLBCL ecosystems capture clinical heterogeneity within existing subtypes and extend beyond cell-of-origin and genotypic classes. These results resolve the DLBCL microenvironment at systems-level resolution and identify opportunities for therapeutic targeting (https://ecotyper.stanford.edu/lymphoma).

    View details for DOI 10.1016/j.ccell.2021.08.011

    View details for PubMedID 34597589

  • Atlas of clinically distinct cell states and ecosystems across human solid tumors. Cell Luca, B. A., Steen, C. B., Matusiak, M., Azizi, A., Varma, S., Zhu, C., Przybyl, J., Espín-Pérez, A., Diehn, M., Alizadeh, A. A., van de Rijn, M., Gentles, A. J., Newman, A. M. 2021

    Abstract

    Determining how cells vary with their local signaling environment and organize into distinct cellular communities is critical for understanding processes as diverse as development, aging, and cancer. Here we introduce EcoTyper, a machine learning framework for large-scale identification and validation of cell states and multicellular communities from bulk, single-cell, and spatially resolved gene expression data. When applied to 12 major cell lineages across 16 types of human carcinoma, EcoTyper identified 69 transcriptionally defined cell states. Most states were specific to neoplastic tissue, ubiquitous across tumor types, and significantly prognostic. By analyzing cell-state co-occurrence patterns, we discovered ten clinically distinct multicellular communities with unexpectedly strong conservation, including three with myeloid and stromal elements linked to adverse survival, one enriched in normal tissue, and two associated with early cancer development. This study elucidates fundamental units of cellular organization in human carcinoma and provides a framework for large-scale profiling of cellular ecosystems in any tissue.

    View details for DOI 10.1016/j.cell.2021.09.014

    View details for PubMedID 34597583

  • Detecting Liquid Remnants of Solid Tumors: Circulating Tumor DNA Minimal Residual Disease. Cancer discovery Moding, E. J., Nabet, B. Y., Alizadeh, A. A., Diehn, M. 2021

    Abstract

    Growing evidence demonstrates that circulating tumor DNA (ctDNA) minimal residual disease (MRD) following treatment for solid tumors predicts relapse. These results suggest that ctDNA MRD could identify candidates for adjuvant therapy and measure response to such treatment. Importantly, factors such as assay type, amount of ctDNA release, and technical and biological background can affect ctDNA MRD results. Furthermore, the clinical utility of ctDNA MRD for treatment personalization remains to be fully established. Here, we review the evidence supporting the value of ctDNA MRD in solid cancers and highlight key considerations in the application of this potentially transformative biomarker. SIGNIFICANCE: ctDNA analysis enables detection of MRD and predicts relapse after definitive treatment for solid cancers, thereby promising to revolutionize personalization of adjuvant and consolidation therapies.

    View details for DOI 10.1158/2159-8290.CD-21-0634

    View details for PubMedID 34785539

  • Short Diagnosis-to-Treatment Interval Is Associated With Higher Circulating Tumor DNA Levels in Diffuse Large B-Cell Lymphoma. Journal of clinical oncology : official journal of the American Society of Clinical Oncology Alig, S. n., Macaulay, C. W., Kurtz, D. M., Dührsen, U. n., Hüttmann, A. n., Schmitz, C. n., Jin, M. C., Sworder, B. J., Garofalo, A. n., Shahrokh Esfahani, M. n., Nabet, B. Y., Soo, J. n., Scherer, F. n., Craig, A. F., Casasnovas, O. n., Westin, J. R., Gaidano, G. n., Rossi, D. n., Roschewski, M. n., Wilson, W. H., Meignan, M. n., Diehn, M. n., Alizadeh, A. A. 2021: JCO2002573

    Abstract

    Patients with Diffuse Large B-cell Lymphoma (DLBCL) in need of immediate therapy are largely under-represented in clinical trials. The diagnosis-to-treatment interval (DTI) has recently been described as a metric to quantify such patient selection bias, with short DTI being associated with adverse risk factors and inferior outcomes. Here, we characterized the relationships between DTI, circulating tumor DNA (ctDNA), conventional risk factors, and clinical outcomes, with the goal of defining objective disease metrics contributing to selection bias.We evaluated pretreatment ctDNA levels in 267 patients with DLBCL treated across multiple centers in Europe and the United States using Cancer Personalized Profiling by Deep Sequencing. Pretreatment ctDNA levels were correlated with DTI, total metabolic tumor volumes (TMTVs), the International Prognostic Index (IPI), and outcome.Short DTI was associated with advanced-stage disease (P < .001) and higher IPI (P < .001). We also found an inverse correlation between DTI and TMTV (RS= -0.37; P < .001). Similarly, pretreatment ctDNA levels were significantly associated with stage, IPI, and TMTV (all P < .001), demonstrating that both DTI and ctDNA reflect disease burden. Notably, patients with shorter DTI had higher pretreatment ctDNA levels (P < .001). Pretreatment ctDNA levels predicted short DTI independent of the IPI (P < .001). Although each risk factor was significantly associated with event-free survival in univariable analysis, ctDNA level was prognostic of event-free survival independent of DTI and IPI in multivariable Cox regression (ctDNA: hazard ratio, 1.5; 95% CI [1.2 to 2.0]; IPI: 1.1 [0.9 to 1.3]; -DTI: 1.1 [1.0 to 1.2]).Short DTI largely reflects baseline tumor burden, which can be objectively measured using pretreatment ctDNA levels. Pretreatment ctDNA levels therefore have utility for quantifying and guarding against selection biases in prospective DLBCL clinical trials.

    View details for DOI 10.1200/JCO.20.02573

    View details for PubMedID 33909455

  • Durvalumab for Patients with Stage III EGFR-Mutated Non-Small Cell Lung Cancer Receiving Definitive Chemoradiotherapy Aredo, J. V., Hellyer, J. A., Neal, J. W., Padda, S. K., McCoach, C. E., Riess, J. W., Cabebe, E. C., Loo, B. W., Diehn, M., Wakelee, H. A. ELSEVIER SCIENCE INC. 2021: S15
  • Durvalumab for Stage III EGFR-Mutated Non-Small Cell Lung Cancer After Definitive Chemoradiotherapy. Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer Aredo, J. V., Mambetsariev, I. n., Hellyer, J. A., Amini, A. n., Neal, J. W., Padda, S. K., McCoach, C. E., Riess, J. W., Cabebe, E. C., Naidoo, J. n., Abuali, T. n., Salgia, R. n., Loo, B. W., Diehn, M. n., Han, S. S., Wakelee, H. A. 2021

    Abstract

    In 2018, durvalumab was FDA approved as consolidation immunotherapy for patients with stage III non-small cell lung cancer (NSCLC) after definitive chemoradiotherapy (CRT). Whether durvalumab benefits patients with EGFR-mutated NSCLC remains unknown.We conducted a multi-institutional retrospective analysis of patients with unresectable stage III EGFR-mutated NSCLC who completed concurrent CRT. Kaplan-Meier analyses evaluated progression-free survival (PFS) between patients who completed CRT with or without durvalumab.Among 37 patients, 13 initiated durvalumab a median of 20 days after CRT completion. Two patients completed 12 months of treatment, with five patients discontinuing durvalumab due to progression and five due to immune-related adverse events (irAEs). Of 24 patients who completed CRT without durvalumab, 16 completed CRT alone and 8 completed CRT with induction or consolidation EGFR tyrosine kinase inhibitors (TKI). Median PFS was 10.3 months in patients who received CRT and durvalumab versus 6.9 months with CRT alone (log-rank P=0.993). CRT and EGFR TKI was associated with a significantly longer median PFS (26.1 months) compared to CRT and durvalumab or CRT alone (log-rank P=0.023). Six patients treated with durvalumab initiated EGFR TKIs after recurrence, with one developing grade 4 pneumonitis on osimertinib.In this study, patients with EGFR-mutated NSCLC did not benefit with consolidation durvalumab and experienced a high frequency of irAEs. Patients who initiate osimertinib after durvalumab may be susceptible to incident irAEs. Consolidation durvalumab should be approached with caution in this setting and concurrent CRT with induction and/or consolidation EGFR TKIs further investigated as definitive treatment.

    View details for DOI 10.1016/j.jtho.2021.01.1628

    View details for PubMedID 33588109

  • A mathematical model of ctDNA shedding predicts tumor detection size. Science advances Avanzini, S., Kurtz, D. M., Chabon, J. J., Moding, E. J., Hori, S. S., Gambhir, S. S., Alizadeh, A. A., Diehn, M., Reiter, J. G. 2020; 6 (50)

    Abstract

    Early cancer detection aims to find tumors before they progress to an incurable stage. To determine the potential of circulating tumor DNA (ctDNA) for cancer detection, we developed a mathematical model of tumor evolution and ctDNA shedding to predict the size at which tumors become detectable. From 176 patients with stage I to III lung cancer, we inferred that, on average, 0.014% of a tumor cell's DNA is shed into the bloodstream per cell death. For annual screening, the model predicts median detection sizes of 2.0 to 2.3 cm representing a ~40% decrease from the current median detection size of 3.5 cm. For informed monthly cancer relapse testing, the model predicts a median detection size of 0.83 cm and suggests that treatment failure can be detected 140 days earlier than with imaging-based approaches. This mechanistic framework can help accelerate clinical trials by precomputing the most promising cancer early detection strategies.

    View details for DOI 10.1126/sciadv.abc4308

    View details for PubMedID 33310847

  • Detection and Diagnostic Utilization of Cellular and Cell-Free Tumor DNA. Annual review of pathology Dudley, J. C., Diehn, M. 2020

    Abstract

    Because cancer is caused by an accumulation of genetic mutations, mutant DNA released by tumors can be used as a highly specific biomarker for cancer. Although this principle was described decades ago, the advent and falling costs of next-generation sequencing have made the use of tumor DNA as a biomarker increasingly practical. This review surveys the use of cellular and cell-free DNA for the detection of cancer, with a focus on recent technological developments and applications to solid tumors. It covers (a) key principles and technology enabling the highly sensitive detection of tumor DNA; (b) assessment of tumor DNA in plasma, including for genotyping, minimal residual disease detection, and early detection of localized cancer; (c) detection of tumor DNA in body cavity fluids, such as urine or cerebrospinal fluid; and (d) challenges posed to the use of tumor DNA as a biomarker by the phenomenon of benign clonal expansions. Expected final online publication date for the Annual Review of Pathology: Mechanisms of Disease, Volume 16 is January 25, 2021. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

    View details for DOI 10.1146/annurev-pathmechdis-012419-032604

    View details for PubMedID 33228464

  • Cardiac Toxicities and Outcomes Following Stereotactic Ablative Radiation to Thoracic Cancers Obeid, J. P., Natarajan, J. M., Ko, R., Jani, K., Sodji, Q., Merriott, D. J., Pickthorn, W., Bush, K., Maxim, P. G., Diehn, M., Loo, B. W. ELSEVIER SCIENCE INC. 2020: E158–E159
  • Pre-Treatment Lung FDG-PET Uptake is Correlated with Radiologic Lung Fibrosis after Stereotactic Ablative Radiotherapy (SABR) Ross, J. B., Merriott, D. J., Alhumaid, S., Schueler, E., Ko, R., Bush, K., Maxim, P. G., Gensheimer, M. F., Loo, B. W., Diehn, M. ELSEVIER SCIENCE INC. 2020: E155
  • Parametric Response Mapping as an Imaging Biomarker for Regional Ventilation in Stereotactic Ablative Radiotherapy Capaldi, D. P., Binkley, M. S., Ko, R., Xing, L., Maxim, P. G., Diehn, M., Loo, B. W. ELSEVIER SCIENCE INC. 2020: E359
  • A noninvasive approach for early prediction of therapeutic benefit from immune checkpoint inhibition for lung cancer Nabet, B. Y., Esfahani, M. S., Hamilton, E. G., Chabon, J. J., Moding, E. J., Rizvi, H., Steen, C. B., Chaudhuri, A. A., Liu, C., Hui, A. B., Stehr, H., Goljenola, L., Jin, M. C., Jeon, Y., Tseng, D., Merghoub, T., Neal, J. W., Wakelee, H. A., Padda, S. K., Ramchandran, K. J., Das, M., Bonilla, R. F., Yoo, C., Chen, E. L., Ko, R. B., Newman, A. M., Hellmann, M. D., Alizadeh, A. A., Diehn, M. AMER ASSOC CANCER RESEARCH. 2020
  • Atlas of clinically-distinct cell states and cellular ecosystems across human solid tumors Luca, B. A., Steen, C. B., Azizi, A., Matusiak, M., Przybyl, J., Neishaboori, N., Perez, A., Diehn, M., Alizadeh, A. A., van de Rijn, M., Gentles, A. J., Newman, A. M. AMER ASSOC CANCER RESEARCH. 2020
  • Chromatin accessibility patterns in cell-free DNA reveal tumor heterogeneity Esfahani, M., Mehrmohamadi, M., Steen, C. B., Hamilton, E. G., King, D. A., Soo, J., Macaulay, C., Jin, M., Kurtz, D. M., Nabet, B., Moding, E., Chabon, J., Newman, A., Diehn, M., Alizadeh, A. A. AMER ASSOC CANCER RESEARCH. 2020
  • ctDNA applications and integration in colorectal cancer: an NCI Colon and Rectal-Anal Task Forces whitepaper. Nature reviews. Clinical oncology Dasari, A., Morris, V. K., Allegra, C. J., Atreya, C., Benson, A. B., Boland, P., Chung, K., Copur, M. S., Corcoran, R. B., Deming, D. A., Dwyer, A., Diehn, M., Eng, C., George, T. J., Gollub, M. J., Goodwin, R. A., Hamilton, S. R., Hechtman, J. F., Hochster, H., Hong, T. S., Innocenti, F., Iqbal, A., Jacobs, S. A., Kennecke, H. F., Lee, J. J., Lieu, C. H., Lenz, H., Lindwasser, O. W., Montagut, C., Odisio, B., Ou, F., Porter, L., Raghav, K., Schrag, D., Scott, A. J., Shi, Q., Strickler, J. H., Venook, A., Yaeger, R., Yothers, G., You, Y. N., Zell, J. A., Kopetz, S. 2020

    Abstract

    An increasing number of studies are describing potential uses of circulating tumour DNA (ctDNA) in the care of patients with colorectal cancer. Owing to this rapidly developing area of research, the Colon and Rectal-Anal Task Forces of the United States National Cancer Institute convened a panel of multidisciplinary experts to summarize current data on the utility of ctDNA in the management of colorectal cancer and to provide guidance in promoting the efficient development and integration of this technology into clinical care. The panel focused on four key areas in which ctDNA has the potential to change clinical practice, including the detection of minimal residual disease, the management of patients with rectal cancer, monitoring responses to therapy, and tracking clonal dynamics in response to targeted therapies and other systemic treatments. The panel also provides general guidelines with relevance for ctDNA-related research efforts, irrespective of indication.

    View details for DOI 10.1038/s41571-020-0392-0

    View details for PubMedID 32632268

  • Analytical validation of iSort digital cytometry for leukocyte enumeration in clinical tumor specimens. Newman, A. M., Nakao, A., Li, K., Wilson, D., Liu, C., Diehn, M., Alizadeh, A. A. LIPPINCOTT WILLIAMS & WILKINS. 2020
  • Integrating genomic features for non-invasive early lung cancer detection. Nature Chabon, J. J., Hamilton, E. G., Kurtz, D. M., Esfahani, M. S., Moding, E. J., Stehr, H., Schroers-Martin, J., Nabet, B. Y., Chen, B., Chaudhuri, A. A., Liu, C. L., Hui, A. B., Jin, M. C., Azad, T. D., Almanza, D., Jeon, Y. J., Nesselbush, M. C., Co Ting Keh, L., Bonilla, R. F., Yoo, C. H., Ko, R. B., Chen, E. L., Merriott, D. J., Massion, P. P., Mansfield, A. S., Jen, J., Ren, H. Z., Lin, S. H., Costantino, C. L., Burr, R., Tibshirani, R., Gambhir, S. S., Berry, G. J., Jensen, K. C., West, R. B., Neal, J. W., Wakelee, H. A., Loo, B. W., Kunder, C. A., Leung, A. N., Lui, N. S., Berry, M. F., Shrager, J. B., Nair, V. S., Haber, D. A., Sequist, L. V., Alizadeh, A. A., Diehn, M. 2020; 580 (7802): 245-251

    Abstract

    Radiologic screening of high-risk adults reduces lung-cancer-related mortality1,2; however, a small minority of eligible individuals undergo such screening in the United States3,4. The availability of blood-based tests could increase screening uptake. Here we introduce improvements to cancer personalized profiling by deep sequencing (CAPP-Seq)5, a method for the analysis of circulating tumour DNA (ctDNA), to better facilitate screening applications. We show that, although levels are very low in early-stage lung cancers, ctDNA is present prior to treatment in most patients and its presence is strongly prognostic. We also find that the majority of somatic mutations in the cell-free DNA (cfDNA) of patients with lung cancer and of risk-matched controls reflect clonal haematopoiesis and are non-recurrent. Compared with tumour-derived mutations, clonal haematopoiesis mutations occur on longer cfDNA fragments and lack mutational signatures that are associated with tobacco smoking. Integrating these findings with other molecular features, we develop and prospectively validate a machine-learning method termed 'lung cancer likelihood in plasma' (Lung-CLiP), which can robustly discriminate early-stage lung cancer patients from risk-matched controls. This approach achieves performance similar to that of tumour-informed ctDNA detection and enables tuning of assay specificity in order to facilitate distinct clinical applications. Our findings establish the potential of cfDNA for lung cancer screening and highlight the importance of risk-matching cases and controls in cfDNA-based screening studies.

    View details for DOI 10.1038/s41586-020-2140-0

    View details for PubMedID 32269342

  • A phase II randomized trial of Observation versus stereotactic ablative RadiatIon for OLigometastatic prostate CancEr (ORIOLE) Tran, P. T., Phillips, R., Shi, W., Lim, S., Antonarakis, E. S., Rowe, S. P., Ross, A., Gorin, M. A., Deville, C., Greco, S. C., Paller, C., DeWeese, T. L., Song, D. Y., Wang, H., Carducci, M., Pienta, K. J., Pomper, M., Dicker, A. P., Eisenberger, M. A., Diehn, M. AMER SOC CLINICAL ONCOLOGY. 2020
  • Circulating Tumor DNA Dynamics Predict Benefit from Consolidation Immunotherapy in Locally Advanced Non-Small Cell Lung Cancer. Nature cancer Moding, E. J., Liu, Y., Nabet, B. Y., Chabon, J. J., Chaudhuri, A. A., Hui, A. B., Bonilla, R. F., Ko, R. B., Yoo, C. H., Gojenola, L., Jones, C. D., He, J., Qiao, Y., Xu, T., Heymach, J. V., Tsao, A., Liao, Z., Gomez, D. R., Das, M., Padda, S. K., Ramchandran, K. J., Neal, J. W., Wakelee, H. A., Loo, B. W., Lin, S. H., Alizadeh, A. A., Diehn, M. 2020; 1 (2): 176-183

    Abstract

    Circulating tumor DNA (ctDNA) molecular residual disease (MRD) following curative-intent treatment strongly predicts recurrence in multiple tumor types, but whether further treatment can improve outcomes in patients with MRD remains unclear. We applied CAPP-Seq ctDNA analysis to 218 samples from 65 patients receiving chemoradiation therapy (CRT) for locally advanced NSCLC, including 28 patients receiving consolidation immune checkpoint inhibition (CICI). Patients with undetectable ctDNA after CRT had excellent outcomes whether or not they received CICI. Among such patients, one died from CICI-related pneumonitis, highlighting the potential utility of only treating patients with MRD. In contrast, patients with MRD after CRT who received CICI had significantly better outcomes than patients who did not receive CICI. Furthermore, the ctDNA response pattern early during CICI identified patients responding to consolidation therapy. Our results suggest that CICI improves outcomes for NSCLC patients with MRD and that ctDNA analysis may facilitate personalization of consolidation therapy.

    View details for DOI 10.1038/s43018-019-0011-0

    View details for PubMedID 34505064

    View details for PubMedCentralID PMC8425388

  • American Society of Clinical Oncology Road to Recovery Report: Learning From the COVID-19 Experience to Improve Clinical Research and Cancer Care. Journal of clinical oncology : official journal of the American Society of Clinical Oncology Pennell, N. A., Dillmon, M. n., Levit, L. A., Moushey, E. A., Alva, A. S., Blau, S. n., Cannon, T. L., Dickson, N. R., Diehn, M. n., Gonen, M. n., Gonzalez, M. M., Hensold, J. O., Hinyard, L. J., King, T. n., Lindsey, S. C., Magnuson, A. n., Marron, J. n., McAneny, B. L., McDonnell, T. M., Mileham, K. F., Nasso, S. F., Nowakowski, G. S., Oettel, K. R., Patel, M. I., Patt, D. A., Perlmutter, J. n., Pickard, T. A., Rodriguez, G. n., Rosenberg, A. R., Russo, B. n., Szczepanek, C. n., Smith, C. B., Srivastava, P. n., Teplinsky, E. n., Thota, R. n., Traina, T. A., Zon, R. n., Bourbeau, B. n., Bruinooge, S. S., Foster, S. n., Grubbs, S. n., Hagerty, K. n., Hurley, P. n., Kamin, D. n., Phillips, J. n., Schenkel, C. n., Schilsky, R. L., Burris, H. A. 2020: JCO2002953

    View details for DOI 10.1200/JCO.20.02953

    View details for PubMedID 33290128

  • Circulating tumor DNA dynamics predict benefit from consolidation immunotherapy in locally advanced non-small-cell lung cancer NATURE CANCER Moding, E. J., Liu, Y., Nabet, B. Y., Chabon, J. J., Chaudhuri, A. A., Hui, A. B., Bonilla, R. F., Ko, R. B., Gojenola, L., Jones, C. D., He, J., Qiao, Y., Heymach, J. V., Tsao, A., Liao, Z., Gomez, D. R., Das, M., Padda, S. K., Ramchandran, K. J., Neal, J. W., Wakelee, H. A., Loo Jr., B. W., Lin, S. H., Alizadeh, A. A., Diehn, M. 2020; 1: 176–183
  • Molecular and immunological signatures are related to clinical benefit from treatment with Vocimagene amiretrorepvec (Toca 511) and 5-fluorocytosine (Toca FC) in patients with glioma. Clinical cancer research : an official journal of the American Association for Cancer Research Accomando, W. P., Rao, A. R., Hogan, D. J., Newman, A. M., Nakao, A. n., Alizadeh, A. A., Diehn, M. n., Diago, O. R., Gammon, D. K., Haghighi, A. n., Gruber, H. E., Jolly, D. J., Ostertag, D. n. 2020

    Abstract

    High grade gliomas are central nervous system tumors with poor prognoses and limited treatment options. Vocimagene amiretrorepvec (Toca 511) is a retroviral replicating vector encoding cytosine deaminase, which converts extended-release 5-fluorocytosine (Toca FC) into the anti-cancer agent 5-fluorouracil. According to preclinical studies, this therapy kills cancer cells and immunosuppressive myeloid cells in the tumor microenvironment, leading to T-cell mediated anti-tumor immune activity. Therefore, we sought to elucidate this immune-related mechanism of action in humans, and to investigate potential molecular and immunological indicators of clinical benefit from therapy.In a Phase I clinical trial (NCT01470794), recurrent high grade glioma patients treated with Toca 511 and Toca FC showed improved survival relative to historical controls, and some had durable complete responses to therapy. As part of this trial, we performed whole exome DNA sequencing, RNA sequencing and multiplex digital ELISA measurements on tumor and blood samples.Genetic analyses suggest mutations, copy number variations and neoantigens are linked to survival. Quantities of tumor immune infiltrates estimated by transcript abundance may potentially predict clinical outcomes. Peak values of cytokines in peripheral blood samples collected during and after therapy could indicate response.These results support an immune-related mechanism of action for Toca 511 and Toca FC, and suggest that molecular and immunological signatures are related to clinical benefit from treatment.

    View details for DOI 10.1158/1078-0432.CCR-20-0536

    View details for PubMedID 32816892

  • Predicting per-lesion local recurrence in locally advanced non-small cell lung cancer following definitive radiation therapy using pre- and mid-treatment metabolic tumor volume. Radiation oncology (London, England) Binkley, M. S., Koenig, J. L., Kashyap, M. n., Xiang, M. n., Liu, Y. n., Sodji, Q. n., Maxim, P. G., Diehn, M. n., Loo, B. W., Gensheimer, M. F. 2020; 15 (1): 114

    Abstract

    We evaluated whether pre- and mid-treatment metabolic tumor volume (MTV) predicts per lesion local recurrence (LR) in patients treated with definitive radiation therapy (RT, dose≥60 Gy) for locally advanced non-small cell lung cancer (NSCLC).We retrospectively reviewed records of patients with stage III NSCLC treated from 2006 to 2018 with pre- and mid-RT PET-CT. We measured the MTV of treated lesions on the pre-RT (MTVpre) and mid-RT (MTVmid) PET-CT. LR was defined per lesion as recurrence within the planning target volume. Receiver operating characteristic (ROC) curves, cumulative incidence rates, and uni- and multivariable (MVA) competing risk regressions were used to evaluate the association between MTV and LR.We identified 111 patients with 387 lesions (112 lung tumors and 275 lymph nodes). Median age was 68 years, 69.4% were male, 46.8% had adenocarcinoma, 39.6% had squamous cell carcinoma, and 95.5% received concurrent chemotherapy. Median follow-up was 38.7 months. 3-year overall survival was 42.3%. 3-year cumulative incidence of LR was 26.8% per patient and 11.9% per lesion. Both MTVpre and MTVmid were predictive of LR by ROC (AUC = 0.71 and 0.76, respectively) and were significantly associated with LR on MVA (P = 0.004 and P = 7.1e-5, respectively). Among lesions at lower risk of LR based on MTVpre, higher MTVmid was associated with LR (P = 0.001).Per-lesion, larger MTVpre and MTVmid predicted for increased risk of LR. MTVmid was more highly predictive of LR than MTVpre and if validated may allow for further discrimination of high-risk lesions at mid-RT informing dose painting strategies.

    View details for DOI 10.1186/s13014-020-01546-y

    View details for PubMedID 32429982

  • Lack of supporting data make the risks of a clinical trial of radiation therapy as a treatment for COVID-19 pneumonia unacceptable. Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology Kirsch, D. G., Diehn, M. n., Cucinoata, F. A., Weichselbaum, R. n. 2020

    View details for DOI 10.1016/j.radonc.2020.04.060

    View details for PubMedID 32413531

    View details for PubMedCentralID PMC7215144

  • Circulating tumor DNA analysis to assess risk of progression after long-term response to PD-(L)1 blockade in NSCLC. Clinical cancer research : an official journal of the American Association for Cancer Research Hellmann, M. D., Nabet, B. Y., Rizvi, H. n., Chaudhuri, A. A., Wells, D. K., Dunphy, M. P., Chabon, J. J., Liu, C. L., Hui, A. B., Arbour, K. C., Luo, J. n., Preeshagul, I. R., Moding, E. J., Almanza, D. n., Bonilla, R. F., Sauter, J. L., Choi, H. n., Tenet, M. n., Abu-Akeel, M. n., Plodkowski, A. J., Perez-Johnston, R. n., Yoo, C. H., Ko, R. B., Stehr, H. n., Gojenola, L. n., Wakelee, H. A., Padda, S. K., Neal, J. W., Chaft, J. E., Kris, M. G., Rudin, C. M., Merghoub, T. n., Li, B. T., Alizadeh, A. A., Diehn, M. n. 2020

    Abstract

    Treatment with PD-(L)1 blockade can produce remarkably durable responses in non-small cell lung cancer (NSCLC) patients. However, a significant fraction of long-term responders ultimately progress and predictors of late progression are unknown. We hypothesized that circulating tumor DNA (ctDNA) analysis of long-term responders to PD-(L)1 blockade may differentiate those who will achieve ongoing benefit from those at risk of eventual progression.In patients with advanced NSCLC achieving long-term benefit from PD-(L)1 blockade (PFS≥12 months), plasma was collected at a surveillance timepoint late during/after treatment to interrogate ctDNA by Cancer Personalized Profiling by Deep Sequencing (CAPP-Seq). Tumor tissue was available for 24 patients and was profiled by whole-exome sequencing (n=18) or by targeted sequencing (n=6).31 NSCLC patients with long-term benefit to PD-(L)1 blockade were identified and ctDNA was analyzed in surveillance blood samples collected at a median of 26.7 months after initiation of therapy. Nine patients also had baseline plasma samples available, and all had detectable ctDNA prior to therapy initiation. At the surveillance timepoint, 27 patients had undetectable ctDNA and 25 (93%) have remained progression-free; by contrast, all four patients with detectable ctDNA eventually progressed (Fisher's p<0.0001; PPV 1 [95% CI 0.51-1]; NPV 0.93 [95% CI 0.80-0.99]).ctDNA analysis can noninvasively identify minimal residual disease in patients with long-term responses to PD-(L)1 and predict the risk of eventual progression. If validated, ctDNA surveillance may facilitate personalization of the duration of immune checkpoint blockade and enable early intervention in patients at high risk for progression.

    View details for DOI 10.1158/1078-0432.CCR-19-3418

    View details for PubMedID 32046999

  • Single cell analysis reveals distinct immune landscapes in transplant and primary sarcomas that determine response or resistance to immunotherapy. Nature communications Wisdom, A. J., Mowery, Y. M., Hong, C. S., Himes, J. E., Nabet, B. Y., Qin, X. n., Zhang, D. n., Chen, L. n., Fradin, H. n., Patel, R. n., Bassil, A. M., Muise, E. S., King, D. A., Xu, E. S., Carpenter, D. J., Kent, C. L., Smythe, K. S., Williams, N. T., Luo, L. n., Ma, Y. n., Alizadeh, A. A., Owzar, K. n., Diehn, M. n., Bradley, T. n., Kirsch, D. G. 2020; 11 (1): 6410

    Abstract

    Immunotherapy fails to cure most cancer patients. Preclinical studies indicate that radiotherapy synergizes with immunotherapy, promoting radiation-induced antitumor immunity. Most preclinical immunotherapy studies utilize transplant tumor models, which overestimate patient responses. Here, we show that transplant sarcomas are cured by PD-1 blockade and radiotherapy, but identical treatment fails in autochthonous sarcomas, which demonstrate immunoediting, decreased neoantigen expression, and tumor-specific immune tolerance. We characterize tumor-infiltrating immune cells from transplant and primary tumors, revealing striking differences in their immune landscapes. Although radiotherapy remodels myeloid cells in both models, only transplant tumors are enriched for activated CD8+ T cells. The immune microenvironment of primary murine sarcomas resembles most human sarcomas, while transplant sarcomas resemble the most inflamed human sarcomas. These results identify distinct microenvironments in murine sarcomas that coevolve with the immune system and suggest that patients with a sarcoma immune phenotype similar to transplant tumors may benefit most from PD-1 blockade and radiotherapy.

    View details for DOI 10.1038/s41467-020-19917-0

    View details for PubMedID 33335088

  • Response Letter: Radiation therapy for COVID-19 pneumopathy. Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology Kirsch, D. G., Diehn, M. n., Cucinotta, F. A., Weichselbaum, R. n. 2020

    View details for DOI 10.1016/j.radonc.2020.05.048

    View details for PubMedID 32505722

  • Early response evaluation using primary tumor and nodal imaging features to predict progression-free survival of locally advanced non-small cell lung cancer. Theranostics Zhang, N., Liang, R., Gensheimer, M. F., Guo, M., Zhu, H., Yu, J., Diehn, M., Loo, B. W., Li, R., Wu, J. 2020; 10 (25): 11707–18

    Abstract

    Prognostic biomarkers that can reliably predict early disease progression of non-small cell lung cancer (NSCLC) are needed for identifying those patients at high risk for progression, who may benefit from more intensive treatment. In this work, we aimed to identify an imaging signature for predicting progression-free survival (PFS) of locally advanced NSCLC. Methods: This retrospective study included 82 patients with stage III NSCLC treated with definitive chemoradiotherapy for whom both baseline and mid-treatment PET/CT scans were performed. They were randomly placed into two groups: training cohort (n=41) and testing cohort (n=41). All primary tumors and involved lymph nodes were delineated. Forty-five quantitative imaging features were extracted to characterize the tumors and involved nodes at baseline and mid-treatment as well as differences between two scans performed at these two points. An imaging signature was developed to predict PFS by fitting an L1-regularized Cox regression model. Results: The final imaging signature consisted of three imaging features: the baseline tumor volume, the baseline maximum distance between involved nodes, and the change in maximum distance between the primary tumor and involved nodes measured at two time points. According to multivariate analysis, the imaging model was an independent prognostic factor for PFS in both the training (hazard ratio [HR], 1.14, 95% confidence interval [CI], 1.04-1.24; P = 0.003), and testing (HR, 1.21, 95% CI, 1.10-1.33; P = 0.048) cohorts. The imaging signature stratified patients into low- and high-risk groups, with 2-year PFS rates of 61.9% and 33.2%, respectively (P = 0.004 [log-rank test]; HR, 4.13, 95% CI, 1.42-11.70) in the training cohort, as well as 43.8% and 22.6%, respectively (P = 0.006 [log-rank test]; HR, 3.45, 95% CI, 1.35-8.83) in the testing cohort. In both cohorts, the imaging signature significantly outperformed conventional imaging metrics, including tumor volume and SUVmax value (C-indices: 0.77-0.79 for imaging signature, and 0.53-0.73 for conventional metrics). Conclusions: Evaluation of early treatment response by combining primary tumor and nodal imaging characteristics may improve the prediction of PFS of locally advanced NSCLC patients.

    View details for DOI 10.7150/thno.50565

    View details for PubMedID 33052242

  • A human lung tumor microenvironment interactome identifies clinically relevant cell-type cross-talk. Genome biology Gentles, A. J., Hui, A. B., Feng, W. n., Azizi, A. n., Nair, R. V., Bouchard, G. n., Knowles, D. A., Yu, A. n., Jeong, Y. n., Bejnood, A. n., Forgó, E. n., Varma, S. n., Xu, Y. n., Kuong, A. n., Nair, V. S., West, R. n., van de Rijn, M. n., Hoang, C. D., Diehn, M. n., Plevritis, S. K. 2020; 21 (1): 107

    Abstract

    Tumors comprise a complex microenvironment of interacting malignant and stromal cell types. Much of our understanding of the tumor microenvironment comes from in vitro studies isolating the interactions between malignant cells and a single stromal cell type, often along a single pathway.To develop a deeper understanding of the interactions between cells within human lung tumors, we perform RNA-seq profiling of flow-sorted malignant cells, endothelial cells, immune cells, fibroblasts, and bulk cells from freshly resected human primary non-small-cell lung tumors. We map the cell-specific differential expression of prognostically associated secreted factors and cell surface genes, and computationally reconstruct cross-talk between these cell types to generate a novel resource called the Lung Tumor Microenvironment Interactome (LTMI). Using this resource, we identify and validate a prognostically unfavorable influence of Gremlin-1 production by fibroblasts on proliferation of malignant lung adenocarcinoma cells. We also find a prognostically favorable association between infiltration of mast cells and less aggressive tumor cell behavior.These results illustrate the utility of the LTMI as a resource for generating hypotheses concerning tumor-microenvironment interactions that may have prognostic and therapeutic relevance.

    View details for DOI 10.1186/s13059-020-02019-x

    View details for PubMedID 32381040

  • Outcomes of Observation vs Stereotactic Ablative Radiation for Oligometastatic Prostate Cancer: The ORIOLE Phase 2 Randomized Clinical Trial. JAMA oncology Phillips, R. n., Shi, W. Y., Deek, M. n., Radwan, N. n., Lim, S. J., Antonarakis, E. S., Rowe, S. P., Ross, A. E., Gorin, M. A., Deville, C. n., Greco, S. C., Wang, H. n., Denmeade, S. R., Paller, C. J., Dipasquale, S. n., DeWeese, T. L., Song, D. Y., Wang, H. n., Carducci, M. A., Pienta, K. J., Pomper, M. G., Dicker, A. P., Eisenberger, M. A., Alizadeh, A. A., Diehn, M. n., Tran, P. T. 2020

    Abstract

    Complete metastatic ablation of oligometastatic prostate cancer may provide an alternative to early initiation of androgen deprivation therapy (ADT).To determine if stereotactic ablative radiotherapy (SABR) improves oncologic outcomes in men with oligometastatic prostate cancer.The Observation vs Stereotactic Ablative Radiation for Oligometastatic Prostate Cancer (ORIOLE) phase 2 randomized study accrued participants from 3 US radiation treatment facilities affiliated with a university hospital from May 2016 to March 2018 with a data cutoff date of May 20, 2019, for analysis. Of 80 men screened, 54 men with recurrent hormone-sensitive prostate cancer and 1 to 3 metastases detectable by conventional imaging who had not received ADT within 6 months of enrollment or 3 or more years total were randomized.Patients were randomized in a 2:1 ratio to receive SABR or observation.The primary outcome was progression at 6 months by prostate-specific antigen level increase, progression detected by conventional imaging, symptomatic progression, ADT initiation for any reason, or death. Predefined secondary outcomes were toxic effects of SABR, local control at 6 months with SABR, progression-free survival, Brief Pain Inventory (Short Form)-measured quality of life, and concordance between conventional imaging and prostate-specific membrane antigen (PSMA)-targeted positron emission tomography in the identification of metastatic disease.In the 54 men randomized, the median (range) age was 68 (61-70) years for patients allocated to SABR and 68 (64-76) years for those allocated to observation. Progression at 6 months occurred in 7 of 36 patients (19%) receiving SABR and 11 of 18 patients (61%) undergoing observation (P = .005). Treatment with SABR improved median progression-free survival (not reached vs 5.8 months; hazard ratio, 0.30; 95% CI, 0.11-0.81; P = .002). Total consolidation of PSMA radiotracer-avid disease decreased the risk of new lesions at 6 months (16% vs 63%; P = .006). No toxic effects of grade 3 or greater were observed. T-cell receptor sequencing identified significant increased clonotypic expansion following SABR and correlation between baseline clonality and progression with SABR only (0.082085 vs 0.026051; P = .03).Treatment with SABR for oligometastatic prostate cancer improved outcomes and was enhanced by total consolidation of disease identified by PSMA-targeted positron emission tomography. SABR induced a systemic immune response, and baseline immune phenotype and tumor mutation status may predict the benefit from SABR. These results underline the importance of prospective randomized investigation of the oligometastatic state with integrated imaging and biological correlates.ClinicalTrials.gov Identifier: NCT02680587.

    View details for DOI 10.1001/jamaoncol.2020.0147

    View details for PubMedID 32215577

  • Targeted Treatment of Multiple Primary Lung Cancers Harboring Distinct EGFR or RET Alterations: A Case Report. Clinical lung cancer Aredo, J. V., Diehn, M. n., Berry, G. J., Wakelee, H. A. 2020

    View details for DOI 10.1016/j.cllc.2020.12.005

    View details for PubMedID 33451914

  • Clinical implications of KEAP1-NFE2L2 mutations in non-small cell lung cancer. Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer Hellyer, J. A., Padda, S. K., Diehn, M. n., Wakelee, H. A. 2020

    Abstract

    The KEAP1-NFE2L2 pathway is an important modulator of cell homeostasis. Mutations in this pathway are common in non-small cell lung cancer (NSCLC) and have been associated with enhanced tumor growth and aggressiveness. In addition, tumors with mutations in the KEAP1-NFE2L2 pathway have been shown in pre-clinical and clinical studies to convey refractoriness to cancer-directed therapy such as radiation, chemotherapy and targeted therapy. The role of immunotherapy in this patient population is less clear and there are conflicting studies on the efficacy of immune checkpoint inhibitors in KEAP1-NFE2L2 mutant NSCLC. Here we review the current clinical evidence on several classes of anti-cancer therapeutics in KEAP1 -NFE2L2 mutant tumors. We also provide an overview of the landscape of the current clinical trials in this patient population, highlighting work being done with mTORC1/2 and glutaminase inhibition.

    View details for DOI 10.1016/j.jtho.2020.11.015

    View details for PubMedID 33307193

  • Deep segmentation networks predict survival of non-small cell lung cancer. Scientific reports Baek, S., He, Y., Allen, B. G., Buatti, J. M., Smith, B. J., Tong, L., Sun, Z., Wu, J., Diehn, M., Loo, B. W., Plichta, K. A., Seyedin, S. N., Gannon, M., Cabel, K. R., Kim, Y., Wu, X. 2019; 9 (1): 17286

    Abstract

    Non-small-cell lung cancer (NSCLC) represents approximately 80-85% of lung cancer diagnoses and is the leading cause of cancer-related death worldwide. Recent studies indicate that image-based radiomics features from positron emission tomography/computed tomography (PET/CT) images have predictive power for NSCLC outcomes. To this end, easily calculated functional features such as the maximum and the mean of standard uptake value (SUV) and total lesion glycolysis (TLG) are most commonly used for NSCLC prognostication, but their prognostic value remains controversial. Meanwhile, convolutional neural networks (CNN) are rapidly emerging as a new method for cancer image analysis, with significantly enhanced predictive power compared to hand-crafted radiomics features. Here we show that CNNs trained to perform the tumor segmentation task, with no other information than physician contours, identify a rich set of survival-related image features with remarkable prognostic value. In a retrospective study on pre-treatment PET-CT images of 96 NSCLC patients before stereotactic-body radiotherapy (SBRT), we found that the CNN segmentation algorithm (U-Net) trained for tumor segmentation in PET and CT images, contained features having strong correlation with 2- and 5-year overall and disease-specific survivals. The U-Net algorithm has not seen any other clinical information (e.g. survival, age, smoking history, etc.) than the images and the corresponding tumor contours provided by physicians. In addition, we observed the same trend by validating the U-Net features against anextramural data set provided by Stanford Cancer Institute. Furthermore, through visualization of the U-Net, we also found convincing evidence that the regions of metastasis and recurrence appear to match with the regions where the U-Net features identified patterns that predicted higher likelihoods of death. We anticipate our findings will be a starting point for more sophisticated non-intrusive patient specific cancer prognosis determination. For example, the deep learned PET/CT features can not only predict survival but also visualize high-risk regions within or adjacent to the primary tumor and hence potentially impact therapeutic outcomes by optimal selection of therapeutic strategy or first-line therapy adjustment.

    View details for DOI 10.1038/s41598-019-53461-2

    View details for PubMedID 31754135

  • An Atlas of Clinically-Distinct Tumor Cellular Ecosystems in Diffuse Large B Cell Lymphoma Steen, C. B., Luca, B. A., Esfahani, M., Nabet, B. Y., Sworder, B., Farshidfar, F., Shamardani, K., Kurtz, D. M., Liu, C., Advani, R. H., Natkunam, Y., Myklebust, J., Diehn, M., Gentles, A., Newman, A. M., Alizadeh, A. A. AMER SOC HEMATOLOGY. 2019
  • Deep Sequencing of Viral Cell-Free DNA for Noninvasive Detection of Immunosuppression-Related Lymphoid Malignancies Garofalo, A., Schroers-Martin, J. G., Soo, J., Kurtz, D. M., Sworder, B., Liu, C., Pinsky, B. A., Luikart, H., Advani, R. H., Natkunam, Y., Khush, K., Diehn, M., Alizadeh, A. A. AMER SOC HEMATOLOGY. 2019
  • Atlas of clinically-distinct cell states and cellular ecosystems across human solid tumors Luca, B., Alizadeh, A., Diehn, M., Newman, A., Gentles, A., Steen, C. BMC. 2019
  • Primary Outcomes of a Phase II Randomized Trial of Observation Versus Stereotactic Ablative RadiatIon for OLigometastatic Prostate CancEr (ORIOLE) Phillips, R., Lim, S. J., Shi, W. Y., Antonarakis, E. S., Rowe, S., Gorin, M., Deville, C., Greco, S. C., Denmeade, S., Paller, C., DeWeese, T. L., Song, D., Wang, H., Carducci, M., Pienta, K., Pomper, M. G., Dicker, A. P., Eisenberger, M., Diehn, M., Tran, P. T. ELSEVIER SCIENCE INC. 2019: 681
  • Broad Genomic Profiling of Bronchoalveolar Lavage Fluid in Lung Cancer Nair, V., Hui, A., Chabon, J., Esfahani, M., Stehr, H., Nabet, B., Benson, J., Chaudhuri, A., Zhou, L., Ayers, K., Bedi, H., Ramsey, M., Van Wert, R., Sung, A., Lui, N., Backhus, L., Berry, M., Massion, P., Shrager, J., Alizadeh, A., Diehn, M. ELSEVIER SCIENCE INC. 2019: S747–S748
  • Circulating Tumor DNA Changes During Chemoradiation for Lung Cancer Predict Patient Outcomes Moding, E. J., Nabet, B. Y., Liu, Y., Chabon, J. J., Chaudhuri, A. A., Hui, A. B., Binkley, M. S., He, J., Qiao, Y., Xu, T., Yao, L., Gandhi, S., Liao, Z., Das, M., Ramchandran, K. J., Padda, S., Neal, W., Wakelee, H. A., Gensheimer, M. F., Loo, B. W., Lin, S. H., Alizadeh, A. A., Diehn, M. ELSEVIER SCIENCE INC. 2019: S113
  • Outcomes of Oligometastatic Colorectal Cancer treated with Stereotactic Ablative Radiotherapy Benson, K., Sandhu, N., Zhang, C., Ko, R. B., Toesca, D. S., Von Eyben, R., Diehn, M., Bush, K., Maxim, P. G., Gensheimer, M. F., Soltys, S. G., Loo, B. W., Pollom, E., Chang, D. T. ELSEVIER SCIENCE INC. 2019: E161–E162
  • Symptomatic Cardiac Events in Patients with Lung Tumors Near The Heart Treated with Stereotactic Ablative Radiotherapy (SABR): A Single Institution Experience Ko, R. B., Jani, K., Sodji, Q., Merriott, D. J., Pickthorn, W., Bush, K., Maxim, P. G., Diehn, M., Loo, B. W. ELSEVIER SCIENCE INC. 2019: S148
  • Influence of Dose and Fractionation on Radiologic Lung Fibrosis after Stereotactic Ablative Radiotherapy (SABR) Ross, J. B., Ross, J. B., Merriott, D. J., Alhumaid, S., Schueler, E., Ko, R. B., Bush, K., Maxim, P. G., Gensheimer, M. F., Loo, B. W., Diehn, M. ELSEVIER SCIENCE INC. 2019: E527–E528
  • Investigating and Validating Metabolic Tumor Volume As a Prognostic Factor for Local Recurrence in Early Stage Lung Cancer Binkley, M. S., Stehr, H., Moding, E. J., Owen, S. G., Ko, R., Maxim, P. G., Loo, B. W., Diehn, M. ELSEVIER SCIENCE INC. 2019: E497
  • Molecular Profiling of Oligometastases and Artificial Intelligence-based Model for Predicting Treatment Outcome in Advance Prostate Cancer Heidari, N., Bagshaw, H. P., Diehn, M., Snyder, M., Buyyounouski, M. K. ELSEVIER SCIENCE INC. 2019: 1195
  • Dynamic Risk Profiling Using Serial Tumor Biomarkers for Personalized Outcome Prediction. Cell Kurtz, D. M., Esfahani, M. S., Scherer, F., Soo, J., Jin, M. C., Liu, C. L., Newman, A. M., Duhrsen, U., Huttmann, A., Casasnovas, O., Westin, J. R., Ritgen, M., Bottcher, S., Langerak, A. W., Roschewski, M., Wilson, W. H., Gaidano, G., Rossi, D., Bahlo, J., Hallek, M., Tibshirani, R., Diehn, M., Alizadeh, A. A. 2019

    Abstract

    Accurate prediction of long-term outcomes remains a challenge in the care of cancer patients. Due to the difficulty of serial tumor sampling, previous prediction tools have focused on pretreatment factors. However, emerging non-invasive diagnostics have increased opportunities for serial tumor assessments. We describe the Continuous Individualized Risk Index (CIRI), a method to dynamically determine outcome probabilities for individual patients utilizing risk predictors acquired over time. Similar to "win probability" models in other fields, CIRI provides a real-time probability by integrating risk assessments throughout a patient's course. Applying CIRI to patients with diffuse large B cell lymphoma, we demonstrate improved outcome prediction compared to conventional risk models. We demonstrate CIRI's broader utility in analogous models of chronic lymphocytic leukemia and breast adenocarcinoma and perform a proof-of-concept analysis demonstrating how CIRI could be used to develop predictive biomarkers for therapy selection. We envision thatdynamic risk assessment will facilitate personalized medicine and enable innovative therapeutic paradigms.

    View details for DOI 10.1016/j.cell.2019.06.011

    View details for PubMedID 31280963

  • Determining cell type abundance and expression from bulk tissues with digital cytometry NATURE BIOTECHNOLOGY Newman, A. M., Steen, C. B., Liu, C., Gentles, A. J., Chaudhuri, A. A., Scherer, F., Khodadoust, M. S., Esfahani, M. S., Luca, B. A., Steiner, D., Diehn, M., Alizadeh, A. A. 2019; 37 (7): 773-+
  • Case series of MET exon 14 skipping mutation-positive non-small-cell lung cancers with response to crizotinib and cabozantinib ANTI-CANCER DRUGS Wang, S. Y., Zhang, B. M., Wakelee, H. A., Koontz, M. Z., Pan, M., Diehn, M., Kunder, C. A., Neal, J. W. 2019; 30 (5): 537–41
  • FLT-PET-CT for the Detection of Disease Recurrence After Stereotactic Ablative Radiotherapy or Hyperfractionation for Thoracic Malignancy: A Prospective Pilot Study FRONTIERS IN ONCOLOGY Hiniker, S. M., Sodji, Q., Quon, A., Gutkin, P. M., Arksey, N., Graves, E. E., Chin, F. T., Maxim, P. G., Diehn, M., Loo, B. W. 2019; 9
  • FLT-PET-CT for the Detection of Disease Recurrence After Stereotactic Ablative Radiotherapy or Hyperfractionation for Thoracic Malignancy: A Prospective Pilot Study. Frontiers in oncology Hiniker, S. M., Sodji, Q., Quon, A., Gutkin, P. M., Arksey, N., Graves, E. E., Chin, F. T., Maxim, P. G., Diehn, M., Loo, B. W. 2019; 9: 467

    Abstract

    Differentiating local recurrence from post-treatment changes on PET scans following stereotactic ablative radiotherapy (SABR) or hyperfractionation for lung tumors is challenging. We performed a prospective pilot study of 3-deoxy-3-[18F]-fluorothymidine (FLT)-PET-CT in patients with equivocal post-radiation FDG-PET-CT to assess disease recurrence. Methods: We prospectively enrolled 10 patients, 9 treated with SABR and 1 with hyperfractionated external beam radiotherapy for thoracic malignancy with subsequent equivocal follow-up FDG-PET-CT, to undergo FLT-PET-CT prior to biopsy or serial imaging. FLT-PET scans were interpreted by a radiologist with experience in reading FLT-PET-CT and blinded to the results of any subsequent biopsy or imaging. Results: Of the 10 patients enrolled, 8 were evaluable after FLT-PET-CT. Based on the FLT-PET-CT, a blinded radiologist accurately predicted disease recurrence vs. inflammatory changes in 7 patients (87.5%). The combination of higher lesion SUVmax and higher ratio of lesion SUVmax to SUVmax of mediastinal blood pool was indicative of recurrence. Qualitative assessment of increased degree of focality of the lesion also appears to be indicative of disease recurrence. Conclusion: Adjunctive FLT-PET-CT imaging can complement FDG-PET-CT scan in distinguishing post-treatment radiation changes from disease recurrence in thoracic malignancies. These findings support the investigation of FLT-PET-CT in a larger prospective study.

    View details for DOI 10.3389/fonc.2019.00467

    View details for PubMedID 31214507

    View details for PubMedCentralID PMC6555304

  • ctDNA analysis for personalization of consolidation immunotherapy in localized non-small cell lung cancer. Moding, E. J., Liu, Y., Nabet, B., Chabon, J. J., Chaudhuri, A., Hui, A. B., He, J., Qiao, Y., Heymach, J., Tsao, A. S., Liao, Z. X., Gomez, D., Ramchandran, K., Neal, J. W., Wakelee, H. A., Loo, B. W., Lin, S. H., Alizadeh, A. A., Diehn, M. AMER SOC CLINICAL ONCOLOGY. 2019
  • SABR-COMET: harbinger of a new cancer treatment paradigm LANCET Loo, B. W., Diehn, M. 2019; 393 (10185): 2013–14
  • SABR-COMET: harbinger of a new cancer treatment paradigm. Lancet (London, England) Loo, B. W., Diehn, M. 2019

    View details for PubMedID 30982688

  • Increases in Serial Pretreatment 18F-FDG PET-CT Metrics Predict Survival in Early Stage Non-Small Cell Lung Cancer Treated With Stereotactic Ablative Radiation Therapy. Advances in radiation oncology Prionas, N. D., von Eyben, R., Yi, E., Aggarwal, S., Shaffer, J., Bazan, J., Eastham, D., Maxim, P. G., Graves, E. E., Diehn, M., Gensheimer, M. F., Loo, B. W. 2019; 4 (2): 429–37

    Abstract

    Purpose: Quantitative changes in positron emission tomography with computed tomography imaging metrics over serial scans may be predictive biomarkers. We evaluated the relationship of pretreatment metabolic tumor growth rate (MTGR) and standardized uptake value velocity (SUVV) with disease recurrence or death in patients with early-stage non-small cell lung cancer treated with stereotactic ablative radiation therapy (SABR).Methods and Materials: Under institutional review board approval, we retrospectively identified patients who underwent positron emission tomography with computed tomography at diagnosis and staging and simulation for SABR. Two cohorts underwent SABR between November 2005 to October 2012 (discovery) and January 2012 to April 2016 (validation). MTGR and SUVV were calculated as the daily change in metabolic tumor volume and maximum standardized uptake value, respectively. Cox proportional hazard models identified predictors of local, regional, and distant recurrence and death for the combined cohort. MTGR and SUVV thresholds dichotomizing risk of death in the discovery cohort were applied to the validation cohort.Results: A total of 152 lesions were identified in 143 patients (92 lesions in 83 discovery cohort patients). In multivariable models, increasing MTGR trended toward increased hazard of distant recurrence (hazard ratio, 6.98; 95% confidence interval, 0.67-72.61; P=.10). In univariable models, SUVV trended toward risk of death (hazard ratio, 11.8, 95% confidence interval, 0.85-165.1, P=.07). MTGR greater than 0.04mL/d was prognostic of decreased survival in discovery (P=.048) and validation cohorts (P<.01).Conclusions: MTGR greater than 0.04mL/d is prognostic of death in patients with non-small cell lung cancer treated with SABR. Increasing SUVV trends, nonsignificantly, toward increased risk of recurrence and death. MTGR and SUVV may be candidate imaging biomarkers to study in trials evaluating systemic therapy with SABR for patients at high risk of out-of-field recurrence.

    View details for PubMedID 31011689

  • Increases in Serial Pretreatment F-18-FDG PET-CT Metrics Predict Survival in Early Stage Non-Small Cell Lung Cancer Treated With Stereotactic Ablative Radiation Therapy ADVANCES IN RADIATION ONCOLOGY Prionas, N. D., von Eyben, R., Yi, E., Aggarwal, S., Shaffer, J., Bazan, J., Eastham, D., Maxim, P. G., Graves, E. E., Diehn, M., Gensheimer, M. F., Loo, B. W. 2019; 4 (2): 429–37
  • Prognostic Value of Circulating Tumor DNA in Diffuse Large B-Cell Lymphoma Reply JOURNAL OF CLINICAL ONCOLOGY Kurtz, D. M., Scherer, F., Jin, M. C., Soo, J., Craig, A. M., Esfahani, M. S., Chabon, J. J., Stehr, H., Liu, C., Tibshirani, R., Maeda, L. S., Gupta, N. K., Khodadoust, M. S., Advani, R. H., Newman, A. M., Duehrsen, U., Huettmann, A., Meignan, M., Casasnovas, O., Westin, J. R., Roschewski, M., Wilson, W. H., Gaidano, G., Rossi, D., Diehn, M., Alizadeh, A. A. 2019; 37 (9): 755-+
  • Reply to J. Wang et al. Journal of clinical oncology : official journal of the American Society of Clinical Oncology Kurtz, D. M., Scherer, F., Jin, M. C., Soo, J., Craig, A. F., Esfahani, M. S., Chabon, J. J., Stehr, H., Liu, C. L., Tibshirani, R., Maeda, L. S., Gupta, N. K., Khodadoust, M. S., Advani, R. H., Newman, A. M., Duhrsen, U., Huttmann, A., Meignan, M., Casasnovas, O., Westin, J. R., Roschewski, M., Wilson, W. H., Gaidano, G., Rossi, D., Diehn, M., Alizadeh, A. A. 2019: JCO1801907

    View details for PubMedID 30753108

  • Case series of MET exon 14 skipping mutation-positive non-small-cell lung cancers with response to crizotinib and cabozantinib. Anti-cancer drugs Wang, S. X., Zhang, B. M., Wakelee, H. A., Koontz, M. Z., Pan, M., Diehn, M., Kunder, C. A., Neal, J. W. 2019

    Abstract

    The mesenchymal-to-epithelial transition (MET) gene is altered and becomes a driver mutation in up to 5% of non-small-cell lung cancer (NSCLC). We report our institutional experience treating patients with MET exon 14 skipping (METex14) mutations, including responses to the MET inhibitors crizotinib and cabozantinib. We identified cases of NSCLC with METex14 mutations using an institutionally developed or commercial next-generation sequencing assay. We assessed patient and disease characteristics by retrospective chart review. Some patients were treated off-label by the physician with crizotinib or cabozantinib, and tumor responses to these agents were assessed. A total of 15 patients with METex14-mutated NSCLC were identified, predominantly male (n=10) with a smoking history (60%) and a median age of 74.0 years. No other actionable somatic mutations were detected. Stage distribution included 26.7% stage I, 6.7% stage II, 6.7% stage III, and 60.0% stage IV. Among patients treated with crizotinib or cabozantinib (n=6), three patients showed partial response and one patient showed stable disease on the basis of RECIST criteria. Four patients experienced side effects requiring drug holiday, reduction, or cessation. Our findings highlight the diversity in presentation and histology of NSCLC with METex14 mutations, which were found in the absence of other actionable driver mutations. We observed evidence of tumor response to crizotinib and cabozantinib, supporting the previous reports that METex14 mutations in NSCLC are actionable driver events.

    View details for PubMedID 30762593

  • Determining cell type abundance and expression from bulk tissues with digital cytometry. Nature biotechnology Newman, A. M., Steen, C. B., Liu, C. L., Gentles, A. J., Chaudhuri, A. A., Scherer, F. n., Khodadoust, M. S., Esfahani, M. S., Luca, B. A., Steiner, D. n., Diehn, M. n., Alizadeh, A. A. 2019

    Abstract

    Single-cell RNA-sequencing has emerged as a powerful technique for characterizing cellular heterogeneity, but it is currently impractical on large sample cohorts and cannot be applied to fixed specimens collected as part of routine clinical care. We previously developed an approach for digital cytometry, called CIBERSORT, that enables estimation of cell type abundances from bulk tissue transcriptomes. We now introduce CIBERSORTx, a machine learning method that extends this framework to infer cell-type-specific gene expression profiles without physical cell isolation. By minimizing platform-specific variation, CIBERSORTx also allows the use of single-cell RNA-sequencing data for large-scale tissue dissection. We evaluated the utility of CIBERSORTx in multiple tumor types, including melanoma, where single-cell reference profiles were used to dissect bulk clinical specimens, revealing cell-type-specific phenotypic states linked to distinct driver mutations and response to immune checkpoint blockade. We anticipate that digital cytometry will augment single-cell profiling efforts, enabling cost-effective, high-throughput tissue characterization without the need for antibodies, disaggregation or viable cells.

    View details for PubMedID 31061481

  • Functional significance of U2AF1 S34F mutations in lung adenocarcinomas Nature Communications Shahrokh Esfahani, M. 2019; 10
  • Interim Circulating Tumor DNA As a Prognostic Biomarker in the Setting of Interim PET-Based Adaptive Therapy for DLBCL American Society of Hematology Macaulay, C., Alig, S., Kurtz, D. M., Jin, M. C., Opat, S., Soo, J., Sworder, B., Hertzberg, M. S., Gandhi, M. K., Diehn, M., Alizadeh, A. A. 2019
  • Circulating DNA for Molecular Response Prediction, Characterization of Resistance Mechanisms and Quantification of CAR T-Cells during Axicabtagene Ciloleucel Therapy American Society of Hematology Sworder, B., Kurtz, D. M., Macaulay, C., Frank, M. J., Alig, S., Garofalo, A., Sahaf, B., Esfahani, M. S., Spiegel, J. Y., Oak, J., Beygi, S., Jin, M. C., Chabon, J. J., Khodadoust, M. S., Majzner, R. G., Mackall, C. L., Diehn, M., Miklos, D. B., Alizadeh, A. A. 2019
  • Towards Non-Invasive Classification of DLBCL Genetic Subtypes By Ctdna Profiling American Society of Hematology Esfahani, M. S., Alig, S., Kurtz, D. M., Soo, J., Jin, M. C., Macaulay, C., Craig, A., Garofalo, A., Steen, C. B., Scherer, F., Sworder, B., Diehn, M., Alizadeh, A. A. 2019
  • Phased Variant Enrichment for Enhanced Minimal Residual Disease Detection from Cell-Free DNA American Society of Hematology Kurtz, D. M., Soo, J., Alig, S., Keh, L. C., Macaulay, C., Jin, M. C., Scherer, F., Hamilton, E. G., Liu, C., Chen, B., Craig, A., Diehn, M., Alizadeh, A. A. 2019
  • Short Diagnosis-to-Treatment Interval Is Associated with Higher Levels of Circulating Tumor DNA in Aggressive B-Cell Non-Hodgkin Lymphoma American Society of Hematology Alig, S., Macaulay, C., Kurtz, D. M., Ulrich, D., Andreas, H., Jin, M. C., Sworder, B., Garofalo, A., Esfahani, M. S., Soo, J., Scherer, F., Craig, A., Casasnovas, O., Westin, J. R., Gaidano, G., Rossi, D., Diehn, M., Alizadeh, A. A. 2019
  • A Feasibility Study of Single-inhalation, Single-energy Xenon-enhanced CT for High-resolution Imaging of Regional Lung Ventilation in Humans ACADEMIC RADIOLOGY Pinkham, D. W., Negandar, M., Yamamoto, T., Mittra, E., Diehn, M., Nair, V. S., Keall, P. J., Maxim, P. G., Loo, B. W. 2019; 26 (1): 38–49
  • The use of texture-based radiomics CT analysis to predict outcomes in early-stage non-small cell lung cancer treated with stereotactic ablative radiotherapy BRITISH JOURNAL OF RADIOLOGY Starkov, P., Aguilera, T. A., Golden, D., Shultz, D. B., Trakul, N., Maxim, P. G., Quynh-Thu Le, Loo, B. W., Diehn, M., Depeursinge, A., Rubin, D. L. 2019; 92 (1094)
  • Stereotactic Ablative Radiotherapy for Central and Ultra-Central Lung Tumors. Therapeutic radiology and oncology Chaudhuri, A. A., Chen, K. n., Diehn, M. n., Loo, B. W. 2019; 3

    Abstract

    Stereotactic ablative radiotherapy (SABR) has emerged as a standard-of-care treatment for patients with early stage non-small cell lung cancer (NSCLC) who are poor surgical candidates. Current evidence supports the consensus that lung SABR with BED ≥100 Gy leads to high local tumor control, and that the treatment is generally well-tolerated when applied to peripheral lung tumors. However, several studies present conflicting evidence for the treatment of central and ultra-central lung tumors, with some showing superb outcomes and others showing concerning rates of morbidity and mortality. Therefore, treatment of central and especially ultra-central lung tumors with SABR remains controversial. In this review, we aim to present the existing evidence for SABR treatment of central and ultra-central lung tumors and delineate the factors that could lead to significant toxicity.

    View details for DOI 10.21037/tro.2019.05.01

    View details for PubMedID 33880444

    View details for PubMedCentralID PMC8054989

  • Circulating tumor DNA analysis for detection of minimal residual disease after chemoradiotherapy for localized esophageal cancer. Gastroenterology Azad, T. D., Chaudhuri, A. A., Fang, P. n., Qiao, Y. n., Esfahani, M. S., Chabon, J. J., Hamilton, E. G., Yang, Y. D., Lovejoy, A. n., Newman, A. M., Kurtz, D. M., Jin, M. n., Schroers-Martin, J. n., Stehr, H. n., Liu, C. L., Bik-Yu Hui, A. n., Patel, V. n., Maru, D. n., Lin, S. H., Alizadeh, A. A., Diehn, M. n. 2019

    Abstract

    Biomarkers are needed to identify patients at risk of tumor progression following chemoradiotherapy for localized esophageal cancer. These could improve identification of patients at risk for cancer progression and selection of therapy.We performed deep sequencing (CAPP-Seq) analyses of plasma cell-free DNA collected from 45 patients before and after chemoradiotherapy for esophageal cancer, as well as DNA from leukocytes, and fixed esophageal tumor biopsies collected during esophagogastroduodenoscopy. Patients were treated from May 2010 through October 2015; 23 patients subsequently underwent esophagectomy and 22 did not undergo surgery. We also sequenced DNA from blood samples from 40 healthy individuals (controls). We analyzed 802 regions of 607 genes for single-nucleotide variants previously associated with esophageal adenocarcinoma or squamous cell carcinoma. Patients underwent imaging analyses 6-8 weeks after chemoradiotherapy and were followed for 5 years. Our primary aim was to determine whether detection of circulating tumor DNA (ctDNA) following chemoradiotherapy is associated with risk of tumor progression (growth of local, regional, or distant tumors, detected by imaging or biopsy).The median proportion of tumor-derived DNA in total cell-free DNA before treatment was 0.07%, indicating that ultrasensitive assays are needed for quantification and analysis of ctDNA from localized esophageal tumors. Detection of ctDNA following chemoradiotherapy was associated with tumor progression (hazard ratio, 18.7; P<.0001), formation of distant metastases (hazard ratio, 32.1; P<.0001), and shorter disease-specific survival times (hazard ratio, 23.1; P<.0001). A higher proportion of patients with tumor progression had new mutations detected in plasma samples collected after chemoradiotherapy than patients without progression (P=.03). Detection of ctDNA after chemoradiotherapy preceded radiographic evidence of tumor progression by an average of 2.8 months. Among patients who received chemoradiotherapy without surgery, combined ctDNA and metabolic imaging analysis predicted progression in 100% of patients with tumor progression, compared with 71% for only ctDNA detection and 57% for only metabolic imaging analysis (P<.001 for comparison of either technique to combined analysis).In an analysis of cell-free DNA in blood samples from patients who underwent chemoradiotherapy for esophageal cancer, detection of ctDNA was associated with tumor progression, metastasis, and disease-specific survival. Analysis of ctDNA might be used to identify patients at highest risk for tumor progression.

    View details for DOI 10.1053/j.gastro.2019.10.039

    View details for PubMedID 31711920

  • Role of KEAP1/NFE2L2 mutations in the chemotherapeutic response of non-small cell lung cancer patients. Clinical cancer research : an official journal of the American Association for Cancer Research Jeong, Y. n., Hellyer, J. A., Stehr, H. n., Hoang, N. T., Niu, X. n., Das, M. n., Padda, S. K., Ramchandran, K. n., Neal, J. W., Wakelee, H. A., Diehn, M. n. 2019

    Abstract

    Activation of NFE2L2 has been linked to chemoresistance in cell line models. Recently, somatic mutations which activate NFE2L2, including mutations in NFE2L2,KEAP1, or CUL3,have been found to be associated with poor outcomes in patients with non-small cell lung cancer (NSCLC). However, the impact of these mutations on chemoresistance remains incompletely explored.We investigated the effect of Keap1 deletion on chemoresistance in cell lines from Trp53-based mouse models of lung squamous cell carcinoma (LSCC) and lung adenocarcinoma (LUAD). Separately, we identified 51 stage IV NSCLC patients with KEAP1, NFE2L2, or CUL3mutations and a matched cohort of 52 wildtype patients. Time to treatment failure after front line platinum doublet chemotherapy and overall survival was compared between the two groups.Deletion of Keap1 in Trp53-null murine LUAD and LSCC resulted in increased clonogenic survival upon treatment with diverse cytotoxic chemotherapies. In NSCLC patients, median time to treatment failure (TTF) after first line chemotherapy for the KEAP1/NFE2L2/CUL3-mutant cohort was 2.8 months compared to 8.3 months in the control group (p < 0.0001) Median overall survival (OS) was 11.2 months in the KEAP1/NFE2L2/CUL3-mutant group and 36.8 months in the control group (p = 0.006). Conclusions: Keap1 deletion confers chemoresistance in murine lung cancer cells. Patients with metastatic NSCLC with mutations in KEAP1, NFE2L2, or CUL3 have shorter time to treatment failure and overall survival after first line platinum doublet chemotherapy compared with matched controls. Novel approaches for improving outcomes in this subset of NSCLC patients are therefore needed.

    View details for DOI 10.1158/1078-0432.CCR-19-1237

    View details for PubMedID 31548347

  • Functional significance of U2AF1 S34F mutations in lung adenocarcinomas. Nature communications Esfahani, M. S., Lee, L. J., Jeon, Y. J., Flynn, R. A., Stehr, H. n., Hui, A. B., Ishisoko, N. n., Kildebeck, E. n., Newman, A. M., Bratman, S. V., Porteus, M. H., Chang, H. Y., Alizadeh, A. A., Diehn, M. n. 2019; 10 (1): 5712

    Abstract

    The functional role of U2AF1 mutations in lung adenocarcinomas (LUADs) remains incompletely understood. Here, we report a significant co-occurrence of U2AF1 S34F mutations with ROS1 translocations in LUADs. To characterize this interaction, we profiled effects of S34F on the transcriptome-wide distribution of RNA binding and alternative splicing in cells harboring the ROS1 translocation. Compared to its wild-type counterpart, U2AF1 S34F preferentially binds and modulates splicing of introns containing CAG trinucleotides at their 3' splice junctions. The presence of S34F caused a shift in cross-linking at 3' splice sites, which was significantly associated with alternative splicing of skipped exons. U2AF1 S34F induced expression of genes involved in the epithelial-mesenchymal transition (EMT) and increased tumor cell invasion. Finally, S34F increased splicing of the long over the short SLC34A2-ROS1 isoform, which was also associated with enhanced invasiveness. Taken together, our results suggest a mechanistic interaction between mutant U2AF1 and ROS1 in LUAD.

    View details for DOI 10.1038/s41467-019-13392-y

    View details for PubMedID 31836708

  • Predicting HLA class II antigen presentation through integrated deep learning. Nature biotechnology Chen, B. n., Khodadoust, M. S., Olsson, N. n., Wagar, L. E., Fast, E. n., Liu, C. L., Muftuoglu, Y. n., Sworder, B. J., Diehn, M. n., Levy, R. n., Davis, M. M., Elias, J. E., Altman, R. B., Alizadeh, A. A. 2019

    Abstract

    Accurate prediction of antigen presentation by human leukocyte antigen (HLA) class II molecules would be valuable for vaccine development and cancer immunotherapies. Current computational methods trained on in vitro binding data are limited by insufficient training data and algorithmic constraints. Here we describe MARIA (major histocompatibility complex analysis with recurrent integrated architecture; https://maria.stanford.edu/ ), a multimodal recurrent neural network for predicting the likelihood of antigen presentation from a gene of interest in the context of specific HLA class II alleles. In addition to in vitro binding measurements, MARIA is trained on peptide HLA ligand sequences identified by mass spectrometry, expression levels of antigen genes and protease cleavage signatures. Because it leverages these diverse training data and our improved machine learning framework, MARIA (area under the curve = 0.89-0.92) outperformed existing methods in validation datasets. Across independent cancer neoantigen studies, peptides with high MARIA scores are more likely to elicit strong CD4+ T cell responses. MARIA allows identification of immunogenic epitopes in diverse cancers and autoimmune disease.

    View details for DOI 10.1038/s41587-019-0280-2

    View details for PubMedID 31611695

  • Impact of KEAP1/NFE2L2/CUL3 mutations on duration of response to EGFR tyrosine kinase inhibitors in EGFR mutated non-small cell lung cancer. Lung cancer (Amsterdam, Netherlands) Hellyer, J. A., Stehr, H. n., Das, M. n., Padda, S. K., Ramchandran, K. n., Neal, J. W., Diehn, M. n., Wakelee, H. A. 2019; 134: 42–45

    Abstract

    For patients with Epidermal Growth Factor Receptor (EGFR)-mutated non-small cell lung cancer (NSCLC), frontline EGFR-tyrosine kinase inhibitor (TKI) therapy compared to chemotherapy improves outcomes. However, resistance to these agents uniformly develops. Recently, mutations in the KEAP1-NFE2L2 pathway have been implicated as a potential mechanism of acquired EGFR TKI resistance.We examined all patients with metastatic NSCLC with mutations in both EGFR and KEAP1/NFE2L2/CUL3 identified on next generation sequencing from 2015 - 2018. These patients were compared to a NSCLC control cohort with mutations in EGFR and wild type in KEAP1/NFE2L2/CUL3 matched on the basis of sex, smoking status, age and race. Time to treatment failure on EGFR TKI therapy and overall survival were examined.Among 228 EGFR mutant NSCLCs, 17 (7%) also carried mutations in KEAP1, NFE2L2, or CUL3. The most common co-mutation in both the KEAP1/NFE2L2/CUL3 mutant and wild-type cohort was TP53. Patients with KEAP1/NFE2L2/CUL3 mutations had a shorter median time to treatment failure on EGFR TKI (4.7 months) compared with the wild-type matched cohort (13.0 months), p= 0.0014. There was no difference in overall survival.For NSCLC patients with mutations in EGFR, co-mutations in KEAP1/NFE2L2/CUL3 are associated with significantly decreased time to treatment failure. Our results suggest that these mutations represent a mechanism of intrinsic resistance to TKI treatment.

    View details for DOI 10.1016/j.lungcan.2019.05.002

    View details for PubMedID 31319993

  • Predictors of Respiratory Decline Following Stereotactic Ablative Radiotherapy to Multiple Lung Tumors. Clinical lung cancer Moding, E. J., Liang, R. n., Lartey, F. M., Maxim, P. G., Sung, A. n., Diehn, M. n., Loo, B. W., Gensheimer, M. F. 2019

    Abstract

    Stereotactic ablative radiotherapy (SABR) is highly effective at controlling early stage primary lung cancer and lung metastases. Although previous studies have suggested that treating multiple lung tumors with SABR is safe, post-treatment changes in respiratory function have not been analyzed in detail.We retrospectively identified patients with 2 or more primary lung cancers or lung metastases treated with SABR and analyzed clinical outcomes and predictors of toxicity. We defined a composite respiratory decline endpoint to include increased oxygen requirement, increased dyspnea scale, or death from respiratory failure not owing to disease progression.A total of 86 patients treated with SABR to 203 lung tumors were analyzed. A total of 21.8% and 41.8% of patients developed composite respiratory decline at 2 and 4 years, respectively. When accounting for intrathoracic disease progression, 12.7% of patients developed composite respiratory decline at 2 years. Of the patients, 7.9% experienced grade 2 or greater radiation pneumonitis. No patient- or treatment-related factor predicted development of respiratory decline. The median overall survival was 46.9 months, and the median progression-free survival was 14.8 months. The cumulative incidence of local failure was 9.7% at 2 years.Although our results confirm that SABR is an effective treatment modality for patients with multiple lung tumors, we observed a high rate of respiratory decline after treatment, which may be owing to a combination of treatment and disease effects. Future studies may help to determine ways to avoid pulmonary toxicity from SABR.

    View details for DOI 10.1016/j.cllc.2019.05.015

    View details for PubMedID 31377143

  • Current Status and Future Perspectives on Neoadjuvant Therapy in Lung Cancer JOURNAL OF THORACIC ONCOLOGY Blumenthal, G. M., Bunn, P. A., Chaft, J. E., McCoach, C. E., Perez, E. A., Scagliotti, G. V., Carbone, D. P., Aerts, H. L., Aisner, D. L., Bergh, J., Berry, D. A., Jarkowski, A., Botwood, N., Cross, D. E., Diehn, M., Drezner, N. L., Doebele, R. C., Blakely, C. M., Eberhardt, W. E., Felip, E., Gianni, L., Keller, S. P., Leavey, P. J., Malik, S., Pignatti, F., Prowell, T. M., Redman, M. W., Rizvi, N. A., Rosell, R., Rusch, V., de Ruysscher, D., Schwartz, L. H., Sridhara, R., Stahel, R. A., Swisher, S., Taube, J. M., Travis, W. D., Keegan, P., Wiens, J. R., Wistuba, I. I., Wynes, M. W., Hirsch, F. R., Kris, M. G. 2018; 13 (12): 1818–31

    Abstract

    This Review Article provides a multi-stakeholder view on the current status of neoadjuvant therapy in lung cancer. Given the success of oncogene-targeted therapy and immunotherapy for patients with advanced lung cancer, there is a renewed interest in studying these agents in earlier disease settings with the opportunity to have an even greater impact on patient outcomes. There are unique opportunities and challenges with the neoadjuvant approach to drug development. To achieve more rapid knowledge turns, study designs, endpoints, and definitions of pathologic response should be standardized and harmonized. Continued dialogue with all stakeholders will be critical to design and test novel induction strategies, which could expedite drug development for patients with early lung cancer who are at high risk for metastatic recurrence.

    View details for PubMedID 30268698

  • Lymphoma Virome Dynamics Revealed By Cell-Free DNA Sequencing Schroers-Martin, J. G., Garofalo, A., Soo, J., Jin, M. C., Kurtz, D. M., Buedts, L., Duehrsen, U., Huettmann, A., Cottereau, A., Meignan, M., Casasnovas, O., Westin, J. R., Gaidano, G., Rossi, D., Roschewski, M., Wilson, W. H., Advani, R. H., Vandenberghe, P., Diehn, M., Khush, K., Alizadeh, A. A. AMER SOC HEMATOLOGY. 2018
  • Distinct Chromatin Accessibility Profiles of Lymphoma Subtypes Revealed By Targeted Cell Free DNA Profiling Mehrmohamadi, M., Esfahani, M. S., Soo, J., Scherer, F., Schroers-Martin, J. G., Chen, B., Kurtz, D. M., Hamilton, E., Liu, C., Diehn, M., Alizadeh, A. A. AMER SOC HEMATOLOGY. 2018
  • Noninvasive Genotyping and Monitoring of Classical Hodgkin Lymphoma Jin, M. C., Schroers-Martin, J. G., Kurtz, D. M., Buedts, L., Esfahani, M. S., Macaulay, C., Sworder, B., Soo, J., Glover, C., Roschewski, M., Wilson, W. H., Duhrsen, U., Huettmann, A., Rossi, D., Gaidano, G., Westin, J. R., Maeda, L. S., Advani, R. H., Vandenberghe, P., Diehn, M., Alizadeh, A. A. AMER SOC HEMATOLOGY. 2018
  • The use of texture-based radiomics CT analysis to predict outcomes in early-stage non-small cell lung cancer treated with stereotactic ablative radiotherapy. The British journal of radiology Starkov, P., Aguilera, T. A., Golden, D. I., Shultz, D. B., Trakul, N., Maxim, P. G., Le, Q., Loo, B. W., Diehn, M., Depeursinge, A., Rubin, D. L. 2018: 20180228

    Abstract

    OBJECTIVE:: Stereotactic ablative radiotherapy (SABR) is being increasingly used as a non-invasive treatment for early-stage non-small cell lung cancer (NSCLC). A non-invasive method to estimate treatment outcomes in these patients would be valuable, especially since access to tissue specimens is often difficult in these cases.METHODS:: We developed a method to predict survival following SABR in NSCLC patients using analysis of quantitative image features on pre-treatment CT images. We developed a Cox Lasso model based on two-dimensional Riesz wavelet quantitative texture features on CT scans with the goal of separating patients based on survival.RESULTS:: The median log-rank p-value for 1000 cross-validations was 0.030. Our model was able to separate patients based upon predicted survival. When we added tumor size into the model, the p-value lost its significance, demonstrating that tumor size is not a key feature in the model but rather decreases significance likely due to the relatively small number of events in the dataset. Furthermore, running the model using Riesz features extracted either from the solid component of the tumor or from the ground glass opacity (GGO) component of the tumor maintained statistical significance. However, the p-value improved when combining features from the solid and the GGO components, demonstrating that there are important data that can be extracted from the entire tumor.CONCLUSIONS:: The model predicting patient survival following SABR in NSCLC may be useful in future studies by enabling prediction of survival-based outcomes using radiomics features in CT images.ADVANCES IN KNOWLEDGE:: Quantitative image features from NSCLC nodules on CT images have been found to significantly separate patient populations based on overall survival (p = 0.04). In the long term, a non-invasive method to estimate treatment outcomes in patients undergoing SABR would be valuable, especially since access to tissue specimens is often difficult in these cases.

    View details for PubMedID 30457885

  • A Quantitative CT Imaging Signature Predicts Survival and Complements Established Prognosticators in Stage I Non-Small Cell Lung Cancer INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS Lee, J., Li, B., Cui, Y., Sun, X., Wu, J., Zhu, H., Yu, J., Gensheimer, M. F., Loo, B. W., Diehn, M., Li, R. 2018; 102 (4): 1098–1106
  • F-18-EF5 PET-based Imageable Hypoxia Predicts Local Recurrence in Tumors Treated With Highly Conformal Radiation Therapy INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS Qian, Y., Von Eyben, R., Liu, Y., Chin, F. T., Miao, Z., Apte, S., Carter, J. N., Binkley, M. S., Pollom, E. L., Harris, J. P., Prionas, N. D., Kissel, M., Simmons, A., Diehn, M., Shultz, D. B., Brown, J., Maxim, P. G., Koong, A. C., Graves, E. E., Loo Jr, B. W. 2018; 102 (4): 1183–92
  • Comparison of Genomic Driver Oncogenes in Vietnamese Patients With Non-Small-Cell Lung Cancer in the United States and Vietnam JOURNAL OF GLOBAL ONCOLOGY Nguyen, K. H., Stehr, H., Zhou, L., Anh-Hoa Nguyen, Pham Nhu Hiep, Nguyen Van Cau, Phan Canh Duy, Thorp, R., Wakelee, H. A., Diehn, M., Neal, J. W. 2018; 4
  • Analysis of Circulating Tumor DNA Kinetics during Stereotactic Ablative Radiation Therapy for Non-Small Cell Lung Cancer Chen, E. L., Chaudhuri, A. A., Nabet, B. Y., Chabon, J. J., Merriott, D. J., Loo, B. W., Alizadeh, A. A., Diehn, M. ELSEVIER SCIENCE INC. 2018: E676
  • Analysis of Urinary Cell-free DNA for Early Detection and Surveillance of Bladder Cancer Dudley, J., Schroers-Martin, J., Lazzareschi, D., Shi, W., Chen, S., Liao, J., Alizadeh, A., Diehn, M. ELSEVIER SCIENCE INC. 2018: 968
  • Comparison of Genomic Driver Oncogenes in Vietnamese Patients With Non-Small-Cell Lung Cancer in the United States and Vietnam. Journal of global oncology Nguyen, K. H., Stehr, H., Zhou, L., Nguyen, A., Hiep, P. N., Van Cau, N., Duy, P. C., Thorp, R., Wakelee, H. A., Diehn, M., Neal, J. W. 2018: 1–9

    Abstract

    PURPOSE: Discoveries of oncogenic driver alterations in non-small-cell lung cancer (NSCLC) have been accompanied by the development of effective targeted therapies. The frequencies of these mutations vary between populations but are less well characterized in the Vietnamese population. In this study, we analyzed the frequencies of lung cancer driver oncogenic alterations in Vietnamese patients compared with Vietnamese patients treated in the United States.METHODS: We collected data on tumor and disease characteristics of Vietnamese patients with NSCLC treated at Stanford. In addition, we collected NSCLC tumor specimens from patients with NSCLC diagnosed in Hue, Vietnam, and performed next-generation-based genotyping on these samples. The molecular and clinical characteristics of these groups were compared.RESULTS: Fifty-nine Vietnamese patients were identified at Stanford. Of the 44 patients with molecular testing results, there were 21 (47.7%) with EGFR alterations, six (13.6%) with ALK alterations, two (4.5%) with KRAS alterations, one (2.3%) with BRAF alterations, and no ROS1 or RET alterations. Across all stages, the median overall survival for patients with a tumor having a targetable genomic alteration driver mutation was 42.4 months, compared with 27.1 months for patients without such alterations. In the 45 genotyped samples from Vietnam, there were 26 (57.8%) with EGFR, 11 (24.4%) with KRAS, and one each (2.2%) with ALK, ROS1, and RET.CONCLUSION: The majority of tumors from both Stanford and Vietnam had targetable oncogenic alterations. This suggests that routine implementation of molecular testing may have a significant, positive impact on the treatment of Vietnamese patients with NSCLC, but affordability of testing and treatments remains a barrier to adoption.

    View details for PubMedID 30422746

  • Radiologic Quantification and Predictors of Lung Fibrosis after Stereotactic Ablative Radiation Therapy(SABR) Ross, J. B., Schueler, E., Ko, R., Bush, K., Maxim, P. G., Gensheimer, M. F., Loo, B. W., Diehn, M. ELSEVIER SCIENCE INC. 2018: E703
  • Esophagitis in Patients Treated with Thoracic Stereotactic Ablative Radiation Therapy (SABR) to Tumors within 2 cm of the Esophagus Quaovi, S., Ko, R., Bush, K., Binkley, M. S., Pickthorn, W., Maxim, P. G., Gensheimer, M. F., Diehn, M., Loo, B. W. ELSEVIER SCIENCE INC. 2018: E666
  • Predicting Per-Lesion Local Recurrence in Locally Advanced Lung Cancer using Metabolic Tumor Volume on Pre- and Mid-Radiation FDG-PET Binkley, M. S., Koenig, J. L., Sodji, Q., Maxim, P. G., Diehn, M., Loo, B. W., Gensheimer, M. F. ELSEVIER SCIENCE INC. 2018: E674
  • Pulmonary Interstitial Lymphography and Patterns of Recurrence after Stereotactic Ablative Radiation Therapy(SABR) of Lung Tumors Ko, R. B., Abelson, J. A., Kothary, N., Fleischmann, D., Hofmann, L., Hovsepian, D., Louie, J. D., Hwang, G., Sze, D. H., Kielar, K., Maxim, P. G., Le, Q. T., Diehn, M., Loo, B. W. ELSEVIER SCIENCE INC. 2018: E689
  • F-18-EF5 PET-based Imageable Hypoxia Predicts Local Recurrence in Tumors Treated with Highly Conformal Radiation Therapy Qian, Y., Von Eyben, R., Liu, Y., Chin, F., Miao, Z., Apte, S., Carter, J. N., Binkley, M. S., Pollom, E., Harris, J. P., Prionas, N. D., Kissel, M., Simmons, A., Diehn, M., Shultz, D. B., Brown, M., Maxim, P. G., Koong, A. C., Graves, E. E., Loo, B. W. ELSEVIER SCIENCE INC. 2018: S114–S115
  • Quantitating circulating tumor DNA in translocation-positive sarcoma patients using CAPP-Seq Shah, A., Azad, T. D., Chabon, J. J., Breese, M., Tanasa, B., Spillinger, A., Leung, S. G., Diehn, M., Alizadeh, A. A., Sweet-Cordero, E. AMER ASSOC CANCER RESEARCH. 2018
  • Invasive nodal evaluation prior to stereotactic ablative radiation for non-small cell lung cancer LUNG CANCER Harris, J. P., Nwachukwu, C., Qian, Y., Pollom, E., Loo, B. W., Das, M., Diehn, M. 2018; 124: 76–85
  • Circulating Tumor DNA Measurements As Early Outcome Predictors in Diffuse Large B-Cell Lymphoma JOURNAL OF CLINICAL ONCOLOGY Kurtz, D. M., Scherer, F., Jin, M. C., Soo, J., Craig, A. M., Esfahani, M., Chabon, J. J., Stehr, H., Liu, C., Tibshirani, R., Maeda, L. S., Gupta, N. K., Khodadoust, M. S., Advani, R. H., Levy, R., Newman, A. M., Duehrsen, U., Huettmann, A., Meignan, M., Casasnovas, R., Westin, J. R., Roschewski, M., Wilson, W. H., Gaidano, G., Rossi, D., Diehn, M., Alizadeh, A. A. 2018; 36 (28): 2845-+
  • Circulating Tumor DNA Analysis in Patients With Cancer American Society of Clinical Oncology and College of American Pathologists Joint Review ARCHIVES OF PATHOLOGY & LABORATORY MEDICINE Merker, J. D., Oxnard, G. R., Compton, C., Diehn, M., Hurley, P., Lazar, A. J., Lindeman, N., Lockwood, C. M., Rai, A. J., Schilsky, R. L., Tsimberidou, A. M., Vasalos, P., Billman, B. L., Oliver, T. K., Bruinooge, S. S., Hayes, D. F., Turner, N. C. 2018; 142 (10): 1242-1253
  • Invasive nodal evaluation prior to stereotactic ablative radiation for non-small cell lung cancer. Lung cancer (Amsterdam, Netherlands) Harris, J. P., Nwachukwu, C., Qian, Y., Pollom, E., Loo, B. W., Das, M., Diehn, M. 2018; 124: 76–85

    Abstract

    INTRODUCTION: Invasive nodal evaluation (INE) is used to improve staging for early stage non-small cell lung cancer (NSCLC), including when stereotactic ablative radiation (SABR) is used. Consensus guidelines from the NCCN recommend performing INE for patients with T2N0 tumors and considering INE for those with T1N0 tumors. We reasoned that if INE results in significant stage migration in the form of substantially fewer patients with occult nodal involvement, then patients treated with SABR who do not undergo INE should have worse overall survival (OS).METHODS: Patients diagnosed 2004-2014 with stage T1-2N0M0 NSCLC and treated with SABR were identified from the National Cancer Database. Factors associated with INE were determined using mixed effects logistic regression. We tested for an association between INE and OS for patients diagnosed 2004-2013 using mixed effects proportional hazards regression methods.RESULTS: 24,603 SABR patients were identified. 6% of the 19,322 patients with T1 tumors and 9% of the 5281 patients with T2 tumors had INE. Median OS was 2.8 years for the no-INE group and 2.7 years for the INE group (log-rank P=0.69). No significant association was observed between the use of INE and OS in the univariate analysis (HR 1.02, 95% CI 0.94-1.11) or the multivariate analysis (HR 0.94, 95% CI 0.86-1.02). These findings were confirmed using propensity score matched and instrumental variable analysis. On subgroup analysis, INE was associated with a non-significant trend for improved OS in patients with T2 tumors (HR 0.87, 95% CI 0.76-1.00) but not T1 tumors (HR 0.98, 95% CI 0.88-1.09).CONCLUSIONS: Despite current NCCN recommendations, the rate of INE was low for patients with stage T1 or T2 tumors. While omitting INE represents a compromise in the completeness of nodal evaluation, we found that it was not associated with a detriment in overall survival.

    View details for PubMedID 30268484

  • Circulating tumor DNA (ctDNA) in B-cell lymphoma Scherer, F., Kurtz, D. M., Newman, A. M., Stehr, H., Craig, A. M., Esfahani, M. S., Lovejoy, A. F., Chabon, J. J., Klass, D. M., Green, M. R., Liu, C. L., Zhou, L., Glover, C., Visser, B. C., Poultsides, G. A., Advani, R. H., Maeda, L. S., Gupta, N. K., Davis, R., Levy, R., Ohgami, R. S., Kunder, C. A., Rossi, D., Westin, J., Diehn, M., Alizadeh, A. A. WILEY. 2018: 16–17
  • Prognostic Value of Pretreatment FDG-PET Parameters in High-dose Image-guided Radiotherapy for Oligometastatic Non-Small-cell Lung Cancer CLINICAL LUNG CANCER Chin, A. L., Kumar, K. A., Guo, H. H., Maxim, P. G., Wakelee, H., Neal, J. W., Diehn, M., Loo, B. W., Gensheimer, M. F. 2018; 19 (5): E581–E588
  • Circulating Tumor DNA Measurements As Early Outcome Predictors in Diffuse Large B-Cell Lymphoma. Journal of clinical oncology : official journal of the American Society of Clinical Oncology Kurtz, D. M., Scherer, F., Jin, M. C., Soo, J., Craig, A. F., Esfahani, M. S., Chabon, J. J., Stehr, H., Liu, C. L., Tibshirani, R., Maeda, L. S., Gupta, N. K., Khodadoust, M. S., Advani, R. H., Levy, R., Newman, A. M., Duhrsen, U., Huttmann, A., Meignan, M., Casasnovas, R., Westin, J. R., Roschewski, M., Wilson, W. H., Gaidano, G., Rossi, D., Diehn, M., Alizadeh, A. A. 2018: JCO2018785246

    Abstract

    Purpose Outcomes for patients with diffuse large B-cell lymphoma remain heterogeneous, with existing methods failing to consistently predict treatment failure. We examined the additional prognostic value of circulating tumor DNA (ctDNA) before and during therapy for predicting patient outcomes. Patients and Methods We studied the dynamics of ctDNA from 217 patients treated at six centers, using a training and validation framework. We densely characterized early ctDNA dynamics during therapy using cancer personalized profiling by deep sequencing to define response-associated thresholds within a discovery set. These thresholds were assessed in two independent validation sets. Finally, we assessed the prognostic value of ctDNA in the context of established risk factors, including the International Prognostic Index and interim positron emission tomography/computed tomography scans. Results Before therapy, ctDNA was detectable in 98% of patients; pretreatment levels were prognostic in both front-line and salvage settings. In the discovery set, ctDNA levels changed rapidly, with a 2-log decrease after one cycle (early molecular response [EMR]) and a 2.5-log decrease after two cycles (major molecular response [MMR]) stratifying outcomes. In the first validation set, patients receiving front-line therapy achieving EMR or MMR had superior outcomes at 24 months (EMR: EFS, 83% v 50%; P = .0015; MMR: EFS, 82% v 46%; P < .001). EMR also predicted superior 24-month outcomes in patients receiving salvage therapy in the first validation set (EFS, 100% v 13%; P = .011). The prognostic value of EMR and MMR was further confirmed in the second validation set. In multivariable analyses including International Prognostic Index and interim positron emission tomography/computed tomography scans across both cohorts, molecular response was independently prognostic of outcomes, including event-free and overall survival. Conclusion Pretreatment ctDNA levels and molecular responses are independently prognostic of outcomes in aggressive lymphomas. These risk factors could potentially guide future personalized risk-directed approaches.

    View details for PubMedID 30125215

  • GFPT2-Expressing Cancer-Associated Fibroblasts Mediate Metabolic Reprogramming in Human Lung Adenocarcinoma CANCER RESEARCH Zhang, W., Bouchard, G., Yu, A., Shafiq, M., Jamali, M., Shrager, J. B., Ayers, K., Bakr, S., Gentles, A. J., Diehn, M., Quon, A., West, R. B., Nair, V., van de Rijn, M., Napel, S., Plevritis, S. K. 2018; 78 (13): 3445–57
  • Circulating Tumor DNA Quantitation for Early Response Assessment of Immune Checkpoint Inhibitors for Metastatic Non-Small Cell Lung Cancer Chaudhuri, A. A., Nabet, B. Y., Merriott, D. J., Jin, M., Chen, E. L., Chabon, J. J., Newman, A. M., Stehr, H., Say, C., Carter, J. N., Walters, S., Becker, H., Das, M., Padda, S. K., Loo, B. W., Wakelee, H. A., Neal, J. W., Alizadeh, A. A., Diehn, M. ELSEVIER SCIENCE INC. 2018: E1–E2
  • Combination Approach for Detecting Different Types of Alterations in Circulating Tumor DNA in Leiomyosarcoma CLINICAL CANCER RESEARCH Przybyl, J., Chabon, J. J., Spans, L., Ganjoo, K. N., Vennam, S., Newman, A. M., Forgo, E., Varma, S., Zhu, S., Debiec-Rychter, M., Alizadeh, A. A., Diehn, M., van de Rijn, M. 2018; 24 (11): 2688–99
  • Circulating Tumor DNA Analysis in Patients With Cancer: American Society of Clinical Oncology and College of American Pathologists Joint Review JOURNAL OF CLINICAL ONCOLOGY Merker, J. D., Oxnard, G. R., Compton, C., Diehn, M., Hurley, P., Lazar, A. J., Lindeman, N., Lockwood, C. M., Rai, A. J., Schilsky, R. L., Tsimberidou, A. M., Vasalos, P., Billman, B. L., Oliver, T. K., Bruinooge, S. S., Hayes, D. F., Turner, N. C. 2018; 36 (16): 1631-+
  • Circulating Tumor DNA Analysis in Patients With Cancer: American Society of Clinical Oncology and College of American Pathologists Joint Review. Journal of clinical oncology : official journal of the American Society of Clinical Oncology Merker, J. D., Oxnard, G. R., Compton, C., Diehn, M., Hurley, P., Lazar, A. J., Lindeman, N., Lockwood, C. M., Rai, A. J., Schilsky, R. L., Tsimberidou, A. M., Vasalos, P., Billman, B. L., Oliver, T. K., Bruinooge, S. S., Hayes, D. F., Turner, N. C. 2018; 36 (16): 1631–41

    Abstract

    Purpose Clinical use of analytical tests to assess genomic variants in circulating tumor DNA (ctDNA) is increasing. This joint review from ASCO and the College of American Pathologists summarizes current information about clinical ctDNA assays and provides a framework for future research. Methods An Expert Panel conducted a literature review on the use of ctDNA assays for solid tumors, including pre-analytical variables, analytical validity, interpretation and reporting, and clinical validity and utility. Results The literature search identified 1,338 references. Of those, 390, plus 31 references supplied by the Expert Panel, were selected for full-text review. There were 77 articles selected for inclusion. Conclusion The evidence indicates that testing for ctDNA is optimally performed on plasma collected in cell stabilization or EDTA tubes, with EDTA tubes processed within 6 hours of collection. Some ctDNA assays have demonstrated clinical validity and utility with certain types of advanced cancer; however, there is insufficient evidence of clinical validity and utility for the majority of ctDNA assays in advanced cancer. Evidence shows discordance between the results of ctDNA assays and genotyping tumor specimens and supports tumor tissue genotyping to confirm undetected results from ctDNA tests. There is no evidence of clinical utility and little evidence of clinical validity of ctDNA assays in early-stage cancer, treatment monitoring, or residual disease detection. There is no evidence of clinical validity and clinical utility to suggest that ctDNA assays are useful for cancer screening, outside of a clinical trial. Given the rapid pace of research, re-evaluation of the literature will shortly be required, along with the development of tools and guidance for clinical practice.

    View details for PubMedID 29504847

  • 18F-EF5 Pet-Based Imageable Hypoxia Predicts for Local Control in Tumors Treated With Conformal Radiotherapy Qian, Y., Liu, Y., Von Eyben, R., Carter, J. N., Pollom, E. L., Harris, J. P., Prionas, N. D., Binkley, M. S., Simmons, A., Diehn, M., Chin, F. T., Shultz, D. B., Brown, J., Maxim, P. G., Koong, A. C., Graves, E. E., Loo, B. W. ELSEVIER SCIENCE INC. 2018: E17–E18
  • Early detection of post-transplant lymphoproliferative disorder using circulating tumor DNA. Soo, J., Schroers-Martin, J., Garofalo, A., Kurtz, D., D'Emilio, N., Grimm, D. AMER SOC CLINICAL ONCOLOGY. 2018
  • Post-transplant head and neck cancers: A prospective analysis of clinical factors for risk stratification. Soo, J., Schroers-Martin, J., Garofalo, A., Kurtz, D., D'Emilio, N., Grimm, D. AMER SOC CLINICAL ONCOLOGY. 2018
  • GFPT2-expressing cancer-associated fibroblasts mediate metabolic reprogramming in human lung adenocarcinoma. Cancer research Zhang, W., Bouchard, G., Yu, A., Shafiq, M., Jamali, M., Shrager, J. B., Ayers, K., Bakr, S., Gentles, A. J., Diehn, M., Quon, A., West, R. B., Nair, V., van de Rijn, M., Napel, S., Plevritis, S. K. 2018

    Abstract

    Metabolic reprogramming of the tumor microenvironment is recognized as a cancer hallmark. To identify new molecular processes associated with tumor metabolism, we analyzed the transcriptome of bulk and flow-sorted human primary non-small cell lung cancer (NSCLC) together with 18FDG-positron emission tomography scans, which provide a clinical measure of glucose uptake. Tumors with higher glucose uptake were functionally enriched for molecular processes associated with invasion in adenocarcinoma (AD) and cell growth in squamous cell carcinoma (SCC). Next, we identified genes correlated to glucose uptake that were predominately overexpressed in a single cell-type comprising the tumor microenvironment. For SCC, most of these genes were expressed by malignant cells, whereas in AD they were predominately expressed by stromal cells, particularly cancer-associated fibroblasts (CAFs). Among these AD genes correlated to glucose uptake, we focused on Glutamine-Fructose-6-Phosphate Transaminase 2 (GFPT2), which codes for the Glutamine-Fructose-6-Phosphate Aminotransferase 2 (GFAT2), a rate-limiting enzyme of the hexosamine biosynthesis pathway (HBP), which is responsible for glycosylation. GFPT2 was predictive of glucose uptake independent of GLUT1, the primary glucose transporter, and was prognostically significant at both gene and protein level. We confirmed that normal fibroblasts transformed to CAF-like cells, following TGF-beta treatment, upregulated HBP genes, including GFPT2, with less change in genes driving glycolysis, pentose phosphate pathway and TCA cycle. Our work provides new evidence of histology-specific tumor-stromal properties associated with glucose uptake in NSCLC and identifies GFPT2 as a critical regulator of tumor metabolic reprogramming in AD.

    View details for PubMedID 29760045

  • Circulating tumor DNA testing in advanced non-small cell lung cancer. Lung cancer (Amsterdam, Netherlands) Moding, E. J., Diehn, M., Wakelee, H. A. 2018; 119: 42–47

    Abstract

    Circulating tumor DNA (ctDNA) shed from cancer cells into the peripheral blood can be non-invasively collected and tested for the presence of tumor-specific mutations. Mutations identified in ctDNA can predict responses to targeted therapies and emerging evidence suggests that changes in ctDNA levels over time can be used to monitor response to therapy and detect disease recurrence. Given the emergence of targeted therapies in advanced non-small cell lung cancer (NSCLC), liquid biopsies utilizing ctDNA testing represent a powerful approach to genotype tumors and monitor for the development of resistance. Here, we review current and potential future clinical applications of ctDNA testing for patients with advanced NSCLC.

    View details for PubMedID 29656751

  • Circulating tumor DNA testing in advanced non-small cell lung cancer LUNG CANCER Moding, E. J., Diehn, M., Wakelee, H. A. 2018; 119: 42–47
  • Interim results of a randomized trial of observation versus SABR for oligometastatic prostate cancer Tran, P., Radwan, N., Phillips, R., Ross, A., Rowe, S., Gorin, M., Antonarakis, E., DeVille, C., Greco, S., Denmeade, S., Paller, C., Song, D., Diehn, M., Wang, H., Carducci, M., Pienta, K., Pomper, M., DeWeese, T., Dicker, A., Eisenberger, M. ELSEVIER IRELAND LTD. 2018: S261
  • The Future of Radiobiology JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE Kirsch, D. G., Diehn, M., Kesarwala, A. H., Maity, A., Morgan, M. A., Schwarz, J. K., Bristow, R., Demaria, S., Eke, I., Griffin, R. J., Haas-Kogan, D., Higgins, G. S., Kimmelman, A. C., Kimple, R. J., Lombaert, I. M., Ma, L., Marples, B., Pajonk, F., Park, C. C., Schaue, D., Bernhard, E. J. 2018; 110 (4): 329–40

    Abstract

    Innovation and progress in radiation oncology depend on discovery and insights realized through research in radiation biology. Radiobiology research has led to fundamental scientific insights, from the discovery of stem/progenitor cells to the definition of signal transduction pathways activated by ionizing radiation that are now recognized as integral to the DNA damage response (DDR). Radiobiological discoveries are guiding clinical trials that test radiation therapy combined with inhibitors of the DDR kinases DNA-dependent protein kinase (DNA-PK), ataxia telangiectasia mutated (ATM), ataxia telangiectasia related (ATR), and immune or cell cycle checkpoint inhibitors. To maintain scientific and clinical relevance, the field of radiation biology must overcome challenges in research workforce, training, and funding. The National Cancer Institute convened a workshop to discuss the role of radiobiology research and radiation biologists in the future scientific enterprise. Here, we review the discussions of current radiation oncology research approaches and areas of scientific focus considered important for rapid progress in radiation sciences and the continued contribution of radiobiology to radiation oncology and the broader biomedical research community.

    View details for PubMedID 29126306

    View details for PubMedCentralID PMC5928778

  • A Feasibility Study of Single-inhalation, Single-energy Xenon-enhanced CT for High-resolution Imaging of Regional Lung Ventilation in Humans. Academic radiology Pinkham, D. W., Negahdar, M., Yamamoto, T., Mittra, E., Diehn, M., Nair, V. S., Keall, P. J., Maxim, P. G., Loo, B. W. 2018

    Abstract

    RATIONALE AND OBJECTIVES: The objective of this study was to assess the feasibility of single-inhalation xenon-enhanced computed tomography (XeCT) to provide clinically practical, high-resolution pulmonary ventilation imaging to clinics with access to only a single-energy computed tomography scanner, and to reduce the subject's overall exposure to xenon by utilizing a higher (70%) concentration for a much shorter time than has been employed in prior studies.MATERIALS AND METHODS: We conducted an institutional review board-approved prospective feasibility study of XeCT for 15 patients undergoing thoracic radiotherapy. For XeCT, we acquired two breath-hold single-energy computed tomography images of the entire lung with a single inhalation each of 100% oxygen and a mixture of 70% xenon and 30% oxygen, respectively. A video biofeedback system for coached patient breathing was used to achieve reproducible breath holds. We assessed the technical success of XeCT acquisition and side effects. We then used deformable image registration to align the breath-hold images with each other to accurately subtract them, producing a map of lung xenon distribution. Additionally, we acquired ventilation single-photon emission computed tomography-computed tomography (V-SPECT-CT) images for 11 of the 15 patients. For a comparative analysis, we partitioned each lung into 12 sectors, calculated the xenon concentration from the Hounsfield unit enhancement in each sector, and then correlated this with the corresponding V-SPECT-CT counts.RESULTS: XeCT scans were tolerated well overall, with a mild (grade 1) dizziness as the only side effect in 5 of the 15 patients. Technical failures in five patients occurred because of inaccurate breathing synchronization with xenon gas delivery, leaving seven patients analyzable for XeCT and single-photon emission computed tomography correlation. Sector-wise correlations were strong (Spearman coefficient >0.75, Pearson coefficient >0.65, P value <.002) for two patients for whom ventilation deficits were visibly pronounced in both scans. Correlations were nonsignificant for the remaining five who had more homogeneous XeCT ventilation maps, as well as strong V-SPECT-CT imaging artifacts attributable to airway deposition of the aerosolized imaging agent. Qualitatively, XeCT demonstrated higher resolution and no central airway deposition artifacts compared to V-SPECT-CT.CONCLUSIONS: In this pilot study, single-breath XeCT ventilation imaging was generally feasible for patients undergoing thoracic radiotherapy, using an imaging protocol that is clinically practical and potentially widely available. In the future, the xenon delivery failures can be addressed by straightforward technical improvements to the patient biofeedback coaching system.

    View details for PubMedID 29606339

  • Circulating Tumor DNA Analysis in Patients With Cancer: American Society of Clinical Oncology and College of American Pathologists Joint Review. Archives of pathology & laboratory medicine Merker, J. D., Oxnard, G. R., Compton, C., Diehn, M., Hurley, P., Lazar, A. J., Lindeman, N., Lockwood, C. M., Rai, A. J., Schilsky, R. L., Tsimberidou, A. M., Vasalos, P., Billman, B. L., Oliver, T. K., Bruinooge, S. S., Hayes, D. F., Turner, N. C. 2018

    Abstract

    PURPOSE: - Clinical use of analytical tests to assess genomic variants in circulating tumor DNA (ctDNA) is increasing. This joint review from the American Society of Clinical Oncology and the College of American Pathologists summarizes current information about clinical ctDNA assays and provides a framework for future research.METHODS: - An Expert Panel conducted a literature review on the use of ctDNA assays for solid tumors, including preanalytical variables, analytical validity, interpretation and reporting, and clinical validity and utility.RESULTS: - The literature search identified 1338 references. Of those, 390, plus 31 references supplied by the Expert Panel, were selected for full-text review. There were 77 articles selected for inclusion.CONCLUSIONS: - The evidence indicates that testing for ctDNA is optimally performed on plasma collected in cell stabilization or EDTA tubes, with EDTA tubes processed within 6 hours of collection. Some ctDNA assays have demonstrated clinical validity and utility with certain types of advanced cancer; however, there is insufficient evidence of clinical validity and utility for the majority of ctDNA assays in advanced cancer. Evidence shows discordance between the results of ctDNA assays and genotyping tumor specimens, and supports tumor tissue genotyping to confirm undetected results from ctDNA tests. There is no evidence of clinical utility and little evidence of clinical validity of ctDNA assays in early-stage cancer, treatment monitoring, or residual disease detection. There is no evidence of clinical validity or clinical utility to suggest that ctDNA assays are useful for cancer screening, outside of a clinical trial. Given the rapid pace of research, reevaluation of the literature will shortly be required, along with the development of tools and guidance for clinical practice.

    View details for PubMedID 29504834

  • Genomic Feature Selection by Coverage Design Optimization. Journal of applied statistics Reid, S., Newman, A. M., Diehn, M., Alizadeh, A. A., Tibshirani, R. 2018; 45 (14): 2658-2676

    Abstract

    We introduce a novel data reduction technique whereby we select a subset of tiles to "cover" maximally events of interest in large-scale biological datasets (e.g., genetic mutations), while minimizing the number of tiles. A tile is a genomic unit capturing one or more biological events, such as a sequence of base pairs that can be sequenced and observed simultaneously. The goal is to reduce significantly the number of tiles considered to those with areas of dense events in a cohort, thus saving on cost and enhancing interpretability. However, the reduction should not come at the cost of too much information, allowing for sensible statistical analysis after its application. We envisage application of our methods to a variety of high throughput data types, particularly those produced by next generation sequencing (NGS) experiments. The procedure is cast as a convex optimization problem, which is presented, along with methods of its solution. The method is demonstrated on a large dataset of somatic mutations spanning 5000+ patients, each having one of 29 cancer types. Applied to these data, our method dramatically reduces the number of gene locations required for broad coverage of patients and their mutations, giving subject specialists a more easily interpretable snapshot of recurrent mutational profiles in these cancers. The locations identified coincide with previously identified cancer genes. Finally, despite considerable data reduction, we show that our covering designs preserve the cancer discrimination ability of multinomial logistic regression models trained on all of the locations (> 1M).

    View details for DOI 10.1080/02664763.2018.1432577

    View details for PubMedID 30294060

    View details for PubMedCentralID PMC6173524

  • Circulating tumor DNA levels correlate with response to treatment in LMS patients Przybyl, J., Chabon, J. J., Spans, L., Ganjoo, K., Vennam, S., Newman, A. M., Forgo, E., Varma, S., Zhu, S., Debiec-Rychter, M., Alizadeh, A., Diehn, M., van de Rijn, M. AMER ASSOC CANCER RESEARCH. 2018: 38–39
  • Line-Enhanced Deformable Registration of Pulmonary Computed Tomography Images Before and After Radiation Therapy With Radiation-Induced Fibrosis TECHNOLOGY IN CANCER RESEARCH & TREATMENT King, M., Sensakovic, W. F., Maxim, P., Diehn, M., Loo, B. W., Xing, L. 2018; 17
  • Detection and surveillance of bladder cancer using urine tumor DNA. Cancer discovery Dudley, J. C., Schroers-Martin, J. n., Lazzareschi, D. V., Shi, W. Y., Chen, S. B., Esfahani, M. S., Trivedi, D. n., Chabon, J. J., Chaudhuri, A. A., Stehr, H. n., Liu, C. L., Lim, H. n., Costa, H. A., Nabet, B. Y., Sin, M. L., Liao, J. C., Alizadeh, A. A., Diehn, M. n. 2018

    Abstract

    Current regimens for the detection and surveillance of bladder cancer (BLCA) are invasive and have suboptimal sensitivity. Here, we present a novel high-throughput sequencing (HTS) method for detection of urine tumor DNA (utDNA) called utDNA CAPP-Seq (uCAPP-Seq) and apply it to 67 healthy adults and 118 patients with early-stage BLCA who either had urine collected prior to treatment or during surveillance. Using this targeted sequencing approach, we detected a median of 6 mutations per BLCA patient and observed surprisingly frequent mutations of the PLEKHS1 promoter (46%), suggesting these mutations represent a useful biomarker for detection of BLCA. We detected utDNA pre-treatment in 93% of cases using a tumor mutation-informed approach and in 84% when blinded to tumor mutation status, with 96-100% specificity. In the surveillance setting, we detected utDNA in 91% of patients who ultimately recurred, with utDNA detection preceding clinical progression in 92% of cases. uCAPP-Seq outperformed a commonly used ancillary test (UroVysion, p=0.02) and cytology and cystoscopy combined (p is less than or equal to 0.006), detecting 100% of BLCA cases detected by cytology and 82% that cytology missed. Our results indicate that uCAPP-Seq is a promising approach for early detection and surveillance of BLCA.

    View details for PubMedID 30578357

  • Deep Sequencing Reveals High Allelic Frequencies of Tumor Mutations in the High Risk Airway Epithelium Atwater, T., Rahman, S., Diehn, M., Massion, P. P. AMER THORACIC SOC. 2018
  • Genomic Profiling of Bronchoalveolar Lavage Fluid in Patients with Non-Small Cell Lung Cancer Nair, V. S., Li, A., Stehr, H., Chabon, J., Chaudhuri, A., Zhou, L., Naemi, H., Ayers, K., Ramsey, M., Bedi, H. S., Van Wert, R., Sung, A. W., Lui, N., Backhus, L., Berry, M., Shrager, J. B., Alizadeh, A., Diehn, M. AMER THORACIC SOC. 2018
  • Prognostic Value of Pretreatment FDG-PET Parameters in High-dose Image-guided Radiotherapy for Oligometastatic Non-Small-cell Lung Cancer. Clinical lung cancer Chin, A. L., Kumar, K. A., Guo, H. H., Maxim, P. G., Wakelee, H. n., Neal, J. W., Diehn, M. n., Loo, B. W., Gensheimer, M. F. 2018

    Abstract

    Emerging data support aggressive local treatment of oligometastatic non-small-cell lung cancer (NSCLC) patients. We sought to determine whether the metabolic burden of disease found by fluorodeoxyglucose positron emission tomography at the time of high-dose radiotherapy (RT) for oligometastatic NSCLC can serve as a prognostic biomarker.We conducted a retrospective cohort study of 67 RT treatment courses in 55 patients with oligometastatic NSCLC who had undergone high-dose RT to all sites of active disease at our institution. The metabolic tumor volume, total lesion glycolysis (TLG), and maximum standardized uptake value of all lesions were measured on the pretreatment fluorodeoxyglucose positron emission tomography scans. Cox regression analysis was used to assess the influence of imaging and clinical factors on overall survival (OS).On univariate analysis, a greater metabolic tumor volume and TLG were predictive of shorter OS (hazard ratio of death, 2.42 and 2.14, respectively; P = .009 and P = .004, respectively). The effects remained significant on multivariate analysis. Neither the maximum standardized uptake value nor the number of lesions was significantly associated with OS. Patients within the highest quartile of TLG values (> 86.8 units) had a shorter median OS than those within the lower 3 quartiles (12.4 vs. 30.1 months; log-rank P = .014).The metabolic tumor burden was prognostic of OS and might help to better select oligometastatic NSCLC patients for locally ablative therapy.

    View details for PubMedID 29759331

  • Genomic feature selection by coverage design optimization Journal of Applied Statistics Reid, S., Newman, A. M., Diehn, M., Alizadeh, A. A., Tibshirani, R. 2018
  • Line-Enhanced Deformable Registration of Pulmonary Computed Tomography Images Before and After Radiation Therapy With Radiation-Induced Fibrosis. Technology in cancer research & treatment King, M., Sensakovic, W. F., Maxim, P., Diehn, M., Loo, B. W., Xing, L. 2018; 17: 1533034617749419

    Abstract

    PURPOSE: The deformable registration of pulmonary computed tomography images before and after radiation therapy is challenging due to anatomic changes from radiation fibrosis. We hypothesize that a line-enhanced registration algorithm can reduce landmark error over the entire lung, including the irradiated regions, when compared to an intensity-based deformable registration algorithm.MATERIALS: Two intensity-based B-spline deformable registration algorithms of pre-radiation therapy and post-radiation therapy images were compared. The first was a control intensity-based algorithm that utilized computed tomography images without modification. The second was a line enhancement algorithm that incorporated a Hessian-based line enhancement filter prior to deformable image registration. Registrations were evaluated based on the landmark error between user-identified landmark pairs and the overlap ratio.RESULTS: Twenty-one patients with pre-radiation therapy and post-radiation therapy scans were included. The median time interval between scans was 1.2 years (range: 0.3-3.3 years). Median landmark errors for the line enhancement algorithm were significantly lower than those for the control algorithm over the entire lung (1.67 vs 1.83 mm; P < .01), as well as within the 0 to 5 Gy (1.40 vs 1.57; P < .01) and >5 Gy (2.25 vs 3.31; P < .01) dose intervals. The median lung mask overlap ratio for the line enhancement algorithm (96.2%) was greater than that for the control algorithm (95.8%; P < .01). Landmark error within the >5 Gy dose interval demonstrated a significant inverse relationship with post-radiation therapy fibrosis enhancement after line enhancement filtration (Pearson correlation coefficient = -0.48; P = .03).CONCLUSION: The line enhancement registration algorithm is a promising method for registering images before and after radiation therapy.

    View details for PubMedID 29343206

  • Combination approach for detecting different types of alterations in circulating tumor DNA in leiomyosarcoma. Clinical cancer research : an official journal of the American Association for Cancer Research Przybyl, J. n., Chabon, J. J., Spans, L. n., Ganjoo, K. n., Vennam, S. n., Newman, A. M., Forgó, E. n., Varma, S. n., Zhu, S. n., Debiec-Rychter, M. n., Alizadeh, A. A., Diehn, M. n., van de Rijn, M. n. 2018

    Abstract

    The clinical utility of circulating tumor DNA (ctDNA) monitoring has been shown in tumors that harbor highly recurrent mutations. Leiomyosarcoma (LMS) represents a type of tumor with a wide spectrum of heterogeneous genomic abnormalities; thus, targeting hotspot mutations or a narrow genomic region for ctDNA detection may not be practical. Here we demonstrate a combinatorial approach that integrates different sequencing protocols for the orthogonal detection of single nucleotide variants (SNVs), small indels and copy number alterations (CNAs) in ctDNA.We employed Cancer Personalized Profiling by deep Sequencing (CAPP-Seq) for the analysis of SNVs and indels, together with a genome-wide interrogation of CNAs by Genome Representation Profiling (GRP). We profiled 28 longitudinal plasma samples and 25 tumor specimens from 7 patients with LMS.We detected ctDNA in 6 of 7 of these patients with >98% specificity for mutant allele fractions down to a level of 0.01%. We show that results from CAPP-Seq and GRP are highly concordant, and the combination of these methods allows for more comprehensive monitoring of ctDNA by profiling a wide spectrum of tumor-specific markers. By analyzing multiple tumor specimens in individual patients obtained from different sites and at different times during treatment, we observed clonal evolution of these tumors that was reflected by ctDNA profiles.Our strategy allows for a comprehensive monitoring of a broad spectrum of tumor-specific markers in plasma. Our approach may be clinically useful not only in LMS but also in other tumor types that lack recurrent genomic alterations.

    View details for PubMedID 29463554

  • 18F-EF5 PET-based Imageable Hypoxia Predicts Local Recurrence in Tumors Treated With Highly Conformal Radiation Therapy. International journal of radiation oncology, biology, physics Qian, Y. n., Von Eyben, R. n., Liu, Y. n., Chin, F. T., Miao, Z. n., Apte, S. n., Carter, J. N., Binkley, M. S., Pollom, E. L., Harris, J. P., Prionas, N. D., Kissel, M. n., Simmons, A. n., Diehn, M. n., Shultz, D. B., Brown, J. M., Maxim, P. G., Koong, A. C., Graves, E. E., Loo, B. W. 2018

    Abstract

    Tumor hypoxia contributes to radiation resistance. A noninvasive assessment of tumor hypoxia would be valuable for prognostication and possibly selection for hypoxia-targeted therapies. 18F-pentafluorinated etanidazole (18F-EF5) is a nitroimidazole derivative that has demonstrated promise as a positron emission tomography (PET) hypoxia imaging agent in preclinical and clinical studies. However, correlation of imageable hypoxia by 18F-EF5 PET with clinical outcomes after radiation therapy remains limited.Our study prospectively enrolled 28 patients undergoing radiation therapy for localized lung or other tumors to receive pretreatment 18F-EF5 PET imaging. Depending on the level of 18F-EF5 tumor uptake, patients underwent functional manipulation of tumor oxygenation with either carbogen breathing or oral dichloroacetate followed by repeated 18F-EF5 PET. The hypoxic subvolume of tumor was defined as the proportion of tumor voxels exhibiting higher 18F-EF5 uptake than the 95th percentile of 18F-EF5 uptake in the blood pool. Tumors with a hypoxic subvolume ≥ 10% on baseline 18F-EF5 PET imaging were classified as hypoxic by imaging. A Cox model was used to assess the correlation between imageable hypoxia and clinical outcomes after treatment.At baseline, imageable hypoxia was demonstrated in 43% of all patients (12 of 28), including 6 of 16 patients with early-stage non-small cell lung cancer treated with stereotactic ablative radiation therapy and 6 of 12 patients with other cancers. Carbogen breathing was significantly associated with decreased imageable hypoxia, while dichloroacetate did not result in a significant change under our protocol conditions. Tumors with imageable hypoxia had a higher incidence of local recurrence at 12 months (30%) than those without (0%) (P < .01).Noninvasive hypoxia imaging by 18F-EF5 PET identified imageable hypoxia in about 40% of tumors in our study population. Local tumor recurrence after highly conformal radiation therapy was higher in tumors with imageable hypoxia.

    View details for PubMedID 29859786

  • Endothelial deletion of Ino80 disrupts coronary angiogenesis and causes congenital heart disease. Nature communications Rhee, S. n., Chung, J. I., King, D. A., D'amato, G. n., Paik, D. T., Duan, A. n., Chang, A. n., Nagelberg, D. n., Sharma, B. n., Jeong, Y. n., Diehn, M. n., Wu, J. C., Morrison, A. J., Red-Horse, K. n. 2018; 9 (1): 368

    Abstract

    During development, the formation of a mature, well-functioning heart requires transformation of the ventricular wall from a loose trabecular network into a dense compact myocardium at mid-gestation. Failure to compact is associated in humans with congenital diseases such as left ventricular non-compaction (LVNC). The mechanisms regulating myocardial compaction are however still poorly understood. Here, we show that deletion of the Ino80 chromatin remodeler in vascular endothelial cells prevents ventricular compaction in the developing mouse heart. This correlates with defective coronary vascularization, and specific deletion of Ino80 in the two major coronary progenitor tissues-sinus venosus and endocardium-causes intermediate phenotypes. In vitro, endothelial cells promote myocardial expansion independently of blood flow in an Ino80-dependent manner. Ino80 deletion increases the expression of E2F-activated genes and endothelial cell S-phase occupancy. Thus, Ino80 is essential for coronary angiogenesis and allows coronary vessels to support proper compaction of the heart wall.

    View details for PubMedID 29371594

  • A Quantitative CT Imaging Signature Predicts Survival and Complements Established Prognosticators in Stage I Non-Small Cell Lung Cancer. International journal of radiation oncology, biology, physics Lee, J. n., Li, B. n., Cui, Y. n., Sun, X. n., Wu, J. n., Zhu, H. n., Yu, J. n., Gensheimer, M. F., Loo, B. W., Diehn, M. n., Li, R. n. 2018

    Abstract

    Prognostic biomarkers are needed to guide the management of early-stage non-small cell lung cancer (NSCLC). This work aims to develop an image-based prognostic signature and assess its complementary value to existing biomarkers.We retrospectively analyzed data of stage I NSCLC in 8 cohorts. On the basis of an analysis of 39 computed tomography (CT) features characterizing tumor and its relation to neighboring pleura, we developed a prognostic signature in an institutional cohort (n = 117) and tested it in an external cohort (n = 88). A third cohort of 89 patients with CT and gene expression data was used to create a surrogate genomic signature of the imaging signature. We conducted further validation using data from 5 gene expression cohorts (n = 639) and built a composite signature by integrating with the cell-cycle progression (CCP) score and clinical variables.An imaging signature consisting of a pleural contact index and normalized inverse difference was significantly associated with overall survival in both imaging cohorts (P = .0005 and P = .0009). Functional enrichment analysis revealed that genes highly correlated with the imaging signature were related to immune response, such as lymphocyte activation and chemotaxis (false discovery rate < 0.05). A genomic surrogate of the imaging signature remained a significant predictor of survival when we adjusted for known prognostic factors (hazard ratio, 1.81; 95% confidence interval, 1.34-2.44; P < .0001) and stratified patients within subgroups as defined by stage, histology, or CCP score. A composite signature outperformed the genomic surrogate, CCP score, and clinical model alone (P < .01) regarding concordance index (0.70 vs 0.62-0.63).The proposed CT imaging signature reflects fundamental biological differences in tumors and predicts overall survival in patients with stage I NSCLC. When combined with established prognosticators, the imaging signature improves survival prediction.

    View details for PubMedID 29439884

  • Mid-radiotherapy PET/CT for prognostication and detection of early progression in patients with stage III non-small cell lung cancer RADIOTHERAPY AND ONCOLOGY Gensheimer, M. F., Hong, J. C., Chang-Halpenny, C., Zhu, H., Eclov, N. W., To, J., Murphy, J. D., Wakelee, H. A., Neal, J. W., Le, Q., Hara, W. Y., Quon, A., Maxim, P. G., Graves, E. E., Olson, M. R., Diehn, M., Loo, B. W. 2017; 125 (2): 338–43

    Abstract

    Pre- and mid-radiotherapy FDG-PET metrics have been proposed as biomarkers of recurrence and survival in patients treated for stage III non-small cell lung cancer. We evaluated these metrics in patients treated with definitive radiation therapy (RT). We also evaluated outcomes after progression on mid-radiotherapy PET/CT.Seventy-seven patients treated with RT with or without chemotherapy were included in this retrospective study. Primary tumor and involved nodes were delineated. PET metrics included metabolic tumor volume (MTV), total lesion glycolysis (TLG), and SUVmax. For mid-radiotherapy PET, both absolute value of these metrics and percentage decrease were analyzed. The influence of PET metrics on time to death, local recurrence, and regional/distant recurrence was assessed using Cox regression.91% of patients had concurrent chemotherapy. Median follow-up was 14months. None of the PET metrics were associated with overall survival. Several were positively associated with local recurrence: pre-radiotherapy MTV, and mid-radiotherapy MTV and TLG (p=0.03-0.05). Ratio of mid- to pre-treatment SUVmax was associated with regional/distant recurrence (p=0.02). 5/77 mid-radiotherapy scans showed early out-of-field progression. All of these patients died.Several PET metrics were associated with risk of recurrence. Progression on mid-radiotherapy PET/CT was a poor prognostic factor.

    View details for PubMedID 28830717

  • Clinical and Pathological Variables Influencing Noninvasive Detection of Early Stage Lung Cancer Using Circulating Tumor DNA Chabon, J., Chaudhuri, A., Azad, T., Kurtz, D., Stehr, H., Liu, C. L., Martin, J., Merriott, D., Carter, J., Ayers, K., Mansfield, A., Jen, J., Ren, H., West, R., Nair, V., Shrager, J., Neal, J., Wakelee, H., Loo, B., Alizadeh, A., Diehn, M. ELSEVIER SCIENCE INC. 2017: S1851
  • Practical workflow for rapid prototyping of radiation therapy positioning devices PRACTICAL RADIATION ONCOLOGY Gensheimer, M. F., Bush, K., Juang, T., Herzberg, B., Villegas, M., Maxim, P. G., Diehn, M., Loo, B. W. 2017; 7 (6): 442–45

    View details for PubMedID 28668669

  • Radiogenomic Analysis of a Peritumoral CT Image Feature and Its Prognostic Value in Early Stage NSCLC Lee, J., Cui, Y., Gensheimer, M. F., Loo, B. W., Diehn, M., Li, R. ELSEVIER SCIENCE INC. 2017: S48
  • Safety and Efficacy of Stereotactic Ablative Radiotherapy (SABR) to Multiple (3 or More) Lung Tumors Moding, E. J., Maxim, P. G., Diehn, M., Loo, B. W., Gensheimer, M. F. ELSEVIER SCIENCE INC. 2017: E482
  • Outcomes of Moderately Hypofractionated Intensity-Modulated Thoracic Radiotherapy with Concurrent Chemotherapy for Treatment of Non-Small Cell Lung Cancer Xiang, M., Gensheimer, M. F., Maxim, P. G., Wakelee, H. A., Neal, J. W., Diehn, M., Loo, B. W. ELSEVIER SCIENCE INC. 2017: E504
  • Mid-radiation Therapy PET/CT for Prognostication and Detection of Early Progression in Patients With Stage III Non-small Cell Lung Cancer Gensheimer, M. F., Hong, J. C., Chang-Halpenny, C. N., Eclov, N., To, J., Murphy, J. D., Wakelee, H. A., Neal, J. W., Le, Q. T., Hara, W., Quon, A., Maxim, P. G., Graves, E. E., Olson, M. R., Diehn, M., Loo, B. W. ELSEVIER SCIENCE INC. 2017: E456
  • Circulating Tumor DNA Analysis during Radiation Therapy for Localized Lung Cancer Predicts Treatment Outcome Chaudhuri, A. A., Lovejoy, A. F., Chabon, J. J., Newman, A., Stehr, H., Merriott, D. J., Carter, J. N., Azad, T. D., Padda, S., Gensheimer, M. F., Wakelee, H. A., Neal, J. W., Loo, B. W., Alizadeh, A. A., Diehn, M. ELSEVIER SCIENCE INC. 2017: S1–S2
  • Comparison of Circulating Tumor DNA Analysis and Surveillance Imaging After Treatment for Localized Lung Cancer Chaudhuri, A. A., Chabon, J. J., Lovejoy, A. F., Newman, A., Stehr, H., Azad, T. D., Carter, J. N., Merriott, D. J., Liu, C. L., Kurtz, D. M., Gensheimer, M. F., Shrager, J. B., Wakelee, H. A., Neal, J. W., Loo, B. W., Alizadeh, A. A., Diehn, M. ELSEVIER SCIENCE INC. 2017: S114
  • Pretreatment Circulating Tumor DNA for Risk Stratification of Locally Advanced Esophageal Cancer Treated With Chemoradiation and Surgery Azad, T. D., Chaudhuri, A. A., Newman, A., Stehr, H., Schroers-Martin, J., Chabon, J. J., Fang, P., Qiao, Y., Liao, Z., Komaki, R. U., Alizadeh, A. A., Lin, S. H., Diehn, M. ELSEVIER SCIENCE INC. 2017: S90–S91
  • Patterns of Care and Health Disparities for Patients With Stage I Non-small Cell Lung Cancer in the US Harris, J. P., Nwachukwu, C. R., Loo, B. W., Das, M., Diehn, M. ELSEVIER SCIENCE INC. 2017: E399
  • Circulating Tumor DNA Quantitation for Early Response Assessment of Immune Checkpoint Inhibitors for Lung Cancer Merriott, D. J., Chaudhuri, A. A., Jin, M., Chabon, J. J., Newman, A., Stehr, H., Say, C., Carter, J. N., Walters, S., Becker, H. R., Das, M., Padda, S., Loo, B. W., Wakelee, H. A., Neal, J. W., Alizadeh, A. A., Diehn, M. ELSEVIER SCIENCE INC. 2017: S20–S21
  • Validation of Temporal Change in Quantitative PET Metrics as Predictors of Recurrence in Early Stage Lung Cancer Patients Treated With SABR Prionas, N. D., Yi, E., Aggarwal, S., Shaffer, J., Von Eyben, R., Graves, E. E., Maxim, P. G., Gensheimer, M. F., Diehn, M., Loo, B. W. ELSEVIER SCIENCE INC. 2017: S18–S19
  • Randomized Phase Phase II Study of Preoperative Chemoradiotherapy +/- Panitumumab Followed by Consolidation Chemotherapy in Potentially Operable Locally Advanced (Stage IIla, N2+) Non-Small Cell Lung Cancer: NRG Oncology RTOG 0839 JOURNAL OF THORACIC ONCOLOGY Edelman, M. J., Hu, C., Quynh-Thu Le, Donington, J. S., D'Souza, W. D., Dicker, A. P., Loo, B. W., Gore, E. M., Videtic, G. M., Evans, N. R., Leach, J. W., Diehn, M., Feigenberg, S. J., Chen, Y., Paulus, R., Bradley, J. D. 2017; 12 (9): 1413–20

    Abstract

    Multimodality therapy has curative potential in locally advanced NSCLC. Mediastinal nodal sterilization (MNS) after induction chemoradiotherapy (CRT) can serve as an intermediate marker for efficacy. NRG Oncology Radiation Therapy Oncology Group (RTOG) 0229 demonstrated the feasibility and efficacy of combining full-dose radiation (61.2 Gy) with chemotherapy followed by resection and chemotherapy. On the basis of that experience and evidence that EGFR antibodies are radiosensitizing, we explored adding panitumumab to CRT followed by resection and consolidation chemotherapy in locally advanced NSCLC with a primary end point of MNS.Patients with resectable locally advanced NSCLC were eligible if deemed suitable for trimodality therapy before treatment. Surgeons were required to demonstrate expertise after CRT and adhere to specific management guidelines. Concurrent CRT consisted of weekly carboplatin (area under the curve = 2.0), paclitaxel (50 mg/m2), and 60 Gy of radiation therapy delivered in 30 fractions. There was a 2:1 randomization in favor of panitumumab at 2.5 mg/kg weekly for 6 weeks. The mediastinum was pathologically reassessed before or at the time of resection. Consolidation chemotherapy was weekly carboplatin (area under the curve = 6) and paclitaxel, 200 mg/m2 every 21 days for two courses. The study was designed to detect an improvement in MNS from 52% to 72%. With use of a 0.15 one-sided type 1 error and 80% power, 97 patients were needed.The study was opened in November 2010 and closed in August 2015 by the Data Monitoring Committee after 71 patients had been accrued for futility and excessive toxicity in the experimental arm. A total of 60 patients were eligible: 19 patients (86%) who received CRT and 29 (76%) who received CRT plus panitumumab and underwent an operation. With regard to postoperative toxicity, there were three grade 4 adverse events (13.6%) and no grade 5 adverse events (0%) among those who received CRT versus six grade 4 (15.8%) and four grade 5 adverse events (10.5%) among those who received CRT plus panitumumab. The MNS rates were 68.2% (95% confidence interval: 45.1-86.1) and 50.0% (95% confidence interval: 33.4-66.6) for CRT and CRT plus panitumumab, respectively (p = 0.95).The addition of panitumumab to CRT did not improve MNS. There was an unexpectedly high mortality rate in the panitumumab arm, although the relationship to panitumumab is unclear. The control arm had outcomes similar to those in NRG Oncology RTOG 0229.

    View details for DOI 10.1016/j.jtho.2017.06.007

    View details for Web of Science ID 000409157900012

    View details for PubMedID 28629896

    View details for PubMedCentralID PMC5594738

  • Normal Tissue Constraints for Abdominal and Thoracic Stereotactic Body Radiotherapy. Seminars in radiation oncology Pollom, E. L., Chin, A. L., Diehn, M., Loo, B. W., Chang, D. T. 2017; 27 (3): 197-208

    Abstract

    Although stereotactic body radiotherapy (SBRT) or stereotactic ablative radiotherapy has become an established standard of care for the treatment of a variety of malignancies, our understanding of normal tissue dose tolerance with extreme hypofractionation remains immature. Since Timmerman initially proposed normal tissue dose constraints for SBRT in the 2008 issue of Seminars of Radiation Oncology, experience with SBRT has grown, and more long-term clinical outcome data have been reported. This article reviews the modern toxicity literature and provides updated clinically practical and useful recommendations of SBRT dose constraints for extracranial sites. We focus on the major organs of the thoracic and upper abdomen, specifically the liver and the lung.

    View details for DOI 10.1016/j.semradonc.2017.02.001

    View details for PubMedID 28577827

  • A phase II randomized trial of Observation versus stereotactic ablative RadiatIon for OLigometastatic prostate CancEr (ORIOLE) BMC CANCER Radwan, N., Phillips, R., Ross, A., Rowe, S. P., Gorin, M. A., Antonarakis, E. S., Deville, C., Greco, S., Denmeade, S., Paller, C., Song, D. Y., Diehn, M., Wang, H., Carducci, M., Pienta, K. J., Pomper, M. G., DeWeese, T. L., Dicker, A., Eisenberger, M., Tran, P. T. 2017; 17: 453

    Abstract

    We describe a randomized, non-blinded Phase II interventional study to assess the safety and efficacy of stereotactic ablative radiotherapy (SABR) for hormone-sensitive oligometastatic prostate adenocarcinoma, and to describe the biology of the oligometastatic state using immunologic, cellular, molecular, and functional imaging correlates. 54 men with oligometastatic prostate adenocarcinoma will be accrued. The primary clinical endpoint will be progression at 6 months from randomization with the hypothesis that SABR to all metastases will forestall progression by disrupting the metastatic process. Secondary clinical endpoints will include local control at 6 months post-SABR, toxicity and quality of life, and androgen deprivation therapy (ADT)-free survival (ADT-FS). Further fundamental analysis of the oligometastatic state with be achieved through correlation with investigational 18F-DCFPyL PET/CT imaging and measurement of circulating tumor cells, circulating tumor DNA, and circulating T-cell receptor repertoires, facilitating an unprecedented opportunity to characterize, in isolation, the effects of SABR on the dynamics of and immunologic response to oligometastatic disease.Patients will be randomized 2:1 to SABR or observation with minimization to balance assignment by primary intervention, prior hormonal therapy, and PSA doubling time. Progression after 6 months will be compared using Fisher's exact test. Hazard ratios and Kaplan-Meier estimates of progression free survival (PFS), ADT free survival (ADT-FS), time to locoregional progression (TTLP) and time to distant progression (TTDP) will be calculated based on an intention-to-treat. Local control will be assessed using Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria. Withdrawal from the study prior to 6 months will be counted as progression. Adverse events will be summarized by type and grade. Quality of life pre- and post- SABR will be measured by Brief Pain Inventory.The ORIOLE trial is the first randomized, non-blinded Phase II interventional study in the North America evaluating the safety and efficacy of SABR in oligometastatic hormone-sensitive prostate cancer. Leading-edge laboratory and imaging correlates will provide unique insight into the effects of SABR on the oligometastatic state.ClinicalTrials.gov Identifier: NCT02680587. URL of Registry: https://clinicaltrials.gov/show/NCT02680587 Date of Registration: 02/08/2016. Date of First Participant Enrollment: 05/23/2016.

    View details for PubMedID 28662647

  • Stereotactic Ablative Radiotherapy for Stage I Non-Small-Cell Lung Cancer Tumors Greater Than 5 cm Anderson, E. M., Sharma, A., Westover, K. D., Timmerman, R., von Eyben, R., Gensheimer, M. F., Maxim, P., Loo, B. W., Diehn, M., Shultz, D. B. ELSEVIER SCIENCE INC. 2017: E38
  • Circulating Tumor DNA Detects Residual Disease and Anticipates Tumor Progression Earlier Than CT Imaging Chaudhuri, A. A., Chabon, J. J., Lovejoy, A. F., Newman, A. M., Stehr, H., Azad, T. D., Zhou, L., Liu, C., Scherer, F., Kurtz, D. M., Esfahani, M. S., Say, C., Carter, J. N., Merriott, D., Dudley, J., Binkley, M. S., Modlin, L., Padda, S. K., Gensheimer, M., West, R. B., Shrager, J. B., Neal, J. W., Wakelee, H. A., Billy, W., Alizadeh, A. A., Diehn, M. ELSEVIER SCIENCE INC. 2017: E4
  • A population-based comparative effectiveness study of chemoradiation regimens and sequences in stage III non-small cell lung cancer LUNG CANCER Harris, J. P., Patel, M. I., Loo, B. W., Wakelee, H. A., Diehn, M. 2017; 108: 173–82

    Abstract

    In patients receiving concurrent chemoradiation for locally advanced non-small cell lung cancer (NSCLC), consolidation chemotherapy is frequently given even though several randomized trials have failed to show a benefit. We explored the potential benefits of consolidation chemotherapy using a population-based comparative effectiveness approach.Surveillance, Epidemiology, and End Results-Medicare was used to identify patients with Stage III NSCLC aged ≥65 and diagnosed 2002-2009. We selected patients who received concurrent chemoradiotherapy and determined whether they were (concurrent-consolidation) or were not (concurrent-alone) treated with consolidation chemotherapy. Outcomes were overall and cancer specific survival using a conditional landmark analysis approach.1688 patients treated with concurrent-alone or concurrent-consolidation were identified with a median follow up of 29 months. Choice of chemotherapy agents did not correlate with outcome. For concurrent-consolidation versus concurrent-alone, the median overall survival was 21 months versus 18 months, respectively (log-rank p=0.008) and the median cancer specific survival was 23 months versus 19 months, respectively (log-rank p=0.03). On multivariate analysis, concurrent-consolidation remained associated with improved overall survival (HR 0.85, p=0.04), and there was a trend for improved cancer specific survival (HR 0.87, p=0.12). Inverse probability of treatment weighting using propensity scores demonstrated similar findings. Importantly, the benefit of concurrent-consolidation held only for patients treated with carboplatin-taxane but not with cisplatin-etoposide.Survival outcomes were similar among the five most commonly employed platinum-based doublets. We found that patients receiving cisplatin during radiation do not appear to benefit from additional chemotherapy. However, for patients receiving carboplatin, consolidation chemotherapy was associated with improved overall and cancer specific survival.

    View details for PubMedID 28625632

  • A phase II randomized trial of observation versus stereotactic ablative radiation for oligometastatic prostate cancer (ORIOLE). Phillips, R., Radwan, N., Ross, A., Rowe, S. P., Gorin, M. A., Antonarakis, E. S., Deville, C., Greco, S. C., Denmeade, S. R., Paller, C., Song, D. Y., Diehn, M., Wang, H., Carducci, M., Pienta, K. J., Pomper, M. G., DeWeese, T. L., Dicker, A. P., Eisenberger, M. A., Tran, P. T. AMER SOC CLINICAL ONCOLOGY. 2017
  • Elucidation of distinct mutational patterns between diffuse large B cell lymphoma subtypes utilizing circulating tumor DNA. Soo, J., Kurtz, D., Scherer, F., Craig, A. M., Jin, M. C., Westin, J. R., Rossi, D., Gaidano, G., Advani, R. H., Diehn, M., Alizadeh, A. A. AMER SOC CLINICAL ONCOLOGY. 2017
  • Noninvasive detection of clinically relevant copy number alterations in diffuse large B-cell lymphoma. Jin, M. C., Kurtz, D., Esfahani, M., Scherer, F., Craig, A. M., Soo, J., Khodadoust, M., Saganty, R., Chabon, J. J., Schroers-Martin, J., Stehr, H., Advani, R. H., Rossi, D., Gaidano, G., Westin, J. R., Diehn, M., Alizadeh, A. A. AMER SOC CLINICAL ONCOLOGY. 2017
  • Circulating tumor DNA analysis for outcome prediction in localized esophageal cancer. Azad, T. D., Chaudhuri, A., Newman, A. M., Stehr, H., Schroers-Martin, J., Chabon, J. J., Fang, P., Qiao, Y., Liao, Z. X., Komaki, R., Alizadeh, A. A., Lin, S. H., Diehn, M. AMER SOC CLINICAL ONCOLOGY. 2017
  • Case Series of MET Exon 14 Skipping Mutation-positive Non-Small Cell Lung Cancers and Response to Crizotinib. International journal of radiation oncology, biology, physics Wang, S. X., Zhang, B., Wakelee, H. A., Diehn, M., Kunder, C., Neal, J. W. 2017; 98 (1): 239-?

    View details for DOI 10.1016/j.ijrobp.2017.01.170

    View details for PubMedID 28587017

  • Pulmonary function after lung tumor stereotactic ablative radiotherapy depends on regional ventilation within irradiated lung. Radiotherapy and oncology Binkley, M. S., King, M. T., Shrager, J. B., Bush, K., Chaudhuri, A. A., Popat, R., Gensheimer, M. F., Maxim, P. G., Henry Guo, H., Diehn, M., Nair, V. S., Loo, B. W. 2017; 123 (2): 270-275

    Abstract

    To determine if regional ventilation within irradiated lung volume predicts change in pulmonary function test (PFT) measurements after stereotactic ablative radiotherapy (SABR) of lung tumors.We retrospectively identified 27 patients treated from 2007 to 2014 at our institution who received: (1) SABR without prior thoracic radiation; (2) pre-treatment 4-dimensional computed tomography (4-D CT) imaging; (3) pre- and post-SABR PFTs <15months from treatment. We defined the ventilation ratio (VR20BED3) as the quotient of mean ventilation (mean Jacobian-based per-voxel volume change on deformably registered inhale/exhale 4-D CT phases) within the 20Gy biologically effective dose (α/β=3Gy) isodose volume and that of the total lung volume (TLV).Most patients had moderate to very severe COPD by GOLD criteria (n=19, 70.1%). Higher VR20BED3 significantly predicted worse change in Forced Expiratory Volume/s normalized by baseline value (ΔFEV1/FEV1pre, p=0.04); n=7 had VR20BED3>1 (high regional ventilation) and worse ΔFEV1/FEV1pre (median=-0.16, range=-0.230 to -0.20). Five had VR20BED3<1 (low regional ventilation) and improved ΔFEV1/FEV1pre (median=0.13, range=0.07 to 0.20). In a multivariable linear model, increasing VR20BED3 and time to post-SABR PFT predicted decreasing ΔFEV1/FEV1pre (R(2)=0.25, p=0.03).After SABR to high versus low functioning lung regions, we found worsened or improved global pulmonary function, respectively. If pre-SABR VR20BED3 is validated as a predictor of eventual post-SABR PFT in larger studies, it may be used for individualized treatment planning to preserve or even improve pulmonary function after SABR.

    View details for DOI 10.1016/j.radonc.2017.03.021

    View details for PubMedID 28460826

  • Sinoatrial node dysfunction after stereotactic ablative radiation therapy in the chest Qian, Y., Dudley, S., Kumar, K., Chaudhuri, A., Chin, A., Harris, J., Prionas, N., Nwachukwu, C., Bagshaw, H., Pollom, E. L., Ben Durkee, Shultz, D., Gensheimer, M. F., Diehn, M., Loo, B. W. AMER SOC CLINICAL ONCOLOGY. 2017
  • ERBB2-Mutated Metastatic Non-Small Cell Lung Cancer: Response and Resistance to Targeted Therapies. Journal of thoracic oncology Chuang, J. C., Stehr, H., Liang, Y., Das, M., Huang, J., Diehn, M., Wakelee, H. A., Neal, J. W. 2017

    Abstract

    Erb-b2 receptor tyrosine kinase 2 gene (ERBB2) (also called HER2) has long been recognized as an oncogenic driver in some breast and gastroesophageal cancers in which amplification of this gene confers sensitivity to treatment with Erb-b2 receptor tyrosine kinase 2 (ERBB2)-directed agents. More recently, somatic mutations in ERBB2 have been reported in 1% to 2% of patients with lung adenocarcinoma. Previous case series have suggested clinical tumor responses using anti-ERBB2 small molecules and antibody therapies.Here we report the outcomes of nine patients with metastatic lung adenocarcinoma with ERBB2 mutations being treated with ERBB2-targeted therapies.Four of the nine patients had response to targeted therapies, with durations of response ranging from 3 to 10 months. We identified a de novo phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha gene (PIK3CA) mutation and ERBB2 copy number gain as potential resistance mechanisms.We showed patients with ERBB2-mutated lung adenocarcinoma can respond to targeted therapies, and we identified potential resistance mechanisms upon progression to targeted therapies.

    View details for DOI 10.1016/j.jtho.2017.01.023

    View details for PubMedID 28167203

  • Role of KEAP1/NRF2 and TP53 Mutations in Lung Squamous Cell Carcinoma Development and Radiation Resistance CANCER DISCOVERY Jeong, Y., Hoang, N. T., Lovejoy, A., Stehr, H., Newman, A. M., Gentles, A. J., Kong, W., Diana Truong, D., Martin, S., Chaudhuri, A., Heiser, D., Zhou, L., Say, C., Carter, J. N., Hiniker, S. M., Loo, B. W., West, R. B., Beachy, P., Alizadeh, A. A., Diehn, M. 2017; 7 (1): 86-101

    Abstract

    Lung squamous cell carcinoma (LSCC) pathogenesis remains incompletely understood, and biomarkers predicting treatment response remain lacking. Here, we describe novel murine LSCC models driven by loss of Trp53 and Keap1, both of which are frequently mutated in human LSCCs. Homozygous inactivation of Keap1 or Trp53 promoted airway basal stem cell (ABSC) self-renewal, suggesting that mutations in these genes lead to expansion of mutant stem cell clones. Deletion of Trp53 and Keap1 in ABSCs, but not more differentiated tracheal cells, produced tumors recapitulating histologic and molecular features of human LSCCs, indicating that they represent the likely cell of origin in this model. Deletion of Keap1 promoted tumor aggressiveness, metastasis, and resistance to oxidative stress and radiotherapy (RT). KEAP1/NRF2 mutation status predicted risk of local recurrence after RT in patients with non-small lung cancer (NSCLC) and could be noninvasively identified in circulating tumor DNA. Thus, KEAP1/NRF2 mutations could serve as predictive biomarkers for personalization of therapeutic strategies for NSCLCs.We developed an LSCC mouse model involving Trp53 and Keap1, which are frequently mutated in human LSCCs. In this model, ABSCs are the cell of origin of these tumors. KEAP1/NRF2 mutations increase radioresistance and predict local tumor recurrence in radiotherapy patients. Our findings are of potential clinical relevance and could lead to personalized treatment strategies for tumors with KEAP1/NRF2 mutations. Cancer Discov; 7(1); 86-101. ©2016 AACR.This article is highlighted in the In This Issue feature, p. 1.

    View details for DOI 10.1158/2159-8290.CD-16-0127

    View details for Web of Science ID 000396017700024

    View details for PubMedCentralID PMC5222718

  • Sinoatrial node toxicity after stereotactic ablative radiation therapy to lung tumors. Practical radiation oncology Qian, Y. n., Zhu, H. n., Pollom, E. L., Durkee, B. Y., Chaudhuri, A. A., Gensheimer, M. F., Diehn, M. n., Shultz, D. B., Loo, B. W. 2017

    Abstract

    Stereotactic ablative radiation therapy (SABR) is an established treatment for selected lung tumors. Sinoatrial node (SAN) toxicity after thoracic SABR has not been reported in the literature. We sought to understand the risk of SAN toxicity owing to incidental dose to the SAN from SABR.We conducted a retrospective review of patients with early-stage lung cancer or limited pulmonary metastases who underwent thoracic SABR to a right-sided central lung tumor (within 2 cm of the mainstem bronchus or other mediastinal structures) between January 2008 and December 2014, analyzed a subset whose treatment imparted dose to the SAN exceeding 10% of the prescription dose, and examined patient and treatment dosimetric characteristics. Mean follow-up interval was 28 months. Time to toxicity was defined from start of SABR.Of 47 patients with central tumors in the right lung treated with SABR reviewed, 13 met our study criteria. A contouring atlas of regional cardiac anatomy was created. One patient treated with SABR for non-small cell lung cancer at the right hilum developed symptomatic sick sinus syndrome, requiring pacemaker placement 6 months after treatment. Her acute presentation and short interval between SABR and onset of symptoms suggest that SAN toxicity was likely due to radiation-induced injury. Both her age and mean dose to her SAN were the third highest in our cohort. She remained free from cancer progression at 24 months' follow-up. Twelve additional patients who received significant dose to the SAN from SABR did not develop toxicity.While uncommon, SAN toxicity from SABR to right-sided central thoracic tumors should be recognized and followed in future studies.

    View details for PubMedID 28669706

  • Data normalization considerations for digital tumor dissection. Genome biology Newman, A. M., Gentles, A. J., Liu, C. L., Diehn, M. n., Alizadeh, A. A. 2017; 18 (1): 128

    Abstract

    In a recently published article in Genome Biology, Li and colleagues introduced TIMER, a gene expression deconvolution approach for studying tumor-infiltrating leukocytes (TILs) in 23 cancer types profiled by The Cancer Genome Atlas. Methods to characterize TIL biology are increasingly important, and the authors offer several arguments in favor of their strategy. Several of these claims warrant further discussion and highlight the critical importance of data normalization in gene expression deconvolution applications.Please see related Li et al correspondence: www.dx.doi.org/10.1186/s13059-017-1256-5 and Zheng correspondence: www.dx.doi.org/10.1186/s13059-017-1258-3.

    View details for PubMedID 28679399

  • High-throughput sequencing for noninvasive disease detection in hematologic malignancies. Blood Scherer, F. n., Kurtz, D. M., Diehn, M. n., Alizadeh, A. A. 2017; 130 (4): 440–52

    Abstract

    Noninvasive monitoring of minimal residual disease (MRD) has led to significant advances in personalized management of patients with hematologic malignancies. Improved therapeutic options and prolonged survival have further increased the need for sensitive tumor assessment that can inform treatment decisions and patient outcomes. At diagnosis or relapse of most hematologic neoplasms, malignant cells are often easily accessible in the blood as circulating tumor cells (CTCs), making them ideal targets to noninvasively profile the molecular features of each patient. In other cancer types, CTCs are generally rare and noninvasive molecular detection relies on circulating tumor DNA (ctDNA) shed from tumor deposits into circulation. The ability to precisely detect and quantify CTCs and ctDNA could minimize invasive procedures and improve prediction of clinical outcomes. Technical advances in MRD detection methods in recent years have led to reduced costs and increased sensitivity, specificity, and applicability. Among currently available tests, high-throughput sequencing (HTS)-based approaches are increasingly attractive for noninvasive molecular testing. HTS-based methods can simultaneously identify multiple genetic markers with high sensitivity and specificity without individual optimization. In this review, we present an overview of techniques used for noninvasive molecular disease detection in selected myeloid and lymphoid neoplasms, with a focus on the current and future role of HTS-based assays.

    View details for PubMedID 28600337

    View details for PubMedCentralID PMC5881609

  • Development and Validation of an Individualized Immune Prognostic Signature in Early-Stage Nonsquamous Non-Small Cell Lung Cancer. JAMA oncology Li, B. n., Cui, Y. n., Diehn, M. n., Li, R. n. 2017

    Abstract

    The prevalence of early-stage non-small cell lung cancer (NSCLC) is expected to increase with recent implementation of annual screening programs. Reliable prognostic biomarkers are needed to identify patients at a high risk for recurrence to guide adjuvant therapy.To develop a robust, individualized immune signature that can estimate prognosis in patients with early-stage nonsquamous NSCLC.This retrospective study analyzed the gene expression profiles of frozen tumor tissue samples from 19 public NSCLC cohorts, including 18 microarray data sets and 1 RNA-Seq data set for The Cancer Genome Atlas (TCGA) lung adenocarcinoma cohort. Only patients with nonsquamous NSCLC with clinical annotation were included. Samples were from 2414 patients with nonsquamous NSCLC, divided into a meta-training cohort (729 patients), meta-testing cohort (716 patients), and 3 independent validation cohorts (439, 323, and 207 patients). All patients underwent surgery with a negative surgical margin, received no adjuvant or neoadjuvant therapy, and had publicly available gene expression data and survival information. Data were collected from July 22 through September 8, 2016.Overall survival.Of 2414 patients (1205 men [50%], 1111 women [46%], and 98 of unknown sex [4%]; median age [range], 64 [15-90] years), a prognostic immune signature of 25 gene pairs consisting of 40 unique genes was constructed using the meta-training data set. In the meta-testing and validation cohorts, the immune signature significantly stratified patients into high- vs low-risk groups in terms of overall survival across and within subpopulations with stage I, IA, IB, or II disease and remained as an independent prognostic factor in multivariate analyses (hazard ratio range, 1.72 [95% CI, 1.26-2.33; P < .001] to 2.36 [95% CI, 1.47-3.79; P < .001]) after adjusting for clinical and pathologic factors. Several biological processes, including chemotaxis, were enriched among genes in the immune signature. The percentage of neutrophil infiltration (5.6% vs 1.8%) and necrosis (4.6% vs 1.5%) was significantly higher in the high-risk immune group compared with the low-risk groups in TCGA data set (P < .003). The immune signature achieved a higher accuracy (mean concordance index [C-index], 0.64) than 2 commercialized multigene signatures (mean C-index, 0.53 and 0.61) for estimation of survival in comparable validation cohorts. When integrated with clinical characteristics such as age and stage, the composite clinical and immune signature showed improved prognostic accuracy in all validation data sets relative to molecular signatures alone (mean C-index, 0.70 vs 0.63) and another commercialized clinical-molecular signature (mean C-index, 0.68 vs 0.65).The proposed clinical-immune signature is a promising biomarker for estimating overall survival in nonsquamous NSCLC, including early-stage disease. Prospective studies are needed to test the clinical utility of the biomarker in individualized management of nonsquamous NSCLC.

    View details for PubMedID 28687838

  • Deactivated CRISPR Associated Protein 9 for Minor-Allele Enrichment in Cell-Free DNA. Clinical chemistry Aalipour, A. n., Dudley, J. C., Park, S. M., Murty, S. n., Chabon, J. J., Boyle, E. A., Diehn, M. n., Gambhir, S. S. 2017

    Abstract

    Cell-free DNA (cfDNA) diagnostics are emerging as a new paradigm of disease monitoring and therapy management. The clinical utility of these diagnostics is relatively limited by a low signal-to-noise ratio, such as with low allele frequency (AF) mutations in cancer. While enriching for rare alleles to increase their AF before sample analysis is one strategy that can greatly improve detection capability, current methods are limited in their generalizability, ease of use, and applicability to point mutations.Leveraging the robust single-base-pair specificity and generalizability of the CRISPR associated protein 9 (Cas9) system, we developed a deactivated Cas9 (dCas9)-based method of minor-allele enrichment capable of efficient single-target and multiplexed enrichment. The dCas9 protein was complexed with single guide RNAs targeted to mutations of interest and incubated with cfDNA samples containing mutant strands at low abundance. Mutation-bound dCas9 complexes were isolated, dissociated, and the captured DNA purified for downstream use.Targeting the 3 most common epidermal growth factor receptor mutations (exon 19 deletion, T790M, L858R) found in nonsmall-cell lung cancer (NSCLC), we achieved >20-fold increases in AF and detected mutations by use of qPCR at an AF of 0.1%. In a cohort of 18 NSCLC patient-derived cfDNA samples, our method enabled detection of 8 out of 13 mutations that were otherwise undetected by qPCR.The dCas9 method provides important application of the CRISPR/Cas9 system outside the realm of genome editing and can provide a step forward for the detection capability of cfDNA diagnostics.

    View details for PubMedID 29038154

  • Prognostic value and molecular correlates of a CT image-based quantitative pleural contact index in early stage NSCLC. European radiology Lee, J. n., Cui, Y. n., Sun, X. n., Li, B. n., Wu, J. n., Li, D. n., Gensheimer, M. F., Loo, B. W., Diehn, M. n., Li, R. n. 2017

    Abstract

    To evaluate the prognostic value and molecular basis of a CT-derived pleural contact index (PCI) in early stage non-small cell lung cancer (NSCLC).We retrospectively analysed seven NSCLC cohorts. A quantitative PCI was defined on CT as the length of tumour-pleura interface normalised by tumour diameter. We evaluated the prognostic value of PCI in a discovery cohort (n = 117) and tested in an external cohort (n = 88) of stage I NSCLC. Additionally, we identified the molecular correlates and built a gene expression-based surrogate of PCI using another cohort of 89 patients. To further evaluate the prognostic relevance, we used four datasets totalling 775 stage I patients with publically available gene expression data and linked survival information.At a cutoff of 0.8, PCI stratified patients for overall survival in both imaging cohorts (log-rank p = 0.0076, 0.0304). Extracellular matrix (ECM) remodelling was enriched among genes associated with PCI (p = 0.0003). The genomic surrogate of PCI remained an independent predictor of overall survival in the gene expression cohorts (hazard ratio: 1.46, p = 0.0007) adjusting for age, gender, and tumour stage.CT-derived pleural contact index is associated with ECM remodelling and may serve as a noninvasive prognostic marker in early stage NSCLC.• A quantitative pleural contact index (PCI) predicts survival in early stage NSCLC. • PCI is associated with extracellular matrix organisation and collagen catabolic process. • A multi-gene surrogate of PCI is an independent predictor of survival. • PCI can be used to noninvasively identify patients with poor prognosis.

    View details for PubMedID 28786009

  • Capturing Genomic Evolution of Lung Cancers through Liquid Biopsy for Circulating Tumor DNA. Journal of oncology Offin, M., Chabon, J. J., Razavi, P., Isbell, J. M., Rudin, C. M., Diehn, M., Li, B. T. 2017; 2017: 4517834-?

    Abstract

    Genetic sequencing of malignancies has become increasingly important to uncover therapeutic targets and capture the tumor's dynamic changes to drug sensitivity and resistance through genomic evolution. In lung cancers, the current standard of tissue biopsy at the time of diagnosis and progression is not always feasible or practical and may underestimate intratumoral heterogeneity. Technological advances in genetic sequencing have enabled the use of circulating tumor DNA (ctDNA) analysis to obtain information on both targetable mutations and capturing real-time Darwinian evolution of tumor clones and drug resistance mechanisms under selective therapeutic pressure. The ability to analyze ctDNA from plasma, CSF, or urine enables a comprehensive view of cancers as systemic diseases and captures intratumoral heterogeneity. Here, we describe these recent advances in the setting of lung cancers and advocate for further research and the incorporation of ctDNA analysis in clinical trials of targeted therapies. By capturing genomic evolution in a noninvasive manner, liquid biopsy for ctDNA analysis could accelerate therapeutic discovery and deliver the next leap forward in precision medicine for patients with lung cancers and other solid tumors.

    View details for DOI 10.1155/2017/4517834

    View details for PubMedID 28392802

  • Evolution and clinical impact of co-occurring genetic alterations in advanced-stage EGFR-mutant lung cancers. Nature genetics Blakely, C. M., Watkins, T. B., Wu, W. n., Gini, B. n., Chabon, J. J., McCoach, C. E., McGranahan, N. n., Wilson, G. A., Birkbak, N. J., Olivas, V. R., Rotow, J. n., Maynard, A. n., Wang, V. n., Gubens, M. A., Banks, K. C., Lanman, R. B., Caulin, A. F., St John, J. n., Cordero, A. R., Giannikopoulos, P. n., Simmons, A. D., Mack, P. C., Gandara, D. R., Husain, H. n., Doebele, R. C., Riess, J. W., Diehn, M. n., Swanton, C. n., Bivona, T. G. 2017; 49 (12): 1693–1704

    Abstract

    A widespread approach to modern cancer therapy is to identify a single oncogenic driver gene and target its mutant-protein product (for example, EGFR-inhibitor treatment in EGFR-mutant lung cancers). However, genetically driven resistance to targeted therapy limits patient survival. Through genomic analysis of 1,122 EGFR-mutant lung cancer cell-free DNA samples and whole-exome analysis of seven longitudinally collected tumor samples from a patient with EGFR-mutant lung cancer, we identified critical co-occurring oncogenic events present in most advanced-stage EGFR-mutant lung cancers. We defined new pathways limiting EGFR-inhibitor response, including WNT/β-catenin alterations and cell-cycle-gene (CDK4 and CDK6) mutations. Tumor genomic complexity increases with EGFR-inhibitor treatment, and co-occurring alterations in CTNNB1 and PIK3CA exhibit nonredundant functions that cooperatively promote tumor metastasis or limit EGFR-inhibitor response. This study calls for revisiting the prevailing single-gene driver-oncogene view and links clinical outcomes to co-occurring genetic alterations in patients with advanced-stage EGFR-mutant lung cancer.

    View details for PubMedID 29106415

    View details for PubMedCentralID PMC5709185

  • Comprehensive Analysis of the Unfolded Protein Response in Breast Cancer Subtypes. JCO precision oncology Jiang, D., Turner, B., Song, J., Li, R., Diehn, M., Le, Q., Khatri, P., Koong, A. C. 2017; 2017

    Abstract

    Purpose: Triple-negative breast cancers (TNBCs) are associated with a worse prognosis and patients with TNBC have fewer therapeutic options than patients with non-TNBC. Recently, the IRE1alpha-XBP1 branch of the unfolded protein response (UPR) was implicated in TNBC prognosis on the basis of a relatively small patient population, suggesting the diagnostic and therapeutic value of this pathway in TNBCs. In addition, the IRE1alpha-XBP1 and hypoxia-induced factor 1 alpha (HIF1alpha) pathways have been identified as interacting partners in TNBC, suggesting a novel mechanism of regulation. To comprehensively evaluate and validate these findings, we investigated the relative activities and relevance to patient survival of the UPR and HIF1alpha pathways in different breast cancer subtypes in large populations of patients.Materials and Methods: We performed a comprehensive analysis of gene expression and survival data from large cohorts of patients with breast cancer. The patients were stratified based on the average expression of the UPR or HIF1alpha gene signatures.Results: We identified a strong positive association between the XBP1 gene signature and estrogen receptor-positive status or the HIF1alpha gene signature, as well as the predictive value of the XBP1 gene signature for survival of patients who are estrogen receptor negative, or have TNBC or HER2+. In contrast, another important UPR branch, the ATF4/CHOP pathway, lacks prognostic value in breast cancer in general. Activity of the HIF1alpha pathway is correlated with patient survival in all the subtypes evaluated.Conclusion: These findings clarify the relevance of the UPR pathways in different breast cancer subtypes and underscore the potential therapeutic importance of the IRE1alpha-XBP1 branch in breast cancer treatment.

    View details for PubMedID 29888341

  • Molecular profiling of single circulating tumor cells from lung cancer patients PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Park, S., Wong, D. J., Ooi, C. C., Kurtz, D. M., Vermesh, O., Aalipour, A., Suh, S., Pian, K. L., Chabon, J. J., Lee, S. H., Jamali, M., Say, C., Carter, J. N., Lee, L. P., Kuschner, W. G., Schwartz, E. J., Shrager, J. B., Neal, J. W., Wakelee, H. A., Diehn, M., Nair, V. S., Wang, S. X., Gambhir, S. S. 2016; 113 (52): E8379-E8386

    Abstract

    Circulating tumor cells (CTCs) are established cancer biomarkers for the "liquid biopsy" of tumors. Molecular analysis of single CTCs, which recapitulate primary and metastatic tumor biology, remains challenging because current platforms have limited throughput, are expensive, and are not easily translatable to the clinic. Here, we report a massively parallel, multigene-profiling nanoplatform to compartmentalize and analyze hundreds of single CTCs. After high-efficiency magnetic collection of CTC from blood, a single-cell nanowell array performs CTC mutation profiling using modular gene panels. Using this approach, we demonstrated multigene expression profiling of individual CTCs from non-small-cell lung cancer (NSCLC) patients with remarkable sensitivity. Thus, we report a high-throughput, multiplexed strategy for single-cell mutation profiling of individual lung cancer CTCs toward minimally invasive cancer therapy prediction and disease monitoring.

    View details for DOI 10.1073/pnas.1608461113

    View details for PubMedID 27956614

  • Reprogramming the immunological microenvironment through radiation and targeting Axl NATURE COMMUNICATIONS Aguilera, T. A., Rafat, M., Castellini, L., Shehade, H., Kariolis, M. S., Hui, A. B., Stehr, H., von Eyben, R., Jiang, D., Ellies, L. G., Koong, A. C., Diehn, M., Rankin, E. B., Graves, E. E., Giaccia, A. J. 2016; 7

    Abstract

    Increasing evidence suggests that ionizing radiation therapy (RT) in combination with checkpoint immunotherapy is highly effective in treating a subset of cancers. To better understand the limited responses to this combination we analysed the genetic, microenvironmental, and immune factors in tumours derived from a transgenic breast cancer model. We identified two tumours with similar growth characteristics but different RT responses primarily due to an antitumour immune response. The combination of RT and checkpoint immunotherapy resulted in cures in the responsive but not the unresponsive tumours. Profiling the tumours revealed that the Axl receptor tyrosine kinase is overexpressed in the unresponsive tumours, and Axl knockout resulted in slower growth and increased radiosensitivity. These changes were associated with a CD8(+) T-cell response, which was improved in combination with checkpoint immunotherapy. These results suggest a novel role for Axl in suppressing antigen presentation through MHCI, and enhancing cytokine release, which promotes a suppressive myeloid microenvironment.

    View details for DOI 10.1038/ncomms13898

    View details for Web of Science ID 000390399500001

    View details for PubMedID 28008921

    View details for PubMedCentralID PMC5196438

  • Absence of Evidence Implicating Hematopoietic Stem Cells As Common Progenitors for DLBCL Mutations Jan, M., Scherer, F., Kurtz, D. M., Newman, A. M., Stehr, H., Liu, C., Zhou, L., Glover, C., Advani, R. H., Maeda, L. S., Gupta, N. K., Levy, R., Kunder, C. A., Sanchez-Garcia, I., Diehn, M., Alizadeh, A. A. AMER SOC HEMATOLOGY. 2016
  • Development and Validation of Biopsy-Free Genotyping for Molecular Subtyping of Diffuse Large B-Cell Lymphoma 58th Annual Meeting and Exposition of the American-Society-of-Hematology Scherer, F., Kurtz, D. M., Newman, A. M., Esfahani, M. S., Craig, A., Stehr, H., Lovejoy, A. F., Chabon, J. J., Liu, C. L., Zhou, L., Glover, C., Visser, B. C., Poultsides, G., Advani, R. H., Maeda, L. S., Gupta, N. K., Levy, R., Ohgami, R. S., Davis, E. R., Gaidano, G., Kunder, C. A., Rossi, D., Westin, J. R., Diehn, M., Alizadeh, A. A. AMER SOC HEMATOLOGY. 2016
  • Noninvasive Detection of Ibrutinib Resistance in Non-Hodgkin Lymphoma Using Cell-Free DNA Scherer, F., Kurtz, D. M., Newman, A. M., Craig, A., Stehr, H., Zhou, L., Glover, C., Kohrt, H., Levy, R., Diehn, M., Alizadeh, A. A. AMER SOC HEMATOLOGY. 2016
  • Noninvasive Detection of BCL2, BCL6, and MYC Translocations in Diffuse Large B-Cell Lymphoma Kurtz, D. M., Scherer, F., Newman, A. M., Craig, A., Jin, M., Stehr, H., Chabon, J. J., Esfahani, M., Liu, C., Zhou, L., Glover, C., Visser, B. C., Poultsides, G., Advani, R. H., Maeda, L. S., Gupta, N. K., Levy, R., Ohgami, R. S., Davis, R., Kunder, C. A., Westin, J. R., Diehn, M., Alizadeh, A. A. AMER SOC HEMATOLOGY. 2016
  • A 3-D Riesz-Covariance Texture Model for Prediction of Nodule Recurrence in Lung CT IEEE TRANSACTIONS ON MEDICAL IMAGING Cirujeda, P., Cid, Y. D., Muller, H., Rubin, D., Aguilera, T. A., Loo, B. W., Diehn, M., Binefa, X., Depeursinge, A. 2016; 35 (12): 2620-2630

    Abstract

    This paper proposes a novel imaging biomarker of lung cancer relapse from 3-D texture analysis of CT images. Three-dimensional morphological nodular tissue properties are described in terms of 3-D Riesz-wavelets. The responses of the latter are aggregated within nodular regions by means of feature covariances, which leverage rich intra- and inter- variations of the feature space dimensions. When compared to the classical use of the average for feature aggregation, feature covariances preserve spatial co-variations between features. The obtained Riesz-covariance descriptors lie on a manifold governed by Riemannian geometry allowing geodesic measurements and differentiations. The latter property is incorporated both into a kernel for support vector machines (SVM) and a manifold-aware sparse regularized classifier. The effectiveness of the presented models is evaluated on a dataset of 110 patients with non-small cell lung carcinoma (NSCLC) and cancer recurrence information. Disease recurrence within a timeframe of 12 months could be predicted with an accuracy of 81.3-82.7%. The anatomical location of recurrence could be discriminated between local, regional and distant failure with an accuracy of 78.3-93.3%. The obtained results open novel research perspectives by revealing the importance of the nodular regions used to build the predictive models.

    View details for DOI 10.1109/TMI.2016.2591921

    View details for Web of Science ID 000391547700011

    View details for PubMedID 27429433

  • Corrigendum: Circulating tumour DNA profiling reveals heterogeneity of EGFR inhibitor resistance mechanisms in lung cancer patients. Nature communications Chabon, J. J., Simmons, A. D., Lovejoy, A. F., Esfahani, M. S., Newman, A. M., Haringsma, H. J., Kurtz, D. M., Stehr, H., Scherer, F., Karlovich, C. A., Harding, T. C., Durkin, K. A., Otterson, G. A., Thomas Purcell, W., Ross Camidge, D., Goldman, J. W., Sequist, L. V., Piotrowska, Z., Wakelee, H. A., Neal, J. W., Alizadeh, A. A., Diehn, M. 2016; 7: 13513-?

    View details for DOI 10.1038/ncomms13513

    View details for PubMedID 27841271

    View details for PubMedCentralID PMC5114547

  • Distinct biological subtypes and patterns of genome evolution in lymphoma revealed by circulating tumor DNA SCIENCE TRANSLATIONAL MEDICINE Scherer, F., Kurtz, D. M., Newman, A. M., Stehr, H., Craig, A. F., Esfahani, M. S., Lovejoy, A. F., Chabon, J. J., Klass, D. M., Liu, C. L., Zhou, L., Glover, C., Visser, B. C., Poultsides, G. A., Advani, R. H., Maeda, L. S., Gupta, N. K., Levy, R., Ohgami, R. S., Kunder, C. A., Diehn, M., Alizadeh, A. A. 2016; 8 (364)

    Abstract

    Patients with diffuse large B cell lymphoma (DLBCL) exhibit marked diversity in tumor behavior and outcomes, yet the identification of poor-risk groups remains challenging. In addition, the biology underlying these differences is incompletely understood. We hypothesized that characterization of mutational heterogeneity and genomic evolution using circulating tumor DNA (ctDNA) profiling could reveal molecular determinants of adverse outcomes. To address this hypothesis, we applied cancer personalized profiling by deep sequencing (CAPP-Seq) analysis to tumor biopsies and cell-free DNA samples from 92 lymphoma patients and 24 healthy subjects. At diagnosis, the amount of ctDNA was found to strongly correlate with clinical indices and was independently predictive of patient outcomes. We demonstrate that ctDNA genotyping can classify transcriptionally defined tumor subtypes, including DLBCL cell of origin, directly from plasma. By simultaneously tracking multiple somatic mutations in ctDNA, our approach outperformed immunoglobulin sequencing and radiographic imaging for the detection of minimal residual disease and facilitated noninvasive identification of emergent resistance mutations to targeted therapies. In addition, we identified distinct patterns of clonal evolution distinguishing indolent follicular lymphomas from those that transformed into DLBCL, allowing for potential noninvasive prediction of histological transformation. Collectively, our results demonstrate that ctDNA analysis reveals biological factors that underlie lymphoma clinical outcomes and could facilitate individualized therapy.

    View details for DOI 10.1126/scitranslmed.aai8545

    View details for PubMedID 27831904

  • Control of inflammation by stromal Hedgehog pathway activation restrains colitis. Proceedings of the National Academy of Sciences of the United States of America Lee, J. J., Rothenberg, M. E., Seeley, E. S., Zimdahl, B., Kawano, S., Lu, W., Shin, K., Sakata-Kato, T., Chen, J. K., Diehn, M., Clarke, M. F., Beachy, P. A. 2016

    Abstract

    Inflammation disrupts tissue architecture and function, thereby contributing to the pathogenesis of diverse diseases; the signals that promote or restrict tissue inflammation thus represent potential targets for therapeutic intervention. Here, we report that genetic or pharmacologic Hedgehog pathway inhibition intensifies colon inflammation (colitis) in mice. Conversely, genetic augmentation of Hedgehog response and systemic small-molecule Hedgehog pathway activation potently ameliorate colitis and restrain initiation and progression of colitis-induced adenocarcinoma. Within the colon, the Hedgehog protein signal does not act directly on the epithelium itself, but on underlying stromal cells to induce expression of IL-10, an immune-modulatory cytokine long known to suppress inflammatory intestinal damage. IL-10 function is required for the full protective effect of small-molecule Hedgehog pathway activation in colitis; this pharmacologic augmentation of Hedgehog pathway activity and stromal IL-10 expression are associated with increased presence of CD4(+)Foxp3(+) regulatory T cells. We thus identify stromal cells as cellular coordinators of colon inflammation and suggest their pharmacologic manipulation as a potential means to treat colitis.

    View details for PubMedID 27815529

  • Hypofractionated Intensity-Modulated Radiotherapy for Patients With Non-Small-Cell Lung Cancer. Clinical lung cancer Pollom, E. L., Qian, Y., Durkee, B. Y., von Eyben, R., Maxim, P. G., Shultz, D. B., Gensheimer, M., Diehn, M., Loo, B. W. 2016; 17 (6): 588-594

    Abstract

    Alternative treatment regimens are needed for patients with non-small cell lung cancer (NSCLC) who cannot receive definitive treatment with concurrent chemoradiotherapy, surgery, or stereotactic ablative radiotherapy (SABR).We report survival, patterns of failure and toxicity outcomes for patients with NSCLC who were not eligible for surgical resection, concurrent chemoradiotherapy, or SABR and underwent hypofractionated intensity-modulated radiotherapy (IMRT). Kaplan-Meier survival analysis was used to evaluate the progression-free and overall survival. Competing risk analysis was used to evaluate in-field, locoregional, and distant failure.A total of 42 patients treated to 52.5 to 60 Gy in 15 fractions were included. Most of the patients had metastatic or recurrent disease (64%) and a relatively large, centrally located tumor burden (74%). The median follow-up period was 13 months (interquartile range, 6-18 months). All patients received the total prescribed dose. The median survival was 15.1 months. The overall and progression-free survival rates at 1 year were 63% and 22.5%, respectively. The pattern of failure was predominantly distant, with only 2% of patients experiencing isolated in-field recurrence. The cumulative incidence of in-field failure at 6 and 12 months was 2.5% (95% confidence interval, 0.4%-15.6%) and 16.1% (95% confidence interval, 7.5%-34.7%), respectively. The risk of esophageal toxicity was associated with the esophageal mean dose, maximal point dose, and dose to the 5 cm(3) volume. The risk of pneumonitis was associated with the lung mean dose and volume receiving 18 Gy.Hypofractionated IMRT without concurrent chemotherapy provides favorable rates of local control and survival for well-selected patients with NSCLC who cannot tolerate standard definitive therapy.

    View details for DOI 10.1016/j.cllc.2016.05.024

    View details for PubMedID 27378172

  • PS01.67: Case Series of MET Exon 14 Skipping Mutation-Positive Non-Small Cell Lung Cancers and Response to Crizotinib: Topic: Medical Oncology. Journal of thoracic oncology Wang, S. X., Zhang, B. M., Wakelee, H., Diehn, M., Kunder, C. A., Neal, J. W. 2016; 11 (11S): S312-S313

    View details for DOI 10.1016/j.jtho.2016.09.102

    View details for PubMedID 27969534

  • Early-Stage Non-Small Cell Lung Cancer: Quantitative Imaging Characteristics of (18)F Fluorodeoxyglucose PET/CT Allow Prediction of Distant Metastasis. Radiology Wu, J., Aguilera, T., Shultz, D., Gudur, M., Rubin, D. L., Loo, B. W., Diehn, M., Li, R. 2016; 281 (1): 270-278

    Abstract

    Purpose To identify quantitative imaging biomarkers at fluorine 18 ((18)F) positron emission tomography (PET) for predicting distant metastasis in patients with early-stage non-small cell lung cancer (NSCLC). Materials and Methods In this institutional review board-approved HIPAA-compliant retrospective study, the pretreatment (18)F fluorodeoxyglucose PET images in 101 patients treated with stereotactic ablative radiation therapy from 2005 to 2013 were analyzed. Data for 70 patients who were treated before 2011 were used for discovery purposes, while data from the remaining 31 patients were used for independent validation. Quantitative PET imaging characteristics including statistical, histogram-related, morphologic, and texture features were analyzed, from which 35 nonredundant and robust features were further evaluated. Cox proportional hazards regression model coupled with the least absolute shrinkage and selection operator was used to predict distant metastasis. Whether histologic type provided complementary value to imaging by combining both in a single prognostic model was also assessed. Results The optimal prognostic model included two image features that allowed quantification of intratumor heterogeneity and peak standardized uptake value. In the independent validation cohort, this model showed a concordance index of 0.71, which was higher than those of the maximum standardized uptake value and tumor volume, with concordance indexes of 0.67 and 0.64, respectively. The prognostic model also allowed separation of groups with low and high risk for developing distant metastasis (hazard ratio, 4.8; P = .0498, log-rank test), which compared favorably with maximum standardized uptake value and tumor volume (hazard ratio, 1.5 and 2.0, respectively; P = .73 and 0.54, log-rank test, respectively). When combined with histologic types, the prognostic power was further improved (hazard ratio, 6.9; P = .0289, log-rank test; and concordance index, 0.80). Conclusion PET imaging characteristics associated with distant metastasis that could potentially help practitioners to tailor appropriate therapy for individual patients with early-stage NSCLC were identified. (©) RSNA, 2016 Online supplemental material is available for this article.

    View details for DOI 10.1148/radiol.2016151829

    View details for PubMedID 27046074

  • CAPP-Seq Circulating Tumor DNA Analysis for Early Detection of Tumor Progression After Definitive Radiation Therapy for Lung Cancer Chaudhuri, A. A., Lovejoy, A. F., Chabon, J. J., Newman, A., Stehr, H., Say, C., Aggarwal, S., Carter, J. N., West, R. B., Neal, J. W., Wakelee, H. A., Loo, B. W., Alizadeh, A., Diehn, M. ELSEVIER SCIENCE INC. 2016: S41–S42
  • Patterns of Failure After Hypofractionated Intensity Modulated Radiation Therapy for Patients With Non-Small Cell Lung Cancer Qian, Y., Pollom, E., Durkee, B. Y., von Eyben, R., Gensheimer, M. F., Shultz, D. B., Diehn, M., Loo, B. W. ELSEVIER SCIENCE INC. 2016: E422–E423
  • Effectiveness of Radiation Therapy for Low- to Intermediate-Grade Neuroendocrine Tumors Carter, J. N., Aggarwal, S., Radish, K., Allen, J. R., Koong, A. C., Chang, D. T., Loo, B. W., Diehn, M., Kunz, P. L., Gensheimer, M. F. ELSEVIER SCIENCE INC. 2016: E202–E203
  • Four-Dimensional Computed Tomography Pulmonary Nodule Elastometry as a Predictor of Regional Recurrence Following Stereotactic Ablative Radiation Therapy for Early-Stage Non-Small Cell Lung Cancer Shaffer, J., Negahdar, M., von Eyben, R., Diehn, M., Maxim, P. G., Loo, B. W. ELSEVIER SCIENCE INC. 2016: E460
  • Temporal Change in Quantitative Positron Emission Tomography Metrics Predicts Recurrence in Early-Stage Lung Cancer Patients Treated With Stereotactic Ablative Radiation Therapy Prionas, N. D., Aggarwal, S., Shaffer, J., von Eyben, R., Graves, E. E., Maxim, P. G., Quon, A., Gensheimer, M. F., Diehn, M., Loo, B. W. ELSEVIER SCIENCE INC. 2016: E457
  • Regional Ventilation Predicts Change in Pulmonary Function After Stereotactic Ablative Radiation Therapy of Lung Tumors Binkley, M. S., King, M., Bush, K., Shrager, J. B., Chaudhuri, A. A., Popat, R., Maxim, P. G., Guo, H. H., Diehn, M., Nair, V. S., Loo, B. W. ELSEVIER SCIENCE INC. 2016: E456–E457
  • Imaging Features Associated With Disease Progression After Stereotactic Ablative Radiation Therapy for Early-Stage Non-Small Cell Lung Cancer: A Multi-Institutional Pooled Analysis Anderson, E., Filippi, A. R., Badellino, S., Ricardi, U., von Eyben, R., Gensheimer, M. F., Diehn, M., Loo, B. W., Shultz, D. B. ELSEVIER SCIENCE INC. 2016: E485–E486
  • Role of Surveillance Imaging Versus Symptoms and Signs in Detection of Recurrence of Non-Small Cell Lung Cancer After Curative Intent Therapy Waliany, S., Shultz, D. B., Gensheimer, M. F., Loo, B. W., Diehn, M. ELSEVIER SCIENCE INC. 2016: S155
  • Vesselness-Based Deformable Registration Algorithms Can Reduce Landmark Errors in the Registration of Pulmonary Computed Tomography Images Before and After Radiation Therapy King, M., Xiong, G., Maxim, P. G., Diehn, M., Loo, B. W., Xing, L. ELSEVIER SCIENCE INC. 2016: S227
  • Intratumor Partitioning of Serial Computed Tomography and FDG Positron Emission Tomography Images Identifies High-Risk Tumor Subregions and Predicts Patterns of Failure in Non-Small Cell Lung Cancer After Radiation Therapy 58th Annual Meeting of the American-Society-for-Radiation-Oncology (ASTRO) Wu, J., Gensheimer, M. F., Dong, X., Rubin, D. L., Napel, S., Diehn, M., Loo, B. W., Li, R. ELSEVIER SCIENCE INC. 2016: S100–S100
  • Robust Intratumor Partitioning to Identify High-Risk Subregions in Lung Cancer: A Pilot Study. International journal of radiation oncology, biology, physics Wu, J., Gensheimer, M. F., Dong, X., Rubin, D. L., Napel, S., Diehn, M., Loo, B. W., Li, R. 2016; 95 (5): 1504-1512

    Abstract

    To develop an intratumor partitioning framework for identifying high-risk subregions from (18)F-fluorodeoxyglucose positron emission tomography (FDG-PET) and computed tomography (CT) imaging and to test whether tumor burden associated with the high-risk subregions is prognostic of outcomes in lung cancer.In this institutional review board-approved retrospective study, we analyzed the pretreatment FDG-PET and CT scans of 44 lung cancer patients treated with radiation therapy. A novel, intratumor partitioning method was developed, based on a 2-stage clustering process: first at the patient level, each tumor was over-segmented into many superpixels by k-means clustering of integrated PET and CT images; next, tumor subregions were identified by merging previously defined superpixels via population-level hierarchical clustering. The volume associated with each of the subregions was evaluated using Kaplan-Meier analysis regarding its prognostic capability in predicting overall survival (OS) and out-of-field progression (OFP).Three spatially distinct subregions were identified within each tumor that were highly robust to uncertainty in PET/CT co-registration. Among these, the volume of the most metabolically active and metabolically heterogeneous solid component of the tumor was predictive of OS and OFP on the entire cohort, with a concordance index or CI of 0.66-0.67. When restricting the analysis to patients with stage III disease (n=32), the same subregion achieved an even higher CI of 0.75 (hazard ratio 3.93, log-rank P=.002) for predicting OS, and a CI of 0.76 (hazard ratio 4.84, log-rank P=.002) for predicting OFP. In comparison, conventional imaging markers, including tumor volume, maximum standardized uptake value, and metabolic tumor volume using threshold of 50% standardized uptake value maximum, were not predictive of OS or OFP, with CI mostly below 0.60 (log-rank P>.05).We propose a robust intratumor partitioning method to identify clinically relevant, high-risk subregions in lung cancer. We envision that this approach will be applicable to identifying useful imaging biomarkers in many cancer types.

    View details for DOI 10.1016/j.ijrobp.2016.03.018

    View details for PubMedID 27212196

  • The impact of audiovisual biofeedback on 4D functional and anatomic imaging: Results of a lung cancer pilot study. Radiotherapy and oncology Yang, J., Yamamoto, T., Pollock, S., Berger, J., Diehn, M., Graves, E. E., Loo, B. W., Keall, P. J. 2016; 120 (2): 267-272

    Abstract

    The impact of audiovisual (AV) biofeedback on four dimensional (4D) positron emission tomography (PET) and 4D computed tomography (CT) image quality was investigated in a prospective clinical trial (NCT01172041).4D-PET and 4D-CT images of ten lung cancer patients were acquired with AV biofeedback (AV) and free breathing (FB). The 4D-PET images were analyzed for motion artifacts by comparing 4D to 3D PET for gross tumor volumes (GTVPET) and maximum standardized uptake values (SUVmax). The 4D-CT images were analyzed for artifacts by comparing normalized cross correlation-based scores (NCCS) and quantifying a visual assessment score (VAS). A Wilcoxon signed-ranks test was used for statistical testing.The impact of AV biofeedback varied widely. Overall, the 3D to 4D decrease of GTVPET was 1.2±1.3cm(3) with AV and 0.6±1.8cm(3) for FB. The 4D-PET increase of SUVmax was 1.3±0.9 with AV and 1.3±0.8 for FB. The 4D-CT NCCS were 0.65±0.27 with AV and 0.60±0.32 for FB (p=0.08). The 4D-CT VAS was 0.0±2.7.This study demonstrated a high patient dependence on the use of AV biofeedback to reduce motion artifacts in 4D imaging. None of the hypotheses tested were statistically significant. Future development of AV biofeedback will focus on optimizing the human-computer interface and including patient training sessions for improved comprehension and compliance.

    View details for DOI 10.1016/j.radonc.2016.05.016

    View details for PubMedID 27256597

  • Identification and genetic manipulation of human and mouse oesophageal stem cells. Gut Jeong, Y., Rhee, H., Martin, S., Klass, D., Lin, Y., Nguyen, L. X., Feng, W., Diehn, M. 2016; 65 (7): 1077-1086

    Abstract

    Human oesophageal stem cell research is hampered by the lack of an optimal assay system to study self-renewal and differentiation. We aimed to identify and characterise human and mouse oesophageal stem/progenitor cells by establishing 3-dimensional organotypic sphere culture systems for both species.Primary oesophageal epithelial cells were freshly isolated and fluorescence-activated cell sorting (FACS)-sorted from human and mouse oesophagus and 3-dimensional organotypic sphere culture systems were developed. The self-renewing potential and differentiation status of novel subpopulations were assessed by sphere-forming ability, cell cycle analysis, immunostaining, qPCR and RNA-Seq.Primary human and mouse oesophageal epithelial cells clonally formed esophagospheres consisting of stratified squamous epithelium. Sphere-forming cells could self-renew and form esophagospheres for over 43 passages in vitro and generated stratified squamous epithelium when transplanted under the kidney capsule of immunodeficient mice. Sphere-forming cells were 10-15-fold enriched among human CD49f(hi)CD24(low) cells and murine CD49f(+)CD24(low)CD71(low) cells compared with the most differentiated cells. Genetic elimination of p63 in mouse and human oesophageal cells dramatically decreased esophagosphere formation and basal gene expression while increasing suprabasal gene expression.We developed clonogenic and organotypic culture systems for the quantitative analyses of human and mouse oesophageal stem/progenitor cells and identified novel cell surface marker combinations that enrich for these cells. Using this system, we demonstrate that elimination of p63 inhibits self-renewal of human oesophageal stem/progenitor cells. We anticipate that these esophagosphere culture systems will facilitate studies of oesophageal stem cell biology and may prove useful for ex vivo expansion of human oesophageal stem cells.

    View details for DOI 10.1136/gutjnl-2014-308491

    View details for PubMedID 25897018

  • Identification and genetic manipulation of human and mouse oesophageal stem cells GUT Jeong, Y., Rhee, H., Martin, S., Klass, D., Lin, Y., Le Xuan Truong Nguyen, L. X., Feng, W., Diehn, M. 2016; 65 (7): 1077-1086

    Abstract

    Human oesophageal stem cell research is hampered by the lack of an optimal assay system to study self-renewal and differentiation. We aimed to identify and characterise human and mouse oesophageal stem/progenitor cells by establishing 3-dimensional organotypic sphere culture systems for both species.Primary oesophageal epithelial cells were freshly isolated and fluorescence-activated cell sorting (FACS)-sorted from human and mouse oesophagus and 3-dimensional organotypic sphere culture systems were developed. The self-renewing potential and differentiation status of novel subpopulations were assessed by sphere-forming ability, cell cycle analysis, immunostaining, qPCR and RNA-Seq.Primary human and mouse oesophageal epithelial cells clonally formed esophagospheres consisting of stratified squamous epithelium. Sphere-forming cells could self-renew and form esophagospheres for over 43 passages in vitro and generated stratified squamous epithelium when transplanted under the kidney capsule of immunodeficient mice. Sphere-forming cells were 10-15-fold enriched among human CD49f(hi)CD24(low) cells and murine CD49f(+)CD24(low)CD71(low) cells compared with the most differentiated cells. Genetic elimination of p63 in mouse and human oesophageal cells dramatically decreased esophagosphere formation and basal gene expression while increasing suprabasal gene expression.We developed clonogenic and organotypic culture systems for the quantitative analyses of human and mouse oesophageal stem/progenitor cells and identified novel cell surface marker combinations that enrich for these cells. Using this system, we demonstrate that elimination of p63 inhibits self-renewal of human oesophageal stem/progenitor cells. We anticipate that these esophagosphere culture systems will facilitate studies of oesophageal stem cell biology and may prove useful for ex vivo expansion of human oesophageal stem cells.

    View details for DOI 10.1136/gutjnl-2014-308491

    View details for Web of Science ID 000377170200005

  • Pre-treatment non-target lung FDG-PET uptake predicts symptomatic radiation pneumonitis following Stereotactic Ablative Radiotherapy (SABR). Radiotherapy and oncology Chaudhuri, A. A., Binkley, M. S., Rigdon, J., Carter, J. N., Aggarwal, S., Dudley, S. A., Qian, Y., Kumar, K. A., Hara, W. Y., Gensheimer, M., Nair, V. S., Maxim, P. G., Shultz, D. B., Bush, K., Trakul, N., Le, Q., Diehn, M., Loo, B. W., Guo, H. H. 2016; 119 (3): 454-460

    Abstract

    To determine if pre-treatment non-target lung FDG-PET uptake predicts for symptomatic radiation pneumonitis (RP) following lung stereotactic ablative radiotherapy (SABR).We reviewed a 258 patient database from our institution to identify 28 patients who experienced symptomatic (grade ⩾ 2) RP after SABR, and compared them to 57 controls who did not develop symptomatic RP. We compared clinical, dosimetric and functional imaging characteristics between the 2 cohorts including pre-treatment non-target lung FDG-PET uptake.Median follow-up time was 26.9 months. Patients who experienced symptomatic RP had significantly higher non-target lung FDG-PET uptake as measured by mean SUV (p < 0.0001) than controls. ROC analysis for symptomatic RP revealed area under the curve (AUC) of 0.74, with sensitivity 82.1% and specificity 57.9% with cutoff mean non-target lung SUV > 0.56. Predictive value increased (AUC of 0.82) when mean non-target lung SUV was combined with mean lung dose (MLD). We developed a 0-2 point model using these 2 variables, 1 point each for SUV > 0.56 or MLD > 5.88 Gy equivalent dose in 2 Gy per fraction (EQD2), predictive for symptomatic RP in our cohort with hazard ratio 10.01 for score 2 versus 0 (p < 0.001).Patients with elevated pre-SABR non-target lung FDG-PET uptake are at increased risk of symptomatic RP after lung SABR. Our predictive model suggests patients with mean non-target lung SUV > 0.56 and MLD > 5.88 Gy EQD2 are at highest risk. Our predictive model should be validated in an external cohort before clinical implementation.

    View details for DOI 10.1016/j.radonc.2016.05.007

    View details for PubMedID 27267049

  • SU-D-207B-05: Robust Intra-Tumor Partitioning to Identify High-Risk Subregions for Prognosis in Lung Cancer. Medical physics Wu, J., Gensheimer, M., Dong, X., Rubin, D., Napel, S., Diehn, M., Loo, B., Li, R. 2016; 43 (6): 3349-?

    View details for DOI 10.1118/1.4955673

    View details for PubMedID 28046308

  • Noninvasive molecular subtyping and risk stratification of DLBCL. Scherer, F., Kurtz, D., Newman, A. M., Stehr, H., Craig, A. M., Esfahani, M. S., Lovejoy, A. F., Chabon, J. J., Klass, D. M., Liu, C., Zhou, L., Glover, C., Advani, R. H., Maeda, L., Gupta, N. K., Levy, R., Ohgami, R. S., Kunder, C., Diehn, M., Alizadeh, A. A. AMER SOC CLINICAL ONCOLOGY. 2016
  • Randomized phase II study of preoperative chemoradiotherapy (CRT) plus /-Panitumumab (P) followed by consolidation chemotherapy (C) in potentially operable locally advanced (stage Ma, N2+) non -small cell lung cancer (LANSCLC): Nrg oncology/RTOG 0839. Edelman, M. J., Hu, C., Le, Q., Donington, J., D'Souza, W. D., Dicker, A., Loo, B. W., Gore, E., Videtic, G. M., Evans, N. R., Leach, J., Diehn, M., Feigenberg, S. J., Chen, Y., Bradley, J. D. AMER SOC CLINICAL ONCOLOGY. 2016
  • Integrated digital error suppression for noninvasive detection of circulating tumor DNA in NSCLC. Newman, A. M., Lovejoy, A. F., Klass, D. M., Kurtz, D., Chabon, J. J., Scherer, F., Stehr, H., Liu, C., Bratman, S., Say, C., Zhou, L., Carter, J. N., West, R. B., Sledge, G. W., Shrager, J. B., Loo, B. W., Neal, J. W., Wakelee, H. A., Alizadeh, A. A., Diehn, M. AMER SOC CLINICAL ONCOLOGY. 2016
  • Inter- and intra-patient heterogeneity of resistance mechanisms to the mutant EGFR selective inhibitor rociletinib. Chabon, J., Simmons, A., Newman, A. M., Lovejoy, A. F., Esfahani, M. S., Haringsma, H., Kurtz, D., Stehr, H., Scherer, F., Durkin, K. A., Otterson, G., Purcell, W. T., Camidge, D., Goldman, J., Sequist, L. V., Piotrowska, Z., Wakelee, H. A., Neal, J. W., Alizadeh, A. A., Diehn, M. AMER SOC CLINICAL ONCOLOGY. 2016
  • Integrated digital error suppression for improved detection of circulating tumor DNA NATURE BIOTECHNOLOGY Newman, A. M., Lovejoy, A. F., Klass, D. M., Kurtz, D. M., Chabon, J. J., Scherer, F., Stehr, H., Liu, C. L., Bratman, S. V., Say, C., Zhou, L., Carter, J. N., West, R. B., Sledge, G. W., Shrager, J. B., Loo, B. W., Neal, J. W., Wakelee, H. A., Diehn, M., Alizadeh, A. A. 2016; 34 (5): 547-555

    Abstract

    High-throughput sequencing of circulating tumor DNA (ctDNA) promises to facilitate personalized cancer therapy. However, low quantities of cell-free DNA (cfDNA) in the blood and sequencing artifacts currently limit analytical sensitivity. To overcome these limitations, we introduce an approach for integrated digital error suppression (iDES). Our method combines in silico elimination of highly stereotypical background artifacts with a molecular barcoding strategy for the efficient recovery of cfDNA molecules. Individually, these two methods each improve the sensitivity of cancer personalized profiling by deep sequencing (CAPP-Seq) by about threefold, and synergize when combined to yield ∼15-fold improvements. As a result, iDES-enhanced CAPP-Seq facilitates noninvasive variant detection across hundreds of kilobases. Applied to non-small cell lung cancer (NSCLC) patients, our method enabled biopsy-free profiling of EGFR kinase domain mutations with 92% sensitivity and >99.99% specificity at the variant level, and with 90% sensitivity and 96% specificity at the patient level. In addition, our approach allowed monitoring of NSCLC ctDNA down to 4 in 10(5) cfDNA molecules. We anticipate that iDES will aid the noninvasive genotyping and detection of ctDNA in research and clinical settings.

    View details for DOI 10.1038/nbt.3520

    View details for PubMedID 27018799

  • Time course and predictive factors for lung volume reduction following stereotactic ablative radiotherapy (SABR) of lung tumors RADIATION ONCOLOGY Binkley, M. S., Shrager, J. B., Chaudhuri, A., Popat, R., Maxim, P. G., Shultz, D. B., Diehn, M., Loo, B. W. 2016; 11

    Abstract

    Stereotactic ablative volume reduction (SAVR) is a potential alternative to lung-volume reduction surgery in patients with severe emphysema and excessive surgical risk. Having previously observed a dose-volume response for localized lobar volume reduction after stereotactic ablative radiotherapy (SABR) for lung tumors, we investigated the time course and factors associated with volume reduction.We retrospectively identified 70 eligible patients receiving lung tumor SABR during 2007-2013. We correlated lobar volume reduction (relative to total, bilateral lung volume [TLV]) with volume receiving high biologically effective doses (VXXBED3) and other pre-treatment factors in all patients, and measured the time course of volume changes on 3-month interval CT scans in patients with large V60BED3 (n = 21, V60BED3 ≥4.1 % TLV).Median CT follow-up was 15 months. Median volume reduction of treated lobes was 4.5 % of TLV (range 0.01-13.0 %), or ~9 % of ipsilateral lung volume (ILV); median expansion of non-target adjacent lobes was 2.2 % TLV (-4.6-9.9 %; ~4 % ILV). Treated lobe volume reduction was significantly greater with larger VXXBED3 (XX = 20-100 Gy, R (2)  = 0.52-0.55, p < 0.0001) and smaller with lower pre-treatment FEV1% (R (2)  = 0.11, p = 0.005) in a multivariable linear model. Maximum volume reduction was reached by ~12 months and persisted.We identified a multivariable model for lobar volume reduction after SABR incorporating dose-volume and pre-treatment FEV1% and characterized its time course.

    View details for DOI 10.1186/s13014-016-0616-8

    View details for Web of Science ID 000372776500001

    View details for PubMedCentralID PMC4791793

  • Dosimetric Factors and Toxicity in Highly Conformal Thoracic Reirradiation. International journal of radiation oncology, biology, physics Binkley, M. S., Hiniker, S. M., Chaudhuri, A., Maxim, P. G., Diehn, M., Loo, B. W., Shultz, D. B. 2016; 94 (4): 808-815

    Abstract

    We determined cumulative dose to critical structures, rates of toxicity, and outcomes following thoracic reirradiation.We retrospectively reviewed our institutional database for patients treated between 2008 and 2014, who received thoracic reirradiation with overlap of 25% prescribed isodose lines. Patients received courses of hyperfractionated (n=5), hypofractionated (n=5), conventionally fractionated (n=21), or stereotactic ablative radiation therapy (n=51). Doses to critical structures were converted to biologically effective dose, expressed as 2 Gy per fraction equivalent dose (EQD2; α/β = 2 for spinal cord; α/β = 3 for other critical structures).We identified 82 courses (44 for retreatment) in 38 patients reirradiated at a median 16 months (range: 1-71 months) following initial RT. Median follow-up was 17 months (range: 3-57 months). Twelve- and 24-month overall survival rates were 79.6% and 57.3%, respectively. Eighteen patients received reirradiation for locoregionally recurrent non-small cell lung cancer with 12-month rates of local failure and regional recurrence and distant metastases rates of 13.5%, 8.1%, and 15.6%, respectively. Critical structures receiving ≥75 Gy EQD2 included spinal cord (1 cm(3); n=1), esophagus (1 cm(3); n=10), trachea (1 cm(3); n=11), heart (1 cm(3); n=9), aorta (1 cm(3); n=16), superior vena cava (1 cm(3); n=12), brachial plexus (0.2 cm(3); n=2), vagus nerve (0.2 cm(3); n=7), sympathetic trunk (0.2 cm(3); n=4), chest wall (30 cm(3); n=12), and proximal bronchial tree (1 cm(3); n=17). Cumulative dose-volume (D cm(3)) toxicity following reirradiation data included esophagitis grade ≥2 (n=3, D1 cm(3) range: 41.0-100.6 Gy), chest wall grade ≥2 (n=4; D30 cm(3) range: 35.0-117.2 Gy), lung grade 2 (n=7; V20combined-lung range: 4.7%-21.7%), vocal cord paralysis (n=2; vagus nerve D0.2 cm(3) range: 207.5-302.2 Gy), brachial plexopathy (n=1; D0.2 cm(3) = 242.5 Gy), and Horner's syndrome (n=1; sympathetic trunk D0.2 cm(3) = 130.8 Gy). No grade ≥4 toxicity was observed.Overlapping courses of reirradiation can be safely delivered with acceptable toxicity. Some toxicities occurred acutely at doses considered safe for a single course of therapy (esophagus). We observed rib fracture, brachial plexopathy, and Horner's syndrome for patients receiving high cumulative doses to corresponding critical structures.

    View details for DOI 10.1016/j.ijrobp.2015.12.007

    View details for PubMedID 26831903

  • Long-Term Survival of a Patient With Non-Small-Cell Lung Cancer Harboring a V600E Mutation in the BRAF Oncogene. Clinical lung cancer Myall, N. J., Neal, J. W., Cho-Phan, C. D., Zhou, L. Y., Stehr, H., Zhou, L., Diehn, M., Wakelee, H. A. 2016; 17 (2): e17-21

    View details for DOI 10.1016/j.cllc.2015.12.001

    View details for PubMedID 26776917

  • Circulating tumor DNA analysis for liquid biopsies: Current status and future opportunities Diehn, M. AMER ASSOC CANCER RESEARCH. 2016
  • Deep sequencing of circulating tumor DNA for personalized lung cancer detection and radiotherapy response monitoring Diehn, M. ELSEVIER SCIENCE INC. 2016: S3
  • Time course and predictive factors for lung volume reduction following stereotactic ablative radiotherapy (SABR) of lung tumors. Radiation oncology Binkley, M. S., Shrager, J. B., Chaudhuri, A., Popat, R., Maxim, P. G., Shultz, D. B., Diehn, M., Loo, B. W. 2016; 11 (1): 40-?

    Abstract

    Stereotactic ablative volume reduction (SAVR) is a potential alternative to lung-volume reduction surgery in patients with severe emphysema and excessive surgical risk. Having previously observed a dose-volume response for localized lobar volume reduction after stereotactic ablative radiotherapy (SABR) for lung tumors, we investigated the time course and factors associated with volume reduction.We retrospectively identified 70 eligible patients receiving lung tumor SABR during 2007-2013. We correlated lobar volume reduction (relative to total, bilateral lung volume [TLV]) with volume receiving high biologically effective doses (VXXBED3) and other pre-treatment factors in all patients, and measured the time course of volume changes on 3-month interval CT scans in patients with large V60BED3 (n = 21, V60BED3 ≥4.1 % TLV).Median CT follow-up was 15 months. Median volume reduction of treated lobes was 4.5 % of TLV (range 0.01-13.0 %), or ~9 % of ipsilateral lung volume (ILV); median expansion of non-target adjacent lobes was 2.2 % TLV (-4.6-9.9 %; ~4 % ILV). Treated lobe volume reduction was significantly greater with larger VXXBED3 (XX = 20-100 Gy, R (2)  = 0.52-0.55, p < 0.0001) and smaller with lower pre-treatment FEV1% (R (2)  = 0.11, p = 0.005) in a multivariable linear model. Maximum volume reduction was reached by ~12 months and persisted.We identified a multivariable model for lobar volume reduction after SABR incorporating dose-volume and pre-treatment FEV1% and characterized its time course.

    View details for DOI 10.1186/s13014-016-0616-8

    View details for PubMedID 26975700

  • Noninvasive Cancer Classification Using Diverse Genomic Features in Circulating Tumor DNA Esfahani, M., Newman, A. M., Scherer, F., Tibshirani, R., Diehn, M., Alizadeh, A. A., ACM ASSOC COMPUTING MACHINERY. 2016: 516
  • Noninvasive Genotyping and Assessment of Treatment Response in Diffuse Large B Cell Lymphoma Scherer, F., Kurtz, D. M., Newman, A. M., Stehr, H., Liu, C., Zhou, L., Craig, A. M., Chabon, J. J., Lovejoy, A. F., Klass, D. M., Glover, C., Ohgami, R. S., Kunder, C. A., Visser, B. C., Poultsides, G., Levy, R., Diehn, M., Alizadeh, A. A. AMER SOC HEMATOLOGY. 2015
  • Dynamic Noninvasive Genomic Monitoring for Outcome Prediction in Diffuse Large B-Cell Lymphoma Kurtz, D. M., Scherer, F., Newman, A. M., Lovejoy, A. F., Klass, D. M., Chabon, J. J., Gambhir, S., Diehn, M., Alizadeh, A. A. AMER SOC HEMATOLOGY. 2015
  • The prognostic landscape of genes and infiltrating immune cells across human cancers Gentles, A. J., Newman, A. M., Liu, C., Bratman, S. V., Feng, W., Kim, D., Nair, V. S., Yue, X., Khuong, A., Hoang, C. D., Diehn, M., West, R. B., Plevritis, S. K., Alizadeh, A. A. AMER ASSOC CANCER RESEARCH. 2015
  • Anatomic optimization of lung tumor stereotactic ablative radiation therapy. Practical radiation oncology Yu, A. S., von Eyben, R., Yamamoto, T., Diehn, M., Shultz, D. B., Loo, B. W., Maxim, P. G. 2015; 5 (6): e607-13

    Abstract

    The purpose of this study was to demonstrate that anatomic optimization through selection of the degree of breath hold that yields the largest separation between the target and nearby organ at risk could result in dosimetrically superior treatment plans.Thirty patients with 41 plans were included in this planned secondary analysis of a prospective trial. Fifteen plans were created for treatment with use of natural end exhale (NEE), and 26 plans used deep inspiration breath hold (DIBH). To evaluate whether the original plan was dosimetrically optimal, we replanned treatment using the opposite respiratory state with the same beam configuration as the original plan. A treatment plan was deemed superior if it met protocol constraints when the other did not. If both plans met or violated the constraints, the plans were deemed equivalent.Of the 26 plans originally planned with DIBH and replanned with NEE, 3 plans were dosimetrically superior with NEE, 1 plan was dosimetrically superior with DIBH, and 22 plans were dosimetrically equivalent. Of the 15 plans originally planned with NEE, 4 plans were dosimetrically superior with NEE, 2 plans were dosimetrically superior with DIBH, and 9 plans were dosimetrically equivalent.For 10 of 41 plans, planning with 1 respiratory state was superior. To obtain uniformly optimal plans, individual anatomic optimization would be needed.

    View details for DOI 10.1016/j.prro.2015.05.008

    View details for PubMedID 26231596

  • Analysis of Circulating Tumor DNA in Esophageal Carcinoma Patients Treated With Chemoradiation Therapy Klass, D., Newman, A., Lovejoy, A. F., Zhou, L., Stehr, H., Xu, T., He, J., Komaki, R. U., Liao, Z., Maru, D., Alizadeh, A., Lin, S. H., Diehn, M. ELSEVIER SCIENCE INC. 2015: S104–S105
  • A Phase I/II Dose-Escalation Trial of 3-Fraction Stereotactic Radiosurgery (SRS) for Large Resection Cavities of Brain Metastases Soltys, S. G., Seiger, K., Modlin, L. A., Gibbs, I. C., Hara, W., Kidd, E. A., Hancock, S. L., Diehn, M., Chang, S. D., Adler, J. R., Harsh, G. R., Li, G., Choi, C. H. ELSEVIER SCIENCE INC. 2015: S38
  • The VarScan2's SNVs-Near-Indel Filter: Is It Necessary? Suarez, C. J., Stehr, H., Fung, E., Kunder, C. A., Ewalt, M. D., Lal, A., Alizadeh, A., Diehn, M., Schrijver, I., Zehnder, J. ELSEVIER SCIENCE INC. 2015: 801
  • Deep sequencing of circulating tumor DNA for personalized cancer detection and monitoring Diehn, M. OXFORD UNIV PRESS. 2015: 3
  • Preradiation Therapy Metabolic Tumor Growth Rate Predicts Survival and Progression in Patients With Non-Small Cell Lung Cancer Wang, A., Diehn, M., Loo, B. W., von Eyben, R., Graves, E. E., Shultz, D. B., Bazan, J. G. ELSEVIER SCIENCE INC. 2015: E405
  • Imaging Based Parameters Associated With Disease Progression of Early-Stage NSCLC Treated With Surgical Resection Wang, A., von Eyben, R., Loo, B. W., Diehn, M., Shrager, J. B., Maxim, P. G., Guo, H. H., Burt, B., Shultz, D. B. ELSEVIER SCIENCE INC. 2015: E414
  • Time Course and Predictive Factors for Lung Volume Reduction Following Stereotactic Ablative Radiation Therapy (SABR) of Lung Tumors Binkley, M. S., Shrager, J. B., Chaudhuri, A., Popat, R., Maxim, P. G., Shultz, D. B., Diehn, M., Loo, B. W. ELSEVIER SCIENCE INC. 2015: E424
  • Acceptable Toxicity Is Observed Following Retreatment of Thoracic Malignancies: Dose Volume Toxicity Data for Repeat Radiation Therapy Binkley, M. S., Hiniker, S. M., Maxim, P. G., Diehn, M., Loo, B. W., Shultz, D. B. ELSEVIER SCIENCE INC. 2015: E429
  • Regional Failure After Stereotactic Ablative Radiation Therapy for Early-Stage Lung Cancer Say, C., Diehn, M., Loo, B. W., Shultz, D. B. ELSEVIER SCIENCE INC. 2015: E437
  • Pretreatment FDG Uptake of Non-Target Lung Tissue is Significantly Associated With Radiation Pneumonitis Following Stereotactic Ablative Radiation Therapy (SABR) Chaudhuri, A., Binkley, M. S., Carter, J. N., Aggarwal, S., Maxim, P. G., Shultz, D. B., Diehn, M., Guo, H. H., Loo, B. W. ELSEVIER SCIENCE INC. 2015: S150–S151
  • Outcomes of Modestly Hypofractionated Radiation for Lung Tumors: Pre- and Mid-Treatment Positron Emission Tomography-Computed Tomography Metrics as Prognostic Factors. Clinical lung cancer Harris, J. P., Chang-Halpenny, C. N., Maxim, P. G., Quon, A., Graves, E. E., Diehn, M., Loo, B. W. 2015; 16 (6): 475-485

    Abstract

    Modestly hypofractionated radiation therapy (HypoRT; 60-66 Gy in 3-Gy fractions) allows patients with locally advanced thoracic tumors and poor performance status to complete treatment within a shorter period without concurrent chemotherapy. We evaluated the outcomes and imaging prognostic factors of HypoRT.We retrospectively reviewed the data from all patients with primary and metastatic intrathoracic tumors treated with HypoRT from 2006 to 2012. We analyzed the survival and toxicity outcomes, including overall survival (OS), progression-free survival (PFS), local recurrence (LR), and distant metastasis. We also evaluated the following tumor metrics in an exploratory analysis: gross tumor volume (GTV), maximum standardized uptake value (SUVMax), and metabolic tumor volume using a threshold of ≥ 50% of the SUVMax (MTV50%) or the maximum gradient of fluorine-18 fluorodeoxyglucose uptake (MTVEdge). We assessed the association of these metrics and their changes from before to mid-RT using positron emission tomography-computed tomography (PET-CT) with OS and PFS.We identified 29 patients, all with pre-RT and 20 with mid-RT PET-CT scans. The median follow-up period was 15 months. The 2-year overall and non-small-cell lung cancer-only rate for OS, PFS, and LR, was 59% and 59%, 52% and 41%, and 27% and 32%, respectively. No grade ≥ 3 toxicities developed. The median decrease in GTV, SUVMax, and MTVEdge was 11%, 24%, and 18%, respectively. Inferior OS was associated with a larger pre-RT MTVEdge (P = .005) and pre-RT MTV50% (P = .007). Inferior PFS was associated with a larger mid-RT SUVMax (P = .003).These findings add to the growing body of data demonstrating promising outcomes and limited toxicity with HypoRT. The pre- and mid-RT PET-CT metrics could be useful for prognostic stratification in future clinical trials.

    View details for DOI 10.1016/j.cllc.2015.01.007

    View details for PubMedID 25770888

  • Predicting Radiotherapy Responses and Treatment Outcomes Through Analysis of Circulating Tumor DNA. Seminars in radiation oncology Chaudhuri, A. A., Binkley, M. S., Osmundson, E. C., Alizadeh, A. A., Diehn, M. 2015; 25 (4): 305-312

    Abstract

    Tumors continually shed DNA into the blood where it can be detected as circulating tumor DNA (ctDNA). Although this phenomenon has been recognized for decades, techniques that are sensitive and specific enough to robustly detect ctDNA have only become available recently. Quantification of ctDNA represents a new approach for cancer detection and disease burden quantification that has the potential to revolutionize response assessment and personalized treatment in radiation oncology. Analysis of ctDNA has many potential applications, including detection of minimal residual disease following radiotherapy, noninvasive tumor genotyping, and early detection of tumor recurrence. Ultimately, ctDNA-based assays could lead to personalization of therapy based on identification of somatic alterations present in tumors and changes in ctDNA concentrations before and after treatment. In this review, we discuss methods of ctDNA detection and clinical applications of ctDNA-based biomarkers in radiation oncology, with a focus on recently developed techniques that use next-generation sequencing for ctDNA quantification.

    View details for DOI 10.1016/j.semradonc.2015.05.001

    View details for PubMedID 26384278

    View details for PubMedCentralID PMC4575502

  • Integrating Tumor and Stromal Gene Expression Signatures With Clinical Indices for Survival Stratification of Early-Stage Non-Small Cell Lung Cancer. Journal of the National Cancer Institute Gentles, A. J., Bratman, S. V., Lee, L. J., Harris, J. P., Feng, W., Nair, R. V., Shultz, D. B., Nair, V. S., Hoang, C. D., West, R. B., Plevritis, S. K., Alizadeh, A. A., Diehn, M. 2015; 107 (10)

    Abstract

    Accurate survival stratification in early-stage non-small cell lung cancer (NSCLC) could inform the use of adjuvant therapy. We developed a clinically implementable mortality risk score incorporating distinct tumor microenvironmental gene expression signatures and clinical variables.Gene expression profiles from 1106 nonsquamous NSCLCs were used for generation and internal validation of a nine-gene molecular prognostic index (MPI). A quantitative polymerase chain reaction (qPCR) assay was developed and validated on an independent cohort of formalin-fixed paraffin-embedded (FFPE) tissues (n = 98). A prognostic score using clinical variables was generated using Surveillance, Epidemiology, and End Results data and combined with the MPI. All statistical tests for survival were two-sided.The MPI stratified stage I patients into prognostic categories in three microarray and one FFPE qPCR validation cohorts (HR = 2.99, 95% CI = 1.55 to 5.76, P < .001 in stage IA patients of the largest microarray validation cohort; HR = 3.95, 95% CI = 1.24 to 12.64, P = .01 in stage IA of the qPCR cohort). Prognostic genes were expressed in distinct tumor cell subpopulations, and genes implicated in proliferation and stem cells portended poor outcomes, while genes involved in normal lung differentiation and immune infiltration were associated with superior survival. Integrating the MPI with clinical variables conferred greatest prognostic power (HR = 3.43, 95% CI = 2.18 to 5.39, P < .001 in stage I patients of the largest microarray cohort; HR = 3.99, 95% CI = 1.67 to 9.56, P < .001 in stage I patients of the qPCR cohort). Finally, the MPI was prognostic irrespective of somatic alterations in EGFR, KRAS, TP53, and ALK.The MPI incorporates genes expressed in the tumor and its microenvironment and can be implemented clinically using qPCR assays on FFPE tissues. A composite model integrating the MPI with clinical variables provides the most accurate risk stratification.

    View details for DOI 10.1093/jnci/djv211

    View details for PubMedID 26286589

  • Integrating Tumor and Stromal Gene Expression Signatures With Clinical Indices for Survival Stratification of Early-Stage Non-Small Cell Lung Cancer. Journal of the National Cancer Institute Gentles, A. J., Bratman, S. V., Lee, L. J., Harris, J. P., Feng, W., Nair, R. V., Shultz, D. B., Nair, V. S., Hoang, C. D., West, R. B., Plevritis, S. K., Alizadeh, A. A., Diehn, M. 2015; 107 (10)

    Abstract

    Accurate survival stratification in early-stage non-small cell lung cancer (NSCLC) could inform the use of adjuvant therapy. We developed a clinically implementable mortality risk score incorporating distinct tumor microenvironmental gene expression signatures and clinical variables.Gene expression profiles from 1106 nonsquamous NSCLCs were used for generation and internal validation of a nine-gene molecular prognostic index (MPI). A quantitative polymerase chain reaction (qPCR) assay was developed and validated on an independent cohort of formalin-fixed paraffin-embedded (FFPE) tissues (n = 98). A prognostic score using clinical variables was generated using Surveillance, Epidemiology, and End Results data and combined with the MPI. All statistical tests for survival were two-sided.The MPI stratified stage I patients into prognostic categories in three microarray and one FFPE qPCR validation cohorts (HR = 2.99, 95% CI = 1.55 to 5.76, P < .001 in stage IA patients of the largest microarray validation cohort; HR = 3.95, 95% CI = 1.24 to 12.64, P = .01 in stage IA of the qPCR cohort). Prognostic genes were expressed in distinct tumor cell subpopulations, and genes implicated in proliferation and stem cells portended poor outcomes, while genes involved in normal lung differentiation and immune infiltration were associated with superior survival. Integrating the MPI with clinical variables conferred greatest prognostic power (HR = 3.43, 95% CI = 2.18 to 5.39, P < .001 in stage I patients of the largest microarray cohort; HR = 3.99, 95% CI = 1.67 to 9.56, P < .001 in stage I patients of the qPCR cohort). Finally, the MPI was prognostic irrespective of somatic alterations in EGFR, KRAS, TP53, and ALK.The MPI incorporates genes expressed in the tumor and its microenvironment and can be implemented clinically using qPCR assays on FFPE tissues. A composite model integrating the MPI with clinical variables provides the most accurate risk stratification.

    View details for DOI 10.1093/jnci/djv211

    View details for PubMedID 26286589

  • Precision Hypofractionated Radiation Therapy in Poor Performing Patients With Non-Small Cell Lung Cancer: Phase 1 Dose Escalation Trial INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS Westover, K. D., Loo, B. W., Gerber, D. E., Iyengar, P., Choy, H., Diehn, M., Hughes, R., Schiller, J., Dowell, J., Wardak, Z., Sher, D., Christie, A., Xie, X., Corona, I., Sharma, A., Wadsworth, M. E., Timmerman, R. 2015; 93 (1): 72-81

    Abstract

    Treatment regimens for locally advanced non-small cell lung cancer (NSCLC) give suboptimal clinical outcomes. Technological advancements such as radiation therapy, the backbone of most treatment regimens, may enable more potent and effective therapies. The objective of this study was to escalate radiation therapy to a tumoricidal hypofractionated dose without exceeding the maximally tolerated dose (MTD) in patients with locally advanced NSCLC.Patients with stage II to IV or recurrent NSCLC and Eastern Cooperative Oncology Group performance status of 2 or greater and not candidates for surgical resection, stereotactic radiation, or concurrent chemoradiation were eligible. Highly conformal radiation therapy was given to treat intrathoracic disease in 15 fractions to a total of 50, 55, or 60 Gy.Fifty-five patients were enrolled: 15 at the 50-Gy, 21 at the 55-Gy, and 19 at the 60-Gy dose levels. A 90-day follow-up was completed in each group without exceeding the MTD. With a median follow-up of 12.5 months, there were 93 grade ≥3 adverse events (AEs), including 39 deaths, although most AEs were considered related to factors other than radiation therapy. One patient from the 55- and 60-Gy dose groups developed grade ≥3 esophagitis, and 5, 4, and 4 patients in the respective dose groups experienced grade ≥3 dyspnea, but only 2 of these AEs were considered likely related to therapy. There was no association between fraction size and toxicity (P=.24). The median overall survival was 6 months with no significant differences between dose levels (P=.59).Precision hypofractionated radiation therapy consisting of 60 Gy in 15 fractions for locally advanced NSCLC is generally well tolerated. This treatment regimen could provide patients with poor performance status a potent alternative to chemoradiation. This study has implications for the cost effectiveness of lung cancer therapy. Additional studies of long-term safety and efficacy of this therapy are warranted.

    View details for DOI 10.1016/j.ijrobp.2015.05.004

    View details for Web of Science ID 000359750100013

  • Precision Hypofractionated Radiation Therapy in Poor Performing Patients With Non-Small Cell Lung Cancer: Phase 1 Dose Escalation Trial. International journal of radiation oncology, biology, physics Westover, K. D., Loo, B. W., Gerber, D. E., Iyengar, P., Choy, H., Diehn, M., Hughes, R., Schiller, J., Dowell, J., Wardak, Z., Sher, D., Christie, A., Xie, X., Corona, I., Sharma, A., Wadsworth, M. E., Timmerman, R. 2015; 93 (1): 72-81

    Abstract

    Treatment regimens for locally advanced non-small cell lung cancer (NSCLC) give suboptimal clinical outcomes. Technological advancements such as radiation therapy, the backbone of most treatment regimens, may enable more potent and effective therapies. The objective of this study was to escalate radiation therapy to a tumoricidal hypofractionated dose without exceeding the maximally tolerated dose (MTD) in patients with locally advanced NSCLC.Patients with stage II to IV or recurrent NSCLC and Eastern Cooperative Oncology Group performance status of 2 or greater and not candidates for surgical resection, stereotactic radiation, or concurrent chemoradiation were eligible. Highly conformal radiation therapy was given to treat intrathoracic disease in 15 fractions to a total of 50, 55, or 60 Gy.Fifty-five patients were enrolled: 15 at the 50-Gy, 21 at the 55-Gy, and 19 at the 60-Gy dose levels. A 90-day follow-up was completed in each group without exceeding the MTD. With a median follow-up of 12.5 months, there were 93 grade ≥3 adverse events (AEs), including 39 deaths, although most AEs were considered related to factors other than radiation therapy. One patient from the 55- and 60-Gy dose groups developed grade ≥3 esophagitis, and 5, 4, and 4 patients in the respective dose groups experienced grade ≥3 dyspnea, but only 2 of these AEs were considered likely related to therapy. There was no association between fraction size and toxicity (P=.24). The median overall survival was 6 months with no significant differences between dose levels (P=.59).Precision hypofractionated radiation therapy consisting of 60 Gy in 15 fractions for locally advanced NSCLC is generally well tolerated. This treatment regimen could provide patients with poor performance status a potent alternative to chemoradiation. This study has implications for the cost effectiveness of lung cancer therapy. Additional studies of long-term safety and efficacy of this therapy are warranted.

    View details for DOI 10.1016/j.ijrobp.2015.05.004

    View details for PubMedID 26279026

  • Colorectal Histology Is Associated With an Increased Risk of Local Failure in Lung Metastases Treated With Stereotactic Ablative Radiation Therapy INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS Binkley, M. S., Trakul, N., Jacobs, L. R., von Eyben, R., Quynh-Thu Le, Q. T., Maxim, P. G., Loo, B. W., Shultz, D. B., Diehn, M. 2015; 92 (5): 1044-1052

    Abstract

    Stereotactic ablative radiation therapy (SABR) is increasingly used to treat lung oligometastases. We set out to determine the safety and efficacy of this approach and to identify factors associated with outcomes.We conducted a retrospective study of patients treated with SABR for metastatic lung tumors at our institution from 2003 to 2014. We assessed the association between various patient and treatment factors with local failure (LF), progression, subsequent treatment, systemic treatment, and overall survival (OS), using univariate and multivariate analyses.We identified 122 tumors in 77 patients meeting inclusion criteria for this study. Median follow-up was 22 months. The 12- and 24-month cumulative incidence rates of LF were 8.7% and 16.2%, respectively; the 24-month cumulative incidence rates of progression, subsequent treatment, and subsequent systemic treatment were 75.2%, 64.5%, and 35.1%, respectively. Twenty-four-month OS was 74.6%, and median OS was 36 months. Colorectal metastases had a significantly higher cumulative incidence of LF at 12 and 24 months (25.5% and 42.2%, respectively), than all other histologies (4.4% and 9.9%, respectively; P<.0004). The 24-month cumulative incidences of LF for colorectal metastases treated with a biologically effective dose at α/β = 10 (BED10) of <100 Gy versus BED10 of ≥100 Gy were 62.5% and 16.7%, respectively (P=.08). Toxicity was minimal, with only a single grade 3 or higher event observed.SABR for metastatic lung tumors appears to be safe and effective with excellent local control, treatment-free intervals, and OS. An exception is metastases from colorectal cancer, which have a high LF rate consistent with a radioresistant phenotype, suggesting a potential role for dose escalation.

    View details for DOI 10.1016/j.ijrobp.2015.04.004

    View details for Web of Science ID 000357900600024

    View details for PubMedID 26025776

  • 3D Riesz-wavelet based Covariance descriptors for texture classification of lung nodule tissue in CT. Conference proceedings : ... Annual International Conference of the IEEE Engineering in Medicine and Biology Society. IEEE Engineering in Medicine and Biology Society. Annual Conference Cirujeda, P., Muller, H., Rubin, D., Aguilera, T. A., Loo, B. W., Diehn, M., Binefa, X., Depeursinge, A. 2015; 2015: 7909-7912

    Abstract

    In this paper we present a novel technique for characterizing and classifying 3D textured volumes belonging to different lung tissue types in 3D CT images. We build a volume-based 3D descriptor, robust to changes of size, rigid spatial transformations and texture variability, thanks to the integration of Riesz-wavelet features within a Covariance-based descriptor formulation. 3D Riesz features characterize the morphology of tissue density due to their response to changes in intensity in CT images. These features are encoded in a Covariance-based descriptor formulation: this provides a compact and flexible representation thanks to the use of feature variations rather than dense features themselves and adds robustness to spatial changes. Furthermore, the particular symmetric definite positive matrix form of these descriptors causes them to lay in a Riemannian manifold. Thus, descriptors can be compared with analytical measures, and accurate techniques from machine learning and clustering can be adapted to their spatial domain. Additionally we present a classification model following a "Bag of Covariance Descriptors" paradigm in order to distinguish three different nodule tissue types in CT: solid, ground-glass opacity, and healthy lung. The method is evaluated on top of an acquired dataset of 95 patients with manually delineated ground truth by radiation oncology specialists in 3D, and quantitative sensitivity and specificity values are presented.

    View details for DOI 10.1109/EMBC.2015.7320226

    View details for PubMedID 26738126

  • The prognostic landscape of genes and infiltrating immune cells across human cancers NATURE MEDICINE Gentles, A. J., Newman, A. M., Liu, C. L., Bratman, S. V., Feng, W., Kim, D., Nair, V. S., Xu, Y., Khuong, A., Hoang, C. D., Diehn, M., West, R. B., Plevritis, S. K., Alizadeh, A. A. 2015; 21 (8): 938-945

    Abstract

    Molecular profiles of tumors and tumor-associated cells hold great promise as biomarkers of clinical outcomes. However, existing data sets are fragmented and difficult to analyze systematically. Here we present a pan-cancer resource and meta-analysis of expression signatures from ∼18,000 human tumors with overall survival outcomes across 39 malignancies. By using this resource, we identified a forkhead box MI (FOXM1) regulatory network as a major predictor of adverse outcomes, and we found that expression of favorably prognostic genes, including KLRB1 (encoding CD161), largely reflect tumor-associated leukocytes. By applying CIBERSORT, a computational approach for inferring leukocyte representation in bulk tumor transcriptomes, we identified complex associations between 22 distinct leukocyte subsets and cancer survival. For example, tumor-associated neutrophil and plasma cell signatures emerged as significant but opposite predictors of survival for diverse solid tumors, including breast and lung adenocarcinomas. This resource and associated analytical tools (http://precog.stanford.edu) may help delineate prognostic genes and leukocyte subsets within and across cancers, shed light on the impact of tumor heterogeneity on cancer outcomes, and facilitate the discovery of biomarkers and therapeutic targets.

    View details for DOI 10.1038/nm.3909

    View details for PubMedID 26193342

  • Inhibition of Mouse Breast Tumor-Initiating Cells by Calcitriol and Dietary Vitamin D MOLECULAR CANCER THERAPEUTICS Jeong, Y., Swami, S., Krishnan, A. V., Williams, J. D., Martin, S., Horst, R. L., Albertelli, M. A., Feldman, B. J., Feldman, D., Diehn, M. 2015; 14 (8): 1951-1961

    Abstract

    The anticancer actions of vitamin D and its hormonally active form, calcitriol, have been extensively documented in clinical and preclinical studies. However, the mechanisms underlying these actions have not been completely elucidated. Here, we examined the effect of dietary vitamin D and calcitriol on mouse breast tumor-initiating cells (TICs, also known as cancer stem cells). We focused on MMTV-Wnt1 mammary tumors, for which markers for isolating TICs have previously been validated. We confirmed that these tumors expressed functional vitamin D receptors and estrogen receptors (ER) and exhibited calcitriol-induced molecular responses including ER downregulation. Following orthotopic implantation of MMTV-Wnt1 mammary tumor cells into mice, calcitriol injections or a vitamin D-supplemented diet caused a striking delay in tumor appearance and growth, whereas a vitamin D-deficient diet accelerated tumor appearance and growth. Calcitriol inhibited TIC tumor spheroid formation in a dose-dependent manner in primary cultures and inhibited TIC self-renewal in secondary passages. A combination of calcitriol and ionizing radiation inhibited spheroid formation more than either treatment alone. Further, calcitriol significantly decreased TIC frequency as evaluated by in vivo limiting dilution analyses. Calcitriol inhibition of TIC spheroid formation could be overcome by the overexpression of β-catenin, suggesting that the inhibition of Wnt/β-catenin pathway is an important mechanism mediating the TIC inhibitory activity of calcitriol in this tumor model. Our findings indicate that vitamin D compounds target breast TICs reducing tumor-initiating activity. Our data also suggest that combining vitamin D compounds with standard therapies may enhance anticancer activity and improve therapeutic outcomes.

    View details for DOI 10.1158/1535-7163.MCT-15-0066

    View details for Web of Science ID 000359324600018

    View details for PubMedID 25934710

    View details for PubMedCentralID PMC4549392

  • Analysis of Long-Term 4-Dimensional Computed Tomography Regional Ventilation After Radiation Therapy INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS King, M. T., Maxim, P. G., Diehn, M., Loo, B. W., Xing, L. 2015; 92 (3): 683-690

    Abstract

    To determine whether regional ventilation, as measured using 4-dimensional computed tomography (4D-CT), declines after radiation therapy (RT).We analyzed pretreatment 4D-CT scans associated with 2 RT courses. We quantified regional pulmonary function over equivalent dose in 2 Gy (EQD2α/β=3) intervals of 0 to 5 Gy, 5 to 20 Gy, 20 to 40 Gy, and >40 Gy using percentile-normalized intensity-based (VentInt) and Jacobian-based (VentJac) ventilation metrics. We modeled the impact of dose on mean ventilation (Vent¯) and regional tidal volume (rTV: tidal volume [TV] within a dose interval normalized to total lung TV). We also identified clinical and dosimetric factors that affected regional ventilation changes (ΔVent¯ and ΔrTV) after RT for the >20 Gy dose interval.After RT, Vent¯Int exhibited statistically significant dose-dependent declines within the 20 to 40 Gy (-5.0%; P=.03) and >40 Gy (-6.8%; P<.01) intervals. Vent¯Jac exhibited a declining trend after RT only for the >40 Gy interval (-4.6%; P=.07). Factors associated with ΔVent¯Int for the >20 Gy dose interval included airway stenosis progression (P=.03) and gross tumor volume (P=.09). Both rTVInt and rTVJac were associated with small (<2%) but significant declines after RT for 20 to 40 Gy and >40 Gy intervals. Factors associated with declining rTVInt (P<.05) for the >20 Gy dose interval included airway stenosis progression, greater V20 (volume of lung receiving >20 Gy), and smaller fraction of emphysema in V20. The association between the absence of chronic obstructive pulmonary disease and declining rTV trended toward significance (P=.09).Regional ventilation, as measured using 4D-CT, demonstrates a dose-dependent decline after RT. Our results support the use of 4D-CT ventilation imaging for monitoring regional pulmonary function change after RT.

    View details for DOI 10.1016/j.ijrobp.2015.02.037

    View details for Web of Science ID 000355636800032

    View details for PubMedID 25936813

  • Stereotactic ablative radiotherapy (SABR) for treatment of central and ultra-central lung tumors LUNG CANCER Chaudhuri, A. A., Tang, C., Binkley, M. S., Jin, M., Wynne, J. F., von Eyben, R., Hara, W. Y., Trakul, N., Loo, B. W., Diehn, M. 2015; 89 (1): 50-56

    Abstract

    Treatment of central and ultra-central lung tumors with stereotactic ablative radiotherapy (SABR) remains controversial due to risks of treatment-related toxicities compared with peripheral tumors. Here we report our institution's experience in treating central and ultra-central lung tumor patients with SABR.We retrospectively reviewed outcomes in 68 patients with single lung tumors, 34 central and 34 peripheral, all treated with SABR consisting of 50 Gy in 4-5 fractions. Tumor centrality was defined per the RTOG 0813 protocol. We defined "ultra-central" tumors as those with GTV directly abutting the central airway.Median follow-up time was 18.4 months and median overall survival was 38.1 months. Two-year overall survival was similar between ultra-central, central, and peripheral NSCLC (80.0% vs. 63.2% vs. 86.6%, P=0.62), as was 2-year local failure (0% vs. 10.0% vs. 16.3%, P=0.64). Toxicity rates were low and comparable between the three groups, with only two cases of grade 3 toxicity (chest wall pain), and one case of grade 4 toxicity (pneumonitis) observed. Patients with ultra-central tumors experienced no symptomatic toxicities over a median follow-up time of 23.6 months. Dosimetric analysis revealed that RTOG 0813 central airway dose constraints were frequently not achieved in central tumor treatment plans, but this did not correlate with increased toxicity rate.Patients with central and ultra-central lung tumors treated with SABR (50 Gy in 4-5 fractions) experienced few toxicities and good outcomes, similar to patients with peripheral lung tumors.

    View details for DOI 10.1016/j.lungcan.2015.04.014

    View details for Web of Science ID 000356546300010

    View details for PubMedID 25997421

  • Noninvasive monitoring of diffuse large B-cell lymphoma by immunoglobulin high-throughput sequencing. Blood Kurtz, D. M., Green, M. R., Bratman, S. V., Scherer, F., Liu, C. L., Kunder, C. A., Takahashi, K., Glover, C., Keane, C., Kihira, S., Visser, B., Callahan, J., Kong, K. A., Faham, M., Corbelli, K. S., Miklos, D., Advani, R. H., Levy, R., Hicks, R. J., Hertzberg, M., Ohgami, R. S., Gandhi, M. K., Diehn, M., Alizadeh, A. A. 2015; 125 (24): 3679-3687

    Abstract

    Recent studies have shown limited utility of routine surveillance imaging for diffuse large B-cell lymphoma (DLBCL) patients achieving remission. Detection of molecular disease by immunoglobulin high-throughput sequencing (Ig-HTS) from peripheral blood provides an alternate strategy for surveillance. We prospectively evaluated the utility of Ig-HTS within 311 blood and 105 tumor samples from 75 patients with DLBCL, comparing Ig-HTS from the cellular (circulating leukocytes) and acellular (plasma cell-free DNA) compartments of peripheral blood to clinical outcomes and (18)fluoro-deoxyglucose positron emission tomography combined with computed tomography (PET/CT; n = 173). Clonotypic immunoglobulin rearrangements were detected in 83% of patients with adequate tumor samples to enable subsequent monitoring in peripheral blood. Molecular disease measured from plasma, compared with circulating leukocytes, was more abundant and better correlated with radiographic disease burden. Before treatment, molecular disease was detected in the plasma of 82% of patients compared with 71% in circulating cells (P = .68). However, molecular disease was detected significantly more frequently in the plasma at time of relapse (100% vs 30%; P = .001). Detection of molecular disease in the plasma often preceded PET/CT detection of relapse in patients initially achieving remission. During surveillance time points before relapse, plasma Ig-HTS demonstrated improved specificity (100% vs 56%, P < .0001) and similar sensitivity (31% vs 55%, P = .4) compared with PET/CT. Given its high specificity, Ig-HTS from plasma has potential clinical utility for surveillance after complete remission.

    View details for DOI 10.1182/blood-2015-03-635169

    View details for PubMedID 25887775

  • TU-AB-201-06: Evaluation of Electromagnetically Guided High- Dose Rate Brachytherapy for Ablative Treatment of Lung Metastases. Medical physics Pinkham, D. W., Shultz, D., Loo, B. W., Sung, A., Diehn, M., Fahimian, B. P. 2015; 42 (6): 3595-?

    Abstract

    The advent of electromagnetic navigation bronchoscopy has enabled minimally invasive access to peripheral lung tumors previously inaccessible by optical bronchoscopes. As an adjunct to Stereotactic Ablative Radiosurgery (SABR), implantation of HDR catheters can provide focal treatments for multiple metastases and sites of retreatments. The authors evaluate a procedure to deliver ablative doses via Electromagnetically-Guided HDR (EMG-HDR) to lung metastases, quantify the resulting dosimetry, and assess its role in the comprehensive treatment of lung cancer.A retrospective study was conducted on ten patients, who, from 2009 to 2011, received a hypo-fractionated SABR regimen with 6MV VMAT to lesions in various lobes ranging from 1.5 to 20 cc in volume. A CT visible pathway was delineated for EM guided placement of an HDR applicator (catheter) and dwell times were optimized to ensure at least 98% prescription dose coverage of the GTV. Normal tissue doses were calculated using inhomogeneity corrections via a grid-based Boltzmann solver (Acuros_BV_1.5.0).With EMG-HDR, an average of 83% (+/-9% standard deviation) of each patient's GTV received over 200% of the prescription dose, as compared to SABR where the patients received an average maximum dose of 125% (+/-5%). EMG-HDR enabled a 59% (+/-12%) decrease in the aorta maximum dose, a 63% (+/-26%) decrease in the spinal cord max dose, and 57% (+/-23%) and 70% (+/-17%) decreases in the volume of the body receiving over 50% and 25% of the prescription dose, respectively.EMG-HDR enables delivery of higher ablative doses to the GTV, while concurrently reducing surrounding normal tissue doses. The single catheter approach shown here is limited to targets smaller than 20 cc. As such, the technique enables ablation of small lesions and a potentially safe and effective retreatment option in situations where external beam utility is limited by normal tissue constraints.

    View details for DOI 10.1118/1.4925544

    View details for PubMedID 26128845

  • Distinct early response dynamics of circulating tumor DNA and circulating tumor cells during therapy of B-cell NHL. Kurtz, D., Scherer, F., Green, M., Khodadoust, M., Klass, D. M., Zhou, L., Krishnan, R., Glover, C., Liu, C., Kong, K. A., Faham, M., Levy, R., Diehn, M., Alizadeh, A. A. AMER SOC CLINICAL ONCOLOGY. 2015
  • Pre-treatment circulating tumor DNA as a biomarker for disease burden in diffuse large B cell lymphoma (DLBCL) Scherer, F., Kurtz, D., Green, M., Newman, A. M., Klass, D. M., Zhou, L., Krishnan, R., Liu, C., Glover, C., Ohgami, R. S., Hicks, R. J., Keane, C., Kong, K. A., Faham, M., Hertzberg, M. S., Gandhi, M. K., Advani, R. H., Levy, R., Diehn, M., Alizadeh, A. A. AMER SOC CLINICAL ONCOLOGY. 2015
  • Robust enumeration of cell subsets from tissue expression profiles. Nature methods Newman, A. M., Liu, C. L., Green, M. R., Gentles, A. J., Feng, W., Xu, Y., Hoang, C. D., Diehn, M., Alizadeh, A. A. 2015; 12 (5): 453-457

    Abstract

    We introduce CIBERSORT, a method for characterizing cell composition of complex tissues from their gene expression profiles. When applied to enumeration of hematopoietic subsets in RNA mixtures from fresh, frozen and fixed tissues, including solid tumors, CIBERSORT outperformed other methods with respect to noise, unknown mixture content and closely related cell types. CIBERSORT should enable large-scale analysis of RNA mixtures for cellular biomarkers and therapeutic targets (http://cibersort.stanford.edu/).

    View details for DOI 10.1038/nmeth.3337

    View details for PubMedID 25822800

  • Robust enumeration of cell subsets from tissue expression profiles NATURE METHODS Newman, A. M., Liu, C. L., Green, M. R., Gentles, A. J., Feng, W., Xu, Y., Hoang, C. D., Diehn, M., Alizadeh, A. A. 2015; 12 (5): 453-?

    Abstract

    We introduce CIBERSORT, a method for characterizing cell composition of complex tissues from their gene expression profiles. When applied to enumeration of hematopoietic subsets in RNA mixtures from fresh, frozen and fixed tissues, including solid tumors, CIBERSORT outperformed other methods with respect to noise, unknown mixture content and closely related cell types. CIBERSORT should enable large-scale analysis of RNA mixtures for cellular biomarkers and therapeutic targets (http://cibersort.stanford.edu/).

    View details for DOI 10.1038/NMETH.3337

    View details for Web of Science ID 000353645800019

    View details for PubMedID 25822800

  • To SABR or Not to SABR? Indications and Contraindications for Stereotactic Ablative Radiotherapy in the Treatment of Early-Stage, Oligometastatic, or Oligoprogressive Non-Small Cell Lung Cancer SEMINARS IN RADIATION ONCOLOGY Shultz, D. B., Diehn, M., Loo, B. W. 2015; 25 (2): 78-86

    Abstract

    Stereotactic ablative radiotherapy (SABR) is a highly effective treatment for early-stage non-small cell lung cancer. Although direct comparisons from randomized trials are not available, rates of both primary tumor control and distant metastasis are similar between SABR and surgery. Overall survival is lower after SABR compared with surgery, largely reflecting that a primary selection criterion for SABR has been medical inoperability because of decreased cardiopulmonary function and other comorbidities that lead to decreased survival independent of non-small cell lung cancer. Survival outcomes between SABR and surgery are much more similar in propensity-matched cohorts. Newer potential indications for SABR include treatment of operable patients; of oligometastatic lung cancer, in which SABR has emerged as an alternative to metastasectomy; and of oligoprogressive lung cancer, an attractive concept especially as improved personalized systemic therapies emerge, and prospective trials are currently being conducted in these settings. Although toxicity in modern series is low, SABR is clearly capable of producing fatal complications, and understanding the risk factors and approaches for mitigating them has been emerging in recent years. Thus, appropriate patient selection is a vital, evolving, and controversial topic.

    View details for DOI 10.1016/j.semradonc.2014.11.005

    View details for Web of Science ID 000351254100003

  • Noninvasive pulmonary nodule elastometry by CT and deformable image registration. Radiotherapy and oncology Negahdar, M., Fasola, C. E., Yu, A. S., von Eyben, R., Yamamoto, T., Diehn, M., Fleischmann, D., Tian, L., Loo, B. W., Maxim, P. G. 2015; 115 (1): 35-40

    Abstract

    To develop a noninvasive method for determining malignant pulmonary nodule (MPN) elasticity, and compare it against expert dual-observer manual contouring.We analyzed breath-hold images at extreme tidal volumes of 23 patients with 30 MPN treated with stereotactic ablative radiotherapy. Deformable image registration (DIR) was applied to the breath-hold images to determine the volumes of the MPNs and a ring of surrounding lung tissue (ring) in each state. MPNs were also manually delineated on deep inhale and exhale images by two observers. Volumes were compared between observers and DIR by Dice similarity. Elasticity was defined as the absolute value of the volume ratio of the MPN minus one normalized to that of the ring.For all 30 tumors the Dice coefficient was 0.79±0.07 and 0.79±0.06 between DIR with observers 1 and 2, respectively, close to the inter-observer Dice value, 0.81±0.1. The elasticity of MPNs was 1.24±0.26, demonstrating that volume change of the MPN was less than that of the surrounding lung.We developed a noninvasive CT elastometry method based on DIR that measures the elasticity of biopsy-proven MPN. Our future direction would be to develop this method to distinguish malignant from benign nodules.

    View details for DOI 10.1016/j.radonc.2015.03.015

    View details for PubMedID 25824979

  • To SABR or not to SABR? Indications and contraindications for stereotactic ablative radiotherapy in the treatment of early-stage, oligometastatic, or oligoprogressive non-small cell lung cancer. Seminars in radiation oncology Shultz, D. B., Diehn, M., Loo, B. W. 2015; 25 (2): 78-86

    Abstract

    Stereotactic ablative radiotherapy (SABR) is a highly effective treatment for early-stage non-small cell lung cancer. Although direct comparisons from randomized trials are not available, rates of both primary tumor control and distant metastasis are similar between SABR and surgery. Overall survival is lower after SABR compared with surgery, largely reflecting that a primary selection criterion for SABR has been medical inoperability because of decreased cardiopulmonary function and other comorbidities that lead to decreased survival independent of non-small cell lung cancer. Survival outcomes between SABR and surgery are much more similar in propensity-matched cohorts. Newer potential indications for SABR include treatment of operable patients; of oligometastatic lung cancer, in which SABR has emerged as an alternative to metastasectomy; and of oligoprogressive lung cancer, an attractive concept especially as improved personalized systemic therapies emerge, and prospective trials are currently being conducted in these settings. Although toxicity in modern series is low, SABR is clearly capable of producing fatal complications, and understanding the risk factors and approaches for mitigating them has been emerging in recent years. Thus, appropriate patient selection is a vital, evolving, and controversial topic.

    View details for DOI 10.1016/j.semradonc.2014.11.005

    View details for PubMedID 25771411

  • Molecular Determinants of Radiation Response in Non-Small Cell Lung Cancer SEMINARS IN RADIATION ONCOLOGY Yom, S. S., Diehn, M., Raben, D. 2015; 25 (2): 67-77

    Abstract

    Non-small cell lung cancers are now recognized to contain considerable heterogeneity and molecular diversity. Substantial progress has been made regarding molecular determinants of response to targeted agents in advanced lung cancer, and recent findings have revealed subsets of patients with driver mutations that respond rapidly to selective inhibitors. In addition, new approaches to disrupting DNA repair and inflammation and activation of the immune system are being explored. A key question in the field is whether therapeutic multimodality options incorporating radiation therapy can capitalize on the gains made in systemic therapy.

    View details for DOI 10.1016/j.semradonc.2014.12.007

    View details for Web of Science ID 000351254100002

    View details for PubMedID 25771410

  • Noninvasive pulmonary nodule elastometry by CT and deformable image registration RADIOTHERAPY AND ONCOLOGY Negandar, M., Fasola, C. E., Yu, A. S., von Eyben, R., Yamamoto, T., Diehn, M., Fleischmann, D., Tian, L., Loo, B. W., Maxim, P. G. 2015; 115 (1): 35-40
  • Potential clinical utility of ultrasensitive circulating tumor DNA detection with CAPP-Seq. Expert review of molecular diagnostics Bratman, S. V., Newman, A. M., Alizadeh, A. A., Diehn, M. n. 2015: 1–5

    Abstract

    Tumors continually shed DNA into the circulation, where it can be noninvasively accessed. The ability to accurately detect circulating tumor DNA (ctDNA) could significantly impact the management of patients with nearly every cancer type. Quantitation of ctDNA could allow objective response assessment, detection of minimal residual disease and noninvasive tumor genotyping. The latter application overcomes the barriers currently limiting repeated tumor tissue sampling during therapy. Recent technical advancements have improved upon the sensitivity, specificity and feasibility of ctDNA detection and promise to enable innovative clinical applications. Here, we focus on the potential clinical utility of ctDNA analysis using CAncer Personalized Profiling by deep Sequencing (CAPP-Seq), a novel next-generation sequencing-based approach for ultrasensitive ctDNA detection. Applications of CAPP-Seq for the personalization of cancer detection and therapy are discussed.

    View details for DOI 10.1586/14737159.2015.1019476

    View details for PubMedID 25773944

  • FACTERA: a practical method for the discovery of genomic rearrangements at breakpoint resolution BIOINFORMATICS Newman, A. M., Bratman, S. V., Stehr, H., Lee, L. J., Liu, C. L., Diehn, M., Alizadeh, A. A. 2014; 30 (23): 3390-3393

    Abstract

    For practical and robust de novo identification of genomic fusions and breakpoints from targeted paired-end DNA sequencing data, we developed Fusion And Chromosomal Translocation Enumeration and Recovery Algorithm (FACTERA). Our method has minimal external dependencies, works directly on a preexisting Binary Alignment/Map file and produces easily interpretable output. We demonstrate FACTERA's ability to rapidly identify breakpoint-resolution fusion events with high sensitivity and specificity in patients with non-small cell lung cancer, including novel rearrangements. We anticipate that FACTERA will be broadly applicable to the discovery and analysis of clinically relevant fusions from both targeted and genome-wide sequencing datasets.http://factera.stanford.edu.

    View details for DOI 10.1093/bioinformatics/btu549

    View details for PubMedID 25143292

  • Increased Rates of Pneumonitis in Patients Receiving Stereotactic Ablative Radiation Therapy for Central Versus Peripheral Lung Tumors Chaudhuri, A., Tang, C., Trakul, N., Wynne, J., Loo, B. W., Diehn, M. ELSEVIER SCIENCE INC. 2014: S78–S79
  • Noninvasive Pulmonary Nodule Elastometry by CT and Deformable Image Registration Negahdar, M., Shultz, D. B., Eyben, R. V., Fasola, C., Yu, A. S., Tian, L., Fleischmann, D., Gable, L., Shan, X., Diehn, M., Loo, B. W., Maxim, P. G. ELSEVIER SCIENCE INC. 2014: S10
  • Ultrasensitive Detection of Circulating Tumor DNA in Non-Small Cell Lung Cancer by Deep Sequencing Diehn, M., Bratman, S. V., Newman, A. M., Neal, J. W., Wakelee, H. A., Merritt, R. E., Shrager, J. B., Loo, B. W., Alizadeh, A. ELSEVIER SCIENCE INC. 2014: S75
  • Galectin-1 Mediates Radiation-Related Lymphopenia and Attenuates NSCLC Radiation Response CLINICAL CANCER RESEARCH Kuo, P., Bratman, S. V., Shultz, D. B., von Eyben, R., Chan, C., Wang, Z., Say, C., Gupta, A., Loo, B. W., Giaccia, A. J., Koong, A. C., Diehn, M., Quynh-Thu Le, Q. T. 2014; 20 (21): 5558-5569

    Abstract

    Radiotherapy can result in lymphopenia, which has been linked to poorer survival. Here, we test the hypothesis that radiotherapy-induced lymphopenia is mediated by a tumor-secreted factor, Galectin-1 (Gal-1), which possesses T-cell proapoptotic activities.Matched Gal-1 wild-type (WT) or null mice were implanted with Lewis lung carcinoma (LLC-1) that either expressed Gal-1 or had Gal-1 stably downregulated. Tumors were irradiated locally and circulating Gal-1 and T cells were measured. Tumor growth, lung metastasis, intratumoral T-cell apoptosis, and microvessel density count were quantified. Thiodigalactoside (TDG), a Gal-1 inhibitor, was used to inhibit Gal-1 function in another group of mice to validate the observations noted with Gal-1 downregulation. Lymphocyte counts, survival, and plasma Gal-1 were analyzed in cohorts of radiotherapy-treated lung [non-small cell lung cancer (NSCLC)] and head and neck cancer patients.LLC irradiation increased Gal-1 secretion and decreased circulating T cells in mice, regardless of host Gal-1 expression. Inhibition of tumor Gal-1 with either shRNA or thiodigalactoside ablated radiotherapy-induced lymphopenia. Irradiated shGal-1 tumors showed significantly less intratumoral CD8(+) T-cell apoptosis and microvessel density, which led to marked tumor growth delay and reduced lung metastasis compared with controls. Similar observations were made after thiodigalactoside treatment. Radiotherapy-induced lymphopenia was associated with poorer overall survival in patients with NSCLC treated with hypofractionated radiotherapy. Plasma Gal-1 increased whereas T-cell decreased after radiation in another group of patients.Radiotherapy-related systemic lymphopenia appeared to be mediated by radiotherapy-induced tumor Gal-1 secretion that could lead to tumor progression through intratumoral immune suppression and enhanced angiogenesis. Clin Cancer Res; 20(21); 5558-69. ©2014 AACR.

    View details for DOI 10.1158/1078-0432.CCR-14-1138

    View details for Web of Science ID 000344759100024

    View details for PubMedCentralID PMC4216761

  • Pulmonary Ventilation Imaging Based on 4-Dimensional Computed Tomography: Comparison With Pulmonary Function Tests and SPECT Ventilation Images INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS Yamamoto, T., Kabus, S., Lorenz, C., Mittra, E., Hong, J. C., Chung, M., Eclov, N., To, J., Diehn, M., Loo, B. W., Keall, P. J. 2014; 90 (2): 414-422

    Abstract

    4-dimensional computed tomography (4D-CT)-based pulmonary ventilation imaging is an emerging functional imaging modality. The purpose of this study was to investigate the physiological significance of 4D-CT ventilation imaging by comparison with pulmonary function test (PFT) measurements and single-photon emission CT (SPECT) ventilation images, which are the clinical references for global and regional lung function, respectively.In an institutional review board-approved prospective clinical trial, 4D-CT imaging and PFT and/or SPECT ventilation imaging were performed in thoracic cancer patients. Regional ventilation (V4DCT) was calculated by deformable image registration of 4D-CT images and quantitative analysis for regional volume change. V4DCT defect parameters were compared with the PFT measurements (forced expiratory volume in 1 second (FEV1; % predicted) and FEV1/forced vital capacity (FVC; %). V4DCT was also compared with SPECT ventilation (VSPECT) to (1) test whether V4DCT in VSPECT defect regions is significantly lower than in nondefect regions by using the 2-tailed t test; (2) to quantify the spatial overlap between V4DCT and VSPECT defect regions with Dice similarity coefficient (DSC); and (3) to test ventral-to-dorsal gradients by using the 2-tailed t test.Of 21 patients enrolled in the study, 18 patients for whom 4D-CT and either PFT or SPECT were acquired were included in the analysis. V4DCT defect parameters were found to have significant, moderate correlations with PFT measurements. For example, V4DCT(HU) defect volume increased significantly with decreasing FEV1/FVC (R=-0.65, P<.01). V4DCT in VSPECT defect regions was significantly lower than in nondefect regions (mean V4DCT(HU) 0.049 vs 0.076, P<.01). The average DSCs for the spatial overlap with SPECT ventilation defect regions were only moderate (V4DCT(HU)0.39 ± 0.11). Furthermore, ventral-to-dorsal gradients of V4DCT were strong (V4DCT(HU) R(2) = 0.69, P=.08), which was similar to VSPECT (R(2) = 0.96, P<.01).An 18-patient study demonstrated significant correlations between 4D-CT ventilation and PFT measurements as well as SPECT ventilation, providing evidence toward the validation of 4D-CT ventilation imaging.

    View details for DOI 10.1016/j.ijrobp.2014.06.006

    View details for Web of Science ID 000341994400026

  • Pulmonary ventilation imaging based on 4-dimensional computed tomography: comparison with pulmonary function tests and SPECT ventilation images. International journal of radiation oncology, biology, physics Yamamoto, T., Kabus, S., Lorenz, C., Mittra, E., Hong, J. C., Chung, M., Eclov, N., To, J., Diehn, M., Loo, B. W., Keall, P. J. 2014; 90 (2): 414-422

    Abstract

    4-dimensional computed tomography (4D-CT)-based pulmonary ventilation imaging is an emerging functional imaging modality. The purpose of this study was to investigate the physiological significance of 4D-CT ventilation imaging by comparison with pulmonary function test (PFT) measurements and single-photon emission CT (SPECT) ventilation images, which are the clinical references for global and regional lung function, respectively.In an institutional review board-approved prospective clinical trial, 4D-CT imaging and PFT and/or SPECT ventilation imaging were performed in thoracic cancer patients. Regional ventilation (V4DCT) was calculated by deformable image registration of 4D-CT images and quantitative analysis for regional volume change. V4DCT defect parameters were compared with the PFT measurements (forced expiratory volume in 1 second (FEV1; % predicted) and FEV1/forced vital capacity (FVC; %). V4DCT was also compared with SPECT ventilation (VSPECT) to (1) test whether V4DCT in VSPECT defect regions is significantly lower than in nondefect regions by using the 2-tailed t test; (2) to quantify the spatial overlap between V4DCT and VSPECT defect regions with Dice similarity coefficient (DSC); and (3) to test ventral-to-dorsal gradients by using the 2-tailed t test.Of 21 patients enrolled in the study, 18 patients for whom 4D-CT and either PFT or SPECT were acquired were included in the analysis. V4DCT defect parameters were found to have significant, moderate correlations with PFT measurements. For example, V4DCT(HU) defect volume increased significantly with decreasing FEV1/FVC (R=-0.65, P<.01). V4DCT in VSPECT defect regions was significantly lower than in nondefect regions (mean V4DCT(HU) 0.049 vs 0.076, P<.01). The average DSCs for the spatial overlap with SPECT ventilation defect regions were only moderate (V4DCT(HU)0.39 ± 0.11). Furthermore, ventral-to-dorsal gradients of V4DCT were strong (V4DCT(HU) R(2) = 0.69, P=.08), which was similar to VSPECT (R(2) = 0.96, P<.01).An 18-patient study demonstrated significant correlations between 4D-CT ventilation and PFT measurements as well as SPECT ventilation, providing evidence toward the validation of 4D-CT ventilation imaging.

    View details for DOI 10.1016/j.ijrobp.2014.06.006

    View details for PubMedID 25104070

  • Galectin-1 mediates radiation-related lymphopenia in non-small cell lung cancer and attenuates tumor radiation response Kuo, P., Bratman, S., Shultz, D., von Eyben, R., Chan, C., Wang, Z., Say, C., Gupta, A., Loo, B. W., Giaccia, A., Koong, A., Diehn, M., Quynh-Thu Le AMER ASSOC CANCER RESEARCH. 2014
  • Increased rates of radiation pneumonitis in patients receiving stereotactic ablative radiotherapy for central versus peripheral lung tumors Chaudhuri, A. A., Tang, C., Trakul, N., Wynne, J., Loo, B., Diehn, M. AMER ASSOC CANCER RESEARCH. 2014
  • Lung Volume Reduction After Stereotactic Ablative Radiation Therapy of Lung Tumors: Potential Application to Emphysema INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS Binkley, M. S., Shrager, J. B., Leung, A. N., Popat, R., Trakul, N., Atwood, T. F., Chaudhuri, A., Maxim, P. G., Diehn, M., Loo, B. W. 2014; 90 (1): 216-223

    Abstract

    Lung volume reduction surgery (LVRS) improves dyspnea and other outcomes in selected patients with severe emphysema, but many have excessive surgical risk for LVRS. We analyzed the dose-volume relationship for lobar volume reduction after stereotactic ablative radiation therapy (SABR) of lung tumors, hypothesizing that SABR could achieve therapeutic volume reduction if applied in emphysema.We retrospectively identified patients treated from 2007 to 2011 who had SABR for 1 lung tumor, pre-SABR pulmonary function testing, and ≥6 months computed tomographic (CT) imaging follow-up. We contoured the treated lobe and untreated adjacent lobe(s) on CT before and after SABR and calculated their volume changes relative to the contoured total (bilateral) lung volume (TLV). We correlated lobar volume reduction with the volume receiving high biologically effective doses (BED, α/β = 3).27 patients met the inclusion criteria, with a median CT follow-up time of 14 months. There was no grade ≥3 toxicity. The median volume reduction of the treated lobe was 4.4% of TLV (range, -0.4%-10.8%); the median expansion of the untreated adjacent lobe was 2.6% of TLV (range, -3.9%-11.6%). The volume reduction of the treated lobe was positively correlated with the volume receiving BED ≥60 Gy (r(2)=0.45, P=.0001). This persisted in subgroups determined by high versus low pre-SABR forced expiratory volume in 1 second, treated lobe CT emphysema score, number of fractions, follow-up CT time, central versus peripheral location, and upper versus lower lobe location, with no significant differences in effect size between subgroups. Volume expansion of the untreated adjacent lobe(s) was positively correlated with volume reduction of the treated lobe (r(2)=0.47, P<.0001).We identified a dose-volume response for treated lobe volume reduction and adjacent lobe compensatory expansion after lung tumor SABR, consistent across multiple clinical parameters. These data serve to inform our ongoing prospective trial of stereotactic ablative volume reduction (SAVR) for severe emphysema in poor candidates for LVRS.

    View details for DOI 10.1016/j.ijrobp.2014.05.025

    View details for Web of Science ID 000341456500029

  • Noninvasive Pulmonary Nodule Elastometry by CT and Deformable Image Registration Negahdar, M., Shultz, D. B., Eyben, R. V., Fasola, C., Yu, A. S., Tian, L., Fleischmann, D., Gable, L., Shan, X., Diehn, M., Loo, B. W., Maxim, P. G. ELSEVIER SCIENCE INC. 2014: S623–S624
  • Lung volume reduction after stereotactic ablative radiation therapy of lung tumors: potential application to emphysema. International journal of radiation oncology, biology, physics Binkley, M. S., Shrager, J. B., Leung, A. N., Popat, R., Trakul, N., Atwood, T. F., Chaudhuri, A., Maxim, P. G., Diehn, M., Loo, B. W. 2014; 90 (1): 216-223

    Abstract

    Lung volume reduction surgery (LVRS) improves dyspnea and other outcomes in selected patients with severe emphysema, but many have excessive surgical risk for LVRS. We analyzed the dose-volume relationship for lobar volume reduction after stereotactic ablative radiation therapy (SABR) of lung tumors, hypothesizing that SABR could achieve therapeutic volume reduction if applied in emphysema.We retrospectively identified patients treated from 2007 to 2011 who had SABR for 1 lung tumor, pre-SABR pulmonary function testing, and ≥6 months computed tomographic (CT) imaging follow-up. We contoured the treated lobe and untreated adjacent lobe(s) on CT before and after SABR and calculated their volume changes relative to the contoured total (bilateral) lung volume (TLV). We correlated lobar volume reduction with the volume receiving high biologically effective doses (BED, α/β = 3).27 patients met the inclusion criteria, with a median CT follow-up time of 14 months. There was no grade ≥3 toxicity. The median volume reduction of the treated lobe was 4.4% of TLV (range, -0.4%-10.8%); the median expansion of the untreated adjacent lobe was 2.6% of TLV (range, -3.9%-11.6%). The volume reduction of the treated lobe was positively correlated with the volume receiving BED ≥60 Gy (r(2)=0.45, P=.0001). This persisted in subgroups determined by high versus low pre-SABR forced expiratory volume in 1 second, treated lobe CT emphysema score, number of fractions, follow-up CT time, central versus peripheral location, and upper versus lower lobe location, with no significant differences in effect size between subgroups. Volume expansion of the untreated adjacent lobe(s) was positively correlated with volume reduction of the treated lobe (r(2)=0.47, P<.0001).We identified a dose-volume response for treated lobe volume reduction and adjacent lobe compensatory expansion after lung tumor SABR, consistent across multiple clinical parameters. These data serve to inform our ongoing prospective trial of stereotactic ablative volume reduction (SAVR) for severe emphysema in poor candidates for LVRS.

    View details for DOI 10.1016/j.ijrobp.2014.05.025

    View details for PubMedID 25015205

  • Circulating Tumor DNA Concentrations Reflect Metabolic Tumor Volume in NSCLC Modlin, L. A., Bratman, S. V., Newman, A. M., Eclov, N. W., Neal, J. W., Wakelee, H. A., Shrager, J. B., Loo, B. W., Alizadeh, A. A., Diehn, M. ELSEVIER SCIENCE INC. 2014: S812
  • Circulating Tumor DNA as a Biomarker for Pancreatic Adenocarcinoma Osmundson, E., Newman, A. M., Bratman, S. V., Klass, D. M., Zhou, L., Pai, J., Longacre, T. A., Alizadeh, A. A., Koong, A. C., Diehn, M. ELSEVIER SCIENCE INC. 2014: S816–S817
  • Improving The Prognostic Value Of FDG-PET For NSCLC Patients Treated With SABR Using Advanced Computational Modeling Li, R., Aguilera, T. A., Shultz, D. B., Rubin, D., Diehn, M., Loo, B. W. ELSEVIER SCIENCE INC. 2014: S7
  • Increased Rates of Pneumonitis in Patients Receiving Stereotactic Ablative Radiation Therapy for Central Versus Peripheral Lung Tumors Chaudhuri, A., Tang, C., Trakul, N., Wynne, J., Loo, B. W., Diehn, M. ELSEVIER SCIENCE INC. 2014: S160
  • Vertebral Fractures After Stereotactic Ablative Radiation Therapy of Lung Tumors Aguilera, T. A., Trakul, N., Shultz, D., Maxim, P. G., Diehn, M., Loo, B. W. ELSEVIER SCIENCE INC. 2014: S160–S161
  • Factors Contributing to the Use of Intensity Modulated Versus 3D Conformal Radiation Therapy for Stage III Non-Small Cell Lung Cancer: A SEER-Medicare Study Harris, J. P., Loo, B. W., Diehn, M. ELSEVIER SCIENCE INC. 2014: S580
  • First in Human High-Resolution Imaging of Regional Lung Function by Single Energy Xenon CT Compared to Ventilation SPECT Negahdar, M., Yamamoto, T., Shultz, D. B., Gable, L., Shan, X., Mittra, E., Diehn, M., Maxim, P. G., Loo, B. W. ELSEVIER SCIENCE INC. 2014: S624
  • Impact of Optimally-Gated PET on Tumor Localization and Quantification Lee, K., Loo, B. W., Diehn, M., Atwood, T. F., Hristov, D. H. ELSEVIER SCIENCE INC. 2014: S795
  • Neurotrophic factor GDNF promotes survival of salivary stem cells. journal of clinical investigation Xiao, N., Lin, Y., Cao, H., Sirjani, D., Giaccia, A. J., Koong, A. C., Kong, C. S., Diehn, M., Le, Q. 2014; 124 (8): 3364-3377

    Abstract

    Stem cell-based regenerative therapy is a promising treatment for head and neck cancer patients that suffer from chronic dry mouth (xerostomia) due to salivary gland injury from radiation therapy. Current xerostomia therapies only provide temporary symptom relief, while permanent restoration of salivary function is not currently feasible. Here, we identified and characterized a stem cell population from adult murine submandibular glands. Of the different cells isolated from the submandibular gland, this specific population, Lin-CD24+c-Kit+Sca1+, possessed the highest capacity for proliferation, self renewal, and differentiation during serial passage in vitro. Serial transplantations of this stem cell population into the submandibular gland of irradiated mice successfully restored saliva secretion and increased the number of functional acini. Gene-expression analysis revealed that glial cell line-derived neurotrophic factor (Gdnf) is highly expressed in Lin-CD24+c-Kit+Sca1+ stem cells. Furthermore, GDNF expression was upregulated upon radiation therapy in submandibular glands of both mice and humans. Administration of GDNF improved saliva production and enriched the number of functional acini in submandibular glands of irradiated animals and enhanced salisphere formation in cultured salivary stem cells, but did not accelerate growth of head and neck cancer cells. These data indicate that modulation of the GDNF pathway may have potential therapeutic benefit for management of radiation-induced xerostomia.

    View details for DOI 10.1172/JCI74096

    View details for PubMedID 25036711

    View details for PubMedCentralID PMC4109543

  • Vagal and recurrent laryngeal neuropathy following stereotactic ablative radiation therapy in the chest. Practical radiation oncology Shultz, D. B., Trakul, N., Maxim, P. G., Diehn, M., Loo, B. W. 2014; 4 (4): 272-278

    Abstract

    To identify clinical and dosimetric factors associated with vagus nerve (VN) and recurrent laryngeal nerve (RecLN) injury following stereotactic ablative radiation therapy (SABR) in the chest.We examined the clinical courses and SABR plans of 67 patients treated for T1 or T2 non-small cell lung cancer of the upper right or left lung, including 2 who developed vocal cord paresis (VCP) following treatment. After developing a contouring atlas for the VN and RecLN in the thorax, dose to those structures was retrospectively determined for each patient, and we identified 12 patients whose treatment imparted significant dose to either nerve and who were assessable for more than 12 months follow-up. Biologically effective doses using linear-quadratic (LQ) and linear quadratic-linear (LQ-L) modeling were correlated with VN and RecLN toxicity.Of 12 patients, 2 developed VCP. The first underwent repeat SABR and received a cumulative single fraction equivalent dose (alpha/beta = 3; SFED3) of 37.4 or 64.5 Gy to the VN and 13.7 or 15.3 Gy to the RecLN (by LQ or LQ-L modeling, respectively). This was the highest VN dose and fifth highest RecLN dose in the cohort. The second had rheumatoid arthritis and connective tissue disease and received a SFED3 of 16 Gy to the VN and 19.5 Gy to the RecLN (by both LQ and LQ-L modeling). This was in the upper tertile of VN and RecLN doses for the cohort.Following SABR for non-small cell lung cancer, VCP was associated with high cumulative dose to the VN in 1 patient and a moderately high dose to the VN and RecLN in another patient with rheumatoid arthritis and connective tissue disease. Particularly in the setting of reirradiation or connective tissue disease, potential toxicity to the VN or RecLN should be considered.

    View details for DOI 10.1016/j.prro.2013.08.005

    View details for PubMedID 25012837

  • Feasibility and potential utility of multicomponent exhaled breath analysis for predicting development of radiation pneumonitis after stereotactic ablative radiotherapy. Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer Moré, J. M., Eclov, N. C., Chung, M. P., Wynne, J. F., Shorter, J. H., Nelson, D. D., Hanlon, A. L., Burmeister, R., Banos, P., Maxim, P. G., Loo, B. W., Diehn, M. 2014; 9 (7): 957-64

    Abstract

    In this prospective pilot study, we evaluated the feasibility and potential utility of measuring multiple exhaled gases as biomarkers of radiation pneumonitis (RP) in patients receiving stereotactic ablative radiotherapy (SABR) for lung tumors.Breath analysis was performed for 26 patients receiving SABR for lung tumors. Concentrations of exhaled nitric oxide (eNO), carbon monoxide (eCO), nitrous oxide (eN2O), and carbon dioxide (eCO2) were measured before and immediately after each fraction using real-time, infrared laser spectroscopy. RP development (CTCAE grade ≥2) was correlated with baseline gas concentrations, acute changes in gas concentrations after each SABR fraction, and dosimetric parameters.Exhaled breath analysis was successfully completed in 77% of patients. Five of 20 evaluable patients developed RP at a mean of 5.4 months after SABR. Acute changes in eNO and eCO concentrations, defined as percent changes between each pre-fraction and post-fraction measurement, were significantly smaller in RP versus non-RP cases (p = 0.022 and 0.015, respectively). In an exploratory analysis, a combined predictor of baseline eNO greater than 24 parts per billion and acute decrease in eCO less than 5.5% strongly correlated with RP incidence (p =0.0099). Neither eN2O nor eCO2 concentrations were significantly associated with RP development. Although generally higher in patients destined to develop RP, dosimetric parameters were not significantly associated with RP development.The majority of SABR patients in this pilot study were able to complete exhaled breath analysis. Baseline concentrations and acute changes in concentrations of exhaled breath components were associated with RP development after SABR. If our findings are validated, exhaled breath analysis may become a useful approach for noninvasive identification of patients at highest risk for developing RP after SABR.

    View details for DOI 10.1097/JTO.0000000000000182

    View details for PubMedID 24926543

  • Targeting Unique Metabolic Properties of Breast Tumor Initiating Cells STEM CELLS Feng, W., Gentles, A., Nair, R. V., Huang, M., Lin, Y., Lee, C. Y., Cai, S., Scheeren, F. A., Kuo, A. H., Diehn, M. 2014; 32 (7): 1734-1745

    Abstract

    Normal stem cells from a variety of tissues display unique metabolic properties compared to their more differentiated progeny. However, relatively little is known about metabolic properties of cancer stem cells, also called tumor initiating cells (TICs). In this study we show that, analogous to some normal stem cells, breast TICs have distinct metabolic properties compared to nontumorigenic cancer cells (NTCs). Transcriptome profiling using RNA-Seq revealed TICs underexpress genes involved in mitochondrial biology and mitochondrial oxidative phosphorylation, and metabolic analyses revealed TICs preferentially perform glycolysis over oxidative phosphorylation compared to NTCs. Mechanistic analyses demonstrated that decreased expression and activity of pyruvate dehydrogenase (Pdh), a key regulator of oxidative phosphorylation, plays a critical role in promoting the proglycolytic phenotype of TICs. Metabolic reprogramming via forced activation of Pdh preferentially eliminated TICs both in vitro and in vivo. Our findings reveal unique metabolic properties of TICs and demonstrate that metabolic reprogramming represents a potential therapeutic strategy for targeting these cells.

    View details for DOI 10.1002/stem.1662

    View details for Web of Science ID 000337785200005

    View details for PubMedCentralID PMC4144791

  • Imaging features associated with disease progression after stereotactic ablative radiotherapy for stage I non-small-cell lung cancer. Clinical lung cancer Shultz, D. B., Trakul, N., Abelson, J. A., Murphy, J. D., Maxim, P. G., Le, Q., Loo, B. W., Diehn, M. 2014; 15 (4): 294-301 e3

    Abstract

    The aim of this study was to identify imaging-based predictors of progression in patients treated with SABR for stage I NSCLC.Between March 2003 and December 2012, 117 patients with stage I NSCLC meeting our study criteria were treated with SABR at Stanford University. Median follow-up was 17 months (range, 3-74 months) for all patients and 19 months for living patients (range, 3-74 months). Tumors were classified according to whether or not they contacted the pleura adjacent to the chest wall or mediastinum (MP), according to their maximum dimension based on computed tomography scans, and, for 102 patients who had archived pretreatment fluorine-18 fluorodeoxyglucose positron-emission tomography scans, according to SUVmax.Ten patients (9%) developed local progression, 17 (15%) developed regional progression, and 19 (16%) developed distant metastasis. Two-year freedom from local progression, freedom from regional progression, and freedom from distant metastasis (FFDM) were 88%, 83%, and 83%, respectively. Overall survival was 70% at 2 years. FFDM was significantly associated with MP contact, maximum tumor dimension, and SUVmax, and these variables could be combined into an exploratory prognostic index that identified patients at highest risk for developing metastases.In our cohort, noninvasive, imaging-based features were associated with distant progression after SABR for early stage NSCLC. If validated, our prognostic index could allow identification of patients who might benefit from systemic therapy after SABR.

    View details for DOI 10.1016/j.cllc.2013.12.011

    View details for PubMedID 24594400

  • Feasibility and Potential Utility of Multicomponent Exhaled Breath Analysis for Predicting Development of Radiation Pneumonitis After Stereotactic Ablative Radiotherapy JOURNAL OF THORACIC ONCOLOGY More, J. M., Eclov, N. C., Chung, M. P., Wynne, J. F., Shorter, J. H., Nelson, D. D., Hanlon, A. L., Burmeister, R., Banos, P., Maxim, P. G., Loo, B. W., Diehn, M. 2014; 9 (7): 957-964

    Abstract

    In this prospective pilot study, we evaluated the feasibility and potential utility of measuring multiple exhaled gases as biomarkers of radiation pneumonitis (RP) in patients receiving stereotactic ablative radiotherapy (SABR) for lung tumors.Breath analysis was performed for 26 patients receiving SABR for lung tumors. Concentrations of exhaled nitric oxide (eNO), carbon monoxide (eCO), nitrous oxide (eN2O), and carbon dioxide (eCO2) were measured before and immediately after each fraction using real-time, infrared laser spectroscopy. RP development (CTCAE grade ≥2) was correlated with baseline gas concentrations, acute changes in gas concentrations after each SABR fraction, and dosimetric parameters.Exhaled breath analysis was successfully completed in 77% of patients. Five of 20 evaluable patients developed RP at a mean of 5.4 months after SABR. Acute changes in eNO and eCO concentrations, defined as percent changes between each pre-fraction and post-fraction measurement, were significantly smaller in RP versus non-RP cases (p = 0.022 and 0.015, respectively). In an exploratory analysis, a combined predictor of baseline eNO greater than 24 parts per billion and acute decrease in eCO less than 5.5% strongly correlated with RP incidence (p =0.0099). Neither eN2O nor eCO2 concentrations were significantly associated with RP development. Although generally higher in patients destined to develop RP, dosimetric parameters were not significantly associated with RP development.The majority of SABR patients in this pilot study were able to complete exhaled breath analysis. Baseline concentrations and acute changes in concentrations of exhaled breath components were associated with RP development after SABR. If our findings are validated, exhaled breath analysis may become a useful approach for noninvasive identification of patients at highest risk for developing RP after SABR.

    View details for DOI 10.1097/JTO.0000000000000182

    View details for Web of Science ID 000338025600015

  • Novel Lung Ventilation Imaging with Single Energy CT After Single Inhalation of Xenon: Comparison with SPECT Ventilation Images Negahdar, M., Yamamoto, T., Shultz, D., Gable, L., Shan, X., Mittra, E., Diehn, M., Loo, B., Maxim, P. WILEY. 2014: 450
  • The Impact of Audiovisual Biofeedback On Image Quality During 4D Functional and Anatomic Imaging: Results of a Prospective Clinical Trial Keall, P., Yang, J., Yamamoto, T., Pollock, S., Diehn, M., Berger, J., Graves, E., Loo, B. WILEY. 2014

    View details for DOI 10.1118/1.4887897

    View details for Web of Science ID 000439377700025

  • Predictive Modeling of Outcome Following SABR for NSCLC Based On Radiomics of FDG-PET Images Li, R., Aguilera, T., Shultz, D., Rubin, D., Diehn, M., Loo, B. WILEY. 2014

    View details for DOI 10.1118/1.4889444

    View details for Web of Science ID 000438448700004

  • Noninvasive and ultrasensitive quantitation of circulating tumor DNA by hybrid capture and deep sequencing. Bratman, S., Newman, A. M., To, J., Wynne, J. F., Neal, J. W., Wakelee, H. A., Shrager, J. B., Loo, B. W., Diehn, M., Alizadeh, A. A. AMER SOC CLINICAL ONCOLOGY. 2014
  • Noninvasive monitoring of cellular versus acellular tumor DNA from immunoglobulin genes for DLBCL. Kurtz, D., Green, M. R., Bratman, S., Liu, C., Glover, C., Keane, C., Kong, K., Faham, M., Miklos, D., Advani, R. H., Levy, R., Hertzberg, M. S., Gandhi, M. K., Diehn, M., Alizadeh, A. A. AMER SOC CLINICAL ONCOLOGY. 2014
  • The effect of arm position on the dosimetry of thoracic stereotactic ablative radiation therapy using volumetric modulated arc therapy. Practical radiation oncology Shultz, D. B., Jang, S. S., Hanlon, A. L., Diehn, M., Loo, B. W., Maxim, P. G. 2014; 4 (3): 192-197

    Abstract

    Patient comfort and positioning stability may be improved in the arms down (AD) compared with the typical arms up (AU) position in thoracic stereotactic ablative radiation therapy (SABR). We compared plan quality for AD vs AU when using volumetric modulated arc therapy (VMAT), and evaluated the sensitivity of AD plans to arm positioning variability.We took plans of 14 patients with 17 lung tumors treated with thoracic SABR using VMAT in the AD position and simulated the same treatments in the AU position by re-optimizing after digitally removing the ipsilateral arm. To evaluate the sensitivity of AD plans to arm positioning variability, all plans were recalculated without re-optimization after assigning water density to the ipsilateral arm (AD-W) and then digitally shifting the arm 2.5 cm anterolaterally (AD-WS).Between AD and AU plans, statistically significant but clinically insignificant (all original planning constraints met) differences were found for the following parameters: mean planning target volume maximum dose, difference of 2.3% of prescription dose (P = .049); mean intermediate dose conformity index, difference of 0.27 (P = .012); median percent lung volume receiving a minimum of 10, 20, and 30 Gy (V10, V20, and V30), differences of 0.5%, 0.2%, and 0.1%, respectively (P = .040, .007, and .001); and median spinal cord maximum dose, difference of 33.5 cGy (P = .017). Similarly, between AD-W and AD-WS plans, statistically significant but clinically insignificant differences were found for median lung V20 and V30, difference of 0.0% for both (P = .034 and .016, by matched pair analysis).Our exploratory planning study suggests that when using VMAT for lung tumor SABR, AD and AU positioning achieve clinically equivalent plan quality, and AD plans are insensitive to relatively large variability in arm position.

    View details for DOI 10.1016/j.prro.2013.07.010

    View details for PubMedID 24766687

  • A Population-Based Comparative Effectiveness Study of Radiation Therapy Techniques in Stage III Non-Small Cell Lung Cancer. International journal of radiation oncology, biology, physics Harris, J. P., Murphy, J. D., Hanlon, A. L., Le, Q., Loo, B. W., Diehn, M. 2014; 88 (4): 872-884

    Abstract

    Concerns have been raised about the potential for worse treatment outcomes because of dosimetric inaccuracies related to tumor motion and increased toxicity caused by the spread of low-dose radiation to normal tissues in patients with locally advanced non-small cell lung cancer (NSCLC) treated with intensity modulated radiation therapy (IMRT). We therefore performed a population-based comparative effectiveness analysis of IMRT, conventional 3-dimensional conformal radiation therapy (3D-CRT), and 2-dimensional radiation therapy (2D-RT) in stage III NSCLC.We used the Surveillance, Epidemiology, and End Results (SEER)-Medicare database to identify a cohort of patients diagnosed with stage III NSCLC from 2002 to 2009 treated with IMRT, 3D-CRT, or 2D-RT. Using Cox regression and propensity score matching, we compared survival and toxicities of these treatments.The proportion of patients treated with IMRT increased from 2% in 2002 to 25% in 2009, and the use of 2D-RT decreased from 32% to 3%. In univariate analysis, IMRT was associated with improved overall survival (OS) (hazard ratio [HR] 0.90, P=.02) and cancer-specific survival (CSS) (HR 0.89, P=.02). After controlling for confounders, IMRT was associated with similar OS (HR 0.94, P=.23) and CSS (HR 0.94, P=.28) compared with 3D-CRT. Both techniques had superior OS compared with 2D-RT. IMRT was associated with similar toxicity risks on multivariate analysis compared with 3D-CRT. Propensity score matched model results were similar to those from adjusted models.In this population-based analysis, IMRT for stage III NSCLC was associated with similar OS and CSS and maintained similar toxicity risks compared with 3D-CRT.

    View details for DOI 10.1016/j.ijrobp.2013.12.010

    View details for PubMedID 24495591

  • Erythropoietin promotes breast tumorigenesis through tumor-initiating cell self-renewal JOURNAL OF CLINICAL INVESTIGATION Zhou, B., Damrauer, J. S., Bailey, S. T., Hadzic, T., Jeong, Y., Clark, K., Fan, C., Murphy, L., Lee, C. Y., Troester, M. A., Miller, C. R., Jin, J., Darr, D., Perou, C. M., Levine, R. L., Diehn, M., Kim, W. Y. 2014; 124 (2): 553-563

    Abstract

    Erythropoietin (EPO) is a hormone that induces red blood cell production. In its recombinant form, EPO is the one of most prescribed drugs to treat anemia, including that arising in cancer patients. In randomized trials, EPO administration to cancer patients has been associated with decreased survival. Here, we investigated the impact of EPO modulation on tumorigenesis. Using genetically engineered mouse models of breast cancer, we found that EPO promoted tumorigenesis by activating JAK/STAT signaling in breast tumor-initiating cells (TICs) and promoted TIC self renewal. We determined that EPO was induced by hypoxia in breast cancer cell lines, but not in human mammary epithelial cells. Additionally, we demonstrated that high levels of endogenous EPO gene expression correlated with shortened relapse-free survival and that pharmacologic JAK2 inhibition was synergistic with chemotherapy for tumor growth inhibition in vivo. These data define an active role for endogenous EPO in breast cancer progression and breast TIC self-renewal and reveal a potential application of EPO pathway inhibition in breast cancer therapy.

    View details for DOI 10.1172/JCI69804

    View details for Web of Science ID 000331413300017

    View details for PubMedID 24435044

  • Illuminating radiogenomic characteristics of glioblastoma multiforme through integration of MR imaging, messenger RNA expression, and DNA copy number variation. Radiology Jamshidi, N., Diehn, M., Bredel, M., Kuo, M. D. 2014; 270 (1): 1-2

    Abstract

    To perform a multilevel radiogenomics study to elucidate the glioblastoma multiforme (GBM) magnetic resonance (MR) imaging radiogenomic signatures resulting from changes in messenger RNA (mRNA) expression and DNA copy number variation (CNV).Radiogenomic analysis was performed at MR imaging in 23 patients with GBM in this retrospective institutional review board-approved HIPAA-compliant study. Six MR imaging features-contrast enhancement, necrosis, contrast-to-necrosis ratio, infiltrative versus edematous T2 abnormality, mass effect, and subventricular zone (SVZ) involvement-were independently evaluated and correlated with matched genomic profiles (global mRNA expression and DNA copy number profiles) in a significant manner that also accounted for multiple hypothesis testing by using gene set enrichment analysis (GSEA), resampling statistics, and analysis of variance to gain further insight into the radiogenomic signatures in patients with GBM.GSEA was used to identify various oncogenic pathways with MR imaging features. Correlations between 34 gene loci were identified that showed concordant variations in gene dose and mRNA expression, resulting in an MR imaging, mRNA, and CNV radiogenomic association map for GBM. A few of the identified gene-to-trait associations include association of the contrast-to-necrosis ratio with KLK3 and RUNX3; association of SVZ involvement with Ras oncogene family members, such as RAP2A, and the metabolic enzyme TYMS; and association of vasogenic edema with the oncogene FOXP1 and PIK3IP1, which is a member of the PI3K signaling network.Construction of an MR imaging, mRNA, and CNV radiogenomic association map has led to identification of MR traits that are associated with some known high-grade glioma biomarkers and association with genomic biomarkers that have been identified for other malignancies but not GBM. Thus, the traits and genes identified on this map highlight new candidate radiogenomic biomarkers for further evaluation in future studies.

    View details for DOI 10.1148/radiol.13130078

    View details for PubMedID 24056404

  • Lung Cancer Stem Cells and Resistance to Radiotherapy CANCER STEM CELLS Bratman, S. V., Diehn, M., Rajasekhar, V. K. 2014: 173–82
  • Neuregulin Autocrine Signaling Promotes Self-Renewal of Breast Tumor-Initiating Cells by Triggering HER2/HER3 Activation CANCER RESEARCH Lee, C. Y., Lin, Y., Bratman, S. V., Feng, W., Kuo, A. H., Scheeren, F. A., Engreitz, J. M., Varma, S., West, R. B., Diehn, M. 2014; 74 (1): 341-352

    Abstract

    Currently, only patients with HER2-positive tumors are candidates for HER2-targeted therapies. However, recent clinical observations suggest that the survival of patients with HER2-low breast cancers, who lack HER2 amplification, may benefit from adjuvant therapy that targets HER2. In this study, we explored a mechanism through which these benefits may be obtained. Prompted by the hypothesis that HER2/HER3 signaling in breast tumor-initiating cells (TIC) promotes self-renewal and survival, we obtained evidence that neuregulin 1 (NRG1) produced by TICs promotes their proliferation and self-renewal in HER2-low tumors, including in triple-negative breast tumors. Pharmacologic inhibition of EGFR, HER2, or both receptors reduced breast TIC survival and self-renewal in vitro and in vivo and increased TIC sensitivity to ionizing radiation. Through a tissue microarray analysis, we found that NRG1 expression and associated HER2 activation occurred in a subset of HER2-low breast cancers. Our results offer an explanation for why HER2 inhibition blocks the growth of HER2-low breast tumors. Moreover, they argue that dual inhibition of EGFR and HER2 may offer a useful therapeutic strategy to target TICs in these tumors. In generating a mechanistic rationale to apply HER2-targeting therapies in patients with HER2-low tumors, this work shows why these therapies could benefit a considerably larger number of patients with breast cancer than they currently reach.

    View details for DOI 10.1158/0008-5472.CAN-13-1055

    View details for Web of Science ID 000329297600033

    View details for PubMedID 24177178

    View details for PubMedCentralID PMC3917843

  • Clinical implementation of intrafraction cone beam computed tomography imaging during lung tumor stereotactic ablative radiation therapy. International journal of radiation oncology, biology, physics Li, R., Han, B., Meng, B., Maxim, P. G., Xing, L., Koong, A. C., Diehn, M., Loo, B. W. 2013; 87 (5): 917-923

    Abstract

    To develop and clinically evaluate a volumetric imaging technique for assessing intrafraction geometric and dosimetric accuracy of stereotactic ablative radiation therapy (SABR).Twenty patients received SABR for lung tumors using volumetric modulated arc therapy (VMAT). At the beginning of each fraction, pretreatment cone beam computed tomography (CBCT) was used to align the soft-tissue tumor position with that in the planning CT. Concurrent with dose delivery, we acquired fluoroscopic radiograph projections during VMAT using the Varian on-board imaging system. Those kilovolt projections acquired during millivolt beam-on were automatically extracted, and intrafraction CBCT images were reconstructed using the filtered backprojection technique. We determined the time-averaged target shift during VMAT by calculating the center of mass of the tumor target in the intrafraction CBCT relative to the planning CT. To estimate the dosimetric impact of the target shift during treatment, we recalculated the dose to the GTV after shifting the entire patient anatomy according to the time-averaged target shift determined earlier.The mean target shift from intrafraction CBCT to planning CT was 1.6, 1.0, and 1.5 mm; the 95th percentile shift was 5.2, 3.1, 3.6 mm; and the maximum shift was 5.7, 3.6, and 4.9 mm along the anterior-posterior, left-right, and superior-inferior directions. Thus, the time-averaged intrafraction gross tumor volume (GTV) position was always within the planning target volume. We observed some degree of target blurring in the intrafraction CBCT, indicating imperfect breath-hold reproducibility or residual motion of the GTV during treatment. By our estimated dose recalculation, the GTV was consistently covered by the prescription dose (PD), that is, V100% above 0.97 for all patients, and minimum dose to GTV >100% PD for 18 patients and >95% PD for all patients.Intrafraction CBCT during VMAT can provide geometric and dosimetric verification of SABR valuable for quality assurance and potentially for treatment adaptation.

    View details for DOI 10.1016/j.ijrobp.2013.08.015

    View details for PubMedID 24113060

  • 4D CT lung ventilation images are affected by the 4D CT sorting method. Medical physics Yamamoto, T., Kabus, S., Lorenz, C., Johnston, E., Maxim, P. G., Diehn, M., Eclov, N., Barquero, C., Loo, B. W., Keall, P. J. 2013; 40 (10): 101907-?

    Abstract

    Four-dimensional (4D) computed tomography (CT) ventilation imaging is a novel promising technique for lung functional imaging. The current standard 4D CT technique using phase-based sorting frequently results in artifacts, which may deteriorate the accuracy of ventilation imaging. The purpose of this study was to quantify the variability of 4D CT ventilation imaging due to 4D CT sorting.4D CT image sets from nine lung cancer patients were each sorted by the phase-based method and anatomic similarity-based method, designed to reduce artifacts, with corresponding ventilation images created for each method. Artifacts in the resulting 4D CT images were quantified with the artifact score which was defined based on the difference between the normalized cross correlation for CT slices within a CT data segment and that for CT slices bordering the interface between adjacent CT data segments. The ventilation variation was quantified using voxel-based Spearman rank correlation coefficients for all lung voxels, and Dice similarity coefficients (DSC) for the spatial overlap of low-functional lung volumes. Furthermore, the correlations with matching single-photon emission CT (SPECT) ventilation images (assumed ground truth) were evaluated for three patients to investigate which sorting method provides higher physiologic accuracy.Anatomic similarity-based sorting reduced 4D CT artifacts compared to phase-based sorting (artifact score, 0.45 ± 0.14 vs 0.58 ± 0.24, p = 0.10 at peak-exhale; 0.63 ± 0.19 vs 0.71 ± 0.31, p = 0.25 at peak-inhale). The voxel-based correlation between the two ventilation images was 0.69 ± 0.26 on average, ranging from 0.03 to 0.85. The DSC was 0.71 ± 0.13 on average. Anatomic similarity-based sorting yielded significantly fewer lung voxels with paradoxical negative ventilation values than phase-based sorting (5.0 ± 2.6% vs 9.7 ± 8.4%, p = 0.05), and improved the correlation with SPECT ventilation regionally.The variability of 4D CT ventilation imaging due to 4D CT sorting was moderate overall and substantial in some cases, suggesting that 4D CT artifacts are an important source of variations in 4D CT ventilation imaging. Reduction of 4D CT artifacts provided more physiologically convincing and accurate ventilation estimates. Further studies are needed to confirm this result.

    View details for DOI 10.1118/1.4820538

    View details for PubMedID 24089909

    View details for PubMedCentralID PMC3785523

  • Clinical impact of dose overestimation by effective path length calculation in stereotactic ablative radiation therapy of lung tumors PRACTICAL RADIATION ONCOLOGY Liu, M. B., Eclov, N. W., Trakul, N., Murphy, J., Diehn, M., Le, Q., Dieterich, S., Maxim, P. G., Loo, B. W. 2013; 3 (4): 294–300
  • Noninvasive and Ultrasensitive Quantitation of Circulating Tumor DNA by Hybrid Capture and Deep Sequencing Bratman, S. V., Newman, A. M., To, J., Wynne, J. F., Neal, J. W., Wakelee, H., Shrager, J., Loo, B. W., Alizadeh, A. A., Diehn, M. ELSEVIER SCIENCE INC. 2013: S92
  • Performance of PET in Evaluating Local Recurrence After Stereotactic Ablative Radiation Therapy for Early Lung Cancer Hiniker, S. M., Modlin, L. A., Harris, J. P., Trakul, N., Quon, A., Maxim, P. G., Graves, E. E., Diehn, M., Loo, B. W. ELSEVIER SCIENCE INC. 2013: S11
  • Validation of Image-Based Biomarkers for Analyzing Long-term Pulmonary Toxicity After Radiation Therapy King, M., Diehn, M., Loo, B., Xing, L. ELSEVIER SCIENCE INC. 2013: S96
  • Analysis of Circulating Tumor Cells in Early Stage Non-Small Cell Lung Cancer Patients Treated With Stereotactic Ablative Radiation Therapy Wynne, J. F., Modlin, L. A., Fan, A., Tran, T., Schwartz, M., Loo, B. W., Diehn, M. ELSEVIER SCIENCE INC. 2013: S200–S201
  • Prognostic Metrics on Serial PET for Lung Tumors Treated With Hypofractionated Radiation Harris, J. P., Chang-Halpenny, C. N., Maxim, P. G., Quon, A., Graves, E. E., Diehn, M., Loo, B. W. ELSEVIER SCIENCE INC. 2013: S511
  • Lung Volume Reduction After Stereotactic Ablative Radiation Therapy of Lung Tumors: Potential Application to Emphysema Binkley, M. S., Shrager, J. B., Trakul, N., Leung, A. N., Popat, R., Atwood, T. F., Maxim, P. G., Diehn, M., Loo, B. W. ELSEVIER SCIENCE INC. 2013: S545–S546
  • Novel Imaging Biomarkers in Stage I Non-Small Cell Lung Cancer Treated With Stereotactic Ablative Radiation Therapy Aguilera, T. A., Daniel, G. I., Shultz, D. B., Trakul, N., Maxim, P. G., Rubin, D. L., Loo, B. W., Diehn, M. ELSEVIER SCIENCE INC. 2013: S546
  • Stromal Contributions to Radiation Resistance of Breast Cancer Stem Cells Bratman, S. V., VanderVorst, K., Feng, W., Diehn, M. ELSEVIER SCIENCE INC. 2013: S633
  • Clinical Implementation of Intrafraction CBCT Imaging During Lung Tumor SABR Li, R., Han, B., Meng, B., Maxim, P., Diehn, M., Xing, L., Koong, A., Loo, B. ELSEVIER SCIENCE INC. 2013: S726
  • The Effect of Arm Position on the Dosimetry of Thoracic Stereotactic Ablative Radiation Therapy Shultz, D. B., Tang, S. S., Diehn, M., Loo, B. W., Maxim, P. ELSEVIER SCIENCE INC. 2013: S736–S737
  • Clinical impact of dose overestimation by effective path length calculation in stereotactic ablative radiation therapy of lung tumors. Practical radiation oncology Liu, M. B., Eclov, N. C., Trakul, N., Murphy, J., Diehn, M., Le, Q., Dieterich, S., Maxim, P. G., Loo, B. W. 2013; 3 (4): 294-300

    Abstract

    To determine the clinical impact of calculated dose differences between effective path length (EPL) and Monte Carlo (MC) algorithms in stereotactic ablative radiation therapy (SABR) of lung tumors.We retrospectively analyzed the treatment plans and clinical outcomes of 77 consecutive patients treated with SABR for 82 lung tumors between 2003 and 2009 at our institution. Sixty treatments were originally planned using EPL, and 22 using MC. All plans were recalculated for the same beam specifications using MC and EPL, respectively. The doses covering 95%, 50%, and 5% (D95, D50, D5, respectively) of the target volumes were compared between EPL and MC (assumed to be the actual delivered dose), both as physical dose and biologically effective dose. Time to local recurrence was correlated with dose by Cox regression analysis. The relationship between tumor control probability (TCP) and biologically effective dose was determined via logistic regression and used to estimate the TCP decrements due to prescribing by EPL calculations.EPL overestimated dose compared with MC in all tumor dose-volume histogram parameters in all plans. The difference was >10% of the MC D95 to the planning target volume and gross tumor volume in 60 of 82 (73%) and 52 of 82 plans (63%), respectively. Local recurrence occurred in 13 of 82 tumors. Controlling for gross tumor volume, higher physical and biologically effective planning target volume D95 correlated significantly with local control (P = .007 and P = .045, respectively). Compared with MC, prescribing based on EPL translated to a median TCP decrement of 4.3% (range, 1.2%-37%) and a >5% decrement in 46% of tumors.Clinical follow-up for local lung tumor control in a sizable cohort of patients treated with SABR demonstrates that EPL overestimates dose by amounts that substantially decrease TCP in a large proportion. EPL algorithms should be avoided for lung tumor SABR.

    View details for DOI 10.1016/j.prro.2012.09.003

    View details for PubMedID 24674401

  • Migration of implanted markers for image-guided lung tumor stereotactic ablative radiotherapy. Journal of applied clinical medical physics Hong, J. C., Eclov, N. C., Yu, Y., Rao, A. K., Dieterich, S., Le, Q., Diehn, M., Sze, D. Y., Loo, B. W., Kothary, N., Maxim, P. G. 2013; 14 (2): 4046-?

    Abstract

    The purpose of this study was to quantify postimplantation migration of percutaneously implanted cylindrical gold seeds ("seeds") and platinum endovascular embolization coils ("coils") for tumor tracking in pulmonary stereotactic ablative radiotherapy (SABR). We retrospectively analyzed the migration of markers in 32 consecutive patients with computed tomography scans postimplantation and at simulation. We implanted 147 markers (59 seeds, 88 coils) in or around 34 pulmonary tumors over 32 procedures, with one lesion implanted twice. Marker coordinates were rigidly aligned by minimizing fiducial registration error (FRE), the root mean square of the differences in marker locations for each tumor between scans. To also evaluate whether single markers were responsible for most migration, we aligned with and without the outlier causing the largest FRE increase per tumor. We applied the resultant transformation to all markers. We evaluated migration of individual markers and FRE of each group. Median scan interval was 8 days. Median individual marker migration was 1.28 mm (interquartile range [IQR] 0.78-2.63 mm). Median lesion FRE was 1.56 mm (IQR 0.92-2.95 mm). Outlier identification yielded 1.03 mm median migration (IQR 0.52-2.21 mm) and 1.97 mm median FRE (IQR 1.44-4.32 mm). Outliers caused a mean and median shift in the centroid of 1.22 and 0.80 mm (95th percentile 2.52 mm). Seeds and coils had no statistically significant difference. Univariate analysis suggested no correlation of migration with the number of markers, contact with the chest wall, or time elapsed. Marker migration between implantation and simulation is limited and unlikely to cause geometric miss during tracking.

    View details for DOI 10.1120/jacmp.v14i2.4046

    View details for PubMedID 23470933

  • Migration of implanted markers for image-guided lung tumor stereotactic ablative radiotherapy JOURNAL OF APPLIED CLINICAL MEDICAL PHYSICS Hong, J. C., Eclov, N. C., Yu, Y., Rao, A. K., Dieterich, S., Quynh-Thu Le, Q. T., Diehn, M., Sze, D. Y., Loo, B. W., Kothary, N., Maxim, P. G. 2013; 14 (2): 77-89
  • The Optimal Use of Radiotherapy in Small Cell Lung Cancer JOURNAL OF THE NATIONAL COMPREHENSIVE CANCER NETWORK Shultz, D. B., Grecula, J. C., Hayman, J., Diehn, M., Loo, B. W. 2013; 11 (1): 107-114
  • Metabolic imaging metrics correlate with survival in early stage lung cancer treated with stereotactic ablative radiotherapy. Lung cancer Abelson, J. A., Murphy, J. D., Trakul, N., Bazan, J. G., Maxim, P. G., Graves, E. E., Quon, A., Le, Q., Diehn, M., Loo, B. W. 2012; 78 (3): 219-224

    Abstract

    To test whether (18)F-fluorodeoxyglucose (FDG) positron emission tomography-computed tomography (PET-CT) imaging metrics correlate with outcomes in patients with stage I non-small cell lung cancer (NSCLC) treated with stereotactic ablative radiotherapy (SABR).Fifty-four patients with stage I NSCLC underwent pre-SABR PET at simulation and/or post-SABR PET within 6 months. We analyzed maximum standardized uptake value (SUV(max)) and metabolic tumor volume defined using several thresholds (MTV50%, or MTV2, 4, 7, and 10). Endpoints included primary tumor control (PTC), progression-free survival (PFS), overall survival (OS) and cancer-specific survival (CSS). We performed Kaplan-Meier, competing risk, and Cox proportional hazards survival analyses.Patients received 25-60 Gy in 1 to 5 fractions. Median follow-up time was 13.2 months. The 1-year estimated PTC, PFS, OS and CSS were 100, 83, 87 and 94%, respectively. Pre-treatment SUV(max) (p=0.014), MTV(7) (p=0.0077), and MTV(10) (p=0.0039) correlated significantly with OS. In the low-MTV(7)vs. high-MTV(7) sub-groups, 1-year estimated OS was 100 vs. 78% (p=0.0077) and CSS was 100 vs. 88% (p=0.082).In this hypothesis-generating study we identified multiple pre-treatment PET-CT metrics as potential predictors of OS and CSS in patients with NSCLC treated with SABR. These could aid risk-stratification and treatment individualization if validated prospectively.

    View details for DOI 10.1016/j.lungcan.2012.08.016

    View details for PubMedID 23009727

  • Metabolic imaging metrics correlate with survival in early stage lung cancer treated with stereotactic ablative radiotherapy LUNG CANCER Abelson, J. A., Murphy, J. D., Trakul, N., Bazan, J. G., Maxim, P. G., Graves, E. E., Quon, A., Quynh-Thu Le, Q. T., Diehn, M., Loo, B. W. 2012; 78 (3): 219-224

    Abstract

    To test whether (18)F-fluorodeoxyglucose (FDG) positron emission tomography-computed tomography (PET-CT) imaging metrics correlate with outcomes in patients with stage I non-small cell lung cancer (NSCLC) treated with stereotactic ablative radiotherapy (SABR).Fifty-four patients with stage I NSCLC underwent pre-SABR PET at simulation and/or post-SABR PET within 6 months. We analyzed maximum standardized uptake value (SUV(max)) and metabolic tumor volume defined using several thresholds (MTV50%, or MTV2, 4, 7, and 10). Endpoints included primary tumor control (PTC), progression-free survival (PFS), overall survival (OS) and cancer-specific survival (CSS). We performed Kaplan-Meier, competing risk, and Cox proportional hazards survival analyses.Patients received 25-60 Gy in 1 to 5 fractions. Median follow-up time was 13.2 months. The 1-year estimated PTC, PFS, OS and CSS were 100, 83, 87 and 94%, respectively. Pre-treatment SUV(max) (p=0.014), MTV(7) (p=0.0077), and MTV(10) (p=0.0039) correlated significantly with OS. In the low-MTV(7)vs. high-MTV(7) sub-groups, 1-year estimated OS was 100 vs. 78% (p=0.0077) and CSS was 100 vs. 88% (p=0.082).In this hypothesis-generating study we identified multiple pre-treatment PET-CT metrics as potential predictors of OS and CSS in patients with NSCLC treated with SABR. These could aid risk-stratification and treatment individualization if validated prospectively.

    View details for DOI 10.1016/j.lungcan.2012.08.016

    View details for Web of Science ID 000311881400008

  • Anatomic and Metabolic Predictors of Failure After Stereotactic Ablative Radiation Therapy for Non-small Cell Lung Cancer Shultz, D. B., Trakul, N., Abelson, J. A., Murphy, J. D., Lee, Q. T., Loo, B. W., Diehn, M. ELSEVIER SCIENCE INC. 2012: S571–S572
  • Improved Outcomes in Stage I NSCLC Patients Treated in the Stereotactic Ablative Radiation Therapy Era: A Population-based Analysis Trakul, N., Murphy, J. D., Loo, B. W., Diehn, M. ELSEVIER SCIENCE INC. 2012: S608
  • Stereotactic Ablative Radiotherapy for Reirradiation of Locally Recurrent Lung Tumors JOURNAL OF THORACIC ONCOLOGY Trakul, N., Harris, J. P., Le, Q., Hara, W. Y., Maxim, P. G., Loo, B. W., Diehn, M. 2012; 7 (9): 1462-1465

    Abstract

    Patients with thoracic tumors that recur after irradiation currently have limited therapeutic options. Retreatment using stereotactic ablative radiotherapy (SABR) is appealing for these patients because of its high conformity but has not been studied extensively. Here we report our experience with SABR for lung tumors in previously irradiated regions.We conducted a retrospective study of patients with primary lung cancer or metastatic lung tumors treated with SABR. We identified 17 such tumors in 15 patients and compared their outcomes with those of a cohort of 135 previously unirradiated lung tumors treated with SABR during the same time period.Twelve-month local control (LC) for retreated tumors was 65.5%, compared with 92.1% for tumors receiving SABR as initial treatment. Twelve-month LC was significantly worse for reirradiated tumors in which the time interval between treatments was 16 months or less (46.7%), compared with those with longer intertreatment intervals (87.5%). SABR reirradiation did not lead to significant increases in treatment-related toxicity.SABR for locally recurrent lung tumors arising in previously irradiated fields seems to be feasible and safe for appropriately selected patients. LC of retreated lesions was significantly lower, likely owing to the lower doses used for retreatment. Shorter time to retreatment was associated with increased risk of local failure, suggesting that these tumors may be particularly radioresistant. Our findings suggest that dose escalation may improve LC while maintaining acceptable levels of toxicity for these patients.

    View details for DOI 10.1097/JTO.0b013e31825f22ce

    View details for Web of Science ID 000308073300024

    View details for PubMedID 22895143

  • Tumor Volume-Adapted Dosing in Stereotactic Ablative Radiotherapy of Lung Tumors INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS Trakul, N., Chang, C. N., Harris, J., Chapman, C., Rao, A., Shen, J., Quinlan-Davidson, S., Filion, E. J., Wakelee, H. A., Colevas, A. D., Whyte, R. I., Dieterich, S., Maxim, P. G., Hristov, D., Tran, P., Quynh-Thu Le, Q. T., Loo, B. W., Diehn, M. 2012; 84 (1): 231-237

    Abstract

    Current stereotactic ablative radiotherapy (SABR) protocols for lung tumors prescribe a uniform dose regimen irrespective of tumor size. We report the outcomes of a lung tumor volume-adapted SABR dosing strategy.We retrospectively reviewed the outcomes in 111 patients with a total of 138 primary or metastatic lung tumors treated by SABR, including local control, regional control, distant metastasis, overall survival, and treatment toxicity. We also performed subset analysis on 83 patients with 97 tumors treated with a volume-adapted dosing strategy in which small tumors (gross tumor volume <12 mL) received single-fraction regimens with biologically effective doses (BED) <100 Gy (total dose, 18-25 Gy) (Group 1), and larger tumors (gross tumor volume ≥12 mL) received multifraction regimens with BED ≥100 Gy (total dose, 50-60 Gy in three to four fractions) (Group 2).The median follow-up time was 13.5 months. Local control for Groups 1 and 2 was 91.4% and 92.5%, respectively (p = 0.24) at 12 months. For primary lung tumors only (excluding metastases), local control was 92.6% and 91.7%, respectively (p = 0.58). Regional control, freedom from distant metastasis, and overall survival did not differ significantly between Groups 1 and 2. Rates of radiation pneumonitis, chest wall toxicity, and esophagitis were low in both groups, but all Grade 3 toxicities developed in Group 2 (p = 0.02).A volume-adapted dosing approach for SABR of lung tumors seems to provide excellent local control for both small- and large-volume tumors and may reduce toxicity.

    View details for DOI 10.1016/j.ijrobp.2011.10.071

    View details for PubMedID 22381907

  • Intrafraction Verification of Gated RapidArc by Using Beam-Level Kilovoltage X-Ray Images INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS Li, R., Mok, E., Chang, D. T., Daly, M., Loo, B. W., Diehn, M., Quynh-Thu Le, Q. T., Koong, A., Xing, L. 2012; 83 (5): E709-E715

    Abstract

    To verify the geometric accuracy of gated RapidArc treatment using kV images acquired during dose delivery.Twenty patients were treated using the gated RapidArc technique with a Varian TrueBeam STx linear accelerator. One to 7 metallic fiducial markers were implanted inside or near the tumor target before treatment simulation. For patient setup and treatment verification purposes, the internal target volume (ITV) was created, corresponding to each implanted marker. The gating signal was generated from the Real-time Position Management (RPM) system. At the beginning of each fraction, individualized respiratory gating amplitude thresholds were set based on fluoroscopic image guidance. During the treatment, we acquired kV images immediately before MV beam-on at every breathing cycle, using the on-board imaging system. After the treatment, all implanted markers were detected, and their 3-dimensional (3D) positions in the patient were estimated using software developed in-house. The distance from the marker to the corresponding ITV was calculated for each patient by averaging over all markers and all fractions.The average 3D distance between the markers and their ITVs was 0.8 ± 0.5 mm (range, 0-1.7 mm) and was 2.1 ± 1.2 mm at the 95th percentile (range, 0-3.8 mm). On average, a left-right margin of 0.6 mm, an anterior-posterior margin of 0.8 mm, and a superior-inferior margin of 1.5 mm is required to account for 95% of the intrafraction uncertainty in RPM-based RapidArc gating.To our knowledge, this is the first clinical report of intrafraction verification of respiration-gated RapidArc treatment in stereotactic ablative radiation therapy. For some patients, the markers deviated significantly from the ITV by more than 2 mm at the beginning of the MV beam-on. This emphasizes the need for gating techniques with beam-on/-off controlled directly by the actual position of the tumor target instead of external surrogates such as RPM.

    View details for DOI 10.1016/j.ijrobp.2012.03.006

    View details for PubMedID 22554582

  • Characterizing a new population of adult mouse submandibular gland stem cells Xiao, N., Lin, Y., Diehn, M., Quynh-Thu Le AMER ASSOC CANCER RESEARCH. 2012
  • A let-7 signaling pathway targets metastatic genes enriched in tumor initiating cells Frankenberger, C. A., Yun, J., Eves, E. M., Diehn, M., Minn, A. J., Rosner, M. R. AMER ASSOC CANCER RESEARCH. 2012
  • RESPONSE TO "STEREOTACTIC ABLATIVE RADIOTHERAPY IN THE FRAMEWORK OF CLASSICAL RADIOBIOLOGY: RESPONSE TO DRS. BROWN, DIEHN, AND LOO." (INT J RADIAT ONCOL BIOL PHYS 2011;79:1599-1600) AND "INFLUENCE OF TUMOR HYPOXIA ON STEREOTACTIC ABLATIVE RADIOTHERAPY (SABR): RESPONSE TO DRS. MAYER AND TIMMERMAN." (INT J RADIATION ONCOL BIOL PHYS 2011;78:1600) REPLY INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS Brown, M., Loo, B. W., Diehn, M., Carlson, D. J. 2011; 81 (4): 1194
  • What the Diagnostic Radiologist Needs to Know about Radiation Oncology RADIOLOGY Terezakis, S. A., Heron, D. E., Lavigne, R. F., Diehn, M., Loo, B. W. 2011; 261 (1): 30-44

    Abstract

    Substantial technologic advances in radiation treatment planning and delivery have made possible exquisite tailoring of three-dimensional radiation dose distributions that conform to the tumor treatment volume while avoiding adjacent normal tissues. Although such highly precise treatment can increase the therapeutic ratio, it also introduces the potential that tumor extension outside the target is missed because it is unrecognized at the time of radiation treatment planning. As a result, accurate targeting of the tumor with radiation is of utmost importance to the radiation oncologist. Communication between diagnostic radiologists and radiation oncologists is essential, particularly given the subtleties that accompany image interpretation, to optimize the care of the cancer patient.

    View details for DOI 10.1148/radiol.11101688

    View details for Web of Science ID 000295039000006

    View details for PubMedID 21931140

  • HIGH RETENTION AND SAFETY OF PERCUTANEOUSLY IMPLANTED ENDOVASCULAR EMBOLIZATION COILS AS FIDUCIAL MARKERS FOR IMAGE-GUIDED STEREOTACTIC ABLATIVE RADIOTHERAPY OF PULMONARY TUMORS INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS Hong, J. C., Yu, Y., Rao, A. K., Ditererich, S., Maxim, P. G., Le, Q., Diehn, M., Sze, D. Y., Kothary, N., Loo, B. W. 2011; 81 (1): 85-90

    Abstract

    To compare the retention rates of two types of implanted fiducial markers for stereotactic ablative radiotherapy (SABR) of pulmonary tumors, smooth cylindrical gold "seed" markers ("seeds") and platinum endovascular embolization coils ("coils"), and to compare the complication rates associated with the respective implantation procedures.We retrospectively analyzed the retention of percutaneously implanted markers in 54 consecutive patients between January 2004 and June 2009. A total of 270 markers (129 seeds, 141 coils) were implanted in or around 60 pulmonary tumors over 59 procedures. Markers were implanted using a percutaneous approach under computed tomography (CT) guidance. Postimplantation and follow-up imaging studies were analyzed to score marker retention relative to the number of markers implanted. Markers remaining near the tumor were scored as retained. Markers in a distant location (e.g., pleural space) were scored as lost. CT imaging artifacts near markers were quantified on radiation therapy planning scans.Immediately after implantation, 140 of 141 coils (99.3%) were retained, compared to 110 of 129 seeds (85.3%); the difference was highly significant (p<0.0001). Of the total number of lost markers, 45% were reported lost during implantation, but 55% were lost immediately afterwards. No additional markers were lost on longer-term follow-up. Implanted lesions were peripherally located for both seeds (mean distance, 0.33 cm from pleural surface) and coils (0.34 cm) (p=0.96). Incidences of all pneumothorax (including asymptomatic) and pneumothorax requiring chest tube placement were lower in implantation of coils (23% and 3%, respectively) vs. seeds (54% and 29%, respectively; p=0.02 and 0.01). The degree of CT artifact was similar between marker types.Retention of CT-guided percutaneously implanted coils is significantly better than that of seed markers. Furthermore, implanting coils is at least as safe as implanting seeds. Using coils should permit implantation of fewer markers and require fewer repeat implantation procedures owing to lost markers.

    View details for DOI 10.1016/j.ijrobp.2010.04.037

    View details for PubMedID 20675070

  • CANCER STEM CELLS AND RADIORESISTANCE Diehn, M. LIPPINCOTT WILLIAMS & WILKINS. 2011: S166
  • MID-RADIATION THERAPY PET CORRELATES WITH SURVIVAL IN LOCALLY ADVANCED NSCLC Loo, B. W., Chang, C., Hong, J., Wakelee, H., Quynh Thu Le, Hara, W. Y., Quon, A., Maxim, P. G., Graves, E. E., Diehn, M., Olson, M. LIPPINCOTT WILLIAMS & WILKINS. 2011: S694–S695
  • Reducing 4D CT artifacts using optimized sorting based on anatomic similarity MEDICAL PHYSICS Johnston, E., Diehn, M., Murphy, J. D., Loo, B. W., Maxim, P. G. 2011; 38 (5): 2424-2429

    Abstract

    Four-dimensional (4D) computed tomography (CT) has been widely used as a tool to characterize respiratory motion in radiotherapy. The two most commonly used 4D CT algorithms sort images by the associated respiratory phase or displacement into a predefined number of bins, and are prone to image artifacts at transitions between bed positions. The purpose of this work is to demonstrate a method of reducing motion artifacts in 4D CT by incorporating anatomic similarity into phase or displacement based sorting protocols.Ten patient datasets were retrospectively sorted using both the displacement and phase based sorting algorithms. Conventional sorting methods allow selection of only the nearest-neighbor image in time or displacement within each bin. In our method, for each bed position either the displacement or the phase defines the center of a bin range about which several candidate images are selected. The two dimensional correlation coefficients between slices bordering the interface between adjacent couch positions are then calculated for all candidate pairings. Two slices have a high correlation if they are anatomically similar. Candidates from each bin are then selected to maximize the slice correlation over the entire data set using the Dijkstra's shortest path algorithm. To assess the reduction of artifacts, two thoracic radiation oncologists independently compared the resorted 4D datasets pairwise with conventionally sorted datasets, blinded to the sorting method, to choose which had the least motion artifacts. Agreement between reviewers was evaluated using the weighted kappa score.Anatomically based image selection resulted in 4D CT datasets with significantly reduced motion artifacts with both displacement (P = 0.0063) and phase sorting (P = 0.00022). There was good agreement between the two reviewers, with complete agreement 34 times and complete disagreement 6 times.Optimized sorting using anatomic similarity significantly reduces 4D CT motion artifacts compared to conventional phase or displacement based sorting. This improved sorting algorithm is a straightforward extension of the two most common 4D CT sorting algorithms.

    View details for DOI 10.1118/1.3577601

    View details for Web of Science ID 000290625700016

    View details for PubMedID 21776777

  • Tumor Volume as a Potential Imaging-Based Risk-Stratification Factor in Trimodality Therapy for Locally Advanced Non-small Cell Lung Cancer JOURNAL OF THORACIC ONCOLOGY Kozak, M. M., Murphy, J. D., Schipper, M. L., Donington, J. S., Zhou, L., Whyte, R. I., Shrager, J. B., Hoang, C. D., Bazan, J., Maxim, P. G., Graves, E. E., Diehn, M., Hara, W. Y., Quon, A., Quynh-Thu Le, Q. T., Wakelee, H. A., Loo, B. W. 2011; 6 (5): 920-926

    Abstract

    The role of trimodality therapy for locally advanced non-small cell lung cancer (NSCLC) continues to be defined. We hypothesized that imaging parameters on pre- and postradiation positron emission tomography (PET)-computed tomography (CT) imaging are prognostic for outcome after preoperative chemoradiotherapy (CRT)/resection/consolidation chemotherapy and could help risk-stratify patients in clinical trials.We enrolled 13 patients on a prospective clinical trial of trimodality therapy for resectable locally advanced NSCLC. PET-CT was acquired for radiation planning and after 45 Gy. Gross tumor volume (GTV) and standardized uptake value were measured at pre- and post-CRT time points and correlated with nodal pathologic complete response, loco-regional and/or distant progression, and overall survival. In addition, we evaluated the performance of automatic deformable image registration (ADIR) software for volumetric response assessment.All patients responded with average total GTV reductions after 45 Gy of 43% (range: 27-64%). Pre- and post-CRT GTVs were highly correlated (R² = 0.9), and their respective median values divided the patients into the same two groups. ADIR measurements agreed closely with manually segmented post-CRT GTVs. Patients with GTV ≥ median (137 ml pre-CRT and 67 ml post-CRT) had 3-year progression-free survival (PFS) of 14% versus 75% for GTV less than median, a significant difference (p = 0.049). Pre- and post-CRT PET-standardized uptake value did not correlate significantly with pathologic complete response, PFS, or overall survival.Preoperative CRT with carboplatin/docetaxel/45 Gy resulted in excellent response rates. In this exploratory analysis, pre- and post-CRT GTV predicted PFS in trimodality therapy, consistent with our earlier studies in a broader cohort of NSCLC. ADIR seems robust enough for volumetric response assessment in clinical trials.

    View details for DOI 10.1097/JTO.0b013e31821517db

    View details for PubMedID 21774104

  • INFLUENCE OF TUMOR HYPOXIA ON STEREOTACTIC ABLATIVE RADIOTHERAPY (SABR): RESPONSE TO DRS. MEYER AND TIMMERMAN INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS Brown, M., Lao, B., Diehn, M., Carlson, D. 2011; 79 (5): 1600
  • Ray-trace Calculation Significantly Overestimates Dose Compared To Monte Carlo Calculation In CyberKnife Stereotactic Ablative Radiotherapy Of Lung Tumors Liu, M. B., Eclov, N., Trakul, N., Diehn, M., Maxim, P. G., Dieterich, S., Loo, B. W. ELSEVIER SCIENCE INC. 2011: S853
  • Mechanisms of Radioresistance in Cancer Stem Cells CANCER STEM CELLS IN SOLID TUMORS Lee, C., Diehn, M., Allan, A. L. 2011: 345–60
  • Impact of Audiovisual Biofeedback on 4D PET Image Quality Yang, J., Yamamoto, T., Gopalan, S., Cui, G., Diehn, M., Berger, J., Loo, B. W., Graves, E. E., Keall, P. J. ELSEVIER SCIENCE INC. 2011: S831–S832
  • Impact of Audiovisual Biofeedback on 4D-CT Image Quality Yamamoto, T., Gopalan, S., Cui, G., Diehn, M., Berger, J., Loo, B. W., Keall, P. J. ELSEVIER SCIENCE INC. 2011: S841–S842
  • The Myc Connection: ES Cells and Cancer CELL Rothenberg, M. E., Clarke, M. F., Diehn, M. 2010; 143 (2): 184-186

    Abstract

    Gene profiling experiments have revealed similarities between cancer and embryonic stem (ES) cells. Kim et al. (2010) dissect the gene expression signature of ES cells into three functional modules and find that the Myc module, including genes targeted by Myc-interacting proteins, accounts for most of the similarity between ES and cancer cells.

    View details for DOI 10.1016/j.cell.2010.09.046

    View details for Web of Science ID 000283052200007

    View details for PubMedID 20946977

  • STEREOTACTIC ABLATIVE RADIOTHERAPY SHOULD BE COMBINED WITH A HYPOXIC CELL RADIOSENSITIZER INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS Brown, J. M., Diehn, M., Loo, B. W. 2010; 78 (2): 323-327

    Abstract

    To evaluate the effect of tumor hypoxia on the expected level of cell killing by regimens of stereotactic ablative radiotherapy (SABR) and to determine the extent to which the negative effect of hypoxia could be prevented using a clinically available hypoxic cell radiosensitizer.We have calculated the expected level of tumor cell killing from regimens of SABR, both with and without the assumption that 20% of the tumor cells are hypoxic, using the standard linear quadratic model and the universal survival curve modification. We compare the results obtained with our own clinical data for lung tumors of different sizes and with published data from other studies. We also have calculated the expected effect on cell survival of adding the hypoxic cell sensitizer etanidazole at clinically achievable drug concentrations. Modeling tumor cell killing with any of the currently used regimens of SABR produces results that are inconsistent with the majority of clinical findings if tumor hypoxia is not considered. However, with the assumption of tumor hypoxia, the expected level of cell killing is consistent with clinical data. For only some of the smallest tumors are the clinical data consistent with no tumor hypoxia, but there could be other reasons for the sensitivity of these tumors. The addition of etanidazole at clinically achievable tumor concentrations produces a large increase in the expected level of tumor cell killing from the large radiation doses used in SABR.The presence of tumor hypoxia is a major negative factor in limiting the curability of tumors by SABR at radiation doses that are tolerable to surrounding normal tissues. However, this negative effect of hypoxia could be overcome by the addition of clinically tolerable doses of the hypoxic cell radiosensitizer etanidazole.

    View details for DOI 10.1016/j.ijrobp.2010.04.070

    View details for Web of Science ID 000282147000002

    View details for PubMedID 20832663

    View details for PubMedCentralID PMC2939040

  • Metastatic Cancer Stem Cells: An Opportunity for Improving Cancer Treatment? CELL STEM CELL Diehn, M., Majeti, R. 2010; 6 (6): 502-503

    View details for DOI 10.1016/j.stem.2010.05.001

    View details for Web of Science ID 000278840700006

    View details for PubMedID 20569685

  • Identification, molecular characterization, clinical prognosis, and therapeutic targeting of human bladder tumor-initiating cells PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Chan, K. S., Espinosa, I., Chao, M., Wong, D., Ailles, L., Diehn, M., Gill, H., Presti, J., Chang, H. Y., van de Rijn, M., Shortliffe, L., Weissman, I. L. 2009; 106 (33): 14016-14021

    Abstract

    Major clinical issues in bladder cancer include the identification of prediction markers and novel therapeutic targets for invasive bladder cancer. In the current study, we describe the isolation and characterization of a tumor-initiating cell (T-IC) subpopulation in primary human bladder cancer, based on the expression of markers similar to that of normal bladder basal cells (Lineage-CD44(+)CK5(+)CK20(-)). The bladder T-IC subpopulation was defined functionally by its enriched ability to induce xenograft tumors in vivo that recapitulated the heterogeneity of the original tumor. Further, molecular analysis of more than 300 bladder cancer specimens revealed heterogeneity among activated oncogenic pathways in T-IC (e.g., 80% Gli1, 45% Stat3, 10% Bmi-1, and 5% beta-catenin). Despite this molecular heterogeneity, we identified a unique bladder T-IC gene signature by gene chip analysis. This T-IC gene signature, which effectively distinguishes muscle-invasive bladder cancer with worse clinical prognosis from non-muscle-invasive (superficial) cancer, has significant clinical value. It also can predict the progression of a subset of recurring non-muscle-invasive cancers. Finally, we found that CD47, a protein that provides an inhibitory signal for macrophage phagocytosis, is highly expressed in bladder T-ICs compared with the rest of the tumor. Blockade of CD47 by a mAb resulted in macrophage engulfment of bladder cancer cells in vitro. In summary, we have identified a T-IC subpopulation with potential prognostic and therapeutic value for invasive bladder cancer.

    View details for DOI 10.1073/pnas.0906549106

    View details for PubMedID 19666525

  • Downregulation of miRNA-200c Links Breast Cancer Stem Cells with Normal Stem Cells CELL Shimono, Y., Zabala, M., Cho, R. W., Lobo, N., Dalerba, P., Qian, D., Diehn, M., Liu, H., Panula, S. P., Chiao, E., Dirbas, F. M., Somlo, G., Pera, R. A., Lao, K., Clarke, M. F. 2009; 138 (3): 592-603

    Abstract

    Human breast tumors contain a breast cancer stem cell (BCSC) population with properties reminiscent of normal stem cells. We found 37 microRNAs that were differentially expressed between human BCSCs and nontumorigenic cancer cells. Three clusters, miR-200c-141, miR-200b-200a-429, and miR-183-96-182 were downregulated in human BCSCs, normal human and murine mammary stem/progenitor cells, and embryonal carcinoma cells. Expression of BMI1, a known regulator of stem cell self-renewal, was modulated by miR-200c. miR-200c inhibited the clonal expansion of breast cancer cells and suppressed the growth of embryonal carcinoma cells in vitro. Most importantly, miR-200c strongly suppressed the ability of normal mammary stem cells to form mammary ducts and tumor formation driven by human BCSCs in vivo. The coordinated downregulation of three microRNA clusters and the similar functional regulation of clonal expansion by miR-200c provide a molecular link that connects BCSCs with normal stem cells.

    View details for DOI 10.1016/j.cell.2009.07.011

    View details for Web of Science ID 000268771900022

    View details for PubMedID 19665978

    View details for PubMedCentralID PMC2731699

  • Association of reactive oxygen species levels and radioresistance in cancer stem cells NATURE Diehn, M., Cho, R. W., Lobo, N. A., Kalisky, T., Dorie, M. J., Kulp, A. N., Qian, D., Lam, J. S., Ailles, L. E., Wong, M., Joshua, B., Kaplan, M. J., Wapnir, I., Dirbas, F. M., Somlo, G., Garberoglio, C., Paz, B., Shen, J., Lau, S. K., Quake, S. R., Brown, J. M., Weissman, I. L., Clarke, M. F. 2009; 458 (7239): 780-U123

    Abstract

    The metabolism of oxygen, although central to life, produces reactive oxygen species (ROS) that have been implicated in processes as diverse as cancer, cardiovascular disease and ageing. It has recently been shown that central nervous system stem cells and haematopoietic stem cells and early progenitors contain lower levels of ROS than their more mature progeny, and that these differences are critical for maintaining stem cell function. We proposed that epithelial tissue stem cells and their cancer stem cell (CSC) counterparts may also share this property. Here we show that normal mammary epithelial stem cells contain lower concentrations of ROS than their more mature progeny cells. Notably, subsets of CSCs in some human and murine breast tumours contain lower ROS levels than corresponding non-tumorigenic cells (NTCs). Consistent with ROS being critical mediators of ionizing-radiation-induced cell killing, CSCs in these tumours develop less DNA damage and are preferentially spared after irradiation compared to NTCs. Lower ROS levels in CSCs are associated with increased expression of free radical scavenging systems. Pharmacological depletion of ROS scavengers in CSCs markedly decreases their clonogenicity and results in radiosensitization. These results indicate that, similar to normal tissue stem cells, subsets of CSCs in some tumours contain lower ROS levels and enhanced ROS defences compared to their non-tumorigenic progeny, which may contribute to tumour radioresistance.

    View details for DOI 10.1038/nature07733

    View details for PubMedID 19194462

  • Therapeutic Implications of the Cancer Stem Cell Hypothesis SEMINARS IN RADIATION ONCOLOGY Diehn, M., Cho, R. W., Clarke, M. F. 2009; 19 (2): 78-86

    Abstract

    A growing body of evidence indicates that subpopulations of cancer stem cells (CSCs) drive and maintain many types of human malignancies. These findings have important implications for the development and evaluation of oncologic therapies and present opportunities for potential gains in patient outcome. The existence of CSCs mandates careful analysis and comparison of normal tissue stem cells and CSCs to identify differences between the two cell types. The development of CSC-targeted treatments will face a number of potential hurdles, including normal stem cell toxicity and the acquisition of treatment resistance, which must be considered in order to maximize the chance that such therapies will be successful.

    View details for DOI 10.1016/j.semradonc.2008.11.002

    View details for Web of Science ID 000264310800003

    View details for PubMedID 19249645

    View details for PubMedCentralID PMC2789266

  • Characterizing metastatic cancer stem cells from human breast cancer Liu, H., Qian, D., Lin, J., Lobo, N., Zhang, H., Dalerba, P., Shimono, Y., Diehn, M., Jeffrey, S., Clarke, M. AMER ASSOC CANCER RESEARCH. 2008
  • Identification of noninvasive imaging surrogates for brain tumor gene-expression modules PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Diehn, M., Nardini, C., Wang, D. S., McGovern, S., Jayaraman, M., Liang, Y., Alclape, K., Cha, S., Kuo, M. D. 2008; 105 (13): 5213-5218

    Abstract

    Glioblastoma multiforme (GBM) is the most common and lethal primary brain tumor in adults. We combined neuroimaging and DNA microarray analysis to create a multidimensional map of gene-expression patterns in GBM that provided clinically relevant insights into tumor biology. Tumor contrast enhancement and mass effect predicted activation of specific hypoxia and proliferation gene-expression programs, respectively. Overexpression of EGFR, a receptor tyrosine kinase and potential therapeutic target, was also directly inferred by neuroimaging and was validated in an independent set of tumors by immunohistochemistry. Furthermore, imaging provided insights into the intratumoral distribution of gene-expression patterns within GBM. Most notably, an "infiltrative" imaging phenotype was identified that predicted patient outcome. Patients with this imaging phenotype had a greater tendency toward having multiple tumor foci and demonstrated significantly shorter survival than their counterparts. Our findings provide an in vivo portrait of genome-wide gene expression in GBM and offer a potential strategy for noninvasively selecting patients who may be candidates for individualized therapies.

    View details for DOI 10.1073/pnas.0801279105

    View details for Web of Science ID 000254723700047

    View details for PubMedID 18362333

    View details for PubMedCentralID PMC2278224

  • Isolation and molecular characterization of cancer stem cells in MMTV-Wnt-1 murine breast tumors STEM CELLS Cho, R. W., Wang, X., Diehn, M., Shedden, K., Chen, G. Y., Sherlock, G., Gurney, A., Lewicki, J., Clarke, M. F. 2008; 26 (2): 364-371

    Abstract

    In human breast cancers, a phenotypically distinct minority population of tumorigenic (TG) cancer cells (sometimes referred to as cancer stem cells) drives tumor growth when transplanted into immunodeficient mice. Our objective was to identify a mouse model of breast cancer stem cells that could have relevance to the study of human breast cancer. To do so, we used breast tumors of the mouse mammary tumor virus (MMTV)-Wnt-1 mice. MMTV-Wnt-1 breast tumors were harvested, dissociated into single-cell suspensions, and sorted by flow cytometry on Thy1, CD24, and CD45. Sorted cells were then injected into recipient background FVB/NJ female syngeneic mice. In six of seven tumors examined, Thy1+CD24+ cancer cells, which constituted approximately 1%-4% of tumor cells, were highly enriched for cells capable of regenerating new tumors compared with cells of the tumor that did not fit this profile ("not-Thy1+CD24+"). Resultant tumors had a phenotypic diversity similar to that of the original tumor and behaved in a similar manner when passaged. Microarray analysis comparing Thy1+CD24+ tumor cells to not-Thy1+CD24+ cells identified a list of differentially expressed genes. Orthologs of these differentially expressed genes predicted survival of human breast cancer patients from two different study groups. These studies suggest that there is a cancer stem cell compartment in the MMTV-Wnt-1 murine breast tumor and that there is a clinical utility of this model for the study of cancer stem cells.

    View details for DOI 10.1634/stemcells.2007-0440

    View details for Web of Science ID 000253372600008

    View details for PubMedID 17975224

  • Type I collagen is overexpressed in medulloblastoma as a component of tumor microenvironment JOURNAL OF NEURO-ONCOLOGY Liang, Y., Diehn, M., Bollen, A. W., Israel, M. A., Gupta, N. 2008; 86 (2): 133-141

    Abstract

    Medulloblastoma is the most common malignant brain tumor of children, and more specific and effective therapeutic management needs to be developed to improve upon existing survival rates and to avoid side-effects from current treatment. Gain of chromosome seven is the most frequent chromosome copy number aberration in medulloblastoma, suggesting that overexpression of genes on chromosome seven might be important for the pathogenesis of medulloblastoma. We used microarrays to identify chromosome seven genes overexpressed in medulloblastoma specimens, and validated using data from published gene expression datasets. The gene encoding the alpha 2 subunit of type I collagen, COL1A2, was overexpressed in all three datasets. Immunohistochemistry of tumor tissues revealed type I collagen in the leptomeninges, and in the extracellular matrix surrounding blood vessels and medulloblastoma cells. Expression of both type I collagen and the beta1 subunit of integrin, a subunit of a known type I collagen receptor, localized to the same area of medulloblastoma. Adherence of D283 medulloblastoma cells to type I collagen matrix in vitro depends on the beta1 subunit of integrin. Because medulloblastoma is characteristic of high vascularity, and because inhibition of type I collagen synthesis has been shown to suppress angiogenesis and tumor growth, our data suggest that type I collagen might be a potential therapeutic target for treating medulloblastoma.

    View details for DOI 10.1007/s11060-007-9457-5

    View details for Web of Science ID 000251488000002

    View details for PubMedID 17653508

  • Analyzing the sensitivity of breast cancer stem cells to ionizing radiation and chemotherapy Diehn, M., Cho, R., Dorie, M., Kulp, A., Weissman, I. L., Brown, M., Clarke, M. F. ELSEVIER SCIENCE INC. 2007: S38-S39
  • Cancer stem cells and radiotherapy: New insights into tumor radioresistance JOURNAL OF THE NATIONAL CANCER INSTITUTE Diehn, M., Clarke, M. F. 2006; 98 (24): 1755-1757

    View details for DOI 10.1093/jnci/djj505

    View details for Web of Science ID 000242973400002

    View details for PubMedID 17179471

  • Cell-type specific gene expression profiles of leukocytes in human peripheral blood BMC GENOMICS Palmer, C., Diehn, M., Alizadeh, A. A., Brown, P. O. 2006; 7

    Abstract

    Blood is a complex tissue comprising numerous cell types with distinct functions and corresponding gene expression profiles. We attempted to define the cell type specific gene expression patterns for the major constituent cells of blood, including B-cells, CD4+ T-cells, CD8+ T-cells, lymphocytes and granulocytes. We did this by comparing the global gene expression profiles of purified B-cells, CD4+ T-cells, CD8+ T-cells, granulocytes, and lymphocytes using cDNA microarrays.Unsupervised clustering analysis showed that similar cell populations from different donors share common gene expression profiles. Supervised analyses identified gene expression signatures for B-cells (427 genes), T-cells (222 genes), CD8+ T-cells (23 genes), granulocytes (411 genes), and lymphocytes (67 genes). No statistically significant gene expression signature was identified for CD4+ cells. Genes encoding cell surface proteins were disproportionately represented among the genes that distinguished among the lymphocyte subpopulations. Lymphocytes were distinguishable from granulocytes based on their higher levels of expression of genes encoding ribosomal proteins, while granulocytes exhibited characteristic expression of various cell surface and inflammatory proteins.The genes comprising the cell-type specific signatures encompassed many of the genes already known to be involved in cell-type specific processes, and provided clues that may prove useful in discovering the functions of many still unannotated genes. The most prominent feature of the cell type signature genes was the enrichment of genes encoding cell surface proteins, perhaps reflecting the importance of specialized systems for sensing the environment to the physiology of resting leukocytes.

    View details for DOI 10.1186/1471-2164-7-115

    View details for Web of Science ID 000238364000001

    View details for PubMedID 16704732

    View details for PubMedCentralID PMC1479811

  • Genome-scale identification of membrane-associated human mRNAs PLOS GENETICS Diehn, M., Bhattacharya, R., Botstein, D., Brown, P. O. 2006; 2 (1): 39-50

    Abstract

    The subcellular localization of proteins is critical to their biological roles. Moreover, whether a protein is membrane-bound, secreted, or intracellular affects the usefulness of, and the strategies for, using a protein as a diagnostic marker or a target for therapy. We employed a rapid and efficient experimental approach to classify thousands of human gene products as either "membrane-associated/secreted" (MS) or "cytosolic/nuclear" (CN). Using subcellular fractionation methods, we separated mRNAs associated with membranes from those associated with the soluble cytosolic fraction and analyzed these two pools by comparative hybridization to DNA microarrays. Analysis of 11 different human cell lines, representing lymphoid, myeloid, breast, ovarian, hepatic, colon, and prostate tissues, identified more than 5,000 previously uncharacterized MS and more than 6,400 putative CN genes at high confidence levels. The experimentally determined localizations correlated well with in silico predictions of signal peptides and transmembrane domains, but also significantly increased the number of human genes that could be cataloged as encoding either MS or CN proteins. Using gene expression data from a variety of primary human malignancies and normal tissues, we rationally identified hundreds of MS gene products that are significantly overexpressed in tumors compared to normal tissues and thus represent candidates for serum diagnostic tests or monoclonal antibody-based therapies. Finally, we used the catalog of CN gene products to generate sets of candidate markers of organ-specific tissue injury. The large-scale annotation of subcellular localization reported here will serve as a reference database and will aid in the rational design of diagnostic tests and molecular therapies for diverse diseases.

    View details for DOI 10.1371/journal.pgen.0020011

    View details for Web of Science ID 000239481100004

    View details for PubMedID 16415983

    View details for PubMedCentralID PMC1326219

  • Correlative MR imaging with GBM cancer genomics Kuo, M., Nardini, C., Cha, S., Diehn, M. DUKE UNIV PRESS. 2005: 399
  • Gene expression profiling reveals molecularly and clinically distinct subtypes of glioblastoma multiforme PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Liang, Y., Diehn, M., Watson, N., Bollen, A. W., Aldape, K. D., Nicholas, M. K., Lamborn, K. R., Berger, M. S., Botstein, D., Brown, P. O., Israel, M. A. 2005; 102 (16): 5814-5819

    Abstract

    Glioblastoma multiforme (GBM) is the most common form of malignant glioma, characterized by genetic instability, intratumoral histopathological variability, and unpredictable clinical behavior. We investigated global gene expression in surgical samples of brain tumors. Gene expression profiling revealed large differences between normal brain samples and tumor tissues and between GBMs and lower-grade oligodendroglial tumors. Extensive differences in gene expression were found among GBMs, particularly in genes involved in angiogenesis, immune cell infiltration, and extracellular matrix remodeling. We found that the gene expression patterns in paired specimens from the same GBM invariably were more closely related to each other than to any other tumor, even when the paired specimens had strikingly divergent histologies. Survival analyses revealed a set of approximately 70 genes more highly expressed in rapidly progressing tumors that stratified GBMs into two groups that differed by >4-fold in median duration of survival. We further investigated one gene from the group, FABP7, and confirmed its association with survival in two unrelated cohorts totaling 105 patients. Expression of FABP7 enhanced the motility of glioma-derived cells in vitro. Our analyses thus identify and validate a prognostic marker of both biologic and clinical significance and provide a series of putative markers for additional evaluation.

    View details for DOI 10.1073/pnas.0402870102

    View details for Web of Science ID 000228565200034

    View details for PubMedID 15827123

    View details for PubMedCentralID PMC556127

  • Differential gene expression in anatomical compartments of the human eye GENOME BIOLOGY Diehn, J. J., Diehn, M., Marmor, M. F., Brown, P. O. 2005; 6 (9)

    Abstract

    The human eye is composed of multiple compartments, diverse in form, function, and embryologic origin, that work in concert to provide us with our sense of sight. We set out to systematically characterize the global gene expression patterns that specify the distinctive characteristics of the various eye compartments.We used DNA microarrays representing approximately 30,000 human genes to analyze gene expression in the cornea, lens, iris, ciliary body, retina, and optic nerve. The distinctive patterns of expression in each compartment could be interpreted in relation to the physiology and cellular composition of each tissue. Notably, the sets of genes selectively expressed in the retina and in the lens were particularly large and diverse. Genes with roles in immune defense, particularly complement components, were expressed at especially high levels in the anterior segment tissues. We also found consistent differences between the gene expression patterns of the macula and peripheral retina, paralleling the differences in cell layer densities between these regions. Based on the hypothesis that genes responsible for diseases that affect a particular eye compartment are likely to be selectively expressed in that compartment, we compared our gene expression signatures with genetic mapping studies to identify candidate genes for diseases affecting the cornea, lens, and retina.Through genome-scale gene expression profiling, we were able to discover distinct gene expression 'signatures' for each eye compartment and identified candidate disease genes that can serve as a reference database for investigating the physiology and pathophysiology of the eye.

    View details for DOI 10.1186/gb-2005-6-9-r74

    View details for PubMedID 16168081

  • MRI-guided insights into differential gene expression patterns in GBMs based on tumor location Kuo, M. D., Nardini, C., Wang, D. S., Cha, S., Diehn, M. AMER ROENTGEN RAY SOC. 2005: 5
  • Genome-scale identification of secreted and membrane-associated tumor markers Diehn, M., Bhattacharya, R., Botstein, D., Brown, P. O. ELSEVIER SCIENCE INC. 2005: S458
  • A method for detecting and correcting feature misidentification on expression microarrays BMC GENOMICS Tu, I. P., Schaner, M., Diehn, M., Sikic, B. I., Brown, P. O., Botstein, D., Fero, M. J. 2004; 5

    Abstract

    Much of the microarray data published at Stanford is based on mouse and human arrays produced under controlled and monitored conditions at the Brown and Botstein laboratories and at the Stanford Functional Genomics Facility (SFGF). Nevertheless, as large datasets based on the Stanford Human array began to accumulate, a small but significant number of discrepancies were detected that required a serious attempt to track down the original source of error. Due to a controlled process environment, sufficient data was available to accurately track the entire process leading to up to the final expression data. In this paper, we describe our statistical methods to detect the inconsistencies in microarray data that arise from process errors, and discuss our technique to locate and fix these errors.To date, the Brown and Botstein laboratories and the Stanford Functional Genomics Facility have together produced 40,000 large-scale (10-50,000 feature) cDNA microarrays. By applying the heuristic described here, we have been able to check most of these arrays for misidentified features, and have been able to confidently apply fixes to the data where needed. Out of the 265 million features checked in our database, problems were detected and corrected on 1.3 million of them.Process errors in any genome scale high throughput production regime can lead to subsequent errors in data analysis. We show the value of tracking multi-step high throughput operations by using this knowledge to detect and correct misidentified data on gene expression microarrays.

    View details for DOI 10.1186/1471-2164-5-64

    View details for Web of Science ID 000224203400001

    View details for PubMedID 15357875

    View details for PubMedCentralID PMC521069

  • Investigating differential gene expression in anatomical compartments of the human eye using cDNA microarrays Diehn, J. J., Diehn, M., Marmor, M. F., Brown, P. O. ASSOC RESEARCH VISION OPHTHALMOLOGY INC. 2004: U324
  • Presynaptic homeostasis at CNS nerve terminals compensates for lack of a key Ca2+ entry pathway PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Piedras-Renteria, E. S., Pyle, J. L., Diehn, M., Glickfeld, L. L., Harata, N. C., Cao, Y. Q., Kavalali, E. T., Brown, P. O., Tsien, R. W. 2004; 101 (10): 3609-3614

    Abstract

    At central synapses, P/Q-type Ca(2+) channels normally provide a critical Ca(2+) entry pathway for neurotransmission. Nevertheless, we found that nerve terminals lacking alpha(1A) (Ca(V)2.1), the pore-forming subunit of P/Q-type channels, displayed a remarkable preservation of synaptic function. Two consistent physiological changes reflective of synaptic homeostasis were observed in cultured hippocampal neurons derived from alpha(1A) (-/-) mice. First, the presynaptic response to an ionophore-mediated Ca(2+) elevation was 50% greater, indicating an enhanced Ca(2+) sensitivity of the release machinery. Second, basal miniature excitatory postsynaptic current frequency in alpha(1A) (-/-) neurons was increased 2-fold compared with WT neurons and occluded the normal response of presynaptic terminals to cAMP elevation, suggesting that the compensatory mechanism in alpha(1A) (-/-) synapses and the modulation of presynaptic function by PKA might share a final common pathway. We used cDNA microarray analysis to identify molecular changes underlying homeostatic regulation in the alpha(1A) (-/-) hippocampus. The 40,000 entries in our custom-made array included likely targets of presynaptic homeostasis, along with many other transcripts, allowing a wide-ranging examination of gene expression. The developmental pattern of changes in transcript levels relative to WT was striking; mRNAs at 5 and 11 days postnatal showed little deviation, but clear differences emerged by 22 days. Many of the transcripts that differed significantly in abundance corresponded to known genes that could be incorporated within a logical pattern consistent with the modulation of presynaptic function. Changes in endocytotic proteins, signal transduction kinases, and candidates for Ca(2+)-sensing molecules were consistent with implications of the direct physiological experiments.

    View details for DOI 10.1073/pnas.0308188100

    View details for Web of Science ID 000220163800052

    View details for PubMedID 14990796

    View details for PubMedCentralID PMC373510

  • Gene expression profiles of primary cutaneous T cell lymphoma with focus on CD 30+ anaplastic large cell lymphoma (ALCL): unique clustering pattern of ALCL with extensive limb presentation Storz, M. N., Kim, Y. H., van de Rijn, M., Dick, S., Hoppe, R. T., Diehn, M., Kohler, S. BLACKWELL PUBLISHING INC. 2004: A20
  • T cell receptor-independent basal signaling via Erk and Abl kinases suppresses RAG gene expression. PLoS biology Roose, J. P., Diehn, M., Tomlinson, M. G., Lin, J., Alizadeh, A. A., Botstein, D., Brown, P. O., Weiss, A. 2003; 1 (2): E53-?

    Abstract

    Signal transduction pathways guided by cellular receptors commonly exhibit low-level constitutive signaling in a continuous, ligand-independent manner. The dynamic equilibrium of positive and negative regulators establishes such a tonic signal. Ligand-independent signaling by the precursors of mature antigen receptors regulates development of B and T lymphocytes. Here we describe a basal signal that controls gene expression profiles in the Jurkat T cell line and mouse thymocytes. Using DNA microarrays and Northern blots to analyze unstimulated cells, we demonstrate that expression of a cluster of genes, including RAG-1 and RAG-2, is repressed by constitutive signals requiring the adapter molecules LAT and SLP-76. This TCR-like pathway results in constitutive low-level activity of Erk and Abl kinases. Inhibition of Abl by the drug STI-571 or inhibition of signaling events upstream of Erk increases RAG-1 expression. Our data suggest that physiologic gene expression programs depend upon tonic activity of signaling pathways independent of receptor ligation.

    View details for PubMedID 14624253

  • T cell receptor-independent basal signaling via Erk and Abl kinases suppresses RAG gene expression PLOS BIOLOGY Roose, J. P., Diehn, M., Tomlinson, M. G., Lin, J., Alizadeh, A. A., Botstein, D., Brown, P. O., Weiss, A. 2003; 1 (2): 271-287

    Abstract

    Signal transduction pathways guided by cellular receptors commonly exhibit low-level constitutive signaling in a continuous, ligand-independent manner. The dynamic equilibrium of positive and negative regulators establishes such a tonic signal. Ligand-independent signaling by the precursors of mature antigen receptors regulates development of B and T lymphocytes. Here we describe a basal signal that controls gene expression profiles in the Jurkat T cell line and mouse thymocytes. Using DNA microarrays and Northern blots to analyze unstimulated cells, we demonstrate that expression of a cluster of genes, including RAG-1 and RAG-2, is repressed by constitutive signals requiring the adapter molecules LAT and SLP-76. This TCR-like pathway results in constitutive low-level activity of Erk and Abl kinases. Inhibition of Abl by the drug STI-571 or inhibition of signaling events upstream of Erk increases RAG-1 expression. Our data suggest that physiologic gene expression programs depend upon tonic activity of signaling pathways independent of receptor ligation.

    View details for DOI 10.1371/journal.pbio.0000053

    View details for Web of Science ID 000188835200018

    View details for PubMedCentralID PMC261890

  • Gene expression patterns in ovarian carcinomas MOLECULAR BIOLOGY OF THE CELL Schaner, M. E., Ross, D. T., Ciaravino, G., Sorlie, T., Troyanskaya, O., Diehn, M., Wang, Y. C., Duran, G. E., Sikic, T. L., Caldeira, S., Skomedal, H., Tu, I. P., Hernandez-Boussard, T., Johnson, S. W., O'Dwyer, P. J., Fero, M. J., Kristensen, G. B., Borresen-Dale, A. L., Hastie, T., Tibshirani, R., van de Rijn, M., Teng, N. N., Longacre, T. A., Botstein, D., Brown, P. O., Sikic, B. I. 2003; 14 (11): 4376-4386

    Abstract

    We used DNA microarrays to characterize the global gene expression patterns in surface epithelial cancers of the ovary. We identified groups of genes that distinguished the clear cell subtype from other ovarian carcinomas, grade I and II from grade III serous papillary carcinomas, and ovarian from breast carcinomas. Six clear cell carcinomas were distinguished from 36 other ovarian carcinomas (predominantly serous papillary) based on their gene expression patterns. The differences may yield insights into the worse prognosis and therapeutic resistance associated with clear cell carcinomas. A comparison of the gene expression patterns in the ovarian cancers to published data of gene expression in breast cancers revealed a large number of differentially expressed genes. We identified a group of 62 genes that correctly classified all 125 breast and ovarian cancer specimens. Among the best discriminators more highly expressed in the ovarian carcinomas were PAX8 (paired box gene 8), mesothelin, and ephrin-B1 (EFNB1). Although estrogen receptor was expressed in both the ovarian and breast cancers, genes that are coregulated with the estrogen receptor in breast cancers, including GATA-3, LIV-1, and X-box binding protein 1, did not show a similar pattern of coexpression in the ovarian cancers.

    View details for PubMedID 12960427

  • Individuality and variation in gene expression patterns in human blood PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Whitney, A. R., Diehn, M., Popper, S. J., Alizadeh, A. A., Boldrick, J. C., Relman, D. A., Brown, P. O. 2003; 100 (4): 1896-1901

    Abstract

    The nature and extent of interindividual and temporal variation in gene expression patterns in specific cells and tissues is an important and relatively unexplored issue in human biology. We surveyed variation in gene expression patterns in peripheral blood from 75 healthy volunteers by using cDNA microarrays. Characterization of the variation in gene expression in healthy tissue is an essential foundation for the recognition and interpretation of the changes in these patterns associated with infections and other diseases, and peripheral blood was selected because it is a uniquely accessible tissue in which to examine this variation in patients or healthy volunteers in a clinical setting. Specific features of interindividual variation in gene expression patterns in peripheral blood could be traced to variation in the relative proportions of specific blood cell subsets; other features were correlated with gender, age, and the time of day at which the sample was taken. An analysis of multiple sequential samples from the same individuals allowed us to discern donor-specific patterns of gene expression. These data help to define human individuality and provide a database with which disease-associated gene expression patterns can be compared.

    View details for DOI 10.1073/pnas.252784499

    View details for Web of Science ID 000181073000082

    View details for PubMedID 12578971

    View details for PubMedCentralID PMC149930

  • SOURCE: a unified genomic resource of functional annotations, ontologies, and gene expression data NUCLEIC ACIDS RESEARCH Diehn, M., Sherlock, G., Binkley, G., Jin, H., Matese, J. C., Hernandez-Boussard, T., Rees, C. A., Cherry, J. M., Botstein, D., Brown, P. O., Alizadeh, A. A. 2003; 31 (1): 219-223

    Abstract

    The explosion in the number of functional genomic datasets generated with tools such as DNA microarrays has created a critical need for resources that facilitate the interpretation of large-scale biological data. SOURCE is a web-based database that brings together information from a broad range of resources, and provides it in manner particularly useful for genome-scale analyses. SOURCE's GeneReports include aliases, chromosomal location, functional descriptions, GeneOntology annotations, gene expression data, and links to external databases. We curate published microarray gene expression datasets and allow users to rapidly identify sets of co-regulated genes across a variety of tissues and a large number of conditions using a simple and intuitive interface. SOURCE provides content both in gene and cDNA clone-centric pages, and thus simplifies analysis of datasets generated using cDNA microarrays. SOURCE is continuously updated and contains the most recent and accurate information available for human, mouse, and rat genes. By allowing dynamic linking to individual gene or clone reports, SOURCE facilitates browsing of large genomic datasets. Finally, SOURCEs batch interface allows rapid extraction of data for thousands of genes or clones at once and thus facilitates statistical analyses such as assessing the enrichment of functional attributes within clusters of genes. SOURCE is available at http://source.stanford.edu.

    View details for DOI 10.1093/nar/gkg014

    View details for Web of Science ID 000181079700050

    View details for PubMedID 12519986

    View details for PubMedCentralID PMC165461

  • Caspase-12 expression is markedly reduced in NF-E2(-/-)megakaryocytes and caspase-12(-/-) platelets exhibit a defect in integrin alpha IIb beta 3 inside-out signaling. Kerrigan, S. W., Murphy, R. P., Alizadeh, A., Diehn, M., Shattil, S. J., Leavitt, A. D. AMER SOC HEMATOLOGY. 2002: 13A
  • Genomic expression programs and the integration of the CD28 costimulatory signal in T cell activation PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Diehn, M., Alizadeh, A. A., Rando, O. J., Liu, C. L., Stankunas, K., Botstein, D., Crabtree, G. R., Brown, P. O. 2002; 99 (18): 11796-11801

    Abstract

    Optimal activation of T cells requires effective occupancy of both the antigen-specific T cell receptor and a second coreceptor such as CD28. We used cDNA microarrays to characterize the genomic expression program in human peripheral T cells responding to stimulation of these receptors. We found that CD28 agonists alone elicited few, but reproducible, changes in gene expression, whereas CD3 agonists elicited a multifaceted temporally choreographed gene expression program. The principal effect of simultaneous engagement of CD28 was to increase the amplitude of the CD3 transcriptional response. The induced genes whose expression was most enhanced by costimulation were significantly enriched for known targets of nuclear factor of activated T cells (NFAT) transcription factors. This enhancement was nearly abolished by blocking the nuclear translocation of NFATc by using the calcineurin inhibitor FK506. CD28 signaling promoted phosphorylation, and thus inactivation, of the NFAT nuclear export kinase glycogen synthase kinase-3 (GSK3), coincident with enhanced dephosphorylation of NFATc proteins. These results provide a detailed picture of the transcriptional program of T cell activation and suggest that enhancement of transcriptional activation by NFAT, through inhibition of its nuclear export, plays a key role in mediating the CD28 costimulatory signal.

    View details for DOI 10.1073/pnas.092284399

    View details for PubMedID 12195013

  • Transformation of follicular lymphoma to diffuse large-cell lymphoma: Alternative patterns with increased or decreased expression of c-myc and its regulated genes PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Lossos, I. S., Alizadeh, A. A., Diehn, M., Warnke, R., Thorstenson, Y., Oefner, P. J., Brown, P. O., Botstein, D., Levy, R. 2002; 99 (13): 8886-8891

    Abstract

    The natural history of follicular lymphoma (FL) is frequently characterized by transformation to a more aggressive diffuse large B cell lymphoma (DLBCL). We compared the gene-expression profiles between transformed DLBCL and their antecedent FL. No genes were observed to increase or decrease their expression in all of the cases of histological transformation. However, two different gene-expression profiles associated with the transformation process were defined, one in which c-myc and genes regulated by c-myc showed increased expression and one in which these same genes showed decreased expression. Further, there was a striking difference in gene-expression profiles between transformed DLBCL and de novo DLBCL, because the gene-expression profile of transformed DLBCL was more similar to their antecedent FL than to de novo DLBCL. This study demonstrates that transformation from FL to DLBCL can occur by alternative pathways and that transformed DLBCL and de novo DLBCL have very different gene-expression profiles that may underlie the different clinical behaviors of these two types of morphologically similar lymphomas.

    View details for DOI 10.1073/pnas.132253599

    View details for Web of Science ID 000176478200075

    View details for PubMedID 12077300

    View details for PubMedCentralID PMC124393

  • Transcriptional response of human mast cells stimulated via the Fc(epsilon)RI and identification of mast cells as a source of IL-11. BMC immunology Sayama, K., Diehn, M., Matsuda, K., Lunderius, C., Tsai, M., Tam, S., Botstein, D., Brown, P. O., Galli, S. J. 2002; 3: 5-?

    Abstract

    In asthma and other allergic disorders, the activation of mast cells by IgE and antigen induces the cells to release histamine and other mediators of inflammation, as well as to produce certain cytokines and chemokines. To search for new mast cell products, we used complementary DNA microarrays to analyze gene expression in human umbilical cord blood-derived mast cells stimulated via the high-affinity IgE receptor (Fc(epsilon)RI).One to two hours after Fc(epsilon)RI-dependent stimulation, more than 2,400 genes (about half of which are of unknown function) exhibited 2-200 fold changes in expression. The transcriptional program included changes in the expression of IL-11 and at least 30 other cytokines and chemokines. Human mast cells secreted 130-529 pg of IL-11/106 cells by 6 h after stimulation with anti-IgE.Our initial analysis of the transcriptional program induced in in vitro-derived human mast cells stimulated via the Fc(epsilon)RI has identified many products that heretofore have not been associated with this cell type, but which may significantly influence mast cell function in IgE-associated host responses. We also have demonstrated that mast cells stimulated via the Fc(epsilon)RI can secrete IL-11. Based on the previously reported biological effects of IL-11, our results suggest that production of IL-11 may represent one link between IgE-dependent mast cell activation in subjects with allergic asthma and the development of a spectrum of structural changes in the airways of these individuals; such changes, collectively termed "airway remodeling," can constitute an important long term consequence of asthma.

    View details for PubMedID 12079505

    View details for PubMedCentralID PMC116674

  • Functional genomic analysis of CD4+CD25+ regulatory T cells. Seeley, E., Ermann, J., Diehn, M., Fathman, C. G. ACADEMIC PRESS INC ELSEVIER SCIENCE. 2002: S68
  • In vivo regulation of human skeletal muscle gene expression by thyroid hormone GENOME RESEARCH Clement, K., Viguerie, N., Diehn, M., Alizadeh, A., Barbe, P., Thalamas, C., Storey, J. D., Brown, P. O., Barsh, G. S., Langin, D. 2002; 12 (2): 281-291

    Abstract

    Thyroid hormones are key regulators of metabolism that modulate transcription via nuclear receptors. Hyperthyroidism is associated with increased metabolic rate, protein breakdown, and weight loss. Although the molecular actions of thyroid hormones have been studied thoroughly, their pleiotropic effects are mediated by complex changes in expression of an unknown number of target genes. Here, we measured patterns of skeletal muscle gene expression in five healthy men treated for 14 days with 75 microg of triiodothyronine, using 24,000 cDNA element microarrays. To analyze the data, we used a new statistical method that identifies significant changes in expression and estimates the false discovery rate. The 381 up-regulated genes were involved in a wide range of cellular functions including transcriptional control, mRNA maturation, protein turnover, signal transduction, cellular trafficking, and energy metabolism. Only two genes were down-regulated. Most of the genes are novel targets of thyroid hormone. Cluster analysis of triiodothyronine-regulated gene expression among 19 different human tissues or cell lines revealed sets of coregulated genes that serve similar biologic functions. These results define molecular signatures that help to understand the physiology and pathophysiology of thyroid hormone action.

    View details for Web of Science ID 000173689600008

    View details for PubMedID 11827947

  • Stereotyped and specific gene expression programs in human innate immune responses to bacteria PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Boldrick, J. C., Alizadeh, A. A., Diehn, M., Dudoit, S., Liu, C. L., Belcher, C. E., Botstein, D., Staudt, L. M., Brown, P. O., Relman, D. A. 2002; 99 (2): 972-977

    Abstract

    The innate immune response is crucial for defense against microbial pathogens. To investigate the molecular choreography of this response, we carried out a systematic examination of the gene expression program in human peripheral blood mononuclear cells responding to bacteria and bacterial products. We found a remarkably stereotyped program of gene expression induced by bacterial lipopolysaccharide and diverse killed bacteria. An intricately choreographed expression program devoted to communication between cells was a prominent feature of the response. Other features suggested a molecular program for commitment of antigen-presenting cells to antigens captured in the context of bacterial infection. Despite the striking similarities, there were qualitative and quantitative differences in the responses to different bacteria. Modulation of this host-response program by bacterial virulence mechanisms was an important source of variation in the response to different bacteria.

    View details for PubMedID 11805339

  • Transcriptional programs activated by exposure of human prostate cancer cells to androgen GENOME BIOLOGY DePrimo, S. E., Diehn, M., Nelson, J. B., Reiter, R. E., Matese, J., Fero, M., Tibshirani, R., Brown, P. O., Brooks, J. D. 2002; 3 (7)

    Abstract

    Androgens are required for both normal prostate development and prostate carcinogenesis. We used DNA microarrays, representing approximately 18,000 genes, to examine the temporal program of gene expression following treatment of the human prostate cancer cell line LNCaP with a synthetic androgen.We observed statistically significant changes in levels of transcripts of more than 500 genes. Many of these genes were previously reported androgen targets, but most were not previously known to be regulated by androgens. The androgen-induced expression programs in three additional androgen-responsive human prostate cancer cell lines, and in four androgen-independent subclones derived from LNCaP, shared many features with those observed in LNCaP, but some differences were observed. A remarkable fraction of the genes induced by androgen appeared to be related to production of seminal fluid and these genes included many with roles in protein folding, trafficking, and secretion.Prostate cancer cell lines retain features of androgen responsiveness that reflect normal prostatic physiology. These results provide a broad view of the effect of androgen signaling on the transcriptional program in these cancer cells, and a foundation for further studies of androgen action.

    View details for Web of Science ID 000207581200008

    View details for PubMedID 12184806

  • Higher-grade transformed follicle center lymphomas (FCL): Gene expression profiling comparison to pre-transformed FCL and to de novo diffuse large B-cell lymphomas (DLBCL). Lossos, I. S., Alizadeh, A. A., Diehn, M., Warnke, R., Brown, P. O., Botstein, D., Levy, R. AMER SOC HEMATOLOGY. 2001: 722A
  • Genetic approaches using primary megakaryocytes to identify effectors of platelet integrin signaling Shattil, S. J., Bertoni, A., Eto, K., Murphy, R., Pampori, N., Shiraga, M., Stuhlmann, H., Tadokoro, S., Kerrigan, S., Alizadeh, A., Diehn, M., Brown, P. O., Leavitt, A. D. AMER SOC CELL BIOLOGY. 2001: 270A
  • Comparing functional genomic datasets: lessons from DNA. microarray analyses of host-pathogen interactions CURRENT OPINION IN MICROBIOLOGY Diehn, M., Relman, D. A. 2001; 4 (1): 95-101

    Abstract

    Functional genomic technologies such as high density DNA microarrays allow biologists to study the structure and behavior of thousands of genes in a single experiment. One of the fields in which microarrays have had an increasingly important impact is host-pathogen interactions. Early investigations in this area over the past two years not only emphasize the utility of this approach, but also highlight the stereotyped gene expression responses of different host cells to diverse infectious stimuli, and the potential value of broad dataset comparisons in revealing fundamental features of innate immunity. The comparative analysis of recently published datasets involving human gene expression responses to two bacterial respiratory pathogens illustrates many of these points. Comparisons between these large, highly parallel sets of experimental observations also emphasize important technical and experimental design issues as future challenges.

    View details for Web of Science ID 000166840200015

    View details for PubMedID 11173041

  • Examining the living genome in health and disease with DNA microarrays JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION Diehn, M., Alizadeh, A. A., Brown, P. O. 2000; 283 (17): 2298-2299

    View details for Web of Science ID 000086671600042

    View details for PubMedID 10807394

  • Large-scale identification of secreted and membrane-associated gene products using DNA microarrays NATURE GENETICS Diehn, M., Eisen, M. B., Botstein, D., Brown, P. O. 2000; 25 (1): 58-62

    Abstract

    Membrane-associated and secreted proteins are an important class of proteins and include receptors, transporters, adhesion molecules, hormones and cytokines. Although algorithms have been developed to recognize potential amino-terminal membrane-targeting signals or transmembrane domains in protein sequences, their accuracy is limited and they require knowledge of the entire coding sequence, including the N terminus, which is not currently available for most of the genes in most organisms, including human. Several experimental approaches for identifying secreted and membrane proteins have been described, but none have taken a comprehensive genomic approach. Furthermore, none of these methods allow easy classification of clones from arrayed cDNA libraries, for which large-scale gene-expression data are now becoming available through the use of DNA microarrays. We describe here a rapid and efficient method for identifying genes that encode secreted or membrane proteins. mRNA species bound to membrane-associated polysomes were separated from other mRNAs by sedimentation equilibrium or sedimentation velocity. The distribution of individual transcripts in the 'membrane-bound' and 'cytosolic' fractions was quantitated for thousands of genes by hybridization to DNA microarrays. Transcripts known to encode secreted or membrane proteins were enriched in the membrane-bound fractions, whereas those known to encode cytoplasmic proteins were enriched in the fractions containing mRNAs associated with free and cytoplasmic ribosomes. On this basis, we identified over 275 human genes and 285 yeast genes that are likely to encode previously unrecognized secreted or membrane proteins.

    View details for Web of Science ID 000086884000017

    View details for PubMedID 10802657

  • Degradation of proteins from the ER of S-cerevisiae requires an intact unfolded protein response pathway MOLECULAR CELL Casagrande, R., Stern, P., Diehn, M., Shamu, C., Osario, M., Zuniga, M., Brown, P. O., Ploegh, H. 2000; 5 (4): 729-735

    Abstract

    To dissect the requirements of membrane protein degradation from the ER, we expressed the mouse major histocompatibility complex class I heavy chain H-2K(b) in yeast. Like other proteins degraded from the ER, unassembled H-2K(b) heavy chains are not transported to the Golgi but are degraded in a proteasome-dependent manner. The overexpression of H-2K(b) heavy chains induces the unfolded protein response (UPR). In yeast mutants unable to mount the UPR, H-2K(b) heavy chains are greatly stabilized. This defect in degradation is suppressed by the expression of the active form of Hac1p, the transcription factor that upregulates UPR-induced genes. These results indicate that induction of the UPR is required for the degradation of protein substrates from the ER.

    View details for Web of Science ID 000086790000013

    View details for PubMedID 10882108

  • Biochemical interactions integrating Itk with the T cell receptor-initiated signaling cascade JOURNAL OF BIOLOGICAL CHEMISTRY Bunnell, S. C., Diehn, M., Yaffe, M. B., Findell, P. R., Cantley, L. C., Berg, L. J. 2000; 275 (3): 2219-2230

    Abstract

    Itk, a Tec family tyrosine kinase, acts downstream of Lck and phosphatidylinositol 3'-kinase to facilitate T cell receptor (TCR)-dependent calcium influxes and increases in extracellular-regulated kinase activity. Here we demonstrate interactions between Itk and crucial components of TCR-dependent signaling pathways. First, the inositide-binding pocket of the Itk pleckstrin homology domain directs the constitutive association of Itk with buoyant membranes that are the primary site of TCR activation and are enriched in both Lck and LAT. This association is required for the transphosphorylation of Itk. Second, the Itk proline-rich region binds to Grb2 and LAT. Third, the Itk Src homology (SH3) 3 and SH2 domains interact cooperatively with Syk-phosphorylated SLP-76. Notably, SLP-76 contains a predicted binding motif for the Itk SH2 domain and binds to full-length Itk in vitro. Finally, we show that kinase-inactive Itk can antagonize the SLP-76-dependent activation of NF-AT. The inhibition of NF-AT activation depends on the Itk pleckstrin homology domain, proline-rich region, and SH2 domain. Together, these observations suggest that multivalent interactions recruit Itk to LAT-nucleated signaling complexes and facilitate the activation of LAT-associated phospholipase Cgamma1 by Itk.

    View details for Web of Science ID 000084940000092

    View details for PubMedID 10636929

  • DNA microarrays as "microscopes" for watching a genome in action Brown, P. O., Botstein, D., Alizadeh, A., Derisi, J., Diehn, M., Eisen, M., Iyer, Perou, C., Pollack, J., Ross, D., Spellman, P., Staudt, L. AMER SOC CELL BIOLOGY. 1998: 2A