Bio


Dr. Dirbas is originally from Brooklyn, NY. He graduated from Stanford University with a B.S. with Departmental Honors in Chemistry in 1981. While in college, Dr. Dirbas worked as a lab tech in Norman Shumway's transplant laboratory during the initial studies of cyclosporin A as an immunosuppressive agent in preclinical studies for heart/lung transplanation. He then completed his M.D. training with A.O.A honors at Columbia University's College of Physician and Surgeons (now the Vagelos School of Medicine). Dr. Dirbas received the Whipple Award as the top surgery student in his medical school class. Internship and residency then followed at Stanford Hospital (now Stanford Health Care). During his professional development years Dr. Dirbas spent two years at the National Institutes of Health during which time he studied immunospression for cardiac transplantion with Dr. Thomas Waldmann by performing heterotopic heart transplants in cynomologous monkeys then treating them with Anti-tac conjugated to Yttrium90. Dr. Dirbas returned to Stanford and in the later years of his residency became more interested in surgical oncology as he finished his chief resident year the completed a 2 year surgical oncology fellowthip with Dr. John Niederhuber who later served as the head of the NCI. After completing his surgical oncology fellowship, Dr. Dirbas worked as a staff surgeon at the Palo Alto VA Hospital and at Stanford for 4 years. During this period, he served as a surgical oncologist and ICU/critical care attending at the Palo Alto VA while also serving as a breast cancer surgeon and trauma surgeon at Stanford Hospital (during which time Stanford achieved recognition as a Level I Trauma Center). In these early years at Stanford Dr. Dirbas routinely contributed tumor tissue to the pioneering work in the Brown/Botstein labs which led to the initial reports of molecular profiling for breast cancer. Dr. Dirbas became an assistant professor in 1999. He initiated and served as PI for Stanford's Phase I/II studies in accelerated, partial breast irradiation, including intraoperative radiotherapy (IORT) making Stanford an early adopter of this technology. From 2010 to 2017 Dr. Dirbas served as the physician leaders of Stanford's Breast Cancer Clinical Care Program: in 2017 an anonymous Medscape poll ranked Stanford in a tie for #7 as the place that Medscape members would most likely recommend for breast cancer care. During this period Dr. Dirbas contributed significantly to the development of Stanford's Women's Cancer Center, Stanford's South Bay Cancer Center, and design elements of Stanford Cancer Hospital. Dr. Dirbas took a partial sabbatical from 2019 to 2021 to devote a portion of his time to renew research programs. He is currently a Co-investigator on Dr. Aaron Newman's NIH R01 grant studying breast cancer stem cells in the triple negative lineage. After created a broad, interdisciplinary team Dr. Dirbas initiated Stanford's research program investigating the merits of FLASH radiotherapy for breast cancer. Dr. Dirbas received a pilot grant from tne Stanford Cancer Institute for this, and more recently received a 2-year grant from tthe California Breast Cancer Research Program. Dr.Dirbas is also the PI on a research agreement between Stanford and Beyond Cancer to develop a Phase II study for use of ultra high concentration gaseous nitric oxide for treatment of solid tumors. Dr. Dirbas also serves in a consulting role with Beyond Cancer as chair of their scientific advisory board. Dr. Dirbas is a board member of the School of Oncoplastic Surgery. Dr. Dirbas continues to maintain an active breast surgery practice at the Stanford Cancer Center/Stanford Hospital/Stanford Health Care with the unique background training in cardiovascular surgery, trauma surgery, ICU/critical care, and surgical oncology,

Clinical Focus


  • Cancer > Breast Cancer
  • Cancer > Breast Cancer > Accelerated Breast Radiation
  • General Surgery
  • MRI in Breast Cancer Staging
  • Minimally Invasive Breast Surgery
  • Targeted Axillary Node Dissection
  • Accelerated, Partial Breast Irradiation (APBI)
  • Intraoperative Radiotherapy for Breast Cancer
  • Nipple Sparing Mastectomy
  • Triple Negative Breast Cancer (see https://med.stanford.edu/dirbas.html)

Academic Appointments


Administrative Appointments


  • Co-Chair, Tissue Committee, Stanford Health Care (2019 - Present)
  • Physician Leader, Breast Cancer Clinical Care Program (CCP), Stanford Cancer Center, Stanford University School of Medicine, Stanford Hospital (2010 - 2017)
  • Co-Leader, Breast Cancer Clinical Research Group, Stanford Cancer Center, Stanford University School of Medicine, Stanford Hospital (2011 - 2015)
  • Director, Clinical Care Sub-team, Breast Disease Management Group, Stanford Cancer Center (2006 - 2010)

Honors & Awards


  • Best Doctors in America, Best Doctors, Inc. (2023)
  • Top Doctors, Castle Connolly (2023)
  • Best Doctors in America, Best Doctors, Inc. (2022)
  • Top Doctors, Castle Connolly (2022)
  • Best Doctors in America, Best Doctors, Inc (2021)
  • Top Doctors, Castle Connolly (2021)
  • Best Doctors in America, Best Doctors, Inc. (2020)
  • Top Doctors, Castle Connolly (2020)
  • Best Doctors in America, Best Doctors, Inc (2019)
  • Top Doctors, Catle Connolly (2019)
  • Best Doctors in America, Best Doctors, Inc (2018)
  • Top Doctors, Castle Connolly (2018)
  • Best Doctors in America, Best Doctors, Inc (2017)
  • Top Doctors, Castle Connolly (2017)
  • Best Doctors in America, Best Doctors, Inc. (2016)
  • Best Doctors in America, Best Doctors, Inc. (2015)
  • Best Doctors in America, Best Doctors, Inc. (2014)
  • Best Doctors in America, Best Doctors, Inc. (2013)
  • Best Doctors in America, Best Doctors, Inc (2012)
  • Best Doctors in America, Best Doctors, Inc. (2011)
  • America's Top Surgeons, Consumers' Research Council of America (2010)
  • Best Doctors in America, Best Doctors, Inc. (2010)
  • America's Top Oncologists, Consumers' Research Council of America (2009)
  • Best Doctors in America, Best Doctors, Inc. (2009)
  • Star Caregiver Award, Silicon Valley Wellness Foundation (2008)
  • Grant Recipient, Vadasz Foundation (2004)
  • IORT for Breast Cancer (http://www.msnbc.msn.com/id/6503963/ns/nightly_news/), NBC (2004)

Boards, Advisory Committees, Professional Organizations


  • Chair, Scientific Advisory Board, Beyond Cancer, Ltd (2023 - Present)
  • Medical Advisory Board, Silicon Valley Innovations, NasoClenz (2021 - Present)
  • Board of Directors, School of Oncoplastic Surgery (2020 - Present)

Professional Education


  • Residency: Stanford University Dept of General Surgery (1992) CA
  • Fellowship: Stanford University Dept of Surgery (1994) CA
  • Fellowship: National Institute of Health (1989) MD
  • Medical Education: Columbia University Office of the Registrar (1985) NY
  • Board Certification: American Board of Surgery, General Surgery (1994)
  • MD, Columbia University College of Physicians and Surgeons (1985)
  • BS with Honors, Stanford University, Chemistry (1981)

Community and International Work


  • Susan G. Komen for the Cure Advisory Council 2011- 2014, San Francisco

    Topic

    Breast Cancer

    Partnering Organization(s)

    Susan G. Komen for the Cure

    Populations Served

    Breast Cancer

    Location

    International

    Ongoing Project

    Yes

    Opportunities for Student Involvement

    No

  • Expert Reviewer Program, Medical Board of California

    Topic

    Breast Cancer

    Partnering Organization(s)

    Medical Board of California

    Populations Served

    California

    Location

    International

    Ongoing Project

    Yes

    Opportunities for Student Involvement

    No

  • Susan G. Komen for the Cure San Francisco Affiliate 2004-2011, San Francisco

    Topic

    Breast Cancer

    Partnering Organization(s)

    Susan G. Komen for the Cure

    Populations Served

    San Francisco Bay Area

    Location

    International

    Ongoing Project

    Yes

    Opportunities for Student Involvement

    No

  • Breast Cancer Connections 2011 - 2014, Palo Alto

    Topic

    Breast Cancer

    Populations Served

    San Francisco Bay Area

    Location

    International

    Ongoing Project

    Yes

    Opportunities for Student Involvement

    No

Patents


  • Frederick Dirbas. "United States Patent 6182047 Medical information log system", Software for Surgeons, Sep 30, 2001
  • Frederick Dirbas. "United States Patent 6125350 Medical information log system", Software for Surgeons, Sep 26, 2000

Current Research and Scholarly Interests


Currently collaborating with Dr's Aaron Newman and Michael Clarke to study cancer stem cells associated with triple negative breast cancer. Advancing studies of FLASH radiotherapy in preclinical models for potential future use in humans. Investigating preclinical use of high dose gaseous nitric oxide in the treatment of solid tumors.

Clinical Trials


  • A Pharmacokinetic and Randomized Trial of Neoadjuvant Treatment With Anastrozole Plus AZD0530 in Postmenopausal Patients With Hormone Receptor Positive Breast Cancer Not Recruiting

    The investigators propose to conduct a Phase I/randomized Phase II study design in order to test the tolerability and efficacy of AZD0530 (also called saracatinib) when used together with anastrozole in therapy for ER+ and/or PR+, postmenopausal breast cancer. The Phase I pharmacokinetic (PK) cohort of the study (cohort A) in postmenopausal women with metastatic breast cancer 2008-2009 showed initial safety,tolerability and good bioavailability of both drugs and determined the doses for use in the ongoing Phase II trial. In the randomized Phase II cohort of the study (cohort B), postmenopausal women with newly diagnosed, previously untreated ER+, HER2 negative breast cancer that is at least 2 cm or more in diameter by clinical exam or radiology will be randomized to either neoadjuvant treatment with anastrozole plus placebo, or anastrozole in combination with AZD0530 (saracatinib). The Phase II cohort will permit extended assays of tolerability, initial estimates of efficacy, and the investigation of molecular predictors of drug efficacy.

    Stanford is currently not accepting patients for this trial. For more information, please contact Annabel Castaneda, 650-498-7977.

    View full details

  • Accelerated Partial Breast Irradiation Following Lumpectomy for Breast Cancer Not Recruiting

    To determine whether an accelerated course of radiotherapy delivered to the lumpectomy cavity plus margin using IORT as a single dose, intracavitary brachytherapy with the MammoSite device over 5 days, partial breast 3-D CRT in 5 days, or stereotactic APBI over 4 days is a feasible and safe alternative to a six and a half week course of whole breast radiotherapy. The study will measure both short and long-term complications of radiation treatment, short and long-term breast cosmesis, local rates of in-breast cancer recurrence, regional recurrences, distant metastases, and overall survival.

    Stanford is currently not accepting patients for this trial. For more information, please contact Sally Bobo, (650) 736 - 1472.

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  • Breast-Conserving Surgery and Radiation Therapy in Patients With Multiple Ipsilateral Breast Cancer Not Recruiting

    RATIONALE: Breast-conserving surgery is a less invasive type of surgery for breast cancer and may have fewer side effects and improve recovery. Radiation therapy uses high-energy x rays to kill tumor cells. Giving radiation therapy after surgery may kill any tumor cells that remain after surgery. PURPOSE: This phase II trial studies how well breast-conserving surgery and radiation therapy work in treating patients with multiple ipsilateral breast cancer

    Stanford is currently not accepting patients for this trial. For more information, please contact Amy Isaacson , 650-723-0501.

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  • Comparison of Axillary Lymph Node Dissection With Axillary Radiation for Patients With Node-Positive Breast Cancer Treated With Chemotherapy Not Recruiting

    This randomized phase III trial studies lymph node dissection and radiation therapy to see how well it works compared to radiation therapy alone in treating patients with breast cancer previously treated with chemotherapy and surgery. Lymph node dissection may remove cancer cells that have spread to nearby lymph nodes in patients with breast cancer. Radiation therapy uses high-energy x rays or protons to kill tumor cells. It is not yet known if radiation therapy works better alone or with lymph node dissection in treating patients with breast cancer previously treated with chemotherapy and surgery.

    Stanford is currently not accepting patients for this trial. For more information, please contact Amy Isaacson, 650-723-0501.

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  • Early Surgery or Standard Palliative Therapy in Treating Patients With Stage IV Breast Cancer Not Recruiting

    RATIONALE: The primary tumor might be a source of re-seeding of distant sites and therefore elimination of this source of metastasizing cells by early local therapy may be of benefit. PURPOSE: This randomized phase III trial is studying early surgery to see how well it works compared to standard palliative therapy in treating patients with stage IV breast cancer.

    Stanford is currently not accepting patients for this trial. For more information, please contact Amy Isaacson, 650-723-0501.

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  • Letrozole in Treating Postmenopausal Women Who Have Received Hormone Therapy for Hormone Receptor-Positive Breast Cancer Not Recruiting

    RATIONALE: Estrogen can cause the growth of breast cancer cells. Hormone therapy using letrozole may fight breast cancer by lowering the amount of estrogen the body makes. It is not yet known whether letrozole is more effective than a placebo in treating patients with hormone receptor-positive breast cancer. PURPOSE: This randomized phase III trial is studying letrozole to see how well it works compared with a placebo in treating postmenopausal women who have received hormone therapy for hormone receptor-positive breast cancer.

    Stanford is currently not accepting patients for this trial. For more information, please contact Marilyn Florero, (650) 724 - 1953.

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  • LYMPHA Procedure for the Prevention of Lymphedema After Axillary Lymphadenectomy Not Recruiting

    Lymphedema is a chronic, progressive, and debilitating condition that occurs with disruption or obstruction of the lymphatic system, which commonly occurs a result of breast cancer therapy. The purpose of this study is to determine if the use of a low risk lymphatic reconstruction procedure at the time of axillary lymph node dissection will reduce the risk of developing lymphedema. Additionally, to determine if this procedure improves objective outcomes of lymphedema and patient quality of life

    Stanford is currently not accepting patients for this trial. For more information, please contact Dung Nguyen, PharmD, 650-498-6004.

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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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  • MRI in Women With Newly Diagnosed Breast Cancer Prior to Breast Conserving Surgery Not Recruiting

    To see if performing breast MRI before a lumpectomy will help the surgeon successfully remove the entire cancer with normal tissue margins in a single operation thereby reducing the need for additional surgical procedures. The study will also measure how well MRI can find unsuspected cancers in the same breast as the known cancer; how well MRI will find unsuspected cancers in the opposite breast; how often MRI will generate false positive MRI findings; whether routinely incorporating breast MRI delays care or adds unnecessary cost; and, whether breast MRI is able to reduce the frequency of cancer recurrence in the treated breast or elsewhere in the body.

    Stanford is currently not accepting patients for this trial. For more information, please contact Sally Bobo, 650-736-1472.

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  • Phase 2 Anastrozole and Vandetanib (ZD6474) in Neoadjuvant Treatment of Postmenopausal Hormone Receptor-Positive Breast Cancer Not Recruiting

    In this study we plan to study the combination of ZD6474, a dual inhibitor of EGFR and VEGFR-2 with anastrozole in the neoadjuvant setting for patients with Stage I-III breast cancer. The aim is to overcome mechanisms of resistance and simultaneously block multiple critical signaling pathways known to stimulate breast cancer.

    Stanford is currently not accepting patients for this trial. For more information, please contact Marcy Chen, (650) 723 - 8686.

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  • Surgery to Remove the Sentinel Lymph Node and Axillary Lymph Nodes After Chemotherapy in Treating Women With Stage II, Stage IIIA, or Stage IIIB Breast Cancer Not Recruiting

    RATIONALE: 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. Giving chemotherapy before surgery may make the tumor smaller and reduce the amount of normal tissue that needs to be removed. PURPOSE: This phase II trial is studying surgery to remove the sentinel lymph node and axillary lymph nodes after chemotherapy in treating women with stage II, stage IIIA, or stage IIIB breast cancer.

    Stanford is currently not accepting patients for this trial. For more information, please contact Sally Bobo, (650) 736 - 1472.

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  • Trial of AVB-620 in Women With Primary, Non-Recurrent Breast Cancer Undergoing Surgery Not Recruiting

    This is a Phase 1, open-label, dose escalation study in women with primary, non-recurrent breast cancer undergoing surgery. AVB-620 will be administered prior to surgery.

    Stanford is currently not accepting patients for this trial.

    View full details

2023-24 Courses


Stanford Advisees


All Publications


  • Single-cell transcriptional diversity is a hallmark of developmental potential. Science (New York, N.Y.) Gulati, G. S., Sikandar, S. S., Wesche, D. J., Manjunath, A. n., Bharadwaj, A. n., Berger, M. J., Ilagan, F. n., Kuo, A. H., Hsieh, R. W., Cai, S. n., Zabala, M. n., Scheeren, F. A., Lobo, N. A., Qian, D. n., Yu, F. B., Dirbas, F. M., Clarke, M. F., Newman, A. M. 2020; 367 (6476): 405–11

    Abstract

    Single-cell RNA sequencing (scRNA-seq) is a powerful approach for reconstructing cellular differentiation trajectories. However, inferring both the state and direction of differentiation is challenging. Here, we demonstrate a simple, yet robust, determinant of developmental potential-the number of expressed genes per cell-and leverage this measure of transcriptional diversity to develop a computational framework (CytoTRACE) for predicting differentiation states from scRNA-seq data. When applied to diverse tissue types and organisms, CytoTRACE outperformed previous methods and nearly 19,000 annotated gene sets for resolving 52 experimentally determined developmental trajectories. Additionally, it facilitated the identification of quiescent stem cells and revealed genes that contribute to breast tumorigenesis. This study thus establishes a key RNA-based feature of developmental potential and a platform for delineation of cellular hierarchies.

    View details for DOI 10.1126/science.aax0249

    View details for PubMedID 31974247

  • Role of epithelial to mesenchymal transition associated genes in mammary gland regeneration and breast tumorigenesis. Nature communications Sikandar, S. S., Kuo, A. H., Kalisky, T. n., Cai, S. n., Zabala, M. n., Hsieh, R. W., Lobo, N. A., Scheeren, F. A., Sim, S. n., Qian, D. n., Dirbas, F. M., Somlo, G. n., Quake, S. R., Clarke, M. F. 2017; 8 (1): 1669

    Abstract

    Previous studies have proposed that epithelial to mesenchymal transition (EMT) in breast cancer cells regulates metastasis, stem cell properties and chemo-resistance; most studies were based on in vitro culture of cell lines and mouse transgenic cancer models. However, the identity and function of cells expressing EMT-associated genes in normal murine mammary gland homeostasis and human breast cancer still remains under debate. Using in vivo lineage tracing and triple negative breast cancer (TNBC) patient derived xenografts we demonstrate that the repopulating capacity in normal mammary epithelial cells and tumorigenic capacity in TNBC is independent of expression of EMT-associated genes. In breast cancer, while a subset of cells with epithelial and mesenchymal phenotypes have stem cell activity, in many cells that have lost epithelial characteristics with increased expression of mesenchymal genes, have decreased tumor-initiating capacity and plasticity. These findings have implications for the development of effective therapeutic agents targeting tumor-initiating cells.

    View details for PubMedID 29162812

    View details for PubMedCentralID PMC5698470

  • Five-year results of a prospective clinical trial investigating accelerated partial breast irradiation using 3D conformal radiotherapy after lumpectomy for early stage breast cancer BREAST Horst, K. C., Fasola, C., Ikeda, D., Daniel, B., Ognibene, G., Goffinet, D. R., Dirbas, F. M. 2016; 28: 178-183

    Abstract

    Accelerated partial breast irradiation (APBI) is emerging as an alternative to whole-breast irradiation. This study presents the results of a prospective trial evaluating 3-dimensional conformal radiotherapy (3D-CRT) to deliver APBI for early-stage breast cancer.Patients with unifocal stage 0-II breast cancer measuring ≤2.5 cm without lymph node involvement were eligible. After lumpectomy, 3D-CRT APBI was delivered to the lumpectomy cavity + margin (34-38.5 Gy in 10 fractions over 5 days).141 patients with 143 breast cancers (2 bilateral) were treated with 3D-CRT APBI. Median age was 60. Median tumor size was 1.1 cm. At a median follow up of 60 months (range, 5-113), the 5-year and 8-year cumulative incidence rate of a true recurrence is 0.9%. The 5-year and 8-year cumulative incidence rates of an elsewhere failure are 2.4% and 4.4%, respectively. The 5-year and 8-year overall survival is 100% and 94%, respectively. Among the 62 patients with follow up >5 years, 95% had excellent/good cosmetic results.Our experience with 3D-CRT APBI demonstrates excellent cosmesis and local control. Longer follow up will be necessary to evaluate long-term efficacy and toxicity of 3D-CRT APBI. CLINICALTRIALS.NCT00185744.

    View details for DOI 10.1016/j.breast.2016.06.001

    View details for Web of Science ID 000379683300027

    View details for PubMedID 27322859

  • Breast Surgical Techniques and Interdisciplinary Management Frederick M. Dirbas, Carol Scott-Conner 2011; Springer
  • Introduction to Gene Expression Profiling in Breast Cancer BREAST SURGICAL TECHNIQUES AND INTERDISCIPLINARY MANAGEMENT Dirbas, F. M., Sotiriou, C., Dirbas, F. M., ScottConner, C. E. 2011: 295–314
  • The evolution of accelerated, partial breast irradiation as a potential treatment option for women with newly diagnosed breast cancer considering breast conservation CANCER BIOTHERAPY AND RADIOPHARMACEUTICALS Dirbas, F. M., Jeffrey, S. S., Goffinet, D. R. 2004; 19 (6): 673-705

    Abstract

    Breast conservation therapy (BCT) is a safe, effective alternative to mastectomy for many women with newly diagnosed breast cancer. This approach involves local excision of the malignancy with tumor-free margins, followed by 5-7 weeks of external beam whole breast (WB) radiotherapy (XRT) to minimize the risk of an in-breast tumor recurrence (IBTR). Though clearly beneficial, the extended course of almost daily postoperative radiotherapy interrupts normal activities and lengthens care. Additional options are now available that shorten the radiotherapy treatment time to 1-5 days (accelerated) and focus an increased dose of radiation on just the breast tissue around the excision cavity (partial breast). Recent trials with accelerated, partial breast irradiation (APBI) have shown promise as a potential replacement to the longer, whole breast treatments for select women with early-stage breast cancer. Current APBI approaches include interstitial brachytherapy, intracavitary (balloon) brachytherapy, and accelerated external beam (3-D conformal) radiotherapy, all of which normally complete treatment over 5 days, while intraoperative radiotherapy (IORT) condenses the entire treatment into a single dose delivered immediately after tumor excision. Each approach has benefits and limitations. This study covers over 2 decades of clinical trials exploring APBI, discusses treatment variables that appear necessary for successful implementation of this new form of radiotherapy, compares and contrasts the various APBI approaches, and summarizes current and planned randomized trials that will shape if and how APBI is introduced into routine clinical care. Some of the more important outcome variables from these trials will be local toxicity, local and regional recurrence, and overall survival. If APBI options are ultimately demonstrated to be as safe and effective as current whole breast radiotherapy approaches, breast conservation may become an even more appealing choice, and the overall impact of treatment may be further reduced for certain women with newly diagnosed breast cancer.

    View details for Web of Science ID 000226744200003

    View details for PubMedID 15665616

  • Management of Local-Regional Recurrence of Breast Cancer CURRENT BREAST CANCER REPORTS Hui, C., Dirbas, F. M., Horst, K. C. 2023
  • Gaseous nitric oxide tumor ablation induces an anti-tumor abscopal effect. Cancer cell international Confino, H., Dirbas, F. M., Goldshtein, M., Yarkoni, S., Kalaora, R., Hatan, M., Puyesky, S., Levi, Y., Malka, L., Johnson, M., Chaisson, S., Monson, J. M., Avniel, A., Lisi, S., Greenberg, D., Wolf, I. 2022; 22 (1): 405

    Abstract

    BACKGROUND: In-situ tumor ablation provides the immune system with the appropriate antigens to induce anti-tumor immunity. Here, we present an innovative technique for generating anti-tumor immunity by delivering exogenous ultra-high concentration (>10,000ppm) gaseous nitric oxide (UHCgNO) intratumorally.METHODS: The capability of UHCgNO to induce apoptosis was tested in vitro in mouse colon (CT26), breast (4T1) and Lewis lung carcinoma (LLC-1) cancer cell lines. In vivo, UHCgNO was studied by treating CT26 tumor-bearing mice in-situ and assessing the immune response using a Challenge assay.RESULTS: Exposing CT26, 4T1 and LLC-1 cell lines to UHCgNO for 10s-2.5min induced cellular apoptosis 24h after exposure. Treating CT26 tumors in-situ with UHCgNO followed by surgical resection 14days later resulted in a significant secondary anti-tumor effect in vivo. 100% of tumor-bearing mice treated with 50,000ppm UHCgNO and 64% of mice treated with 20,000ppm UHCgNO rejected a second tumor inoculation, compared to 0% in the naive control for 70days. Additionally, more dendrocytes infiltrated the tumor 14days post UHCgNO treatment versus the nitrogen control. Moreover, T-cell penetration into the primary tumor was observed in a dose-dependent manner. Systemic increases in T- and B-cells were seen in UHCgNO-treated mice compared to nitrogen control. Furthermore, polymorphonuclear-myeloid-derived suppressor cells were downregulated in the spleen in the UHCgNO-treated groups.CONCLUSIONS: Taken together, our data demonstrate that UHCgNO followed by the surgical removal of the primary tumor 14days later induces a strong and potent anti-tumor response.

    View details for DOI 10.1186/s12935-022-02828-z

    View details for PubMedID 36514083

  • Identification of a minority population of LMO2+ breast cancer cells that integrate into the vasculature and initiate metastasis. Science advances Sikandar, S. S., Gulati, G. S., Antony, J., Fetter, I., Kuo, A. H., Ho, W. H., Haro-Acosta, V., Das, S., Steen, C. B., Pereira, T. A., Qian, D., Beachy, P. A., Dirbas, F., Red-Horse, K., Rabbitts, T. H., Thiery, J. P., Newman, A. M., Clarke, M. F. 2022; 8 (45): eabm3548

    Abstract

    Metastasis is responsible for most breast cancer-related deaths; however, identifying the cellular determinants of metastasis has remained challenging. Here, we identified a minority population of immature THY1+/VEGFA+ tumor epithelial cells in human breast tumor biopsies that display angiogenic features and are marked by the expression of the oncogene, LMO2. Higher abundance of LMO2+ basal cells correlated with tumor endothelial content and predicted poor distant recurrence-free survival in patients. Using MMTV-PyMT/Lmo2CreERT2 mice, we demonstrated that Lmo2 lineage-traced cells integrate into the vasculature and have a higher propensity to metastasize. LMO2 knockdown in human breast tumors reduced lung metastasis by impairing intravasation, leading to a reduced frequency of circulating tumor cells. Mechanistically, we find that LMO2 binds to STAT3 and is required for STAT3 activation by tumor necrosis factor-α and interleukin-6. Collectively, our study identifies a population of metastasis-initiating cells with angiogenic features and establishes the LMO2-STAT3 signaling axis as a therapeutic target in breast cancer metastasis.

    View details for DOI 10.1126/sciadv.abm3548

    View details for PubMedID 36351009

  • Effect of Perioperative Gabapentin on Postoperative Pain Resolution and Opioid Cessation in a Mixed Surgical Cohort: A Randomized Clinical Trial (vol 153, pg 303, 2018) JAMA SURGERY Hah, J., Mackey, S. C., Schmidt, P. 2022; 157 (6): 553
  • Use of breast MRI to distinguish treatment failure versus new primary tumor following single fraction breast intraoperative radiotherapy for breast cancer (SF-IORT). Payne, S., Payne, S., Horst, K. C., Ikeda, D. M., Dirbas, F. M. LIPPINCOTT WILLIAMS & WILKINS. 2022
  • Effect of Perioperative Gabapentin on Postoperative Pain Resolution and Opioid Cessation in a Mixed Surgical Cohort: A Randomized Clinical Trial (vol 153, pg 303, 2018) JAMA SURGERY Hah, J., Mackey, S. C., Schmidt, P. 2022
  • Impact of COVID-19 on breast cancer care at a Bay Area academic center Wu, J., Bobo, S., Henry, S., Mills, M., Kurian, A., Dirbas, F. AMER ASSOC CANCER RESEARCH. 2021
  • Return to work and productivity loss after surgery: A health economic evaluation. International journal of surgery (London, England) M Hah, J., Lee, E., Shrestha, R., Pirrotta, L., Huddleston, J., Goodman, S., Amanatullah, D. F., Dirbas, F. M., Carroll, I. R., Schofield, D. 2021: 106100

    Abstract

    We aimed to identify preoperative psychosocial factors associated with return-to-work (RTW) and the associated cost of productivity loss due to work absenteeism following surgery. Research demonstrates a high economic burden from productivity loss after surgery, but the comparative cost of productivity loss relative to income across different operations has not been examined.A mixed surgical cohort recruited for a randomized controlled trial were prospectively followed for up to two years following surgery with daily phone assessments to three months, weekly assessments thereafter to six months, then monthly assessments thereafter to determine RTW status, opioid use and pain.183 of 207 (88.3%) patients in paid employment prior to surgery, who provided at least one day of follow-up, were included in this analysis. The average cost of productivity loss due to work absenteeism was $13 761 (median $9064). Patients who underwent total knee replacement incurred the highest income loss. Medical claims filed before surgery were significantly associated with relative income loss (AOR 5.09; 95% CI 1.73-14.96; p < 0.01) and delayed postoperative RTW. Elevated preoperative PTSD symptoms were associated with delayed RTW (HR 0.78; 95%CI 0.63-0.96; p-value = 0.02) while male gender (HR 1.63; 95%CI 1.11-2.38; p-value = 0.01) was associated with faster postoperative RTW.Surgery places a high economic burden on individuals due to postoperative productivity loss. Multidisciplinary approaches, such as pathways, that facilitate the operation and recovery may mitigate the economic consequences for patients, employers, and the healthcare system.

    View details for DOI 10.1016/j.ijsu.2021.106100

    View details for PubMedID 34600123

  • Development of a Classification Tree to Predict Implant-Based Reconstruction Failure with or without Postmastectomy Radiation Therapy for Breast Cancer. Annals of surgical oncology Chen, J. J., von Eyben, R., Gutkin, P. M., Hawley, E., Dirbas, F. M., Lee, G. K., Horst, K. C. 2020

    Abstract

    PURPOSE: The aim of this study was to determine the complications, incidence, and predictors of implant-based reconstruction failure (RF) among patients treated with mastectomy for breast cancer.METHODS: We retrospectively reviewed 108 patients who underwent mastectomy, tissue expander, and implant-based breast reconstruction with or without radiation therapy (RT) at our institution (2000-2014). Descriptive statistics determined complication incidences, with major complications defined as any complications requiring surgical intervention or inpatient management. Chi square and Fisher's exact tests determined differences in RF incidences, defined as implant loss. Logistic regression analyses identified predictors of RF.RESULTS: Median follow-up was 42.5months. Sixty patients (55.6%) experienced major complications. Overall, 27 patients (25%) experienced RF. Incidences of RF were significantly increased in patients who had any major complication (43.3% vs. 2.1%; p<0.0001), especially infection (61.3% vs. 10.4%; p<0.0001), delayed wound healing (83.3% vs. 21.7%; p=0.004), and implant exposure (80.0% vs. 19.4%; p=0.0002). Receiving RT, but not timing of RT, significantly predicted RF [odds ratio (OR) 4.00, 95% confidence interval (CI) 1.11-14.47; p=0.03]. On multivariable analysis, infection (OR 7.69, 95% CI 2.12-27.89; p=0.002) and delayed wound healing (OR 17.86, 95% CI 1.59-200.48; p=0.02) independently predicted for RF. Our newly developed classification tree, which includes stepwise assessment of major infection, delayed wound healing, implant exposure, age ≥50years, and total number of lymph nodes removed ≥10, accurately predicted 74% of RF events and 75% of non-RF events.CONCLUSIONS: Infection or delayed wound healing requiring surgical intervention or hospitalization and receipt of RT, but not radiation timing, were significant predictors of RF. Our classification tree demonstrated >70% accuracy for stepwise prediction of RF.

    View details for DOI 10.1245/s10434-020-09068-3

    View details for PubMedID 32875465

  • Impact of mastectomy for breast cancer on spinal curvature: Considerations when treating patients with scoliosis. The breast journal Gutkin, P. M., Kapp, D. S., von Eyben, R., Dirbas, F. M., Horst, K. C. 2020

    Abstract

    OBJECTIVE: Mastectomy has been shown to influence body posture in women; however, there are limited data outlining changes in spine curvature after mastectomy in patients with scoliosis. We sought to quantify changes in spine curvature after mastectomy for breast cancer.METHODS: We conducted a retrospective review of 62 patients with scoliosis who underwent mastectomy for breast cancer at a single institution between 1995 and 2018. Preoperative and postoperative radiographs were used to measure Cobb angles to assess lateral spinal curvature. Changes in Cobb angle were compared using paired two-tailed t-tests. The relationship between mass of breast removed and changes in Cobb angle was modeled using a linear regression.RESULTS: The median follow-up after mastectomy was 7.9years (range 0.9-21.5). Median age was 62years (range 30-85). Of 62 patients, 10 (16%) expressed that their back pain became worse after mastectomy. Nineteen patients had evaluable radiographs before and after mastectomy. In these patients, the average change in Cobb angle was 4.7° (range -0.2-12.2). Cobb angle significantly increased after mastectomy (P<.0001). Although not statistically significant, average Cobb angle was greater for patients who underwent unilateral compared to bilateral mastectomy (P=.09). Mass of breast removed significantly correlated with the difference in Cobb angle for patients who underwent unilateral mastectomy (P=.0006), but not for bilateral mastectomy (P=.55).CONCLUSIONS: In this understudied patient population, mastectomy significantly increased the change in spine curvature. Further care should be taken to assess patient-reported pain and quality of life in patients with spine morbidity who undergo mastectomy for breast cancer.

    View details for DOI 10.1111/tbj.14018

    View details for PubMedID 32841452

  • LEFTY1 Is a Dual-SMAD Inhibitor that Promotes Mammary Progenitor Growth and Tumorigenesis. Cell stem cell Zabala, M., Lobo, N. A., Antony, J., Heitink, L. S., Gulati, G. S., Lam, J., Parashurama, N., Sanchez, K., Adorno, M., Sikandar, S. S., Kuo, A. H., Qian, D., Kalisky, T., Sim, S., Li, L., Dirbas, F. M., Somlo, G., Newman, A., Quake, S. R., Clarke, M. F. 2020

    Abstract

    SMAD pathways govern epithelial proliferation, and transforming growth factor beta (TGF-beta and BMP signaling through SMAD members has distinct effects on mammary development and homeostasis. Here, we show that LEFTY1, a secreted inhibitor of NODAL/SMAD2 signaling, is produced by mammary progenitor cells and, concomitantly, suppresses SMAD2 and SMAD5 signaling to promote long-term proliferation of normal and malignant mammary epithelial cells. In contrast, BMP7, a NODAL antagonist with context-dependent functions, is produced by basal cells and restrains progenitor cell proliferation. In normal mouse epithelium, LEFTY1 expression in a subset of luminal cells and rare basal cells opposes BMP7 to promote ductal branching. LEFTY1 binds BMPR2 to suppress BMP7-induced activation of SMAD5, and this LEFTY1-BMPR2 interaction is specific to tumor-initiating cells in triple-negative breast cancer xenografts that rely on LEFTY1 for growth. These results suggest that LEFTY1 is an endogenous dual-SMAD inhibitor and that suppressing its function may represent a therapeutic vulnerability in breast cancer.

    View details for DOI 10.1016/j.stem.2020.06.017

    View details for PubMedID 32693087

  • Patterns of Failure in Women Who Have Residual Nodal Disease After Neoadjuvant Chemotherapy for Breast Cancer According to Extent of Lymph Node Surgery. Clinical breast cancer Kozak, M. M., Horst, K. C., Gutkin, P. M., Jacobson, C. E., Walck, E., von Eyben, R., Dirbas, F. M. 2020

    Abstract

    BACKGROUND: Optimal surgical management of limited axillary nodal disease following neoadjuvant chemotherapy (NAC) for breast cancer is evolving. Concerns exist with respect to leaving residual disease in the axilla when omitting axillary lymph node dissection (ALND) in this setting. We sought to determine whether extent of nodal surgery altered patterns of failure and patient outcomes.PATIENTS AND METHODS: We identified 70 patients with breast cancer who were confirmed cN0 after NAC yet had residual nodal disease (ypN1) on sentinel lymph node biopsy (SLNB). Twenty-eight patients underwent SLNB alone and 42 underwent SLNB+completion (c)ALND in a non-randomized fashion. Most (n= 65) patients underwent adjuvant regional nodal irradiation (RNI). Detailed patterns of failure data were obtained for each patient.RESULTS: The median follow-up was 43.5 months. There were 30 (43%) recurrences. Of these, 5 were isolated locoregional failures, and 24 were distant failures. There were no significant differences in local (P= .13), regional (P= .62), or distant (P= .47) failure between patients who underwent SLNB alone versus SLNB+cALND. Seventeen (24%) patients died. Overall survival was similar in both groups with median overall survival not reached for those who underwent SLNB and 109 months for those who underwent SLNB+cALND (P= .45).CONCLUSIONS: There were no differences in patterns of recurrence among patients with 1 to 3 involved lymph nodes after NAC who underwent SLNB alone versus SLNB+cALND in the setting of RNI. We await the results of ongoing, prospective clinical trials to confirm the relative merits of RNI in lieu of cALND in these patients.

    View details for DOI 10.1016/j.clbc.2020.04.008

    View details for PubMedID 32522481

  • A randomized phase II study comparing surgical excision versus NeOadjuvant Radiotherapy followed by delayed surgical excision of Ductal carcinoma In Situ (NORDIS) Wapnir, I., DeMartini, W., Allison, K., Stone, K., Dirbas, F., Marquez, C., Ikeda, D., Pal, S., Tsai, J., Yang, R., West, R., McMillan, A., Telli, M., Horst, K. AMER ASSOC CANCER RESEARCH. 2020
  • Breast cancer induces systemic immune changes on cytokine signaling in peripheral blood monocytes and lymphocytes. EBioMedicine Wang, L. n., Simons, D. L., Lu, X. n., Tu, T. Y., Avalos, C. n., Chang, A. Y., Dirbas, F. M., Yim, J. H., Waisman, J. n., Lee, P. P. 2020; 52: 102631

    Abstract

    It is increasingly recognized that cancer progression induces systemic immune changes in the host. Alterations in number and function of immune cells have been identified in cancer patients' peripheral blood and lymphoid organs. Recently, we found dysregulated cytokine signaling in peripheral blood T cells from breast cancer (BC) patients, even those with localized disease.We used phosphoflow cytometry to determine the clinical significance of cytokine signaling responsiveness in peripheral blood monocytes from non-metastatic BC patients at diagnosis. We also examined the correlation between cytokine signaling in peripheral monocytes and the number of tumor-infiltrating macrophages in paired breast tumors.Our results show that cytokine (IFNγ) signaling may also be dysregulated in peripheral blood monocytes at diagnosis, specifically in BC patients who later relapsed. Some patients exhibited concurrent cytokine signaling defects in monocytes and lymphocytes at diagnosis, which predict the risk of future relapse in two independent cohorts of BC patients. Moreover, IFNγ signaling negatively correlates with expression of CSF1R on monocytes, thus modulating their ability to infiltrate into tumors.Our results demonstrate that tumor-induced systemic immune changes are evident in peripheral blood immune cells for both myeloid and lymphoid lineages, and point to cytokine signaling responsiveness as important biomarkers to evaluate the overall immune status of BC patients.This study was supported by the Department of Defense Breast Cancer Research Program (BCRP), The V Foundation, Stand Up to Cancer (SU2C), and Breast Cancer Research Foundation (BCRF).

    View details for DOI 10.1016/j.ebiom.2020.102631

    View details for PubMedID 31981982

  • Angiosarcoma of the Breast: Management and Outcomes. American journal of clinical oncology Gutkin, P. M., Ganjoo, K. N., Lohman, M. n., von Eyben, R. n., Charville, G. W., Nazerali, R. S., Dirbas, F. M., Horst, K. C. 2020

    Abstract

    Angiosarcoma of the breast is rare and has a poor prognosis. We reviewed our institution's experience with this disease to characterize presentation, identify management patterns, and report outcomes.Fifty-eight patients with nonmetastatic angiosarcoma were identified from 1998 to 2019 and retrospectively reviewed. Overall survival (OS) and recurrence-free survival (RFS) were calculated using the Kaplan-Meier analysis and log-rank test.The median follow-up was 43.4 months (range: 1.8 to 203.3 mo). Twenty-four patients had primary angiosarcoma (PAS) and 34 patients had secondary angiosarcoma (SAS). Patients with PAS were significantly younger than those with SAS (P<0.0001). Mastectomy was the main surgical treatment in our cohort (n=47) and 3 underwent a lumpectomy. The multifocal disease was found in 5/23 patients with PAS and 11/35 patients with SAS. Twenty-eight patients received chemotherapy. Radiation was administered to 13 patients with PAS and 3 patients with SAS. Five-year OS was 73.7% for PAS and 63.5% for SAS. Local recurrence occurred in a greater proportion of patients with margins <5 mm than those with margins ≥5 mm. Chemotherapy did not impact RFS and was not associated with OS in PAS (P=0.35). Those with SAS treated with chemotherapy had significantly greater OS than those who did not receive chemotherapy (P=0.043). Radiation did not significantly influence RFS or OS.Five-year OS was higher than anticipated. Margins >5 mm appear important for local control. Patients with SAS, but not PAS, may achieve improved survival with chemotherapy. National trials using prespecified agents may be needed to identify an optimal chemotherapy regimen for women with SAS.

    View details for DOI 10.1097/COC.0000000000000753

    View details for PubMedID 32889893

  • Two Patient Studies of a Companion Diagnostic Immuno-Positron Emission Tomography (PET) Tracer for Measuring Human CA6 Expression in Cancer for Antibody Drug Conjugate (ADC) Therapy. Molecular imaging Natarajan, A., Srinivas, S. M., Azevedo, C., Greene, L., Bauchet, A., Jouannot, E., Lacoste-Bourgeacq, A., Guizon, I., Cohen, P., Naneix, A., Ilovich, O., Cisneros, J., Rupanarayan, K., Chin, F. T., Iagaru, A., Dirbas, F. M., Karam, A., Gambhir, S. S. 2020; 19: 1536012120939398

    Abstract

    An antigen binding fragment (BFab) derived from a tumor-associated mucin 1-sialoglycotope antigen (CA6) targeting antibody (huDS6) was engineered. We synthesized a companion diagnostic positron emission tomography (PET) tracer by radiolabeling BFab with [64Cu] to measure CA6 expression on cancer tissues prior to anti-human CA6 (huDS6-DM4 antibody-drug conjugate) therapy for ovarian and breast cancer patients. After chemotherapy, the ovarian patient received PET scan with 18F-2-fluoro-2-deoxyglucose ([18F]FDG: 10 mCi), followed by [64Cu]-DOTA-BFab ([64Cu]BFab; 5.5 mCi) 1 week later for PET scanning of CA6 expression and subsequent surgery. The breast cancer patient was treated with chemotherapy before primary tumor resection and subsequent [18F]FDG-PET scan. 4 weeks later the patient received of [64Cu]BFab (11.7 mCi) for CA6 PET scan. Whole body [18F]FDG-PET of the breast cancer patient indicated FDG-avid tumor metastases to the liver, bilateral hila and thoracic spine, but no uptake was observed for the ovarian patient. Each patient was also imaged by PET/CT with [64Cu]BFab at 1 and 24 hours after tracer administration. The [64Cu]BFab tracer was well tolerated by both patients without adverse effects, and no significant tracer uptake was observed in both patients. Immunohistochemistry (IHC) data indicated CA6 expressions were weak to intermediate and matched with the [64Cu]BFab-PET signals.

    View details for DOI 10.1177/1536012120939398

    View details for PubMedID 33104454

  • Preoperative Factors Associated with Remote Postoperative Pain Resolution and Opioid Cessation in a Mixed Surgical Cohort: Post Hoc Analysis of a Perioperative Gabapentin Trial. Journal of pain research Hah, J. M., Hilmoe, H. n., Schmidt, P. n., McCue, R. n., Trafton, J. n., Clay, D. n., Sharifzadeh, Y. n., Ruchelli, G. n., Hernandez Boussard, T. n., Goodman, S. n., Huddleston, J. n., Maloney, W. J., Dirbas, F. M., Shrager, J. n., Costouros, J. G., Curtin, C. n., Mackey, S. C., Carroll, I. n. 2020; 13: 2959–70

    Abstract

    Preoperative patient-specific risk factors may elucidate the mechanisms leading to the persistence of pain and opioid use after surgery. This study aimed to determine whether similar or discordant preoperative factors were associated with the duration of postoperative pain and opioid use.In this post hoc analysis of a randomized, double-blind, placebo-controlled trial of perioperative gabapentin vs active placebo, 410 patients aged 18-75 years, undergoing diverse operations underwent preoperative assessments of pain, opioid use, substance use, and psychosocial variables. After surgery, a modified Brief Pain Inventory was administered over the phone daily up to 3 months, weekly up to 6 months, and monthly up to 2 years after surgery. Pain and opioid cessation were defined as the first of 5 consecutive days of 0 out of 10 pain or no opioid use, respectively.Overall, 36.1%, 19.8%, and 9.5% of patients continued to report pain, and 9.5%, 2.4%, and 1.7% reported continued opioid use at 3, 6, and 12 months after surgery. Preoperative pain at the future surgical site (every 1-point increase in the Numeric Pain Rating Scale; HR 0.93; 95% CI 0.87-1.00; P=0.034), trait anxiety (every 10-point increase in the Trait Anxiety Inventory; HR 0.79; 95% CI 0.68-0.92; P=0.002), and a history of delayed recovery after injury (HR 0.62; 95% CI 0.40-0.96; P=0.034) were associated with delayed pain cessation. Preoperative opioid use (HR 0.60; 95% CI 0.39-0.92; P=0.020), elevated depressive symptoms (every 5-point increase in the Beck Depression Inventory-II score; HR 0.88; 95% CI 0.80-0.98; P=0.017), and preoperative pain outside of the surgical site (HR 0.94; 95% CI 0.89-1.00; P=0.046) were associated with delayed opioid cessation, while perioperative gabapentin promoted opioid cessation (HR 1.37; 95% CI 1.06-1.77; P=0.016).Separate risk factors for prolonged post-surgical pain and opioid use indicate that preoperative risk stratification for each outcome may identify patients needing personalized care to augment universal protocols for perioperative pain management and conservative opioid prescribing to improve long-term outcomes.

    View details for DOI 10.2147/JPR.S269370

    View details for PubMedID 33239904

    View details for PubMedCentralID PMC7680674

  • Factors Associated With Acute Pain Estimation, Postoperative Pain Resolution, Opioid Cessation, and Recovery Secondary Analysis of a Randomized Clinical Trial JAMA NETWORK OPEN Hah, J. M., Cramer, E., Hilmoe, H., Schmidt, P., McCue, R., Trafton, J., Clay, D., Sharifzadeh, Y., Ruchelli, G., Goodman, S., Huddleston, J., Maloney, W. J., Dirbas, F. M., Shrager, J., Costouros, J. G., Curtin, C., Mackey, S. C., Carroll, I. 2019; 2 (3)
  • Rising rates of bilateral mastectomy with reconstruction following neoadjuvant chemotherapy INTERNATIONAL JOURNAL OF CANCER Pollom, E. L., Qian, Y., Chin, A. L., Dirbas, F. M., Asch, S. M., Kurian, A. W., Horst, K. C., Tsai, C. 2018; 143 (12): 3262–72

    View details for DOI 10.1002/ijc.31747

    View details for Web of Science ID 000451115900020

  • The DLK1-DIO3 imprinted region regulates long-term proliferation in normal and malignant breast epithelium Zabala, M., Lobo, N. A., Seoane, J. A., Stelzer, Y., Luong, A. V., Isobe, T., Zarnegar, M. A., Watanabe, N., Antonana, S., Lam, J., Qian, D., Sikandar, S. S., Kuo, A. H., Heitink, L. S., Shimono, Y., Scheeren, F. A., Cai, S., Hisamori, S., Sahoo, D., Dirbas, F. M., Somlo, G., Jaenisch, R., Christina, C., Clarke, M. F. AMER ASSOC CANCER RESEARCH. 2018: 95
  • National trends in mastectomy for operable breast cancers treated with neoadjuvant chemotherapy Pollom, E., Qian, Y., Dirbas, F., Horst, K., Tsai, C. AMER ASSOC CANCER RESEARCH. 2018
  • Rising rates of bilateral mastectomy with reconstruction following neoadjuvant chemotherapy. International journal of cancer Pollom, E. L., Qian, Y. n., Chin, A. L., Dirbas, F. M., Asch, S. M., Kurian, A. W., Horst, K. C., Tsai, C. J. 2018

    Abstract

    Neoadjuvant chemotherapy is used to allow more limited breast surgery without compromising local control. We sought to evaluate nationwide surgical trends in patients with operable breast cancer treated with neoadjuvant chemotherapy and factors associated with surgical type. We used the National Cancer Database to identify 235,339 women with unilateral T1-3N0-3M0 breast cancer diagnosed between 2010 and 2014, and treated with surgery and chemotherapy. Of these, 59,568 patients (25.3%) were treated with neoadjuvant chemotherapy. Rates of pathologic complete response to neoadjuvant chemotherapy increased from 33.3% at the start of the study period in 2010 to 46.3% at the end of the period in 2014 (p=0.02). Rates of breast-conserving surgery changed little, from 37.0% to 40.8% (p=0.22). While rates of unilateral mastectomy decreased from 43.3% to 34.7% (p=0.02) and rates of bilateral mastectomy without immediate reconstruction remained similar (11.7% to 11.5%, p=0.82), rates of bilateral mastectomy with immediate reconstruction rose from 8.0% to 13.1% (p=0.02). Patients who were younger, with private/managed care insurance, and diagnosed in more recent years were more likely to achieve pathologic complete response; however, these same characteristics were associated with receipt of bilateral mastectomy (versus breast-conserving surgery). Additionally, non-Hispanic white race and higher area education attainment were both associated with bilateral mastectomy. These findings did not differ by age or molecular subtype. Further study of non-clinical factors that influence selection of more extensive surgery despite excellent response to neoadjuvant chemotherapy is warranted. This article is protected by copyright. All rights reserved.

    View details for PubMedID 29992582

  • T cell receptor sequencing of early-stage breast cancer tumors identifies altered clonal structure of the T cell repertoire PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Beausang, J. F., Wheeler, A. J., Chan, N. H., Hanft, V. R., Dirbas, F. M., Jeffrey, S. S., Quake, S. R. 2017; 114 (48): E10409–E10417
  • T cell receptor sequencing of early-stage breast cancer tumors identifies altered clonal structure of the T cell repertoire. Proceedings of the National Academy of Sciences of the United States of America Beausang, J. F., Wheeler, A. J., Chan, N. H., Hanft, V. R., Dirbas, F. M., Jeffrey, S. S., Quake, S. R. 2017

    Abstract

    Tumor-infiltrating T cells play an important role in many cancers, and can improve prognosis and yield therapeutic targets. We characterized T cells infiltrating both breast cancer tumors and the surrounding normal breast tissue to identify T cells specific to each, as well as their abundance in peripheral blood. Using immune profiling of the T cell beta-chain repertoire in 16 patients with early-stage breast cancer, we show that the clonal structure of the tumor is significantly different from adjacent breast tissue, with the tumor containing 2.5-fold greater density of T cells and higher clonality compared with normal breast. The clonal structure of T cells in blood and normal breast is more similar than between blood and tumor, and could be used to distinguish tumor from normal breast tissue in 14 of 16 patients. Many T cell sequences overlap between tissue and blood from the same patient, including 50% of T cells between tumor and normal breast. Both tumor and normal breast contain high-abundance "enriched" sequences that are absent or of low abundance in the other tissue. Many of these T cells are either not detected or detected with very low frequency in the blood, suggesting the existence of separate compartments of T cells in both tumor and normal breast. Enriched T cell sequences are typically unique to each patient, but a subset is shared between many different patients. We show that many of these are commonly generated sequences, and thus unlikely to play an important role in the tumor microenvironment.

    View details for PubMedID 29138313

  • IL6 Signaling in Peripheral Blood T Cells Predicts Clinical Outcome in Breast Cancer. Cancer research Wang, L., Miyahira, A. K., Simons, D. L., Lu, X., Chang, A. Y., Wang, C., Suni, M. A., Maino, V. C., Dirbas, F. M., Yim, J., Waisman, J., Lee, P. P. 2017; 77 (5): 1119-1126

    Abstract

    IL6 is a pleiotropic cytokine with both pro- and anti-inflammatory properties, which acts directly on cancer cells to promote their survival and proliferation. Elevated serum IL6 levels negatively correlate with survival of cancer patients, which is generally attributed to the direct effects of IL6 on cancer cells. How IL6 modulates the host immune response in cancer patients is unclear. Here, we show the IL6 signaling response in peripheral blood T cells is impaired in breast cancer patients and is associated with blunted Th17 differentiation. The mechanism identified involved downregulation of gp130 and IL6Rα in breast cancer patients and was independent of plasma IL6 levels. Importantly, defective IL6 signaling in peripheral blood T cells at diagnosis correlated with worse relapse-free survival. These results indicate that intact IL6 signaling in T cells is important for controlling cancer progression. Furthermore, they highlight a potential for IL6 signaling response in peripheral blood T cells at diagnosis as a predictive biomarker for clinical outcome of breast cancer patients. Cancer Res; 77(5); 1119-26. ©2016 AACR.

    View details for DOI 10.1158/0008-5472.CAN-16-1373

    View details for PubMedID 27879265

  • Improving Care With a Portfolio of Physician-Led Cancer Quality Measures at an Academic Center Improving Care With a Portfolio of Physician-Led Cancer Quality Measures at an Academic Center Porter, J. B. 2017; 13 (8): e673-e682

    Abstract

    Development and implementation of robust reporting processes to systematically provide quality data to care teams in a timely manner is challenging. National cancer quality measures are useful, but the manual data collection required is resource intensive, and reporting is delayed. We designed a largely automated measurement system with our multidisciplinary cancer care programs (CCPs) to identify, measure, and improve quality metrics that were meaningful to the care teams and their patients.Each CCP physician leader collaborated with the cancer quality team to identify metrics, abiding by established guiding principles. Financial incentive was provided to the CCPs if performance at the end of the study period met predetermined targets. Reports were developed and provided to the CCP physician leaders on a monthly or quarterly basis, for dissemination to their CCP teams.A total of 15 distinct quality measures were collected in depth for the first time at this cancer center. Metrics spanned the patient care continuum, from diagnosis through end of life or survivorship care. All metrics improved over the study period, met their targets, and earned a financial incentive for their CCP.Our quality program had three essential elements that led to its success: (1) engaging physicians in choosing the quality measures and prespecifying goals, (2) using automated extraction methods for rapid and timely feedback on improvement and progress toward achieving goals, and (3) offering a financial team-based incentive if prespecified goals were met.

    View details for DOI 10.1200/JOP.2017.021139

    View details for PubMedCentralID PMC5880618

  • CT-Guided Wire Localization for Involved Axillary Lymph Nodes After Neo-adjuvant Chemotherapy in Patients With Initially Node-Positive Breast Cancer BREAST JOURNAL Long Trinh, L., Miyake, K. K., Dirbas, F. M., Kothary, N., Horst, K. C., Lipson, J. A., Carpenter, C., Thompson, A. C., Ikeda, D. M. 2016; 22 (4): 390-396

    Abstract

    Resection of biopsy-proven involved axillary lymph nodes (iALNs) is important to reduce the false-negative rates of sentinel lymph node (SLN) biopsy after neo-adjuvant chemotherapy (NAC) in patients with initially node-positive breast cancer. Preoperative wire localization for iALNs marked with clips placed during biopsy is a technique that may help the removal of iALNs after NAC. However, ultrasound (US)-guided localization is often difficult because the clips cannot always be reliably visible on US. Computed tomography (CT)-guided wire localization can be used; however, to date there have been no reports on CT-guided wire localization for iALNs. The aim of this study was to describe a series of patients who received CT-guided wire localization for iALN removal after NAC and to evaluate the feasibility of this technique. We retrospectively analyzed five women with initially node-positive breast cancer (age, 41-52 years) who were scheduled for SLN biopsy after NAC and received preoperative CT-guided wire localization for iALNs. CT visualized all the clips that were not identified on post-NAC US. The wire tip was deployed beyond or at the target, with the shortest distance between the wire and the index clip ranging from 0 to 2.5 mm. The total procedure time was 21-38 minutes with good patient tolerance and no complications. In four of five cases, CT wire localization aided in identification and resection of iALNs that were not identified with lymphatic mapping. Residual nodal disease was confirmed in two cases: both had residual disease in wire-localized lymph nodes in addition to SLNs. Although further studies with more cases are required, our results suggest that CT-guided wire localization for iALNs is a feasible technique that facilitates identification and removal of the iALNs as part of SLN biopsy after NAC in situations where US localization is unsuccessful.

    View details for DOI 10.1111/tbj.12597

    View details for PubMedID 27061012

  • Breast Cancer After Hodgkin Lymphoma: The Price of Success. Oncology (Williston Park, N.Y.) Manzo, V. n., Dirbas, F. n., Telli, M. L. 2016; 30 (12)

    View details for PubMedID 27987199

  • Pain Duration and Resolution following Surgery: An Inception Cohort Study PAIN MEDICINE Carroll, I. R., Hah, J. M., Barelka, P. L., Wang, C. K., Wang, B. M., Gillespie, M. J., McCue, R., Younger, J. W., Trafton, J., Humphreys, K., Goodman, S. B., Dirbas, F. M., Mackey, S. C. 2015; 16 (12): 2386-2396

    Abstract

    Preoperative determinants of pain duration following surgery are poorly understood. We identified preoperative predictors of prolonged pain after surgery in a mixed surgical cohort.We conducted a prospective longitudinal study of patients undergoing mastectomy, lumpectomy, thoracotomy, total knee replacement, or total hip replacement. We measured preoperative psychological distress and substance use, and then measured pain and opioid use after surgery until patients reported the cessation of both opioid consumption and pain. The primary endpoint was time to opioid cessation, and those results have been previously reported. Here, we report preoperative determinants of time to pain resolution following surgery in Cox proportional hazards regression.Between January 2007 and April 2009, we enrolled 107 of 134 consecutively approached patients undergoing the aforementioned surgical procedures. In the final multivariate model, preoperative self-perceived risk of addiction predicted more prolonged pain. Unexpectedly, anxiety sensitivity predicted more rapid pain resolution after surgery. Each one-point increase (on a four point scale) of self-perceived risk of addiction was associated with a 38% (95% CI 3-61) reduction in the rate of pain resolution (P = 0.04). Furthermore, higher anxiety sensitivity was associated with an 89% (95% CI 23-190) increased rate of pain resolution (P = 0.004).Greater preoperative self-perceived risk of addiction, and lower anxiety sensitivity predicted a slower rate of pain resolution following surgery. Each of these factors was a better predictor of pain duration than preoperative depressive symptoms, post-traumatic stress disorder symptoms, past substance use, fear of pain, gender, age, preoperative pain, or preoperative opioid use.

    View details for DOI 10.1111/pme.12842

    View details for Web of Science ID 000368297000020

    View details for PubMedCentralID PMC4706803

  • Pain Duration and Resolution following Surgery: An Inception Cohort Study. Pain medicine Carroll, I. R., Hah, J. M., Barelka, P. L., Wang, C. K., Wang, B. M., Gillespie, M. J., McCue, R., Younger, J. W., Trafton, J., Humphreys, K., Goodman, S. B., Dirbas, F. M., Mackey, S. C. 2015; 16 (12): 2386-2396

    Abstract

    Preoperative determinants of pain duration following surgery are poorly understood. We identified preoperative predictors of prolonged pain after surgery in a mixed surgical cohort.We conducted a prospective longitudinal study of patients undergoing mastectomy, lumpectomy, thoracotomy, total knee replacement, or total hip replacement. We measured preoperative psychological distress and substance use, and then measured pain and opioid use after surgery until patients reported the cessation of both opioid consumption and pain. The primary endpoint was time to opioid cessation, and those results have been previously reported. Here, we report preoperative determinants of time to pain resolution following surgery in Cox proportional hazards regression.Between January 2007 and April 2009, we enrolled 107 of 134 consecutively approached patients undergoing the aforementioned surgical procedures. In the final multivariate model, preoperative self-perceived risk of addiction predicted more prolonged pain. Unexpectedly, anxiety sensitivity predicted more rapid pain resolution after surgery. Each one-point increase (on a four point scale) of self-perceived risk of addiction was associated with a 38% (95% CI 3-61) reduction in the rate of pain resolution (P = 0.04). Furthermore, higher anxiety sensitivity was associated with an 89% (95% CI 23-190) increased rate of pain resolution (P = 0.004).Greater preoperative self-perceived risk of addiction, and lower anxiety sensitivity predicted a slower rate of pain resolution following surgery. Each of these factors was a better predictor of pain duration than preoperative depressive symptoms, post-traumatic stress disorder symptoms, past substance use, fear of pain, gender, age, preoperative pain, or preoperative opioid use.

    View details for DOI 10.1111/pme.12842

    View details for PubMedID 26179223

  • A cell-intrinsic role for TLR2-MYD88 in intestinal and breast epithelia and oncogenesis. Nature cell biology Scheeren, F. A., Kuo, A. H., van Weele, L. J., Cai, S., Glykofridis, I., Sikandar, S. S., Zabala, M., Qian, D., Lam, J. S., Johnston, D., Volkmer, J. P., Sahoo, D., van de Rijn, M., Dirbas, F. M., Somlo, G., Kalisky, T., Rothenberg, M. E., Quake, S. R., Clarke, M. F. 2014; 16 (12): 1238-1248

    Abstract

    It has been postulated that there is a link between inflammation and cancer. Here we describe a role for cell-intrinsic toll-like receptor-2 (TLR2; which is involved in inflammatory response) signalling in normal intestinal and mammary epithelial cells and oncogenesis. The downstream effectors of TLR2 are expressed by normal intestinal and mammary epithelia, including the stem/progenitor cells. Deletion of MYD88 or TLR2 in the intestinal epithelium markedly reduces DSS-induced colitis regeneration and spontaneous tumour development in mice. Limiting dilution transplantations of breast epithelial cells devoid of TLR2 or MYD88 revealed a significant decrease in mammary repopulating unit frequency compared with the control. Inhibition of TLR2, its co-receptor CD14, or its downstream targets MYD88 and IRAK1 inhibits growth of human breast cancers in vitro and in vivo. These results suggest that inhibitors of the TLR2 pathway merit investigation as possible therapeutic and chemoprevention agents.

    View details for DOI 10.1038/ncb3058

    View details for PubMedID 25362351

  • A cell-intrinsic role for TLR2 MYD88 in intestinal and breast epithelia and oncogenesis NATURE CELL BIOLOGY Scheeren, F. A., Kuo, A. H., van Weele, L. J., Cai, S., Glykofridis, I., Sikandar, S. S., Zabala, M., Qian, D., Lam, J. S., Johnston, D., Volkmer, J. P., Sahoo, D., van de Rijn, M., Dirbas, F. M., Somlo, G., Kalisky, T., Rothenberg, M. E., Quake, S. R., Clarke, M. F. 2014; 16 (12): 1238-U245

    Abstract

    It has been postulated that there is a link between inflammation and cancer. Here we describe a role for cell-intrinsic toll-like receptor-2 (TLR2; which is involved in inflammatory response) signalling in normal intestinal and mammary epithelial cells and oncogenesis. The downstream effectors of TLR2 are expressed by normal intestinal and mammary epithelia, including the stem/progenitor cells. Deletion of MYD88 or TLR2 in the intestinal epithelium markedly reduces DSS-induced colitis regeneration and spontaneous tumour development in mice. Limiting dilution transplantations of breast epithelial cells devoid of TLR2 or MYD88 revealed a significant decrease in mammary repopulating unit frequency compared with the control. Inhibition of TLR2, its co-receptor CD14, or its downstream targets MYD88 and IRAK1 inhibits growth of human breast cancers in vitro and in vivo. These results suggest that inhibitors of the TLR2 pathway merit investigation as possible therapeutic and chemoprevention agents.

    View details for DOI 10.1038/ncb3058

    View details for Web of Science ID 000345777300014

    View details for PubMedID 25362351

  • miR-142 regulates the tumorigenicity of human breast cancer stem cells through the canonical WNT signaling pathway ELIFE Isobe, T., Hisamori, S., Hogan, D. J., Zabala, M., Hendrickson, D. G., Dalerba, P., Cai, S., Scheeren, F., Kuo, A. H., Sikandar, S. S., Lam, J. S., Qian, D., Dirbas, F. M., Somlo, G., Lao, K., Brown, P. O., Clarke, M. F., Shimono, Y. 2014; 3

    Abstract

    MicroRNAs (miRNAs) are important regulators of stem and progenitor cell functions. We previously reported that miR-142 and miR-150 are upregulated in human breast cancer stem cells (BCSCs) as compared to the non-tumorigenic breast cancer cells. In this study, we report that miR-142 efficiently recruits the APC mRNA to an RNA-induced silencing complex, activates the canonical WNT signaling pathway in an APC-suppression dependent manner, and activates the expression of miR-150. Enforced expression of miR-142 or miR-150 in normal mouse mammary stem cells resulted in the regeneration of hyperproliferative mammary glands in vivo. Knockdown of endogenous miR-142 effectively suppressed organoid formation by BCSCs and slowed tumor growth initiated by human BCSCs in vivo. These results suggest that in some tumors, miR-142 regulates the properties of BCSCs at least in part by activating the WNT signaling pathway and miR-150 expression.

    View details for DOI 10.7554/eLife.01977

    View details for Web of Science ID 000345638500001

  • Self-Loathing Aspects of Depression Reduce Postoperative Opioid Cessation Rate PAIN MEDICINE Hah, J. M., Mackey, S., Barelka, P. L., Wang, C. K., Wang, B. M., Gillespie, M. J., McCue, R., Younger, J. W., Trafton, J., Humphreys, K., Goodman, S. B., Dirbas, F. M., Schmidt, P. C., Carroll, I. R. 2014; 15 (6): 954-964

    Abstract

    We previously reported that increased preoperative Beck Depression Inventory II (BDI-II) scores were associated with a 47% (95% CI 24%-64%) reduction in the rate of opioid cessation following surgery. We aimed to identify the underlying factors of the BDI-II (affective/cognitive vs somatic) associated with a decreased rate of opioid cessation after surgery.We conducted a secondary analysis of the data from a previously reported prospective, longitudinal, observational study of opioid use after five distinct surgical procedures (total hip replacement, total knee replacement, thoracotomy, mastectomy, and lumpectomy) in 107 patients. The primary endpoint was time to opioid cessation. After exploratory factor analysis of the BDI-II, mean summary scores were calculated for each identified factor. These scores were evaluated as predictors of time to opioid cessation using Cox proportional hazards regression.The exploratory factor analysis produced three factors (self-loathing symptoms, motivational symptoms, emotional symptoms). All three factors were significant predictors in univariate analysis. Of the three identified factors of the BDI-II, only preoperative self-loathing symptoms (past failure, guilty feelings, self-dislike, self-criticalness, suicidal thoughts, worthlessness) independently predicted a significant decrease in opioid cessation rate after surgery in the multivariate analysis (HR 0.86, 95% CI 0.75-0.99, P value 0.037).Our results identify a set of negative cognitions predicting prolonged time to postoperative opioid cessation. Somatic symptoms captured by the BDI-II were not primarily responsible for the association between preoperative BDI-II scores and postoperative prolonged opioid use.

    View details for DOI 10.1111/pme.12439

    View details for Web of Science ID 000338025900009

    View details for PubMedCentralID PMC4083472

  • Breast Magnetic Resonance Imaging Alters Patient Selection for Accelerated Partial Breast Irradiation AMERICAN JOURNAL OF CLINICAL ONCOLOGY-CANCER CLINICAL TRIALS Horst, K. C., Ikeda, D. M., Fero, K. E., Daniel, B. L., Goffinet, D. R., Dirbas, F. M. 2014; 37 (3): 248-254

    Abstract

    OBJECTIVES:: To determine whether pretreatment contrast-enhanced breast magnetic resonance imaging (MRI) alters patient selection for accelerated partial breast irradiation (APBI). MATERIALS AND METHODS:: Women aged 40 years or older with unifocal invasive or intraductal carcinoma ≤2.5 cm on physical examination, mammography, and ultrasound (US) were evaluated with breast MRI before enrollment on an APBI trial using single-fraction intraoperative radiotherapy (IORT) or fractionated 3-dimensional conformal radiotherapy. Abnormal MRI findings were evaluated with US-guided or MRI-guided biopsy. RESULTS:: Between December 2002 and March 2005, 51 women (median age=61 y; range, 40 to 83 y) who met inclusion criteria underwent breast MRI before APBI. MRI demonstrated limited disease in 41 patients (80.4%): 34 received APBI using IORT (22) or 3DCRT (12), whereas 7 elected standard whole-breast radiotherapy. Ten of the 51 patients (19.6%) had indeterminate or suspicious enhancement patterns on MRI. Five of these 10 (9.8% of MRI cohort) underwent US-guided or MRI-guided biopsy revealing normal breast tissue without atypia: 3 were treated with APBI using IORT (5.9% of MRI cohort) and 2 underwent standard breast conservation therapy (3.9% of MRI cohort). The remaining 5 patients (9.8% of MRI cohort) had MRI findings revealing previously unsuspected pectoral fascia involvement (1), multifocal disease (3), or multicentric disease (1): 2 were treated with standard breast conservation therapy, whereas 3 underwent mastectomy without adjuvant radiotherapy. CONCLUSIONS:: Pretreatment breast MRI altered patient selection for APBI by identifying additional disease in 9.8% of the candidates, all of whom fit into the "cautionary" or "unsuitable" categories as defined by the American Society for Radiation Oncology APBI consensus guidelines. The clinical significance of these findings will be clarified with the results of ongoing randomized trials of APBI that do not incorporate breast MRI as part of the selection criteria.

    View details for DOI 10.1097/COC.0b013e318277d7c8

    View details for Web of Science ID 000336958200006

  • Breast magnetic resonance imaging alters patient selection for accelerated partial breast irradiation. American journal of clinical oncology Horst, K. C., Ikeda, D. M., Fero, K. E., Daniel, B. L., Goffinet, D. R., Dirbas, F. M. 2014; 37 (3): 248-254

    Abstract

    OBJECTIVES:: To determine whether pretreatment contrast-enhanced breast magnetic resonance imaging (MRI) alters patient selection for accelerated partial breast irradiation (APBI). MATERIALS AND METHODS:: Women aged 40 years or older with unifocal invasive or intraductal carcinoma ≤2.5 cm on physical examination, mammography, and ultrasound (US) were evaluated with breast MRI before enrollment on an APBI trial using single-fraction intraoperative radiotherapy (IORT) or fractionated 3-dimensional conformal radiotherapy. Abnormal MRI findings were evaluated with US-guided or MRI-guided biopsy. RESULTS:: Between December 2002 and March 2005, 51 women (median age=61 y; range, 40 to 83 y) who met inclusion criteria underwent breast MRI before APBI. MRI demonstrated limited disease in 41 patients (80.4%): 34 received APBI using IORT (22) or 3DCRT (12), whereas 7 elected standard whole-breast radiotherapy. Ten of the 51 patients (19.6%) had indeterminate or suspicious enhancement patterns on MRI. Five of these 10 (9.8% of MRI cohort) underwent US-guided or MRI-guided biopsy revealing normal breast tissue without atypia: 3 were treated with APBI using IORT (5.9% of MRI cohort) and 2 underwent standard breast conservation therapy (3.9% of MRI cohort). The remaining 5 patients (9.8% of MRI cohort) had MRI findings revealing previously unsuspected pectoral fascia involvement (1), multifocal disease (3), or multicentric disease (1): 2 were treated with standard breast conservation therapy, whereas 3 underwent mastectomy without adjuvant radiotherapy. CONCLUSIONS:: Pretreatment breast MRI altered patient selection for APBI by identifying additional disease in 9.8% of the candidates, all of whom fit into the "cautionary" or "unsuitable" categories as defined by the American Society for Radiation Oncology APBI consensus guidelines. The clinical significance of these findings will be clarified with the results of ongoing randomized trials of APBI that do not incorporate breast MRI as part of the selection criteria.

    View details for DOI 10.1097/COC.0b013e318277d7c8

    View details for PubMedID 23275271

  • Self-loathing aspects of depression reduce postoperative opioid cessation rate. Pain medicine Hah, J. M., Mackey, S., Barelka, P. L., Wang, C. K., Wang, B. M., Gillespie, M. J., McCue, R., Younger, J. W., Trafton, J., Humphreys, K., Goodman, S. B., Dirbas, F. M., Schmidt, P. C., Carroll, I. R. 2014; 15 (6): 954-964

    Abstract

    We previously reported that increased preoperative Beck Depression Inventory II (BDI-II) scores were associated with a 47% (95% CI 24%-64%) reduction in the rate of opioid cessation following surgery. We aimed to identify the underlying factors of the BDI-II (affective/cognitive vs somatic) associated with a decreased rate of opioid cessation after surgery.We conducted a secondary analysis of the data from a previously reported prospective, longitudinal, observational study of opioid use after five distinct surgical procedures (total hip replacement, total knee replacement, thoracotomy, mastectomy, and lumpectomy) in 107 patients. The primary endpoint was time to opioid cessation. After exploratory factor analysis of the BDI-II, mean summary scores were calculated for each identified factor. These scores were evaluated as predictors of time to opioid cessation using Cox proportional hazards regression.The exploratory factor analysis produced three factors (self-loathing symptoms, motivational symptoms, emotional symptoms). All three factors were significant predictors in univariate analysis. Of the three identified factors of the BDI-II, only preoperative self-loathing symptoms (past failure, guilty feelings, self-dislike, self-criticalness, suicidal thoughts, worthlessness) independently predicted a significant decrease in opioid cessation rate after surgery in the multivariate analysis (HR 0.86, 95% CI 0.75-0.99, P value 0.037).Our results identify a set of negative cognitions predicting prolonged time to postoperative opioid cessation. Somatic symptoms captured by the BDI-II were not primarily responsible for the association between preoperative BDI-II scores and postoperative prolonged opioid use.

    View details for DOI 10.1111/pme.12439

    View details for PubMedID 24964916

  • Patient-derived xenografts of triple-negative breast cancer reproduce molecular features of patient tumors and respond to mTOR inhibition BREAST CANCER RESEARCH Zhang, H., Cohen, A. L., Krishnakumar, S., Wapnir, I. L., Veeriah, S., Deng, G., Coram, M. A., Piskun, C. M., Longacre, T. A., Herrler, M., Frimannsson, D. O., Telli, M. L., Dirbas, F. M., Matin, A. C., Dairkee, S. H., Larijani, B., Glinsky, G. V., Bild, A. H., Jeffrey, S. S. 2014; 16 (2)

    View details for DOI 10.1186/bcr3640

    View details for Web of Science ID 000338990900021

  • miR-142 regulates the tumorigenicity of human breast cancer stem cells through the canonical WNT signaling pathway. eLife Isobe, T., Hisamori, S., Hogan, D. J., Zabala, M., Hendrickson, D. G., Dalerba, P., Cai, S., Scheeren, F., Kuo, A. H., Sikandar, S. S., Lam, J. S., Qian, D., Dirbas, F. M., Somlo, G., Lao, K., Brown, P. O., Clarke, M. F., Shimono, Y. 2014; 3

    Abstract

    MicroRNAs (miRNAs) are important regulators of stem and progenitor cell functions. We previously reported that miR-142 and miR-150 are upregulated in human breast cancer stem cells (BCSCs) as compared to the non-tumorigenic breast cancer cells. In this study, we report that miR-142 efficiently recruits the APC mRNA to an RNA-induced silencing complex, activates the canonical WNT signaling pathway in an APC-suppression dependent manner, and activates the expression of miR-150. Enforced expression of miR-142 or miR-150 in normal mouse mammary stem cells resulted in the regeneration of hyperproliferative mammary glands in vivo. Knockdown of endogenous miR-142 effectively suppressed organoid formation by BCSCs and slowed tumor growth initiated by human BCSCs in vivo. These results suggest that in some tumors, miR-142 regulates the properties of BCSCs at least in part by activating the WNT signaling pathway and miR-150 expression.

    View details for DOI 10.7554/eLife.01977

    View details for PubMedID 25406066

  • Defining an optimal role for breast magnetic resonance imaging when evaluating patients otherwise eligible for accelerated partial breast irradiation. Radiotherapy and oncology Horst, K. C., Fero, K. E., Ikeda, D. M., Daniel, B. L., Dirbas, F. M. 2013; 108 (2): 220-225

    Abstract

    BACKGROUND AND PURPOSE: Pre-treatment breast magnetic resonance imaging (MRI) findings in a cohort of women prospectively evaluated for accelerated partial breast irradiation (APBI) are reviewed and characterized to determine the optimal use of MRI in these patients. MATERIALS AND METHODS: Candidates initially deemed eligible for a prospective APBI trial based on physical examination, mammography, and ultrasound (US) were further evaluated with breast MRI before treatment. All abnormal MRI findings were biopsied. RESULTS: Between 2002 and 2011, 180 women who met inclusion criteria for APBI underwent breast MRI prior to treatment (median age=59; range 38-86). 126 tumors (70%) were invasive carcinomas with or without associated DCIS, while 54 (30%) were pure DCIS. Breast MRI confirmed unifocal disease in 109 patients with 111 cancers (60.5% of MRI cohort). Multifocal disease was identified in 19 patients (10.5% of MRI cohort), while multicentric disease was present in 3 patients (1.6% of MRI cohort). Five patients (4%) had an MRI-detected contralateral cancer. False positive MRI findings were seen in 45 patients (25% of MRI cohort). Pre-menopausal patients and patients with tumors >2cm were more likely to have MRI-detected multifocal/multicentric disease. While there was no statistically significant correlation between multifocal/multicentric disease and breast density, tumor histology, grade, ER status, or Her2/Neu expression, numbers in each category were small, suggesting a lack of statistical power to detect differences that may be clinically meaningful. One hundred and fifty-two of the 180 patients (84.4%) successfully completed lumpectomy and APBI, while 6.7% of the cohort underwent mastectomy. CONCLUSIONS: Breast MRI identified additional disease in 12% of APBI candidates. Premenopausal women and patients with tumors >2cm were more likely to have MRI-detected multifocal/multicentric disease.

    View details for DOI 10.1016/j.radonc.2013.01.019

    View details for PubMedID 23597699

  • Altered local and systemic immune profiles underlie lymph node metastasis in breast cancer patients INTERNATIONAL JOURNAL OF CANCER Zuckerman, N. S., Yu, H., Simons, D. L., Bhattacharya, N., Carcamo-Cavazos, V., Yan, N., Dirbas, F. M., Johnson, D. L., Schwartz, E. J., Lee, P. P. 2013; 132 (11): 2537-2547

    Abstract

    Cancer-mediated immune dysfunction contributes to tumor progression and correlates with patient outcome. Metastasis to tumor draining lymph nodes (TDLNs) is an important step in breast cancer progression and is used to predict patient outcome and survival. Although lymph nodes are important immune organs, the role of immune cells in TDLNs has not been thoroughly investigated. We hypothesized that the host immune response in node negative (NN) patients is more intact and thereby can resist tumor invasion compared to node positive (NP) patients. As such, lymph node metastasis requires breakdown of the host immune response in addition to escape of cancer cells from the tumor. To investigate the immunological differences between NN and NP breast cancer patients, we purified and profiled immune cells from the three major compartments where cancer and immune cells interact: tumor, TDLNs and peripheral blood. Significant down-regulation of genes associated with immune-related pathways and up-regulation of genes associated with tumor-promoting pathways was consistently observed in NP patients' TDLNs compared to NN patients. Importantly, these signatures were seen even in NP patients' tumor-free TDLNs, suggesting that such immune changes are not driven solely by local tumor invasion. Furthermore, similar patterns were also observed in NP patients' tumor and blood immune cells, suggesting that immunological differences between NN and NP patients are systemic. Together, these findings suggest that alterations in overall immune function may underlie risk for LN metastasis in breast cancer patients.

    View details for DOI 10.1002/ijc.27933

    View details for PubMedID 23136075

  • Identification of cytokine network signaling abnormalities in immune cells from cancer patients. Miyahira, A. K., Simons, D. L., Dirbas, F., Guardino, E., Sheth, S., Carlson, R., Lee, P. P. AMER ASSOC CANCER RESEARCH. 2013
  • PRC2/EED-EZH2 Complex Is Up-Regulated in Breast Cancer Lymph Node Metastasis Compared to Primary Tumor and Correlates with Tumor Proliferation In Situ PLOS ONE Yu, H., Simons, D. L., Segall, I., Carcamo-Cavazos, V., Schwartz, E. J., Yan, N., Zuckerman, N. S., Dirbas, F. M., Johnson, D. L., Holmes, S. P., Lee, P. P. 2012; 7 (12)

    Abstract

    Lymph node metastasis is a key event in the progression of breast cancer. Therefore it is important to understand the underlying mechanisms which facilitate regional lymph node metastatic progression.We performed gene expression profiling of purified tumor cells from human breast tumor and lymph node metastasis. By microarray network analysis, we found an increased expression of polycomb repression complex 2 (PRC2) core subunits EED and EZH2 in lymph node metastatic tumor cells over primary tumor cells which were validated through real-time PCR. Additionally, immunohistochemical (IHC) staining and quantitative image analysis of whole tissue sections showed a significant increase of EZH2 expressing tumor cells in lymph nodes over paired primary breast tumors, which strongly correlated with tumor cell proliferation in situ. We further explored the mechanisms of PRC2 gene up-regulation in metastatic tumor cells and found up-regulation of E2F genes, MYC targets and down-regulation of tumor suppressor gene E-cadherin targets in lymph node metastasis through GSEA analyses. Using IHC, the expression of potential EZH2 target, E-cadherin was examined in paired primary/lymph node samples and was found to be significantly decreased in lymph node metastases over paired primary tumors.This study identified an over expression of the epigenetic silencing complex PRC2/EED-EZH2 in breast cancer lymph node metastasis as compared to primary tumor and its positive association with tumor cell proliferation in situ. Concurrently, PRC2 target protein E-cadherin was significant decreased in lymph node metastases, suggesting PRC2 promotes epithelial mesenchymal transition (EMT) in lymph node metastatic process through repression of E-cadherin. These results indicate that epigenetic regulation mediated by PRC2 proteins may provide additional advantage for the outgrowth of metastatic tumor cells in lymph nodes. This opens up epigenetic drug development possibilities for the treatment and prevention of lymph node metastasis in breast cancer.

    View details for DOI 10.1371/journal.pone.0051239

    View details for PubMedID 23251464

  • A Pilot Cohort Study of the Determinants of Longitudinal Opioid Use After Surgery ANESTHESIA AND ANALGESIA Carroll, I., Barelka, P., Wang, C. K., Wang, B. M., Gillespie, M. J., McCue, R., Younger, J. W., Trafton, J., Humphreys, K., Goodman, S. B., Dirbas, F., Whyte, R. I., Donington, J. S., Cannon, W. B., Mackey, S. C. 2012; 115 (3): 694-702

    Abstract

    Determinants of the duration of opioid use after surgery have not been reported. We hypothesized that both preoperative psychological distress and substance abuse would predict more prolonged opioid use after surgery.Between January 2007 and April 2009, a prospective, longitudinal inception cohort study enrolled 109 of 134 consecutively approached patients undergoing mastectomy, lumpectomy, thoracotomy, total knee replacement, or total hip replacement. We measured preoperative psychological distress and substance use, and then measured the daily use of opioids until patients reported the cessation of both opioid consumption and pain. The primary end point was time to opioid cessation. All analyses were controlled for the type of surgery done.Overall, 6% of patients continued on new opioids 150 days after surgery. Preoperative prescribed opioid use, depressive symptoms, and increased self-perceived risk of addiction were each independently associated with more prolonged opioid use. Preoperative prescribed opioid use was associated with a 73% (95% confidence interval [CI] 0.51%-87%) reduction in the rate of opioid cessation after surgery (P = 0.0009). Additionally, each 1-point increase (on a 4-point scale) of self-perceived risk of addiction was associated with a 53% (95% CI 23%-71%) reduction in the rate of opioid cessation (P = 0.003). Independent of preoperative opioid use and self-perceived risk of addiction, each 10-point increase on a preoperative Beck Depression Inventory II was associated with a 42% (95% CI 18%-58%) reduction in the rate of opioid cessation (P = 0.002). The variance in the duration of postoperative opioid use was better predicted by preoperative prescribed opioid use, self-perceived risk of addiction, and depressive symptoms than postoperative pain duration or severity.Preoperative factors, including legitimate prescribed opioid use, self-perceived risk of addiction, and depressive symptoms each independently predicted more prolonged opioid use after surgery. Each of these factors was a better predictor of prolonged opioid use than postoperative pain duration or severity.

    View details for DOI 10.1213/ANE.0b013e31825c049f

    View details for PubMedID 22729963

  • Toward MR-guided high intensity focused ultrasound for presurgical localization: Focused ultrasound lesions in cadaveric breast tissue JOURNAL OF MAGNETIC RESONANCE IMAGING Bitton, R. R., Kaye, E., Dirbas, F. M., Daniel, B. L., Pauly, K. B. 2012; 35 (5): 1089-1097

    Abstract

    To investigate magnetic resonance image-guided high intensity focused ultrasound (MR-HIFU) as a surgical guide for nonpalpable breast tumors by assessing the palpability of MR-HIFU-created lesions in ex vivo cadaveric breast tissue.MR-HIFU ablations spaced 5 mm apart were made in 18 locations using the ExAblate2000 system. Ablations formed a square perimeter in mixed adipose and fibroglandular tissue. Ablation was monitored using T1-weighted fast spin echo images. MR-acoustic radiation force impulse (MR-ARFI) was used to remotely palpate each ablation location, measuring tissue displacement before and after thermal sonications. Displacement profiles centered at each ablation spot were plotted for comparison. The cadaveric breast was manually palpated to assess stiffness of ablated lesions and dissected for gross examination. This study was repeated on three cadaveric breasts.MR-ARFI showed a collective postablation reduction in peak displacement of 54.8% ([4.41 ± 1.48] μm pre, [1.99 ± 0.82] μm post), and shear wave velocity increase of 65.5% ([10.69 ± 1.60] mm pre, [16.33 ± 3.10] mm post), suggesting tissue became stiffer after the ablation. Manual palpation and dissection of the breast showed increased palpability, a darkening of ablation perimeter, and individual ablations were visible in mixed adipose/fibroglandular tissue.The results of this preliminary study show MR-HIFU has the ability to create palpable lesions in ex vivo cadaveric breast tissue, and may potentially be used to preoperatively localize nonpalpable breast tumors.

    View details for DOI 10.1002/jmri.23529

    View details for PubMedID 22170814

  • Accelerated, Partial Breast Irradiation with Intraoperative Radiotherapy BREAST SURGICAL TECHNIQUES AND INTERDISCIPLINARY MANAGEMENT Baynosa, J., Horst, K. C., Dirbas, F. M., Dirbas, F. M., ScottConner, C. E. 2011: 883–97
  • Accelerated, Partial Breast Irradiation Overview BREAST SURGICAL TECHNIQUES AND INTERDISCIPLINARY MANAGEMENT Wheeler, A. J., Dirbas, F. M., Horst, K. C., Dirbas, F. M., ScottConner, C. E. 2011: 829–36
  • Clinical Management of Breast Pain BREAST SURGICAL TECHNIQUES AND INTERDISCIPLINARY MANAGEMENT Millet, A. V., Leal, A., Dirbas, F. M., Dirbas, F. M., ScottConner, C. E. 2011: 147–53
  • Office-Based Diagnostic Procedures BREAST SURGICAL TECHNIQUES AND INTERDISCIPLINARY MANAGEMENT Chow, C. E., Dirbas, F. M., Dirbas, F. M., ScottConner, C. E. 2011: 211–22
  • Image-Guided Breast Biopsy BREAST SURGICAL TECHNIQUES AND INTERDISCIPLINARY MANAGEMENT Chandra, V., Dirbas, F. M., Ikeda, D. M., Dirbas, F. M., ScottConner, C. E. 2011: 223–40
  • Breast Imaging Following Breast Conservation Therapy BREAST SURGICAL TECHNIQUES AND INTERDISCIPLINARY MANAGEMENT Gutierrez, R., Horst, K. C., Dirbas, F. M., Ikeda, D. M., Dirbas, F. M., ScottConner, C. E. 2011: 975–95
  • Cancer stem cells from human breast tumors are involved in spontaneous metastases in orthotopic mouse models PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Liu, H., Patel, M. R., Prescher, J. A., Patsialou, A., Qian, D., Lin, J., Wen, S., Chang, Y., Bachmann, M. H., Shimono, Y., Dalerba, P., Adorno, M., Lobo, N., Bueno, J., Dirbas, F. M., Goswami, S., Somlo, G., Condeelis, J., Contag, C. H., Gambhir, S. S., Clarke, M. F. 2010; 107 (42): 18115-18120

    Abstract

    To examine the role of breast cancer stem cells (BCSCs) in metastasis, we generated human-in-mouse breast cancer orthotopic models using patient tumor specimens, labeled with optical reporter fusion genes. These models recapitulate human cancer features not captured with previous models, including spontaneous metastasis in particular, and provide a useful platform for studies of breast tumor initiation and progression. With noninvasive imaging approaches, as few as 10 cells of stably labeled BCSCs could be tracked in vivo, enabling studies of early tumor growth and spontaneous metastasis. These advances in BCSC imaging revealed that CD44(+) cells from both primary tumors and lung metastases are highly enriched for tumor-initiating cells. Our metastatic cancer models, combined with noninvasive imaging techniques, constitute an integrated approach that could be applied to dissect the molecular mechanisms underlying the dissemination of metastatic CSCs (MCSCs) and to explore therapeutic strategies targeting MCSCs in general or to evaluate individual patient tumor cells and predict response to therapy.

    View details for DOI 10.1073/pnas.1006732107

    View details for Web of Science ID 000283184800050

    View details for PubMedID 20921380

    View details for PubMedCentralID PMC2964232

  • Freehand MRI-Guided Preoperative Needle Localization of Breast Lesions After MRI-Guided Vacuum-Assisted Core Needle Biopsy Without Marker Placement JOURNAL OF MAGNETIC RESONANCE IMAGING van de Ven, S. M., Lin, M. C., Daniel, B. L., Sareen, P., Lipson, J. A., Pal, S., Dirbas, F. M., Ikeda, D. M. 2010; 32 (1): 101-109

    Abstract

    To evaluate the feasibility of magnetic resonance imaging (MRI)-guided preoperative needle localization (PNL) of breast lesions previously sampled by MRI-guided vacuum-assisted core needle biopsy (VACNB) without marker placement.We reviewed 15 women with 16 breast lesions undergoing MRI-guided VACNB without marker placement who subsequently underwent MRI-guided PNL, both on an open 0.5T magnet using freehand techniques. Mammograms and specimen radiographs were rated for lesion visibility; MRI images were rated for lesion visibility and hematoma formation. Imaging findings were correlated with pathology.The average prebiopsy lesion size was 16 mm (range 4-50 mm) with 13/16 lesions located in mammographically dense breasts. Eight hematomas formed during VACNB (average size 13 mm, range 8-19 mm). PNL was performed for VACNB pathologies of cancer (5), high-risk lesions (5), or benign but discordant findings (6) at 2-78 days following VACNB. PNL targeted the lesion (2), hematoma (4), or surrounding breast architecture (10). Wire placement was successful in all 16 lesions. Final pathology showed six cancers, five high-risk lesions, and five benign findings.MRI-guided PNL is successful in removing lesions that have previously undergone VACNB without marker placement by targeting the residual lesion, hematoma, or surrounding breast architecture, even in mammographically dense breasts.

    View details for DOI 10.1002/jmri.22148

    View details for Web of Science ID 000279439600013

    View details for PubMedID 20575077

  • 3.0-T MR-Guided Focused Ultrasound for Preoperative Localization of Nonpalpable Breast Lesions: An Initial Experimental Ex Vivo Study JOURNAL OF MAGNETIC RESONANCE IMAGING Schmitz, A. C., Van den Bosch, M. A., Rieke, V., Dirbas, F. M., Pauly, K. B., Mali, W. P., Daniel, B. L. 2009; 30 (4): 884-889

    Abstract

    To compare the accuracy of magnetic resonance-guided focused ultrasound (MRgFUS) with MR-guided needle-wire placement (MRgNW) for the preoperative localization of nonpalpable breast lesions.In this experimental ex vivo study, 15 turkey breasts were used. In each breast phantom an artificial nonpalpable "tumor" was created by injecting an aqueous gel containing gadolinium. MRgFUS (n = 7) was performed with the ExAblate 2000 system (InSightec). With MRgFUS the ablated tissue changes in color and increases in stiffness. A rim of palpable and visible ablations was created around the tumor to localize the tumor and facilitate excision. MRgNW (n = 8) was performed by MR-guided placement of an MR-compatible needle-wire centrally in the tumor. After surgical excision of the tumor, MR images were used to evaluate tumor-free margins (negative/positive), minimum tumor-free margin (mm), and excised tissue volume (cm(3)).With MRgFUS localization no positive margins were found after excision (0%). With MRgNW two excision specimens (25%) had positive margins (P = 0.48). Mean minimum tumor-free margin (+/-SD) with MRgFUS was significantly larger (5.5 +/- 2.4 mm) than with MRgNW (0.9 +/- 1.4 mm) (P < 0.001). Mean volume +/- SD of excised tissue did not differ between MRgFUS and MRgNW localization, ie, 44.0 +/- 9.4 cm(3) and 39.5 +/- 10.7 cm(3) (P = 0.3).The results of this experimental ex vivo study indicate that MRgFUS can potentially be used to localize nonpalpable breast lesions in vivo.

    View details for DOI 10.1002/jmri.21896

    View details for PubMedID 19787736

  • 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

  • Impaired interferon signaling is a common immune defect in human cancer PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Critchley-Thorne, R. J., Simons, D. L., Yan, N., Miyahira, A. K., Dirbas, F. M., Johnson, D. L., Swetter, S. M., Carlson, R. W., Fisher, G. A., Koong, A., Holmes, S., Lee, P. P. 2009; 106 (22): 9010-9015

    Abstract

    Immune dysfunction develops in patients with many cancer types and may contribute to tumor progression and failure of immunotherapy. Mechanisms underlying cancer-associated immune dysfunction are not fully understood. Efficient IFN signaling is critical to lymphocyte function; animals rendered deficient in IFN signaling develop cancer at higher rates. We hypothesized that altered IFN signaling may be a key mechanism of immune dysfunction common to cancer. To address this, we assessed the functional responses to IFN in peripheral blood lymphocytes from patients with 3 major cancers: breast cancer, melanoma, and gastrointestinal cancer. Type-I IFN (IFN-alpha)-induced signaling was reduced in T cells and B cells from all 3 cancer-patient groups compared to healthy controls. Type-II IFN (IFN-gamma)-induced signaling was reduced in B cells from all 3 cancer patient groups, but not in T cells or natural killer cells. Impaired-IFN signaling was equally evident in stage II, III, and IV breast cancer patients, and downstream functional defects in T cell activation were identified. Taken together, these findings indicate that defects in lymphocyte IFN signaling arise in patients with breast cancer, melanoma, and gastrointestinal cancer, and these defects may represent a common cancer-associated mechanism of immune dysfunction.

    View details for DOI 10.1073/pnas.0901329106

    View details for PubMedID 19451644

  • Optimized imaging of the growth and metastasis of human breast cancer stem cells in immunodeficient mice Liu, H., Patel, M., Prescher, J., Qian, D., Dalerba, P., Lin, J., Shimono, Y., Dirbas, F., Contag, C., Gambhir, S., Clarke, M. AMER ASSOC CANCER RESEARCH. 2009
  • 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

  • Accelerated Partial Breast Irradiation: Where Do We Stand? JOURNAL OF THE NATIONAL COMPREHENSIVE CANCER NETWORK Dirbas, F. M. 2009; 7 (2): 215-225

    Abstract

    Accelerated partial breast irradiation (APBI) is a new form of postlumpectomy radiotherapy delivered over 1 to 5 days. Early trials showed high local recurrence rates. More recent single and multiinstitutional studies, as well as a single phase III trial, have shown local control more comparable to whole breast radiotherapy. Patient selection and surgical technique are important variables preparatory to irradiation, which is delivered using 1 of 4 accelerated radiotherapy methods. Phase I/II studies have produced most of the information currently available regarding APBI. Additional phase III studies are underway to determine whether any or all of these accelerated radiotherapy approaches may safely substitute for whole breast radiotherapy in women seeking breast conservation.

    View details for Web of Science ID 000270264400008

    View details for PubMedID 19200419

  • New models and online calculator for predicting non-sentinel lymph node status in sentinel lymph node positive breast cancer patients 30th Annual San Antonio Breast Cancer Symposium Kohrt, H., Olshen, R., Bermas, H., GOODSON, W., Henry, S., Rouse, R., Bailey, L., Philben, V., Dirbas, F., Dunn, J., Johnson, D., Wapnir, I., Carlson, R., STOCKDALE, F., Hansen, N., JEFFREY, S. SPRINGER. 2008: 588–88
  • New models and online calculator for predicting non-sentinel lymph node status in sentinel lymph node positive breast cancer patients BMC CANCER Kohrt, H. E., Olshen, R. A., Bermas, H. R., Goodson, W. H., Wood, D. J., Henry, S., Rouse, R. V., Bailey, L., Philben, V. J., Dirbas, F. M., Dunn, J. J., Johnson, D. L., Wapnir, I. L., Carlson, R. W., Stockdale, F. E., Hansen, N. M., Jeffrey, S. S. 2008; 8

    Abstract

    Current practice is to perform a completion axillary lymph node dissection (ALND) for breast cancer patients with tumor-involved sentinel lymph nodes (SLNs), although fewer than half will have non-sentinel node (NSLN) metastasis. Our goal was to develop new models to quantify the risk of NSLN metastasis in SLN-positive patients and to compare predictive capabilities to another widely used model.We constructed three models to predict NSLN status: recursive partitioning with receiver operating characteristic curves (RP-ROC), boosted Classification and Regression Trees (CART), and multivariate logistic regression (MLR) informed by CART. Data were compiled from a multicenter Northern California and Oregon database of 784 patients who prospectively underwent SLN biopsy and completion ALND. We compared the predictive abilities of our best model and the Memorial Sloan-Kettering Breast Cancer Nomogram (Nomogram) in our dataset and an independent dataset from Northwestern University.285 patients had positive SLNs, of which 213 had known angiolymphatic invasion status and 171 had complete pathologic data including hormone receptor status. 264 (93%) patients had limited SLN disease (micrometastasis, 70%, or isolated tumor cells, 23%). 101 (35%) of all SLN-positive patients had tumor-involved NSLNs. Three variables (tumor size, angiolymphatic invasion, and SLN metastasis size) predicted risk in all our models. RP-ROC and boosted CART stratified patients into four risk levels. MLR informed by CART was most accurate. Using two composite predictors calculated from three variables, MLR informed by CART was more accurate than the Nomogram computed using eight predictors. In our dataset, area under ROC curve (AUC) was 0.83/0.85 for MLR (n = 213/n = 171) and 0.77 for Nomogram (n = 171). When applied to an independent dataset (n = 77), AUC was 0.74 for our model and 0.62 for Nomogram. The composite predictors in our model were the product of angiolymphatic invasion and size of SLN metastasis, and the product of tumor size and square of SLN metastasis size.We present a new model developed from a community-based SLN database that uses only three rather than eight variables to achieve higher accuracy than the Nomogram for predicting NSLN status in two different datasets.

    View details for DOI 10.1186/1471-2407-8-66

    View details for PubMedID 18315887

  • Axillary surgery in breast cancer patients CLINICAL & TRANSLATIONAL ONCOLOGY Millet, A., FUSTER, C. A., Lluch, A., Dirbas, F. 2007; 9 (8): 513-520

    Abstract

    Surgeons have routinely removed ipsilateral axillary lymph nodes from women with breast cancer for over 100 years. The procedure provides important staging information, enhances regional control of the malignancy and may improve survival. As screening of breast cancer has increased, the mean size of newly diagnosed primary invasive breast cancers has steadily decreased and so has the number of women with lymph node metastases. Recognising that the therapeutic benefit of removing normal nodes may be low, alternatives to the routine level I/II axillary lymph node dissection have been sought. A decade ago sentinel lymph node biopsy (SLNB) was introduced. Because of its high accuracy and relatively low morbidity, this technique is now widely used to identify women with histologically involved nodes prior to the formal axillary node dissection. Specifically, SLNB has allowed surgeons to avoid a formal axillary lymph node biopsy in women with histologically uninvolved sentinel nodes, while identifying women with involved sentinel nodes who derive the most benefit from a completion axillary node dissection. Despite the increasing use of SLNB for initial management of the axilla in women with breast cancer, important questions remain regarding patient selection criteria and optimal surgical methods for performing the biopsy. This article discusses the evolution of axillary node surgery for women with breast cancer.

    View details for DOI 10.1007/s12094-007-0095-3

    View details for Web of Science ID 000256944200007

    View details for PubMedID 17720654

  • Phyllodes tumors of the breast: natural history, diagnosis, and treatment. Journal of the National Comprehensive Cancer Network Telli, M. L., Horst, K. C., Guardino, A. E., Dirbas, F. M., Carlson, R. W. 2007; 5 (3): 324-330

    Abstract

    Phyllodes tumors of the breast are unusual fibroepithelial tumors that exhibit a wide range of clinical behavior. These tumors are categorized as benign, borderline, or malignant based on a combination of histologic features. The prognosis of phyllodes tumors is favorable, with local recurrence occurring in approximately 15% of patients overall and distant recurrence in approximately 5% to 10% overall. Wide excision with a greater than 1 cm margin is definitive primary therapy. Adjuvant systemic therapy is of no proven value. Patients with locally recurrent disease should undergo wide excision of the recurrence with or without subsequent radiotherapy.

    View details for PubMedID 17439760

  • Mastalgia (breast pain) CAMBRIDGE HANDBOOK OF PSYCHOLOGY, HEALTH AND MEDICINE, 2ND EDITION Millet, A. V., Dirbas, F. M., Ayers, S., Baum, A., McManus, C., Newman, S., Wallston, K., Weinman, J., West, R. 2007: 774–76
  • Impact of increasing margin around the lumpectomy cavity to define the planning target volume for 3d conformal external beam accelerated partial breast irradiation 47th Annual Meeting of the American-Society-for-Therapeutic-Radiology-and-Oncology Cox, B. W., Horst, K. C., Thornton, S., Dirbas, F. M. ELSEVIER SCIENCE INC. 2007: 254–62

    Abstract

    The purpose of this study was to evaluate the dose to normal tissues as a function of increasing margins around the lumpectomy cavity in accelerated partial breast irradiation (APBI) using 3D-conformal radiotherapy (3DCRT). Eight patients with Stage 0-I breast cancer underwent treatment planning for 3DCRT APBI. The clinical target volume (CTV) was defined as a 15-mm expansion around the cavity limited by the chest wall and skin. Three planning target volumes (PTV1, PTV2, PTV3) were generated for each patient using a 0, 5-, and 10-mm expansion around the CTV, for a total margin of 15, 20, and 25 mm. Three treatment plans were generated for every patient using the 3 PTVs, and dose-volume analysis was performed for each plan. For each 5-mm increase in margin, the mean PTV:total breast volume ratio increased 10% and the relative increase in the mean ipsilateral breast dose was 15%. The mean volume of ipsilateral breast tissue receiving 75%, 50%, and 25% of the prescribed dose increased 6% to 7% for every 5 mm increase in PTV margin. Compared to lesions located in the upper outer quadrant, plans for medially located tumors revealed higher mean ipsilateral breast doses and 20% to 22% more ipsilateral breast tissue encompassed by the 25% IDL. The use of 3DCRT for APBI delivers higher doses to normal breast tissue as the PTV increases around the lumpectomy cavity. Efforts should be made to minimize the overall PTV when this technique is used. Ongoing studies will be necessary to determine the clinical relevance of these findings.

    View details for DOI 10.1016/j.meddos.2007.02.003

    View details for Web of Science ID 000251075200004

    View details for PubMedID 17980825

  • Outcomes of women with metachronous breast and ovarian carcinomas GYNECOLOGIC ONCOLOGY Liou, W., Hamilton, C. A., Cheung, M. K., Osann, K., Longacre, T. A., Teng, N. N., Husain, A., Dirbas, F. M., Chan, J. K. 2006; 103 (1): 190-194

    Abstract

    Women with a history of breast cancer have a significantly increased risk of developing a second primary ovarian cancer and vice versa. We proposed to determine the characteristics and outcomes of women diagnosed with metachronous breast and ovarian cancer.Patients were identified from the Surveillance, Epidemiology, and End Results program database between 1988 and 2001. Kaplan-Meier and Cox proportional hazards regression tests were used to determine survival outcomes.Of 704 women, 526 developed breast cancer then ovarian cancer (B-O) and 178 developed ovarian cancer then breast cancer (O-B). The mean age at diagnosis of the first cancer in the B-O versus O-B group was 60.3 versus 58.9 years, respectively (P = 0.23). Twenty-five percent of women in the B-O group had stage I-II ovarian cancer versus 63% in the O-B group (P < 0.001). The percentage of those with stage I-II breast cancer was 94% and 91% in the B-O versus O-B group, respectively (P = 0.13). Women in the B-O group had more high grade of ovarian cancer compared to those in the O-B group (P < 0.001). The mean time interval between diagnoses of breast then ovarian versus ovarian then breast cancer was 58 versus 56 months, respectively (P = 0.42).In the largest series to date, we found that women diagnosed with ovarian cancer first had significantly more early stage and lower grade ovarian cancers with better survival compared to those with breast cancer followed by ovarian cancer. Since half of the women had their second cancer beyond 5 years, continued surveillance of these high risk patients is recommended.

    View details for DOI 10.1016/j.ygyno.2006.02.022

    View details for Web of Science ID 000240887100036

    View details for PubMedID 16569424

  • Predicting non-sentinel lymph node involvement in breast cancer patients. 42nd Annual Meeting of the American-Society-of-Clinical-Oncology Kohrt, H. E., Olshen, R. A., Goodson, W. H., Rouse, R. V., Bailey, L., Philben, V., Dirbas, F. M., Stockdale, F. E., Carlson, R. W., Jeffrey, S. S. AMER SOC CLINICAL ONCOLOGY. 2006: 10S–10S
  • Streamlining clinical breast examination JOURNAL OF THE NATIONAL CANCER INSTITUTE Goodson, W. H., Grissom, N. A., Moore, D. H., Dirbas, F. M. 2005; 97 (19): 1476-1477

    View details for DOI 10.1093/jnci/dji309

    View details for Web of Science ID 000232953400016

    View details for PubMedID 16204698

  • Pathologic correlates of false positive breast magnetic resonance imaging findings: which lesions warrant biopsy? 6th Annual Meeting of the American-Society-of-Breast-Surgeons Langer, S. A., Horst, K. C., Ikeda, D. M., Daniel, B. L., Kong, C. S., Dirbas, F. M. EXCERPTA MEDICA INC-ELSEVIER SCIENCE INC. 2005: 633–40

    Abstract

    Contrast-enhanced breast magnetic resonance imaging (MRI) is highly sensitive for breast cancer. However, adoption of breast MRI is hampered by frequent false positive (FP) findings. Though ultimately proven benign, these suspicious findings require biopsy due to abnormal morphology and/or kinetic enhancement curves that simulate malignancy on MRI. We hypothesized that analysis of a series of FP MRI findings could reveal a pattern of association between certain "suspicious" lesions and benign disease that might help avoid unnecessary biopsy of such lesions in the future.A retrospective chart review identified women undergoing breast MRI between June 1995 and March 2002 with FP findings identified by MRI alone. Lesions were retrospectively characterized according to an MRI Breast Imaging-Reporting and Data System lexicon and matched to pathology.Twenty-two women were identified with 29 FP lesions. Morphology revealed 1 focus (3.5%), 5 masses less than 5 mm (17%), 11 masses greater than 5 mm (38%), 1 (3.5%) linear enhancement, and 11 (38%) non-mass-like enhancement. Kinetic curves were suspicious in 15 (52%). Histology demonstrated 20 (69%) variants of normal tissue and 9 (31%) benign masses. MRI lesions less than 5 mm (n = 6, 20.5%) were small, well-delineated nodules of benign breast tissue.Suspicious MRI lesions less than 5 mm often represent benign breast tissue and could potentially undergo surveillance instead of biopsy.

    View details for DOI 10.1016/j.amjsurg.2005.06.030

    View details for PubMedID 16164938

  • Rates of reexcision for breast cancer after magnetic resonance imaging-guided bracket wire localization JOURNAL OF THE AMERICAN COLLEGE OF SURGEONS Wallace, A. M., Daniel, B. L., Jeffrey, S. S., Birdwell, R. L., Nowels, K. W., Dirbas, F. M., Schraedley-Desmond, P., Ikeda, D. M. 2005; 200 (4): 527-537

    Abstract

    We performed this study to determine rates of close or transected cancer margins after magnetic resonance imaging-guided bracket wire localization for nonpalpable breast lesions.Of 243 women undergoing MRI-guided wire localizations, 26 had MRI bracket wire localization to excise either a known cancer (n = 19) or a suspicious MRI-detected lesion (n = 7). We reviewed patient age, preoperative diagnosis, operative intent, mammographic breast density, MRI lesion size, MRI enhancement curve and morphology, MRI Breast Imaging Reporting and Data System (BI-RADS) assessment code, number of bracket wires, and pathology size. We analyzed these findings for their relationship to obtaining clear margins at first operative excision.Twenty-one of 26 (81%) patients had cancer. Of 21 patients with cancer, 12 (57%) had negative margins at first excision and 9 (43%) had close/transected margins. MRI size > or = 4 cm was associated with a higher reexcision rate (7 of 9, 78%) than those < 4 cm (2 of 12, 17%) (p = 0.009). MRI BI-RADS score, enhancement curve, morphology, and preoperative core biopsy demonstrating ductal carcinoma in situ (DCIS) were not predictive of reexcision. The average number of wires used for bracketing increased with lesion size, but was not associated with improved outcomes. On pathology, cancer size was smaller in patients with negative margins (12 patients, 1.2 cm) than in those with close/transected margins (9 patients, 4.6 cm) (p < 0.001). Reexcision was based on close/transected margins involving DCIS alone (6, 67%), infiltrating ductal carcinoma and DCIS (2, 22%), or infiltrating ductal carcinoma alone (1, 11%). Reexcision pathology demonstrated DCIS (3, 33%), no residual cancer (5, 55%), and 1 patient was lost to followup (1, 11%). Interestingly, cancer patients who required reexcision were younger (p = 0.022), but breast density was not associated with reexcision.To our knowledge, this is the first report of MRI-guided bracket wire localization. Patients with MRI-detected lesions less than 4 cm had clear margins at first excision; larger MRI-detected lesions were more likely to have close/transected margins. Reexcision was often because of DCIS and was the only pathology found at reexcision, perhaps because MRI is more sensitive for detecting invasive carcinoma than DCIS.

    View details for DOI 10.1016/j.jamcollsurg.2004.12.013

    View details for Web of Science ID 000228085200005

    View details for PubMedID 15804466

  • Survival analysis of women with double primary breast and ovarian carcinomas 53rd Annual Clinical Meeting of the American-College-of-Obstetricians-and-Gynecologists Liou, W. S., Cheung, M. K., Hamilton, C., Osann, K., Dirbas, F., Chan, J. K. LIPPINCOTT WILLIAMS & WILKINS. 2005: 86S–86S
  • Breast magnetic resonance imaging alters patient selection for accelerated, partial breast irradiation 47th Annual Meeting of the American-Society-for-Therapeutic-Radiology-and-Oncology Horst, K. C., Ikeda, D. M., Birdwell, R. L., Daniel, B. L., Goffinet, D. R., Pal, S., Nowels, K. W., Dirbas, F. M. ELSEVIER SCIENCE INC. 2005: S4–S5
  • Magnetic resonance imaging of suspicious breast masses seen on one mammographic view. breast journal Offodile, R. S., Daniel, B. L., Jeffrey, S. S., Wapnir, I., Dirbas, F. M., Ikeda, D. M. 2004; 10 (5): 416-422

    Abstract

    The purpose of this study was to assess the utility of contrast-enhanced breast magnetic resonance imaging (MRI) in identifying lesions unidentified on the craniocaudal projection. The authors reviewed five patients with suspicious mammographic lesions not imaged on the craniocaudal mammogram who were referred for contrast-enhanced MRI and underwent subsequent preoperative needle localization in four of the five cases. Five patients, ages 56 to 69 years, had suspicious lesions identified on mediolateral oblique (MLO) or mediolateral (ML) projections only. Ultrasound did not identify the lesion in any of these cases. MRI identified suspicious breast lesions measuring 5 to 12 mm in size. These were located high on the chest wall or in the upper inner quadrant. Suspicious lesions seen only on the MLO or ML projections may reside high on the chest wall or in the upper inner quadrant. Lesions in these locations may be typically excluded on the craniocaudal projection during mammography. Breast MRI has the advantage of imaging the entire breast and is particularly useful for these lesions. In this series, MRI prevented delay in breast cancer diagnosis.

    View details for PubMedID 15327495

  • Breast magnetic resonance image screening and ductal lavage in women at high genetic risk for breast carcinoma CANCER Hartman, A. R., Daniel, B. L., Kurian, A. W., Mills, M. A., Nowels, K. W., Dirbas, F. M., Kingham, K. E., Chun, N. M., Herfkens, R. J., Ford, J. M., Plevritis, S. K. 2004; 100 (3): 479-489

    Abstract

    Intensive screening is an alternative to prophylactic mastectomy in women at high risk for developing breast carcinoma. The current article reports preliminary results from a screening protocol using high-quality magnetic resonance imaging (MRI), ductal lavage (DL), clinical breast examination, and mammography to identify early malignancy and high-risk lesions in women at increased genetic risk of breast carcinoma.Women with inherited BRCA1 or BRCA2 mutations or women with a >10% risk of developing breast carcinoma at 10 years, as estimated by the Claus model, were eligible. Patients were accrued from September 2001 to May 2003. Enrolled patients underwent biannual clinical breast examinations and annual mammography, breast MRI, and DL.Forty-one women underwent an initial screen. Fifteen of 41 enrolled women (36.6%) either had undergone previous bilateral oophorectomy and/or were on tamoxifen at the time of the initial screen. One patient who was a BRCA1 carrier had high-grade ductal carcinoma in situ (DCIS) that was screen detected by MRI but that was missed on mammography. High-risk lesions that were screen detected by MRI in three women included radial scars and atypical lobular hyperplasia. DL detected seven women with cellular atypia, including one woman who had a normal MRI and mammogram.Breast MRI identified high-grade DCIS and high-risk lesions that were missed by mammography. DL detected cytologic atypia in a high-risk cohort. A larger screening trial is needed to determine which subgroups of high-risk women will benefit and whether the identification of malignant and high-risk lesions at an early stage will impact breast carcinoma incidence and mortality.

    View details for DOI 10.1002/cncr.11926

    View details for PubMedID 14745863

  • A pilot breast cancer screening trial for women at high inherited risk using clinical breast exam, mammography, breast magnetic resonance imaging, and ductal lavage: updated results after median follow-up of fourteen months. 27th Annual San Antonio Breast Cancer Symposium Kurian, A. W., Daniel, B. L., Mills, M. A., Nowels, K. W., Ford, J. M., Plevritis, S. K., Kingham, K. E., Chun, N. M., Herfkens, R. J., Dirbas, F. M., Garber, J. M., Hartman, A. R. SPRINGER. 2004: S187–S188
  • A simplified clinical breast examination will work. 27th Annual San Antonio Breast Cancer Symposium Goodson, W. H., Dirbas, F. M., Grissom, N. A., Moore, D. H. SPRINGER. 2004: S189–S189
  • Results from a pilot breast cancer screening trial using a combination of clincal breast exam, mammography, breast MRI, and ductal lavage in a high-risk population 26th Annual San Antonio Breast Cancer Symposium Hartman, A. R., Kurian, A., Mills, M. A., Daniel, B. L., Ford, J. M., Kingham, K. E., Chun, N. M., Nowels, K. W., Herfkens, R. J., Dirbas, F. M., Plevritis, S. K. SPRINGER. 2003: S22–S23
  • Comprehensive screening using breast MRI and ductal lavage in high-risk women. 25th San Antonio Breast Cancer Symposium Hartman, A. R., Daniel, B. L., Ford, J. M., Chun, N. M., Kingham, K. E., Mills, M. A., Grekowicz, A. M., Jacobs, C. D., Herfkens, R. J., Nowels, K. W., Dirbas, F. M., Plevritis, S. K. SPRINGER. 2002: S152–S152
  • Clinical management of breast pain: A review OBSTETRICAL & GYNECOLOGICAL SURVEY Millet, A. V., Dirbas, F. M. 2002; 57 (7): 451-461

    Abstract

    Breast pain (mastalgia) is a common cause of anxiety among women and frequently leads to a primary care clinic for consultation. Fortunately, mild premenstrual breast discomfort lasting for 1 to 4 days can be considered "normal." However, moderate-to-severe breast pain lasting over 5 days can interfere with usual activities, lead to unnecessary medical tests, and potentially invite the use of ineffective, occasionally harmful medications. Despite the severity of some patients' symptoms, mastalgia is still considered a trivial complaint by many physicians; often it is felt to be psychological in nature. Careful evaluation to rule out breast cancer and reassure the patient is enough to make the pain resolve in most cases. In a few patients, however, mastalgia is severe enough to deserve further evaluation and treatment. Overall, 92% of patients with cyclical mastalgia (CM) and 64% with noncyclical mastalgia (NCM) can obtain relief of their pain with the judicious use of several available therapies.

    View details for Web of Science ID 000176771600002

    View details for PubMedID 12172222

  • Freehand iMRI-guided large-gauge core needle biopsy: A new minimally invasive technique for diagnosis of enhancing breast lesions 7th Annual Meeting of the International-Society-for-Magnetic-Resonance-in-Medicine (ISMRM) Daniel, B. L., Birdwell, R. L., Butts, K., Nowels, K. W., Ikeda, D. M., Heiss, S. G., Cooper, C. R., Jeffrey, S. S., Dirbas, F. M., Herfkens, R. J. JOHN WILEY & SONS INC. 2001: 896–902

    Abstract

    The lack of reliable methods for minimally invasive biopsy of suspicious enhancing breast lesions has hindered the utilization of contrast-enhanced magnetic resonance imaging (MRI) for the detection and diagnosis of breast cancer. In this study, a freehand method was developed for large-gauge core needle biopsy (LCNB) guided by intraprocedural MRI (iMRI). Twenty-seven lesions in nineteen patients were biopsied using iMRI-guided LCNB without significant complications. Diagnostic tissue was obtained in all cases. Nineteen of the 27 lesions were subsequently surgically excised. Histopathologic analysis confirmed that iMRI-guided LCNB correctly distinguished benign lesions from malignancy in 18 of the 19 lesions. The histology revealed by core biopsy was partially discrepant with surgical biopsy in 2 of the other 19 lesions. Freehand iMRI-guided LCNB of enhancing breast lesions is promising. Larger studies are needed to determine the smallest lesion that can be sampled reliably and to precisely measure the accuracy of iMRI-guided LCNB as a minimally invasive tool to diagnose suspicious lesions found by breast MRI. J. Magn. Reson. Imaging 2001;13:896-902.

    View details for Web of Science ID 000171296500013

    View details for PubMedID 11382950

  • Locally advanced breast cancer: is surgery necessary? breast journal Favret, A. M., Carlson, R. W., Goffinet, D. R., Jeffrey, S. S., Dirbas, F. M., Stockdale, F. E. 2001; 7 (2): 131-137

    Abstract

    A retrospective analysis of the treatment of locally advanced breast cancer (LABC) was undertaken at Stanford Medical Center to assess the outcome of patients who did not undergo surgical removal of their tumors. Between 1981 and 1998, 64 patients with locally advanced breast cancer were treated with induction chemotherapy, radiation with or without breast surgery, and additional chemotherapy. Sixty-two (97%) patients received cyclophosphamide, doxorubicin, and 5-fluorouracil (CAF) induction chemotherapy. Induction chemotherapy was followed by local radiotherapy in 59 (92%) patients. Based on the clinical response to chemotherapy and patient preference, 44 (69%) patients received no local breast surgery. Radiotherapy was followed by an additional, non-doxorubicin-containing chemotherapy in all patients. The mean age of patients was 49 years. Of the 65 locally advanced breast cancers in 64 patients, 26 (41%) were stage IIIA, 35 (55%) were stage IIIB, and 4 (6%) were stage IV (supraclavicular lymph nodes only). Response to induction chemotherapy was seen in 59 patients (92%), with 29 (45%) achieving a complete clinical response and 30 (47%) a partial clinical response. With a mean follow-up of 51 months (range 7-187 months), 43 patients (67.2%) have no evidence of recurrent disease. Eight (12.5%) have recurred locally, and 21 (32.8%) have recurred with distant metastasis. Actuarial 5-year survival is 75%, disease-free survival is 58%, and local control rate is 87.5%. These data indicate that the routine inclusion of breast surgery in a combined modality treatment program for LABC does not appear necessary for the majority of patients who experience a response to induction chemotherapy.

    View details for PubMedID 11328324

  • Radiofrequency ablation of breast cancer - First report of an emerging technology ARCHIVES OF SURGERY Jeffrey, S. S., Birdwell, R. L., Ikeda, D. M., Daniel, B. L., Nowels, K. W., Dirbas, F. M., Griffey, S. M. 1999; 134 (10): 1064-1068

    Abstract

    Radiofrequency (RF) energy applied to breast cancers will result in cancer cell death.Prospective nonrandomized interventional trial.A university hospital tertiary care center.Five women with locally advanced invasive breast cancer, aged 38 to 66 years, who were undergoing surgical resection of their tumor. One patient underwent preoperative chemotherapy and radiation therapy, 3 patients received preoperative chemotherapy, and 1 had no preoperative therapy. All patients completed the study.While patients were under general anesthesia and just before surgical resection, a 15-gauge insulated multiple-needle electrode was inserted into the tumor under sonographic guidance. Radiofrequency energy was applied at a low power by a preset protocol for a period of up to 30 minutes. Only a portion of the tumor was treated to evaluate the zone of RF ablation and the margin between ablated and nonablated tissue. Immediately after RF ablation, the tumor was surgically resected (4 mastectomies, 1 lumpectomy). Pathologic analysis included hematoxylin-eosin staining and enzyme histochemical analysis of cell viability with nicotinamide adenine dinucleotide-diaphorase (NADH-diaphorase) staining of snap-frozen tissue to assess immediate cell death.Cancer cell death as visualized on hematoxylin-eosin-stained paraffin section and NADH-diaphorase cell viability stains.There was evidence of cell death in all patients. Hematoxylin-eosin staining showed complete cell death in 2 patients. In 3 patients there was a heterogeneous pattern of necrotic and normal-appearing cells within the ablated tissue. The ablated zone extended around the RF electrode for a diameter of 0.8 to 1.8 cm. NADH-diaphorase cell viability stains of the ablated tissue showed complete cell death in 4 patients. The fifth patient had a single focus of viable cells (<1 mm) partially lining a cyst. There were no perioperative complications related to RF ablation.Intraoperative RF ablation results in invasive breast cancer cell death. Based on this initial report of the use of RF ablation in breast cancer, this technique merits further investigation as a percutaneous minimally invasive modality for the local treatment of breast cancer.

    View details for Web of Science ID 000083020900010

    View details for PubMedID 10522847

  • Parathyroid localization with high-resolution ultrasound and technetium Tc 99m sestamibi 70th Annual Session of the Pacific-Coast-Surgical-Association Purcell, G. P., Dirbas, F. M., Jeffrey, R. B., Lane, M. J., Desser, T., McDougall, R., Weigel, R. J. AMER MEDICAL ASSOC. 1999: 824–28

    Abstract

    High-resolution ultrasound and technetium Tc 99m sestamibi scanning can be used for preoperative localization of abnormal parathyroid glands in patients with hyperparathyroidism.Ultrasound and sestamibi scanning were performed in patients undergoing neck exploration for hyperparathyroidism. If the 2 scans agreed in identifying a single adenoma, and surgery confirmed the location of a single adenoma and an ipsilateral normal gland, a unilateral exploration was performed.University tertiary care center.Sixty-one consecutive patients undergoing surgery for hyperparathyroidism from September 1, 1994, through September 30, 1997.High-resolution ultrasound was performed in 59 patients and sestamibi scanning in 58 patients; all patients underwent neck exploration by a single surgeon.The results of preoperative ultrasound and sestamibi scanning were compared with operative and histological findings.All patients were cured of hypercalcemia. Specificity of ultrasound and sestamibi scanning was 98% and 99%, respectively; however, their sensitivity was only 57% and 54%, respectively. Both imaging modalities had lower sensitivities in the setting of multigland disease. If both imaging studies were considered as a single test, sensitivity for imaging in patients with primary hyperparathyroidism reached 78%. Our localization protocol allowed a unilateral approach in 43% of patients (23 of 53).These results confirm the value of preoperative localization in patients with hyperparathyroidism. A unilateral approach can be used with a high degree of success in cases when ultrasound and sestamibi scanning agree in the identification of a single adenoma confirmed by surgical exploration with the identification of a normal ipsilateral gland.

    View details for Web of Science ID 000081876300006

    View details for PubMedID 10443804

  • Perforated jejunal diverticula Southeastern-Surgical-Congress 63rd Annual Scientific Meeting and Postgraduate Course Program Koger, K. E., Shatney, C. H., Dirbas, F. M., McClenathan, J. H. SOUTHEASTERN SURGICAL CONGRESS. 1996: 26–29

    Abstract

    Jejunal diverticular (JD) perforation is an uncommon cause of acute abdominal pain in the elderly. From 1971 to 1994 we treated 13 such patients, 9 men and 4 women, with a mean age of 68 years. All patients experienced sudden onset of abdominal pain, nausea and vomiting, and leukocytosis (range of white blood cell counts, 14,000-21,000). On physical examination, three patients had localized peritonitis, were thought to have appendicitis, and underwent immediate laparotomy and segmental jejunal resection for perforated JD. The remaining 10 patients had abdominal tenderness without peritoneal signs. They were hospitalized and managed expectantly. All experienced worsening signs and symptoms and underwent exploratory laparotomy and resection of the involved jejunal segment 13 hours to 8 days after admission. Although 6 of 13 patients had had JD documented previously, in only 2 patients was perforated JD diagnosed preoperatively. In 8 of 13 patients peritoneal contamination was minimal and was contained within the leaves of the mesentery. Soilage was severe with abscess formation in 5 patients. The longer the delay in operative intervention, the greater the peritoneal soilage. The 3 patients undergoing immediate surgery had minimal contamination. Of the 10 patients initially observed, the mean interval before operation was 74 hours in the 5 patients with severe soilage versus 21 hours in those with minimal contamination. The postoperative course was uneventful in 11 patients. Two patients died. Surgical consultation was delayed (8 days, 12 days) in both patients, who had severe peritoneal contamination and died of sepsis. In conclusion, JD perforation is an uncommon and frequently overlooked cause of acute abdominal pain in elderly patients. Timely operative intervention and resection of the involved jejunum are the keys to a successful outcome. Because the presentation and physical findings of perforated JD can be highly variable, a history of preexisting JD should arouse suspicion for JD perforation as the etiology of acute abdominal pain in the elderly.

    View details for Web of Science ID A1996TM58900005

    View details for PubMedID 8540641

  • HUMANIZED ANTIBODY-DIRECTED TO THE IL-2 RECEPTOR BETA-CHAIN PROLONGS PRIMATE CARDIAC ALLOGRAFT SURVIVAL JOURNAL OF IMMUNOLOGY TINUBU, S. A., Hakimi, J., KONDAS, J. A., Bailon, P., Familletti, P. C., Spence, C., Crittenden, M. D., Parenteau, G. L., Dirbas, F. M., Tsudo, M., BACHER, J. D., KASTENSPORTES, C., MARTINUCCI, J. L., Goldman, C. K., Clark, R. E., Waldmann, T. A. 1994; 153 (9): 4330-4338

    Abstract

    IL-2Rs are expressed by T cells activated in response to foreign histocompatibility Ags but not by normal cells. This difference in IL-2R expression is exploited by blockade of IL-2Rs to achieve immunosuppression. High affinity IL-2Rs involve three subunits, IL-2R alpha, IL-2R beta, and IL-2R gamma. Murine Mik beta 1, a mAb that blocks IL-2 binding to IL-2R beta, was developed as an immunosuppressive agent. There was modest prolongation of cynomolgus cardiac allograft survival in animals treated with murine Mik beta 1 (mean survival 11.8 +/- 1.6 days compared with 8.2 +/- 0.4 days in untreated animals; p = 0.06). However, murine Mik beta 1 is ineffective in recruiting primate effector cells and is neutralized by monkey Abs directed toward the infused Ab. To circumvent these limitations, a humanized form of Mik beta 1, which is a largely human IgG1k Ab, except that murine hypervariable regions are retained, was developed. In vivo plasma survival of humanized Mik beta 1 was threefold longer than simultaneously administered murine Mik beta 1 (terminal t1/2, 104 +/- 10 h vs 37 +/- 2 h). Furthermore, humanized Mik beta 1 manifests Ab-dependent cellular cytotoxicity, an activity that is absent with the parental murine Mik beta 1. Graft survival was significantly prolonged by humanized Mik beta 1 treatment with survivals of 22, 22, 24, 27, 44, and > 300 days (p vs control < 0.01; p vs murine Mik beta 1 < 0.01). Survival was not prolonged further (p > 0.3) by the addition of humanized anti-Tac, which blocks interaction of IL-2 with IL-2R alpha subunits. There was no toxicity attributable to the use of Mik beta 1 Abs. Thus, humanized Mik beta 1 prolonged cardiac allograft survival in primates without toxicity and may be effective as an adjunct to standard immunosuppressive therapy.

    View details for Web of Science ID A1994PN07100049

    View details for PubMedID 7930631

  • PROLONGATION OF GRAFT-SURVIVAL IN PRIMATE ALLOGRAFT TRANSPLANTATION BY YTTRIUM-90-LABELED ANTI-TAC IN CONJUNCTION WITH GRANULOCYTE COLONY-STIMULATING FACTOR TRANSPLANTATION Parenteau, G. L., Dirbas, F. M., Garmestani, K., Brechbiel, M. W., BUKOWSKI, M. A., Goldman, C. K., Clark, R., Gansow, O. A., Waldmann, T. A. 1992; 54 (6): 963-968

    Abstract

    High-affinity IL-2 receptors are expressed by T cells activated in response to foreign histocompatibility antigens but not by normal resting T cells. To exploit this difference in IL-2R expression, anti-Tac, a murine monoclonal antibody specific for the IL-2R alpha subunit, was used to inhibit organ allograft rejection. To enhance its effector function, anti-Tac was armed by chelation with yttrium-90, a pure beta-emitting radionuclide. Animals received no immunosuppression (n = 5, group I, controls), unmodified anti-Tac (n = 5, 1 mg/kg q.o.d., group II), or 90Y-anti-Tac (n = 5, 1.6 mCi/kg divided into four doses, group III). The animals in group IV (n = 4) were treated identically to those in group III with the exception that 5 micrograms/kg/dose of granulocyte colony-stimulating factor was administered intramuscularly on the days when the yttrium-90 was given and on postoperative days 12 through 35 in order to reduce hematopoietic toxicity. Mean graft survival +/- S.E.M. for the control group was 8.2 +/- 0.5 days as compared with 13.8 +/- 2.1 days (P < 0.05) for those monkeys treated with unmodified anti-Tac. Graft survival was further prolonged in animals of group III that received 90Y-anti-Tac, with a mean graft survival of 45.0 +/- 11.8 days; however, three of the five monkeys retained viable grafts within this group but died secondary to bone marrow suppression. In comparison, the monkeys in group IV that were treated with G-CSF in conjunction with 90Y-anti-Tac had a mean graft survival of 49.2 +/- 2.9 days. In contrast to group III there were no deaths in the group (IV) receiving G-CSF. Furthermore, animals in group IV had a reduced magnitude and shortened duration of irradiation-induced neutropenia when compared with that observed in group III animals that did not receive G-CSF. Thus, treatment with 90Y-anti-Tac in conjunction with G-CSF may have potential applications in organ transplantation and the treatment of IL-2 receptor-expressing neoplastic diseases.

    View details for Web of Science ID A1992KD06200004

    View details for PubMedID 1281566

  • ANTI-TAC-H, A HUMANIZED ANTIBODY TO THE INTERLEUKIN-2 RECEPTOR, PROLONGS PRIMATE CARDIAC ALLOGRAFT SURVIVAL PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Brown, P. S., Parenteau, G. L., Dirbas, F. M., Garsia, R. J., Goldman, C. K., BUKOWSKI, M. A., Junghans, R. P., Queen, C., Hakimi, J., BENJAMIN, W. R., Clark, R. E., Waldmann, T. A. 1991; 88 (7): 2663-2667

    Abstract

    High-affinity interleukin 2 receptors (IL-2Rs) are expressed by T cells activated in response to foreign histocompatibility antigens but not by normal resting T cells. To exploit this difference in IL-2R expression, anti-Tac-M, a murine monoclonal antibody specific for the IL-2R alpha chain, was used to inhibit organ allograft rejection. However, the use of murine anti-Tac as an immunosuppressive agent was limited by neutralization by human anti-murine antibodies and by weak recruitment of effector functions. To circumvent these difficulties, a humanized antibody to the IL-2R, anti-Tac-H, was prepared. This molecule is human with the exception of the hypervariable segments, which are retained from the mouse. In vivo survival of anti-Tac-H is 2.5-fold longer than simultaneously administered anti-Tac-M (terminal t1/2, 103 hr vs. 38 hr). In addition, anti-Tac-H is less immunogenic than anti-Tac-M when administered to cynomolgus monkeys undergoing heterotopic cardiac allografting. Specifically, all monkeys treated with anti-Tac-M developed measurable anti-anti-Tac-M levels by day 15 (mean onset, 11 days). In contrast, none of the animals receiving anti-Tac-H produced measurable antibodies to this monoclonal antibody before day 33. Finally, there was a prolongation of graft survival in the cynomolgus heterotopic cardiac allograft model in animals receiving anti-Tac. In animals that received anti-Tac-M, the allograft survival was prolonged compared to that of the control group (mean survival, 14 +/- 1.98 days compared to 9.2 +/- 0.48 days; P less than 0.025). Graft survival was further prolonged by anti-Tac-H with a mean survival of 20.0 +/- 0.55 days (compared to controls, P less than 0.001; compared to anti-Tac-M, P less than 0.02). There was no toxicity attributable to the administration of either form of anti-Tac. Thus, anti-Tac-H significantly prolonged allograft survival in primates, without toxic side effects, and may be of value as an adjunct to standard immunosuppressive therapy in humans.

    View details for Web of Science ID A1991FE86400011

    View details for PubMedID 2011577

  • DISSEMINATED CUTANEOUS HERPES-ZOSTER FOLLOWING CARDIAC-SURGERY JOURNAL OF CARDIOVASCULAR SURGERY Dirbas, F. M., Swain, J. A. 1990; 31 (4): 531-532

    Abstract

    Our case report describes disseminated cutaneous Herpes Zoster in the early post-operative period following cardiac surgery with cardiopulmonary bypass. This has not been reported previously in the absence of immunosuppressive therapy. Despite associated neurologic and respiratory impairment, our patient was treated successfully with intravenous Acyclovir and subsequently discharged.

    View details for Web of Science ID A1990DY91000023

    View details for PubMedID 2211810

  • CONTROLLED REPERFUSION FOLLOWING REGIONAL ISCHEMIA ANNALS OF THORACIC SURGERY Lazar, H. L., Wei, J., Dirbas, F. M., Haasler, G. B., Spotnitz, H. M. 1987; 44 (4): 350-355

    Abstract

    The ability to reverse acute coronary occlusion with fibrinolytic agents and percutaneous transluminal angioplasty has increased interest in the revascularization of ischemic myocardium. This study defines changes in global ventricular function, mass, and compliance during acute coronary occlusion and following reperfusion with blood in the beating and arrested heart. In 17 dogs on cardiopulmonary bypass, the proximal left anterior descending coronary artery was occluded for 45 minutes. In 12 dogs, flow was reestablished by releasing the coronary snare in the beating heart. In the other 5 dogs, the snare was released during a continuous 10-minute infusion of blood potassium cardioplegia in the arrested heart. Coronary occlusion resulted in significant decreases in stroke work index and left ventricular (LV) mass, but compliance was unchanged. Reperfusion in the beating heart increased LV mass compared with the values measured before ischemia (104 +/- 5 versus 95 +/- 5 gm; p less than 0.05) and decreased LV compliance (39 +/- 4 versus 53 +/- 4 ml at LV end-diastolic pressure of 8 mm Hg; p less than 0.05). In contrast, with blood cardioplegia-based reperfusion in the arrested heart, LV mass and LV compliance remained unchanged from control values. We conclude that revascularization of acutely ischemic myocardium in the beating heart further impairs LV function by increasing LV mass and decreasing compliance. This damage can be avoided by reperfusion with blood cardioplegia in the arrested heart.

    View details for Web of Science ID A1987K491900004

    View details for PubMedID 3662681

  • CONTROLLED REPERFUSION OF REGIONAL ISCHEMIA SURGICAL FORUM Lazar, H. L., Wei, J., Dirbas, F. M., Spotnitz, H. M. 1983; 34: 257-258
  • EXPERIMENTS ON THE ABIOTIC AMPLIFICATION OF OPTICAL-ACTIVITY ORIGINS OF LIFE AND EVOLUTION OF BIOSPHERES Bonner, W. A., Blair, N. E., Dirbas, F. M. 1981; 11 (1-2): 119-134

    Abstract

    Our earlier experiments are briefly reviewed, involving the abiotic generation of optical activity by exposure of DL-amino acids to various "chiral" physical forces. The enantiomeric enrichments so obtained were low, however, and additional experiments were undertaken with the objective of abiotically enhancing such small enantiomeric excesses. D not equal to L Mixtures of leucine N-carboxy anhydride gave enantiomerically enriched polymers on partial polymerization, while valine NCA mixtures behaved oppositely. Leucine polymers were also found to hydrolyze stereoselectively, providing for additional enantiomeric enhancement. A repetitive sequence of partial polymerization-hydrolysis steps is suggested as a possible mechanism for the abiotic genesis of optically enriched polypeptides on the primitive Earth.

    View details for Web of Science ID A1981LJ65100011

    View details for PubMedID 7231975

  • STEREOSELECTIVE HYDROLYSIS OF LEUCINE OLIGOMERS TETRAHEDRON Blair, N. E., Dirbas, F. M., Bonner, W. A. 1981; 37 (1): 27-29