Dr. Shrager assumed the role of Professor and Chief of the Division of Thoracic Surgery in July 2008. He came to Stanford from the University of Pennsylvania School of Medicine where he served as Associate Professor and Chief of Thoracic Surgery at the Hospital of the University of Pennsylvania and Pennsylvania Hospital. He earned his medical degree at Harvard, trained in surgery at Penn, and completed his thoracic surgery training at Massachusetts General Hospital.

Dr. Shrager has been identified as one of “America’s Top Doctors” and one of “America’s Top Doctors for Cancer” in Castle Connolly’s prestigious listings for multiple years running. Dr. Shrager has been awarded US News and World Report “Top Doctor” recognition in every year since that rating system was inaugurated in 2012 ; this award places him among the top 1% of thoracic surgeons nationwide based upon reviews by physician-peers. Evidence of his expert status among his peers also includes membership on the editorial board of the Annals of Thoracic Surgery.

Dr. Shrager practices all aspects of thoracic surgery but has specials interest and experience in lung cancer, surgery for emphysema, and mediastinal diseases. His clinical publications reflect these interests. In all cases, he looks towards minimally invasive approaches where appropriate, including VATS (thoracoscopic) lobectomy for early stage lung cancer and transcervical thymectomy.

In the basic research realm, Dr. Shrager has focused upon the responses of the respiratory muscles to various disease states and interventions. His lab’s work has been published in important journals such as The New England Journal of Medicine, The Journal of Thoracic and Cardiovascular Surgery, and The American Journal of Respiratory and Critical Care Medicine.

Clinical Focus

  • Cancer > Thoracic Oncology
  • Thoracic Surgery
  • Video Assisted Thoracic Surgery
  • Lung Cancer
  • Thymoma
  • Esophageal Cancer
  • Mediastinal Diseases
  • Lung Volume Reduction
  • VATS
  • Sympathectomy
  • Mediastinal Cyst
  • Thoracoscopy
  • Thymectomy
  • Myasthenia Gravis
  • Emphysema Surgery
  • Bullectomy
  • Minimally Invasive Surgical Procedures
  • Pneumothorax
  • Pleural Diseases
  • sarcoma

Academic Appointments

Administrative Appointments

  • Director, Stanford Respiratory Muscle Research Laboratory (2008 - Present)
  • Member, STS Workforce on Evidence-based Surgery (2006 - Present)
  • Member, AATS Workforce on Education (2008 - Present)
  • Editorial Board Member, Annals of Thoracic Surgery (2001 - Present)
  • Chief, Section of General Thoracic Surgery, UPenn (2003 - 2007)
  • Chief, Stanford Division of Thoracic Surgery (2008 - Present)
  • Physician Leader Thoracic Oncology DMG, Stanford Cancer Center (2010 - Present)

Honors & Awards

  • Phi Beta Kappa, Junior year induction, Amherst College (1983)
  • Elected Member, Society for Clinical Surgery (2008)
  • Summa Cum Lauda, Amherst College (1984)
  • Manstein Graduation Prize, Amherst College (Top Premed Athlete) (1984)
  • Havighurst Graduation Prize, Amherst College (Top History Thesis) (1984)
  • Simpson Fellowship, (For study at Harvard Medical School) (1984-1988)
  • Cabot Graduation Prize, Harvard Medical School (1988)
  • William I Inouye Award for Excellence in Teaching, Department of Surgery, University of Pennsylvania Sch. of Med. (1991)
  • National Research Service Award, National Institutes of Health (1990-1992)
  • 2nd Edward D. Churchill Research Scholarship, American Association for Thoracic Surgery (1999-2001)
  • Fellow, American College of Chest Physicians (2000)
  • Fellow, American College of Surgeons (2001)
  • "Top Doctors" Listing, San Francisco Magazine (2009, 10, 11, 12, 13, 14, 15, 17)
  • “Top Docs” Listing, Philadelphia Magazine (2002, 2005, 2006, 2007)
  • "Top Doctors" Listing, “America’s Top Doctors for Cancer -- peer-elected (2006,07,08 09 10 11 12 13 14 15 16 17)
  • "Top Doctors" Listing, “America’s Top Doctors” - peer elected (2007,08,09,10,11,12, 13, 14, 15, 16, 17)
  • Elected Member, American Association for Thoracic Surgery (2002)
  • Elected Member, Society of Clinical Surgery (2008)
  • Elected Member, American Surgical Association (2010)

Professional Education

  • Residency:Massachusetts General Hospital Thoracic Surgery Residency (1997) MA
  • Residency:Hospital of University of Pennsylvania Surgery Residency (1995) PA
  • Board Certification: General Surgery, American Board of Surgery (1996)
  • Medical Education:Harvard Medical School (1988) MA
  • Board Certification: Thoracic Surgery, American Board of Thoracic Surgery (1999)
  • Thoracic Surgery, Massachusetts General Hospital, Thoracic Surgery (1997)
  • Surgery Training, Hospital of the Univ of Penn, Surgery (1995)
  • MD, Harvard University, Medicine (1988)

Current Research and Scholarly Interests

In clinical research, Dr. Shrager has been an innovator studying outcomes in a variety of areas within Thoracic Surgery including: parenchyma-sparing operations and minimally invasive resections for lung cancer, transcervical thymectomy for myasthenia gravis, and surgical treatment of emphysema.

In the lab, Dr. Shrager is focused on the impact of disease states upon the diaphragm. His group published the seminal paper (NEJM) describing diaphragm atrophy assoc'd with mechanical ventilation.

Clinical Trials

  • Microarray Analysis of Gene Expression and Identification of Progenitor Cells in Lung Carcinoma Recruiting

    This study will investigate gene expression profiles in normal human lung tissue, lung carcinoma and metastatic tumor to the lung. The expression of up to 20,000 genes in a given lung tissue sample will be examined by cDNA microarray analysis and compared to normal lung tissue. In addition, we hope to identify a particular subset of lung cancer cells with an enhanced capacity for proliferation and self-renewal , analogous to the stem cells recently identified for certain types of leukemia, breast cancer and brain tumors.

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  • 4D-CT-based Ventilation Imaging for Adaptive Functional Guidance in Radiotherapy Not Recruiting

    To develop and investigate a novel radiotherapy technique for preserving lung function based on a map of lung function.

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

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  • A Clinical Study Evaluating the Safety and Effectiveness of a New Pleural Catheter for the Medical Management of Symptomatic, Recurrent, Malignant Pleural Effusions Compared to Approved Pleural Catheter. Not Recruiting

    The purpose of this study is to determine whether a new catheter is safe and effective in treating malignant pleural effusions compared to approve catheter.

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

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  • Chemotherapy and Radiation Therapy With or Without Panitumumab in Treating Patients With Stage IIIA Non-Small Cell Lung Cancer Not Recruiting

    RATIONALE: Drugs used in chemotherapy (CT), such as paclitaxel and carboplatin, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Radiation therapy (RT) uses high-energy x-rays to kill tumor cells. Monoclonal antibodies, such as panitumumab, can block tumor growth in different ways. Some block the ability of tumor cells to grow and spread. Others find tumor cells and help kill them or carry tumor-killing substances to them. Giving these treatments before surgery may make the tumor smaller and reduce the amount of normal tissue that needs to be removed. It is not yet known whether chemotherapy and radiation therapy are more effective when given with or without panitumumab in treating patients with non-small cell lung cancer. PURPOSE: This randomized phase II trial is studying chemotherapy and radiation therapy to see how well they work when given with or without panitumumab in treating patients with stage IIIA non-small cell lung cancer.

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

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

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

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

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  • GSK1572932A Antigen-Specific Cancer Immunotherapeutic as Adjuvant Therapy in Patients With Non-Small Cell Lung Cancer Not Recruiting

    The purpose of this clinical trial is to demonstrate the benefit of the immunotherapeutic product GSK1572932A when given to patients with Non-Small Cell Lung Cancer, after removal of their tumor. A course of 13 injections will be administered over 27 months. The Protocol Posting has been updated in order to comply with the FDA Amendment Act, Sep 2007.

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

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  • Imaging and Biomarkers of Hypoxia in Solid Tumors Not Recruiting

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

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

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  • JAK Inhibition to Prevent Ventilator-induced Diaphragm Dysfunction Not Recruiting

    We intend, with this study, to prove that blocking the molecular mechanisms whose blockade prevents VIDD in animals, will indeed prevent the development of VIDD in humans as well. We believe that this evidence will serve as the required basis for proceeding with large, ICU-based clinical trial(s) of a drug to prevent VIDD.

    Stanford is currently not accepting patients for this trial. For more information, please contact Study team, 650-721-2086.

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  • Pulmonary Interstitial Lymphography in Early Stage Lung Cancer Not Recruiting

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

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

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

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

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

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  • Radiation Therapy Regimens in Treating Patients With Limited-Stage Small Cell Lung Cancer Receiving Cisplatin and Etoposide Not Recruiting

    Radiation therapy uses high-energy x-rays to kill tumor cells. Drugs used in chemotherapy, such as etoposide, carboplatin and cisplatin, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. It is not yet known which radiation therapy regimen is more effective when given together with chemotherapy in treating patients with limited-stage small cell lung cancer. This randomized phase III trial is comparing different chest radiation therapy regimens to see how well they work in treating patients with limited-stage small cell lung cancer.

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

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

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

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

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

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

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

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2018-19 Courses

Graduate and Fellowship Programs

All Publications

  • 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): e190168


    Importance: Acute postoperative pain is associated with the development of persistent postsurgical pain, but it is unclear which aspect is most estimable.Objective: To identify patient clusters based on acute pain trajectories, preoperative psychosocial characteristics associated with the high-risk cluster, and the best acute pain predictor of remote outcomes.Design, Setting, and Participants: A secondary analysis of the Stanford Accelerated Recovery Trial randomized, double-blind clinical trial was conducted at a single-center, tertiary, referral teaching hospital. A total of 422 participants scheduled for thoracotomy, video-assisted thoracoscopic surgery, total hip replacement, total knee replacement, mastectomy, breast lumpectomy, hand surgery, carpal tunnel surgery, knee arthroscopy, shoulder arthroplasty, or shoulder arthroscopy were enrolled between May 25, 2010, and July 25, 2014. Data analysis was performed from January 1 to August 1, 2018.Interventions: Patients were randomized to receive gabapentin (1200 mg, preoperatively, and 600 mg, 3 times a day postoperatively) or active placebo (lorazepam, 0.5 mg preoperatively, inactive placebo postoperatively) for 72 hours.Main Outcomes and Measures: A modified Brief Pain Inventory prospectively captured 3 surgical site pain outcomes: average pain and worst pain intensity over the past 24 hours, and current pain intensity. Within each category, acute pain trajectories (first 10 postoperative pain scores) were compared using a k-means clustering algorithm. Fifteen descriptors of acute pain were compared as predictors of remote postoperative pain resolution, opioid cessation, and full recovery.Results: Of the 422 patients enrolled, 371 patients (≤10% missing pain scores) were included in the analysis. Of these, 146 (39.4%) were men; mean (SD) age was 56.67 (11.70) years. Two clusters were identified within each trajectory category. The high pain cluster of the average pain trajectory significantly predicted prolonged pain (hazard ratio [HR], 0.63; 95% CI, 0.50-0.80; P<.001) and delayed opioid cessation (HR, 0.52; 95% CI, 0.41-0.67; P<.001) but was not a predictor of time to recovery in Cox proportional hazards regression (HR, 0.89; 95% CI, 0.69-1.14; P=.89). Preoperative risk factors for categorization to the high average pain cluster included female sex (adjusted relative risk [ARR], 1.36; 95% CI, 1.08-1.70; P=.008), elevated preoperative pain (ARR, 1.11; 95% CI, 1.07-1.15; P<.001), a history of alcohol or drug abuse treatment (ARR,1.90; 95% CI, 1.42-2.53; P<.001), and receiving active placebo (ARR, 1.27; 95% CI, 1.03-1.56; P=.03). Worst pain reported on postoperative day 10 was the best predictor of time to pain resolution (HR, 0.83; 95% CI, 0.78-0.87; P<.001), opioid cessation (HR, 0.84; 95% CI, 0.80-0.89; P<.001), and complete surgical recovery (HR, 0.91; 95% CI, 0.86-0.96; P<.001).Conclusions and Relevance: This study has shown a possible uniform predictor of remote postoperative pain, opioid use, and recovery that can be easily assessed. Future work is needed to replicate these findings.Trial Registration: Identifier: NCT01067144.

    View details for DOI 10.1001/jamanetworkopen.2019.0168

    View details for PubMedID 30821824

  • A radiogenomic dataset of non-small cell lung cancer. Scientific data Bakr, S., Gevaert, O., Echegaray, S., Ayers, K., Zhou, M., Shafiq, M., Zheng, H., Benson, J. A., Zhang, W., Leung, A. N., Kadoch, M., D Hoang, C., Shrager, J., Quon, A., Rubin, D. L., Plevritis, S. K., Napel, S. 2018; 5: 180202


    Medical image biomarkers of cancer promise improvements in patient care through advances in precision medicine. Compared to genomic biomarkers, image biomarkers provide the advantages of being non-invasive, and characterizing a heterogeneous tumor in its entirety, as opposed to limited tissue available via biopsy. We developed a unique radiogenomic dataset from a Non-Small Cell Lung Cancer (NSCLC) cohort of 211 subjects. The dataset comprises Computed Tomography (CT), Positron Emission Tomography (PET)/CT images, semantic annotations of the tumors as observed on the medical images using a controlled vocabulary, and segmentation maps of tumors in the CT scans. Imaging data are also paired with results of gene mutation analyses, gene expression microarrays and RNA sequencing data from samples of surgically excised tumor tissue, and clinical data, including survival outcomes. This dataset was created to facilitate the discovery of the underlying relationship between tumor molecular and medical image features, as well as the development and evaluation of prognostic medical image biomarkers.

    View details for DOI 10.1038/sdata.2018.202

    View details for PubMedID 30325352



    Extra-adrenal pheochromocytomas, or paragangliomas, originate from neural crest chromaffin cells and can be found anywhere along the sympathetic chain from head to toe.A 34-year-old female presented 4 days postpartum with episodes of palpitations, hypertension, and shortness of breath. Two episodes in the emergency department confirmed hypertension and supraventricular tachycardia (SVT). A mediastinal mass was noted during workup for pulmonary embolus and was subsequently diagnosed as a cardiac paraganglioma. Our patient underwent surgical resection and was doing well 3 months postoperatively. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: This case represents a rare presentation of mediastinal paraganglioma with episodic SVT and hypertension postpartum, diagnosed during workup for pulmonary embolus. Although exceedingly rare, emergency physicians should consider paragangliomas in the differential of pregnant or postpartum women who present with episodic hypertension, palpitations, headache, and sweating.

    View details for DOI 10.1016/j.jemermed.2018.05.034

    View details for Web of Science ID 000445520600004

    View details for PubMedID 30037518

  • Examination of Optimal Timing of Post-Surgical Surveillance for Early Stage Lung Cancer Patients and Association with Outcomes Colwell, E., Bhandari, P., Benson, J., He, H., Lui, N., Berry, M., Shrager, J., Backhus, L. ELSEVIER SCIENCE INC. 2018: S819
  • Small Molecule Derived From Carboxyethylpyrrole Protein Adducts Promotes Angiogenesis in a Mouse Model of Peripheral Arterial Disease. Journal of the American Heart Association Hou, L., Yang, G., Tang, S., Alcazar, C., Joshi, P., Strassberg, Z., Kim, M., Kawamura, M., Woo, Y. J., Shrager, J., Ding, S., Huang, N. F. 2018; 7 (18): e009234


    Background CEP (omega-[2-carboxyethyl]pyrrole) protein adducts are the end products of lipid oxidation associated with inflammation and have been implicated in the induction of angiogenesis in pathological conditions such as tissue ischemia. We synthesized small molecules derived from CEP protein adducts and evaluated the angiogenic effect of the CEP analog CEP 03 in the setting of peripheral arterial disease. Methods and Results The angiogenic effect of CEP 03 was assessed by invitro analysis of primary human microvascular endothelial cell proliferation and tubelike formation in Matrigel (Corning). In the presence of CEP 03, proliferation of endothelial cells invitro increased by 27±18% under hypoxic (1% O2) conditions, reaching similar levels to that of VEGF A (vascular endothelial growth factor A) stimulation (22±10%), relative to the vehicle control treatment. A similar effect of CEP 03 was demonstrated in the increased number of tubelike branches in Matrigel, reaching >70% induction in hypoxia, compared with the vehicle control. The therapeutic potential of CEP 03 was further evaluated in a mouse model of peripheral arterial disease by quantification of blood perfusion recovery and capillary density. In the ischemic hind limb, treatment of CEP 03 encapsulated within Matrigel significantly enhanced blood perfusion by 2-fold after 14days compared with those treated with Matrigel alone. Moreover, these results concurred with histological finding that treatment of CEP 03 in Matrigel resulted in a significant increase in microvessel density compared with Matrigel alone. Conclusions Our data suggest that CEP 03 has a profound positive effect on angiogenesis and neovessel formation and thus has therapeutic potential for treatment of peripheral arterial disease.

    View details for DOI 10.1161/JAHA.118.009234

    View details for PubMedID 30371212

  • Synchronous primary lung adenocarcinomas harboring distinct MET Exon 14 splice site mutations. Lung cancer (Amsterdam, Netherlands) Wang, S. X., Lei, L., Guo, H. H., Shrager, J., Kunder, C. A., Neal, J. W. 2018; 122: 187–91


    When a patient is found to have multiple lung tumors, distinguishing whether they represent metastatic nodules or separate primary cancers is crucial for staging and therapy. We report the case of a 79-year-old patient with two surgically resected synchronous left upper lobe adenocarcinomas initially pathologically staged as T3 (IIB), indicating adjuvant chemotherapy should be recommended. However, the tumors appeared radiographically distinct, so next-generation sequencing was performed on each nodule. Each tumor harbored a different mesenchymal-to-epithelial transition (MET) exon 14 skipping mutation, an emerging targetable mutation, suggestive of distinct clonality. While the in frame protein deletion was the same in each tumor, the nucleotide base substitutions were different. Thus, the patient was down-staged to having two separate IA tumors, spared of adjuvant chemotherapy, and routine surveillance was recommended. This case highlights the utility of using molecular analysis in diagnosing and treating multifocal lung tumors, and the process of convergent molecular evolution toward a common oncogenic driver mutation. This is the first case of multiple synchronous lung tumors each harboring a distinct MET exon 14 splice site mutation.

    View details for DOI 10.1016/j.lungcan.2018.06.019

    View details for PubMedID 30032829

  • Minimally Invasive Thymectomy and Lung Volume Reduction in a Patient with Myasthenia Gravis. The Annals of thoracic surgery Salna, M., Kidambi, S., Sampson, J., Shrager, J. B. 2018


    We describe the case of a patient with myasthenia gravis and severe pulmonary emphysema who underwent concomitant bilateral video/robotic-assisted thymectomy with unilateral lung volume reduction surgery. We review the important pathophysiological considerations that must be appreciated to ensure safe surgery in this unusual situation with two diseases that independently affect the respiratory system - each of which requires preoperative optimization.

    View details for DOI 10.1016/j.athoracsur.2018.04.067

    View details for PubMedID 29807007

  • The Signaling Network Resulting in Ventilator-induced Diaphragm Dysfunction. American journal of respiratory cell and molecular biology Tang, H., Shrager, J. B. 2018


    Mechanical ventilation (MV) is a life-saving measure for those incapable of adequately ventilating or oxygenating without assistance. Unfortunately, even brief periods of MV result in diaphragm weakness (i.e., "ventilator-induced diaphragm dysfunction" - VIDD) that may render it difficult to wean the ventilator. Prolonged MV is associated with cascading complications and is a strong risk factor for death. Thus, prevention of VIDD may have a dramatic impact on mortality rates. Here, we summarized the current understanding of the pathogenic events underlying VIDD. Numerous alterations have been proven important in both human and animal MV diaphragm. These include protein degradation via the ubiquitin proteasome system, autophagy, apoptosis, and calpain activity - all causing diaphragm muscle fiber atrophy; altered energy supply via compromised oxidative phosphorylation and upregulation of glycolysis; and also mitochondrial dysfunction and oxidative stress. Mitochondrial oxidative stress (MOS) in fact appears to be a central factor in each of these events. Recent studies by our group and others indicate that mitochondrial function is modulated by several signaling molecules including Smad3, STAT3 and FoxO. Mechanical ventilation rapidly activates Smad3 and STAT3, which upregulate MOS. Additional roles may be played by angiotensin II and leaky ryanodine receptors causing elevated calcium levels. We present, here, a hypothetical scaffold for understanding the molecular pathogenesis of VIDD which links together these elements. These pathways harbor several drug targets that could soon move toward testing in clinical trials. We hope that this review will shape a short list of the most promising candidates.

    View details for DOI 10.1165/rcmb.2018-0022TR

    View details for PubMedID 29768017

  • GFPT2-expressing cancer-associated fibroblasts mediate metabolic reprogramming in human lung adenocarcinoma. Cancer research Zhang, W., Bouchard, G., Yu, A., Shafiq, M., Jamali, M., Shrager, J. B., Ayers, K., Bakr, S., Gentles, A. J., Diehn, M., Quon, A., West, R. B., Nair, V., van de Rijn, M., Napel, S., Plevritis, S. K. 2018


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

    View details for DOI 10.1158/0008-5472.CAN-17-2928

    View details for PubMedID 29760045

  • Computed Tomography Features associated With the Eighth Edition TNM Stage Classification for Thymic Epithelial Tumors JOURNAL OF THORACIC IMAGING Padda, S. K., Terrone, D., Tian, L., Khuong, A., Neal, J. W., Riess, J. W., Berry, M. F., Hoang, C. D., Burt, B. M., Leung, A. N., Schwartz, E. J., Shrager, J. B., Wakelee, H. A. 2018; 33 (3): 176–83


    The eighth edition of the TNM classification of malignant tumors for the first time includes an official staging system for thymic epithelial tumors (TETs) recognized by the American Joint Committee on Cancer (AJCC) and the Union for International Cancer Control (UICC). Staging is critical for the management of TETs, and determining stage accurately from imaging has the potential to improve clinical outcomes. We examine preoperative computed tomography (CT) characteristics of TETs associated with AJCC/UICC pathologic TNM stage.In this retrospective study, patients were included if they met all the following criteria: (1) diagnosis of TET, (2) had primary curative intent surgery performed at Stanford University, and (3) had available preoperative CT imaging for review. Tumor pathology was staged according to the eighth edition TNM classification. Fifteen CT scan features were examined from each patient case according to the International Thymic Malignancy Interest Group standard report terms in a blinded manner. A Lasso-regularized multivariate model was used to produce a weighted scoring system predictive of pathologic TNM stage.Examining the 54 patients included, the following CT characteristics were associated with higher pathologic TNM stage when using the following scoring system: elevated hemidiaphragm (score of 6), vascular endoluminal invasion (score of 6), pleural nodule (score of 2), lobulated contour (score of 2), and heterogeneous internal density (score of 1). Area under the receiver operating characteristic curve was 0.76.TETs with clearly invasive or metastatic features seen on CT are associated with having higher AJCC/UICC pathologic TNM stage, as expected. However, features of lobulated contour and heterogeneous internal density are also associated with higher stage disease. These findings need to be validated in an independent cohort.

    View details for DOI 10.1097/RTI.0000000000000310

    View details for Web of Science ID 000430930800006

    View details for PubMedID 29219888

  • Paraneoplastic Syndromes and Thymic Malignancies: An Examination of the International Thymic Malignancy Interest Group Retrospective Database JOURNAL OF THORACIC ONCOLOGY Padda, S. K., Yao, X., Antonicelli, A., Riess, J. W., Shang, Y., Shrager, J. B., Korst, R., Detterbeck, F., Huang, J., Burt, B. M., Wakelee, H. A., Badve, S. S. 2018; 13 (3): 436–46


    Thymic epithelial tumors (TETs) are associated with paraneoplastic/autoimmune (PN/AI) syndromes. Myasthenia gravis is the most common PN/AI syndrome associated with TETs.The International Thymic Malignancy Interest Group retrospective database was examined to determine (1) baseline and treatment characteristics associated with PN/AI syndromes and (2) the prognostic role of PN/AI syndromes for patients with TETs. The competing risks model was used to estimate cumulative incidence of recurrence (CIR) and the Kaplan-Meier method was used to calculate overall survival (OS). A Cox proportional hazards model was used for multivariate analysis.A total of 6670 patients with known PN/AI syndrome status from 1951 to 2012 were identified. PN/AI syndromes were associated with younger age, female sex, thymoma histologic type, earlier stage, and an increased rate of total thymectomy and complete resection status. There was a statistically significant lower CIR in the group with a PN/AI syndrome than in the group without a PN/AI syndrome (10-year CIR 17.3% versus 21.2%, respectively [p = 0.0003]). The OS was improved in the group with a PN/AI syndrome compared to the group without a PN/AI syndrome (median OS 21.6 years versus 17.0 years, respectively [hazard ratio = 0.63, 95% confidence interval: 0.54-0.74, p < 0.0001]). However, in the multivariate model for recurrence-free survival and OS, PN/AI syndrome was not an independent prognostic factor.Previously, there have been mixed data regarding the prognostic role of PN/AI syndromes for patients with TETs. Here, using the largest data set in the world for TETs, PN/AI syndromes were associated with favorable features (i.e., earlier stage and complete resection status) but were not an independent prognostic factor for patients with TETs.

    View details for DOI 10.1016/j.jtho.2017.11.118

    View details for Web of Science ID 000429213700023

    View details for PubMedID 29191778

    View details for PubMedCentralID PMC5983900

  • Stage IB: To give (chemo), or not to give? That is the question JOURNAL OF THORACIC AND CARDIOVASCULAR SURGERY Shrager, J. B. 2018; 155 (3): 1206

    View details for DOI 10.1016/j.jtcvs.2017.10.016

    View details for Web of Science ID 000425915100104

    View details for PubMedID 29128110

  • Intraoperative costs of video-assisted thoracoscopic lobectomy can be dramatically reduced without compromising outcomes JOURNAL OF THORACIC AND CARDIOVASCULAR SURGERY Richardson, M. T., Backhus, L. M., Berry, M. F., Vail, D. G., Ayers, K. C., Benson, J. A., Bhandari, P., Teymourtash, M., Shrager, J. B. 2018; 155 (3): 1267-+


    To determine whether surgeon selection of instrumentation and other supplies during video-assisted thoracoscopic lobectomy (VATSL) can safely reduce intraoperative costs.In this retrospective, cost-focused review of all video-assisted thoracoscopic surgery anatomic lung resections performed by 2 surgeons at a single institution between 2010 and 2014, we compared VATSL hospital costs and perioperative outcomes between the surgeons, as well as costs of VATSL compared with thoracotomy lobectomy (THORL).A total of 100 VATSLs were performed by surgeon A, and 70 were performed by surgeon B. The preoperative risk factors did not differ significantly between the 2 groups of surgeries. Mean VATSL total hospital costs per case were 24% percent greater for surgeon A compared with surgeon B (P = .0026). Intraoperative supply costs accounted for most of this cost difference and were 85% greater for surgeon A compared with surgeon B (P < .0001). The use of nonstapler supplies, including energy devices, sealants, and disposables, drove intraoperative costs, accounting for 55% of the difference in intraoperative supply costs between the surgeons. Operative time was 25% longer for surgeon A compared with surgeon B (P < .0001), but this accounted for only 11% of the difference in total cost. Surgeon A's overall VATSL costs per case were similar to those of THORLs (n = 100) performed over the same time period, whereas surgeon B's VATSL costs per case were 24% less than those of THORLs. On adjusted analysis, there was no difference in VATSL perioperative outcomes between the 2 surgeons.The costs of VATSL differ substantially among surgeons and are heavily influenced by the use of disposable equipment/devices. Surgeons can substantially reduce the costs of VATSL to far lower than those of THORL without compromising surgical outcomes through prudent use of costly instruments and technologies.

    View details for DOI 10.1016/j.jtcvs.2017.08.146

    View details for Web of Science ID 000425915100117

    View details for PubMedID 29224839

  • Induction therapy for locally advanced distal esophageal adenocarcinoma: Is radiation Always necessary? The Journal of thoracic and cardiovascular surgery Liou, D. Z., Backhus, L. M., Lui, N. S., Shrager, J. B., Berry, M. F. 2018


    OBJECTIVE: To compare outcomes between induction chemotherapy alone (ICA) and induction chemoradiation (ICR) in patients with locally advanced distal esophageal adenocarcinoma.METHODS: Patients in the National Cancer Database treated with ICA or ICR followed by esophagectomy between 2006 and 2012 for cT1-3N1M0 or T3N0M0 adenocarcinoma of the distal esophagus were compared using logistic regression, Kaplan-Meier analysis, and Cox proportional hazards methods.RESULTS: The study group included 4763 patients, of whom 4323 patients (90.8%) received ICR and 440 patients (9.2%) received ICA. There were no differences in age, sex, race, Charlson Comorbidity Index, treatment facility type, clinical T or N status between the 2 groups. Tumor size ≥5cm (odds ratio, 1.46; P=.006) was the only factor that predicted ICR use. Higher rates of T downstaging (39.7% vs 33.4%; P=.012), N downstaging (32.0% vs 23.4%; P<.001), and complete pathologic response (13.1% vs 5.9%; P<.001) occurred in ICR patients. Positive margins were seen more often in ICA patients (9.6% vs 5.5%; P=.001), but there was no difference in 5-year survival (ICR 35.9% vs ICA 37.2%; P=.33), and ICR was not associated with survival in multivariable analysis (hazard ratio=1.04; P=.61).CONCLUSIONS: ICR for locally advanced distal esophageal adenocarcinoma is associated with a better local treatment effect, but not improved survival compared with ICA, which suggests that radiation can be used selectively in this clinical situation.

    View details for DOI 10.1016/j.jtcvs.2017.12.136

    View details for PubMedID 29530567

  • Presence of Even a Small Ground-Glass Component in Lung Adenocarcinoma Predicts Better Survival CLINICAL LUNG CANCER Berry, M. F., Gao, R., Kunder, C. A., Backhus, L., Khuong, A., Kadoch, M., Leung, A., Shrager, J. 2018; 19 (1): E47–E51


    While lepidic-predominant lung adenocarcinomas are known to have better outcomes than similarly sized solid tumors, the impact of smaller noninvasive foci within predominantly solid tumors is less clearly characterized. We tested the hypothesis that lung adenocarcinomas with even a small ground-glass opacity (GGO) component have a better prognosis than otherwise similar pure solid (PS) adenocarcinomas.The maximum total and solid-component diameters were determined by preoperative computed tomography in patients who underwent lobar or sublobar resection of clinical N0 adenocarcinomas without induction therapy between May 2003 and August 2013. Survival between patients with PS tumors (0% GGO) or tumors with a minor ground-glass (MGG) component (1%-25% GGO) was compared by Kaplan-Meier and Cox analyses.A total of 123 patients met the inclusion criteria, comprising 54 PS (44%) and 69 MGG (56%) whose mean ground-glass component was 18 ± 7%. The solid component tumor diameter was not significantly different between the groups (2.3 ± 1.2 cm vs. 2.5 ± 1.3 cm, P = .2). Upstaging to pN1-2 was more common for the PS group (13% [7/54] vs. 3% [2/69], P = .04), but the distribution of pathologic stage was not significantly different between the groups (PS 76% stage I [41/54] vs. MGG 80% stage I [55/69], P = .1). Having a MGG component was associated with markedly better survival in both univariate analysis (MGG 5-year overall survival 86.7% vs. PS 64.5%, P = .001) and multivariable survival analysis (hazard ratio, 0.30, P = .01).Patients with resected cN0 lung adenocarcinoma who have even a small GGO component have markedly better survival than patients with PS tumors, which may have implications for both treatment and surveillance strategies.

    View details for DOI 10.1016/j.cllc.2017.06.020

    View details for Web of Science ID 000418750800007

    View details for PubMedID 28743420

  • Genomic Profiling of Bronchoalveolar Lavage Fluid in Patients with Non-Small Cell Lung Cancer Nair, V. S., Li, A., Stehr, H., Chabon, J., Chaudhuri, A., Zhou, L., Naemi, H., Ayers, K., Ramsey, M., Bedi, H. S., Van Wert, R., Sung, A. W., Lui, N., Backhus, L., Berry, M., Shrager, J. B., Alizadeh, A., Diehn, M. AMER THORACIC SOC. 2018
  • Bioengineered Viral Platform for Intramuscular Passive Vaccine Delivery to Human Skeletal Muscle. Molecular therapy. Methods & clinical development Paulk, N. K., Pekrun, K., Charville, G. W., Maguire-Nguyen, K., Wosczyna, M. N., Xu, J., Zhang, Y., Lisowski, L., Yoo, B., Vilches-Moure, J. G., Lee, G. K., Shrager, J. B., Rando, T. A., Kay, M. A. 2018; 10: 144–55


    Skeletal muscle is ideal for passive vaccine administration as it is easily accessible by intramuscular injection. Recombinant adeno-associated virus (rAAV) vectors are in consideration for passive vaccination clinical trials for HIV and influenza. However, greater human skeletal muscle transduction is needed for therapeutic efficacy than is possible with existing serotypes. To bioengineer capsids with therapeutic levels of transduction, we utilized a directed evolution approach to screen libraries of shuffled AAV capsids in pools of surgically resected human skeletal muscle cells from five patients. Six rounds of evolution were performed in various muscle cell types, and evolved variants were validated against existing muscle-tropic serotypes rAAV1, 6, and 8. We found that evolved variants NP22 and NP66 had significantly increased primary human and rhesus skeletal muscle fiber transduction from surgical explants ex vivo and in various primary and immortalized myogenic lines in vitro. Importantly, we demonstrated reduced seroreactivity compared to existing serotypes against normal human serum from 50 adult donors. These capsids represent powerful tools for human skeletal muscle expression and secretion of antibodies from passive vaccines.

    View details for DOI 10.1016/j.omtm.2018.06.001

    View details for PubMedID 30101152

    View details for PubMedCentralID PMC6077147

  • Non-Small Cell Lung Cancer Radiogenomics Map Identifies Relationships between Molecular and Imaging Phenotypes with Prognostic Implications. Radiology Zhou, M., Leung, A., Echegaray, S., Gentles, A., Shrager, J. B., Jensen, K. C., Berry, G. J., Plevritis, S. K., Rubin, D. L., Napel, S., Gevaert, O. 2018; 286 (1): 307–15


    Purpose To create a radiogenomic map linking computed tomographic (CT) image features and gene expression profiles generated by RNA sequencing for patients with non-small cell lung cancer (NSCLC). Materials and Methods A cohort of 113 patients with NSCLC diagnosed between April 2008 and September 2014 who had preoperative CT data and tumor tissue available was studied. For each tumor, a thoracic radiologist recorded 87 semantic image features, selected to reflect radiologic characteristics of nodule shape, margin, texture, tumor environment, and overall lung characteristics. Next, total RNA was extracted from the tissue and analyzed with RNA sequencing technology. Ten highly coexpressed gene clusters, termed metagenes, were identified, validated in publicly available gene-expression cohorts, and correlated with prognosis. Next, a radiogenomics map was built that linked semantic image features to metagenes by using the t statistic and the Spearman correlation metric with multiple testing correction. Results RNA sequencing analysis resulted in 10 metagenes that capture a variety of molecular pathways, including the epidermal growth factor (EGF) pathway. A radiogenomic map was created with 32 statistically significant correlations between semantic image features and metagenes. For example, nodule attenuation and margins are associated with the late cell-cycle genes, and a metagene that represents the EGF pathway was significantly correlated with the presence of ground-glass opacity and irregular nodules or nodules with poorly defined margins. Conclusion Radiogenomic analysis of NSCLC showed multiple associations between semantic image features and metagenes that represented canonical molecular pathways, and it can result in noninvasive identification of molecular properties of NSCLC. Online supplemental material is available for this article.

    View details for DOI 10.1148/radiol.2017161845

    View details for PubMedID 28727543

    View details for PubMedCentralID PMC5749594

  • Smad3 initiates oxidative stress and proteolysis that underlies diaphragm dysfunction during mechanical ventilation SCIENTIFIC REPORTS Tang, H., Kennedy, C. L., Lee, M., Gao, Y., Xia, H., Olguin, F., Fraga, D. A., Ayers, K., Choi, S., Kim, M., Tehrani, A., Sowb, Y. A., Rando, T. A., Shrager, J. B. 2017; 7: 14530


    Prolonged use of mechanical ventilation (MV) leads to atrophy and dysfunction of the major inspiratory muscle, the diaphragm, contributing to ventilator dependence. Numerous studies have shown that proteolysis and oxidative stress are among the major effectors of ventilator-induced diaphragm muscle dysfunction (VIDD), but the upstream initiator(s) of this process remain to be elucidated. We report here that periodic diaphragm contraction via phrenic nerve stimulation (PNS) substantially reduces MV-induced proteolytic activity and oxidative stress in the diaphragm. We show that MV rapidly induces phosphorylation of Smad3, and PNS nearly completely prevents this effect. In cultured cells, overexpressed Smad3 is sufficient to induce oxidative stress and protein degradation, whereas inhibition of Smad3 activity suppresses these events. In rats subjected to MV, inhibition of Smad3 activity by SIS3 suppresses oxidative stress and protein degradation in the diaphragm and prevents the reduction in contractility that is induced by MV. Smad3's effect appears to link to STAT3 activity, which we previously identified as a regulator of VIDD. Inhibition of Smad3 suppresses STAT3 signaling both in vitro and in vivo. Thus, MV-induced diaphragm inactivity initiates catabolic changes via rapid activation of Smad3 signaling. An early intervention with PNS and/or pharmaceutical inhibition of Smad3 may prevent clinical VIDD.

    View details for DOI 10.1038/s41598-017-11978-4

    View details for Web of Science ID 000414415000030

    View details for PubMedID 29109401

    View details for PubMedCentralID PMC5673963

  • Prediction of EGFR and KRAS mutation in non-small cell lung cancer using quantitative 18F FDG-PET/CT metrics. Oncotarget Minamimoto, R., Jamali, M., Gevaert, O., Echegaray, S., Khuong, A., Hoang, C. D., Shrager, J. B., Plevritis, S. K., Rubin, D. L., Leung, A. N., Napel, S., Quon, A. 2017


    This study investigated the relationship between epidermal growth factor receptor (EGFR) and Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations in non-small-cell lung cancer (NSCLC) and quantitative FDG-PET/CT parameters including tumor heterogeneity. 131 patients with NSCLC underwent staging FDG-PET/CT followed by tumor resection and histopathological analysis that included testing for the EGFR and KRAS gene mutations. Patient and lesion characteristics, including smoking habits and FDG uptake parameters, were correlated to each gene mutation. Never-smoker (P < 0.001) or low pack-year smoking history (p = 0.002) and female gender (p = 0.047) were predictive factors for the presence of the EGFR mutations. Being a current or former smoker was a predictive factor for the KRAS mutations (p = 0.018). The maximum standardized uptake value (SUVmax) of FDG uptake in lung lesions was a predictive factor of the EGFR mutations (p = 0.029), while metabolic tumor volume and total lesion glycolysis were not predictive. Amongst several tumor heterogeneity metrics included in our analysis, inverse coefficient of variation (1/COV) was a predictive factor (p < 0.02) of EGFR mutations status, independent of metabolic tumor diameter. Multivariate analysis showed that being a never-smoker was the most significant factor (p < 0.001) for the EGFR mutations in lung cancer overall. The tumor heterogeneity metric 1/COV and SUVmax were both predictive for the EGFR mutations in NSCLC in a univariate analysis. Overall, smoking status was the most significant factor for the presence of the EGFR and KRAS mutations in lung cancer.

    View details for DOI 10.18632/oncotarget.17782

    View details for PubMedID 28538213

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


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

    View details for DOI 10.1016/j.radonc.2017.03.021

    View details for PubMedID 28460826

  • Predictive radiogenomics modeling of EGFR mutation status in lung cancer SCIENTIFIC REPORTS Gevaert, O., Echegaray, S., Khuong, A., Hoang, C. D., Shrager, J. B., Jensen, K. C., Berry, G. J., Guo, H. H., Lau, C., Plevritis, S. K., Rubin, D. L., Napel, S., Leung, A. N. 2017; 7


    Molecular analysis of the mutation status for EGFR and KRAS are now routine in the management of non-small cell lung cancer. Radiogenomics, the linking of medical images with the genomic properties of human tumors, provides exciting opportunities for non-invasive diagnostics and prognostics. We investigated whether EGFR and KRAS mutation status can be predicted using imaging data. To accomplish this, we studied 186 cases of NSCLC with preoperative thin-slice CT scans. A thoracic radiologist annotated 89 semantic image features of each patient's tumor. Next, we built a decision tree to predict the presence of EGFR and KRAS mutations. We found a statistically significant model for predicting EGFR but not for KRAS mutations. The test set area under the ROC curve for predicting EGFR mutation status was 0.89. The final decision tree used four variables: emphysema, airway abnormality, the percentage of ground glass component and the type of tumor margin. The presence of either of the first two features predicts a wild type status for EGFR while the presence of any ground glass component indicates EGFR mutations. These results show the potential of quantitative imaging to predict molecular properties in a non-invasive manner, as CT imaging is more readily available than biopsies.

    View details for DOI 10.1038/srep41674

    View details for Web of Science ID 000393094200001

    View details for PubMedID 28139704

    View details for PubMedCentralID PMC5282551

  • Determinants of Complete Resection of Thymoma by Minimally Invasive and Open Thymectomy: Analysis of an International Registry JOURNAL OF THORACIC ONCOLOGY Burt, B. M., Yao, X., Shrager, J., Antonicelli, A., Padda, S., Reiss, J., Wakelee, H., Su, S., Huang, J., Scott, W. 2017; 12 (1): 129-136


    Minimally invasive thymectomy (MIT) is a surgical approach to thymectomy that has more favorable short-term outcomes for myasthenia gravis than open thymectomy (OT). The oncologic outcomes of MIT performed for thymoma have not been rigorously evaluated. We analyzed determinants of complete (R0) resection among patients undergoing MIT and OT in a large international database.The retrospective database of the International Thymic Malignancy Interest Group was queried. Chi-square and Wilcoxon rank sum tests, multivariate logistic regression models, and propensity matching were performed.A total of 2514 patients underwent thymectomy for thymoma between 1997 and 2012; 2053 of them (82%) underwent OT and 461 (18%) underwent MIT, with the use of MIT increasing significantly in recent years. The rate of R0 resection among patients undergoing OT was 86%, and among those undergoing MIT it was 94% (p < 0.0001). In propensity-matched MIT and OT groups (n = 266 in each group); however, the rate of R0 resection did not differ significantly (96% in both the MIT and OT groups, p = 0.7). Multivariate analyses were performed to identify determinants of R0 resection. Factors independently associated with R0 resection were geographical region, later time period, less advanced Masaoka stage, total thymectomy, and the absence of radiotherapy. Surgical approach, whether minimally invasive or open, was not associated with completeness of resection.The use of MIT for resection of thymoma has been increasing substantially over time, and MIT can achieve rates of R0 resection for thymoma similar to those achieved with OT.

    View details for DOI 10.1016/j.jtho.2016.08.131

    View details for Web of Science ID 000391518500015

  • Effect of Perioperative Gabapentin on Postoperative Pain Resolution and Opioid Cessation in a Mixed Surgical Cohort: A Randomized Clinical Trial. JAMA surgery Hah, J., Mackey, S. C., Schmidt, P., McCue, R., Humphreys, K., Trafton, J., Efron, B., Clay, D., Sharifzadeh, Y., Ruchelli, G., Goodman, S., Huddleston, J., Maloney, W. J., Dirbas, F. M., Shrager, J., Costouros, J., Curtin, C., Carroll, I. 2017


    Guidelines recommend using gabapentin to decrease postoperative pain and opioid use, but significant variation exists in clinical practice.To determine the effect of perioperative gabapentin on remote postoperative time to pain resolution and opioid cessation.A randomized, double-blind, placebo-controlled trial of perioperative gabapentin was conducted at a single-center, tertiary referral teaching hospital. A total of 1805 patients aged 18 to 75 years scheduled for surgery (thoracotomy, video-assisted thoracoscopic surgery, total hip replacement, total knee replacement, mastectomy, breast lumpectomy, hand surgery, carpal tunnel surgery, knee arthroscopy, shoulder arthroplasty, and shoulder arthroscopy) were screened. Participants were enrolled from May 25, 2010, to July 25, 2014, and followed up for 2 years postoperatively. Intention-to-treat analysis was used in evaluation of the findings.Gabapentin, 1200 mg, preoperatively and 600 mg, 3 times a day postoperatively or active placebo (lorazepam, 0.5 mg) preoperatively followed by inactive placebo postoperatively for 72 hours.Primary outcome was time to pain resolution (5 consecutive reports of 0 of 10 possible levels of average pain at the surgical site on the numeric rating scale of pain). Secondary outcomes were time to opioid cessation (5 consecutive reports of no opioid use) and the proportion of participants with continued pain or opioid use at 6 months and 1 year.Of 1805 patients screened for enrollment, 1383 were excluded, including 926 who did not meet inclusion criteria and 273 who declined to participate. Overall, 8% of patients randomized were lost to follow-up. A total of 202 patients were randomized to active placebo and 208 patients were randomized to gabapentin in the intention-to-treat analysis (mean [SD] age, 56.7 [11.7] years; 256 (62.4%) women and 154 (37.6%) men). Baseline characteristics of the groups were similar. Perioperative gabapentin did not affect time to pain cessation (hazard ratio [HR], 1.04; 95% CI, 0.82-1.33; P = .73) in the intention-to-treat analysis. However, participants receiving gabapentin had a 24% increase in the rate of opioid cessation after surgery (HR, 1.24; 95% CI, 1.00-1.54; P = .05). No significant differences were noted in the number of adverse events as well as the rate of medication discontinuation due to sedation or dizziness (placebo, 42 of 202 [20.8%]; gabapentin, 52 of 208 [25.0%]).Perioperative administration of gabapentin had no effect on postoperative pain resolution, but it had a modest effect on promoting opioid cessation after surgery. The routine use of perioperative gabapentin may be warranted to promote opioid cessation and prevent chronic opioid use. Optimal dosing and timing of perioperative gabapentin in the context of specific operations to decrease opioid use should be addressed in further Identifier: NCT01067144.

    View details for DOI 10.1001/jamasurg.2017.4915

    View details for PubMedID 29238824

  • Early detection of molecular residual disease in localized lung cancer by circulating tumor DNA profiling. Cancer discovery Chaudhuri, A. A., Chabon, J. J., Lovejoy, A. F., Newman, A. M., Stehr, H., Azad, T. D., Khodadoust, M. S., Esfahani, M. S., Liu, C. L., Zhou, L., Scherer, F., Kurtz, D. M., Say, C., Carter, J. N., Merriott, D. J., Dudley, J. C., Binkley, M. S., Modlin, L., Padda, S. K., Gensheimer, M. F., West, R. B., Shrager, J. B., Neal, J. W., Wakelee, H. A., Loo, B. W., Alizadeh, A. A., Diehn, M. 2017


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

    View details for DOI 10.1158/2159-8290.CD-17-0716

    View details for PubMedID 28899864

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


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

    View details for DOI 10.1073/pnas.1608461113

    View details for Web of Science ID 000391090800003

    View details for PubMedID 27956614

    View details for PubMedCentralID PMC5206556

  • Video-assisted thoracoscopic diaphragm plication using a running suture technique is durable and effective. journal of thoracic and cardiovascular surgery Demos, D. S., Berry, M. F., Backhus, L. M., Shrager, J. B. 2016


    Surgeons have hesitated to adopt minimally invasive diaphragm plication techniques because of technical limitations rendering the procedure cumbersome or leading to early failure or reduced efficacy. We sought to demonstrate efficacy and durability of our thoracoscopic plication technique using a single running suture.We retrospectively reviewed patients who underwent our technique for diaphragm plication since 2008. We used a single, buttressed, double-layered, to-and-fro running suture with additional plicating horizontal mattress sutures as needed.Eighteen patients underwent thoracoscopic plication from 2008 to 2015. There were no operative mortalities and 2 unrelated late deaths. Median hospital stay was 3 days (range, 1-12). Atrial fibrillation occurred in 1 patient (5.5%), pneumonia occurred in 2 patients (11%), reintubation occurred in 1 patient (5.5%), and ileus occurred in 1 patient (5.5%). Of 14 patients with complete follow-up, median follow-up was 29.4 months (range, 3.4-84.7). Significant increases between preoperative and postoperative pulmonary function tests (% predicted values) were found for mean forced expiratory volume in 1 second (73.5% ± 3.5% to 88.8% ± 4.5%, P = .002) and mean forced vital capacity (70.6% ± 3.5% to 82.3% ± 3.5%, P = .002). Preoperative mean Baseline Dyspnea Index was 8.1 ± 0.7. Mean Transitional Dyspnea Index 6 months postoperatively was 7.1 ± 0.6 (moderate to major improvement). Transitional Dyspnea Index at last contact (median 29.4 months postoperatively) was 7.2 ± 0.6 (P = .38). Compared with previously published results, this is at least equivalent.Thoracoscopic diaphragm plication with a running suture is safe and achieves excellent early and long-term improvements. This addresses technical challenges of tying multiple interrupted sutures by video-assisted thoracoscopic surgery without any apparent compromise to efficacy or durability.

    View details for DOI 10.1016/j.jtcvs.2016.11.062

    View details for PubMedID 28087113

  • Determinants of Complete Resection of Thymoma by Minimally Invasive and Open Thymectomy: Analysis of an International Registry. Journal of thoracic oncology Burt, B. M., Yao, X., Shrager, J., Antonicelli, A., Padda, S., Reiss, J., Wakelee, H., Su, S., Huang, J., Scott, W. 2016


    Minimally invasive thymectomy (MIT) is a surgical approach to thymectomy that has more favorable short-term outcomes for myasthenia gravis than open thymectomy (OT). The oncologic outcomes of MIT performed for thymoma have not been rigorously evaluated. We analyzed determinants of complete (R0) resection among patients undergoing MIT and OT in a large international database.The retrospective database of the International Thymic Malignancy Interest Group was queried. Chi-square and Wilcoxon rank sum tests, multivariate logistic regression models, and propensity matching were performed.A total of 2514 patients underwent thymectomy for thymoma between 1997 and 2012; 2053 of them (82%) underwent OT and 461 (18%) underwent MIT, with the use of MIT increasing significantly in recent years. The rate of R0 resection among patients undergoing OT was 86%, and among those undergoing MIT it was 94% (p < 0.0001). In propensity-matched MIT and OT groups (n = 266 in each group); however, the rate of R0 resection did not differ significantly (96% in both the MIT and OT groups, p = 0.7). Multivariate analyses were performed to identify determinants of R0 resection. Factors independently associated with R0 resection were geographical region, later time period, less advanced Masaoka stage, total thymectomy, and the absence of radiotherapy. Surgical approach, whether minimally invasive or open, was not associated with completeness of resection.The use of MIT for resection of thymoma has been increasing substantially over time, and MIT can achieve rates of R0 resection for thymoma similar to those achieved with OT.

    View details for DOI 10.1016/j.jtho.2016.08.131

    View details for PubMedID 27566187

  • An artificial niche preserves the quiescence of muscle stem cells and enhances their therapeutic efficacy. Nature biotechnology Quarta, M., Brett, J. O., DiMarco, R., de Morree, A., Boutet, S. C., Chacon, R., Gibbons, M. C., Garcia, V. A., Su, J., Shrager, J. B., Heilshorn, S., Rando, T. A. 2016; 34 (7): 752-759


    A promising therapeutic strategy for diverse genetic disorders involves transplantation of autologous stem cells that have been genetically corrected ex vivo. A major challenge in such approaches is a loss of stem cell potency during culture. Here we describe an artificial niche for maintaining muscle stem cells (MuSCs) in vitro in a potent, quiescent state. Using a machine learning method, we identified a molecular signature of quiescence and used it to screen for factors that could maintain mouse MuSC quiescence, thus defining a quiescence medium (QM). We also engineered muscle fibers that mimic the native myofiber of the MuSC niche. Mouse MuSCs maintained in QM on engineered fibers showed enhanced potential for engraftment, tissue regeneration and self-renewal after transplantation in mice. An artificial niche adapted to human cells similarly extended the quiescence of human MuSCs in vitro and enhanced their potency in vivo. Our approach for maintaining quiescence may be applicable to stem cells isolated from other tissues.

    View details for DOI 10.1038/nbt.3576

    View details for PubMedID 27240197

    View details for PubMedCentralID PMC4942359

  • Concordant and Discordant EGFR Mutations in Patients With Multifocal Adenocarcinomas: Implications for EGFR-Targeted Therapy. Clinical therapeutics Chuang, J. C., Shrager, J. B., Wakelee, H. A., Neal, J. W. 2016; 38 (7): 1567-1576


    Adenocarcinoma remains the most common subtype of lung cancer in the United States. Most patients present with tumors that are invasive and often metastatic, but in some patients, multiple precursor in situ or minimally invasive adenocarcinoma tumors develop that can be synchronous and metachronous. These precursor lesions harbor the same spectrum of genetic mutations found in purely invasive adenocarcinomas, such as EGFR, KRAS, and p53 mutations. It is less clear, however, whether separate lesions in patients who present with multifocal disease share common underlying genetic driver mutations.Here we review the relevant literature on molecular driver alterations in adenocarcinoma precursor lesions. We then report 4 patients with multifocal EGFR mutant adenocarcinomas in whom we performed molecular testing on 2 separate lesions.In 2 of these patients, the mutations are concordant, and in 2 patients, the mutations are discordant. A review of the literature demonstrates increasing evidence that lesions with discordant mutations may confer a more favorable prognosis because they are unlikely to represent metastases.Our findings suggest that the emergence of the dominant EGFR driver alteration is often independent between lesions in patients with multifocal adenocarcinomas, and thus the same targeted therapy may not be effective for all lesions. However, genetic testing of multiple lesions can help to distinguish separate primary tumors from metastatic disease.

    View details for DOI 10.1016/j.clinthera.2016.06.005

    View details for PubMedID 27368115

    View details for PubMedCentralID PMC4985173

  • Invited Commentary. Annals of thoracic surgery Shrager, J. 2016; 101 (6): 2146-2147

    View details for DOI 10.1016/j.athoracsur.2016.01.034

    View details for PubMedID 27211933

  • Integrated digital error suppression for improved detection of circulating tumor DNA NATURE BIOTECHNOLOGY Newman, A. M., Lovejoy, A. F., Klass, D. M., Kurtz, D. M., Chabon, J. J., Scherer, F., Stehr, H., Liu, C. L., Bratman, S. V., Say, C., Zhou, L., Carter, J. N., West, R. B., Sledge, G. W., Shrager, J. B., Loo, B. W., Neal, J. W., Wakelee, H. A., Diehn, M., Alizadeh, A. A. 2016; 34 (5): 547-555


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

    View details for DOI 10.1038/nbt.3520

    View details for Web of Science ID 000375735000036

    View details for PubMedID 27018799

    View details for PubMedCentralID PMC4907374

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


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

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

    View details for Web of Science ID 000372776500001

    View details for PubMedCentralID PMC4791793

  • CRISPR/Cas-mediated genome editing to treat EGFR-mutant lung cancer: apersonalized molecular surgical therapy EMBO MOLECULAR MEDICINE Tang, H., Shrager, J. B. 2016; 8 (2): 83-85
  • Diameter of Solid Tumor Component Alone Should be Used to Establish T Stage in Lung Adenocarcinoma ANNALS OF SURGICAL ONCOLOGY Burt, B. M., Leung, A. N., Yanagawa, M., Chen, W., Groth, S. S., Hoang, C. D., Nair, V. S., Shrager, J. B. 2015; 22: S1318-S1323
  • Pruritus as a Paraneoplastic Symptom of Thymoma JOURNAL OF THORACIC ONCOLOGY Padda, S. K., Shrager, J. B., Riess, J. W., Pagtama, J. Y., Tisch, A. J., Kwong, B. Y., Liang, Y., Schwartz, E. J., Loo, B. W., Neal, J. W., Hardy, R., Wakelee, H. A. 2015; 10 (11): E110-E112

    View details for DOI 10.1097/JTO.0000000000000623

    View details for Web of Science ID 000363312300001

    View details for PubMedID 26536199

    View details for PubMedCentralID PMC4720251

  • The Prevention and Management of Air Leaks Following Pulmonary Resection. Thoracic surgery clinics Burt, B. M., Shrager, J. B. 2015; 25 (4): 411-419

    View details for DOI 10.1016/j.thorsurg.2015.07.002

    View details for PubMedID 26515941

  • Ex Vivo Expansion and In Vivo Self-Renewal of Human Muscle Stem Cells STEM CELL REPORTS Charville, G. W., Cheung, T. H., Yoo, B., Santos, P. J., Lee, G. K., Shrager, J. B., Rando, T. A. 2015; 5 (4): 621-632


    Adult skeletal muscle stem cells, or satellite cells (SCs), regenerate functional muscle following transplantation into injured or diseased tissue. To gain insight into human SC (huSC) biology, we analyzed transcriptome dynamics by RNA sequencing of prospectively isolated quiescent and activated huSCs. This analysis indicated that huSCs differentiate and lose proliferative potential when maintained in high-mitogen conditions ex vivo. Further analysis of gene expression revealed that p38 MAPK acts in a transcriptional network underlying huSC self-renewal. Activation of p38 signaling correlated with huSC differentiation, while inhibition of p38 reversibly prevented differentiation, enabling expansion of huSCs. When transplanted, expanded huSCs differentiated to generate chimeric muscle and engrafted as SCs in the sublaminar niche with a greater frequency than freshly isolated cells or cells cultured without p38 inhibition. These studies indicate characteristics of the huSC transcriptome that promote expansion ex vivo to allow enhanced functional engraftment of a defined population of self-renewing huSCs.

    View details for DOI 10.1016/j.stemcr.2015.08.004

    View details for Web of Science ID 000364990900015

    View details for PubMedID 26344908

    View details for PubMedCentralID PMC4624935

  • Failure to Isolate the Right Lung with an EZ-Blocker. A & A case reports Obaidi, R. A., O'Hear, K. E., Kulkarni, V. N., Brodsky, J. B., Shrager, J. B. 2014; 3 (8): 110-111

    View details for DOI 10.1213/XAA.0000000000000056

    View details for PubMedID 25611759

  • Lung Volume Reduction After Stereotactic Ablative Radiation Therapy of Lung Tumors: Potential Application to Emphysema INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS Binkley, M. S., Shrager, J. B., Leung, A. N., Popat, R., Trakul, N., Atwood, T. F., Chaudhuri, A., Maxim, P. G., Diehn, M., Loo, B. W. 2014; 90 (1): 216-223


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

    View details for DOI 10.1016/j.ijrobp.2014.05.025

    View details for Web of Science ID 000341456500029

  • Circulating Tumor Microemboli Diagnostics for Patients with Non-Small-Cell Lung Cancer JOURNAL OF THORACIC ONCOLOGY Carlsson, A., Nair, V. S., Luttgen, M. S., Keu, K. V., Horng, G., Vasanawala, M., Kolatkar, A., Jamali, M., Iagaru, A. H., Kuschner, W., Loo, B. W., Shrager, J. B., Bethel, K., Hoh, C. K., Bazhenova, L., Nieva, J., Kuhn, P., Gambhir, S. S. 2014; 9 (8): 1111-1119


    Circulating tumor microemboli (CTM) are potentially important cancer biomarkers, but using them for cancer detection in early-stage disease has been assay limited. We examined CTM test performance using a sensitive detection platform to identify stage I non-small-cell lung cancer (NSCLC) patients undergoing imaging evaluation.First, we prospectively enrolled patients during 18F-FDG PET-CT imaging evaluation for lung cancer that underwent routine phlebotomy where CTM and circulating tumor cells (CTCs) were identified in blood using nuclear (DAPI), cytokeratin (CK), and CD45 immune-fluorescent antibodies followed by morphologic identification. Second, CTM and CTC data were integrated with patient (age, gender, smoking, and cancer history) and imaging (tumor diameter, location in lung, and maximum standard uptake value [SUVmax]) data to develop and test multiple logistic regression models using a case-control design in a training and test cohort followed by cross-validation in the entire group.We examined 104 patients with NSCLC, and the subgroup of 80 with stage I disease, and compared them to 25 patients with benign disease. Clinical and imaging data alone were moderately discriminating for all comers (Area under the Curve [AUC] = 0.77) and by stage I disease only (AUC = 0.77). However, the presence of CTM combined with clinical and imaging data was significantly discriminating for diagnostic accuracy in all NSCLC patients (AUC = 0.88, p value = 0.001) and for stage I patients alone (AUC = 0.87, p value = 0.002).CTM may add utility for lung cancer diagnosis during imaging evaluation using a sensitive detection platform.

    View details for Web of Science ID 000340138700012

    View details for PubMedID 25157764

  • Thoracoscopic lobectomy is associated with acceptable morbidity and mortality in patients with predicted postoperative forced expiratory volume in 1 second or diffusing capacity for carbon monoxide less than 40% of normal. journal of thoracic and cardiovascular surgery Burt, B. M., Kosinski, A. S., Shrager, J. B., Onaitis, M. W., Weigel, T. 2014; 148 (1): 19-?


    A predicted postoperative (ppo) forced expiratory volume in 1 second (FEV1%) or diffusing capacity of the lung for carbon monoxide (DLCO%) of <40% has traditionally been considered to convey a high risk of lobectomy owing to elevated postoperative morbidity and mortality. These recommendations, however, were largely derived from the pre-video-assisted thoracoscopic surgical (VATS) era. We hypothesized that VATS lobectomy would be associated with acceptable morbidity and mortality at ppoFEV1% and ppoDLCO% values < 40%.PpoFEV1% and ppoDLCO% were calculated for patients undergoing open or VATS lobectomy for lung cancer in the Society of Thoracic Surgeons General Thoracic database from 2009 to 2011. Univariate comparisons, multivariate analyses, and 1:1 propensity matching were performed.A total of 13,376 patients underwent lobectomy (50.9% open, 49.1% VATS). A decreased ppoFEV1% and ppoDLCO% were each independent predictors for both cardiopulmonary complications and mortality in the open group (all P ≤ .008). In the VATS group, ppoFEV1% was an independent predictor of complications (P = .001) but not mortality (P = .77), and ppoDLCO% was an independent predictor of complications (P = .046) and mortality (P = .008). With decreasing ppoFEV1% or ppoDLCO%, complications and mortality increased at a greater rate in the open lobectomy than in a propensity-matched VATS group (n = 4215 each). For patients with ppoFEV1% < 40%, mortality was greater in the open (4.8%) than in the matched VATS group (0.7%, P = .003). Similar results were seen for ppoDLCO% < 40% (5.2% open, 2.0% VATS, P = .003). The rate of complications was significantly greater at ppoFEV1% < 40% in the open (21.9%) than in the matched VATS (12.8%, P = .005) group and similar results were seen with ppoDLCO% < 40% (14.9% open, 10.4% VATS, P = .016).VATS lobectomy can be performed with acceptable rates of morbidity and mortality in patients with reduced ppoFEV1% or ppoDLCO%.

    View details for DOI 10.1016/j.jtcvs.2014.03.007

    View details for PubMedID 24766848

  • Malignant pleural mesothelioma and the Society of Thoracic Surgeons Database: an analysis of surgical morbidity and mortality. journal of thoracic and cardiovascular surgery Burt, B. M., Cameron, R. B., Mollberg, N. M., Kosinski, A. S., Schipper, P. H., Shrager, J. B., Vigneswaran, W. T. 2014; 148 (1): 30-35


    To date, reported surgical morbidity and mortality for pleurectomy/decortication and extrapleural pneumonectomy performed for malignant pleural mesothelioma primarily represent the experience of a few specialized centers. For comparison, we examined early outcomes of pleurectomy/decortication and extrapleural pneumonectomy from a broader group of centers/surgeons participating in the Society of Thoracic Surgeons-General Thoracic Database.All patients in the Society of Thoracic Surgeons-General Thoracic Database (version 2.081, representing 2009-2011) who underwent pleurectomy/decortication or extrapleural pneumonectomy for malignant pleural mesothelioma were identified. Patient characteristics, morbidity, mortality, center volume, and procedure were examined using univariable and multivariable analyses.A total of 225 patients underwent pleurectomy/decortication (n = 130) or extrapleural pneumonectomy (n = 95) for malignant pleural mesothelioma at 48 centers. Higher volumes of procedures (≥5/y) were performed at 3 pleurectomy/decortication and 2 extrapleural pneumonectomy centers. Patient characteristics were statistically equivalent between pleurectomy/decortication and extrapleural pneumonectomy groups, except those undergoing extrapleural pneumonectomy were younger (63.2 ± 7.8 years vs 68.3 ± 9.5 years; P < .001) and more likely to have received preoperative chemotherapy (30.1% vs 17.8%; P = .036). Major morbidity was greater after extrapleural pneumonectomy, including acute respiratory distress syndrome (8.4% vs 0.8%; P = .005), reintubation (14.7% vs 2.3%; P = .001), unexpected reoperation (9.5% vs 1.5%; P = .01), and sepsis (4.2% vs 0%; P = .03), as was mortality (10.5% vs 3.1%; P = .03). Multivariate analyses revealed that extrapleural pneumonectomy was an independent predictor of major morbidity or mortality (odds ratio, 6.51; P = .001). Compared with high-volume centers, increased acute respiratory distress syndrome was seen in low-volume centers performing extrapleural pneumonectomy (0% vs 12.5%; P = .05).Extrapleural pneumonectomy is associated with greater morbidity and mortality compared with pleurectomy/decortication when performed by participating surgeons of the Society of Thoracic Surgeons-General Thoracic Database. Effects of center volume require further study.

    View details for DOI 10.1016/j.jtcvs.2014.03.011

    View details for PubMedID 24726744

  • A Meta-analysis of Lung Cancer Gene Expression Identifies PTK7 as a Survival Gene in Lung Adenocarcinoma. Cancer research Chen, R., Khatri, P., Mazur, P. K., Polin, M., Zheng, Y., Vaka, D., Hoang, C. D., Shrager, J., Xu, Y., Vicent, S., Butte, A. J., Sweet-Cordero, E. A. 2014; 74 (10): 2892-2902


    Lung cancer remains the most common cause of cancer-related death worldwide and it continues to lack effective treatment. The increasingly large and diverse public databases of lung cancer gene expression constitute a rich source of candidate oncogenic drivers and therapeutic targets. To define novel targets for lung adenocarcinoma, we conducted a large-scale meta-analysis of genes specifically overexpressed in adenocarcinoma. We identified an 11-gene signature that was overexpressed consistently in adenocarcinoma specimens relative to normal lung tissue. Six genes in this signature were specifically overexpressed in adenocarcinoma relative to other subtypes of non-small cell lung cancer (NSCLC). Among these genes was the little studied protein tyrosine kinase PTK7. Immunohistochemical analysis confirmed that PTK7 is highly expressed in primary adenocarcinoma patient samples. RNA interference-mediated attenuation of PTK7 decreased cell viability and increased apoptosis in a subset of adenocarcinoma cell lines. Further, loss of PTK7 activated the MKK7-JNK stress response pathway and impaired tumor growth in xenotransplantation assays. Our work defines PTK7 as a highly and specifically expressed gene in adenocarcinoma and a potential therapeutic target in this subset of NSCLC. Cancer Res; 74(10); 2892-902. ©2014 AACR.

    View details for DOI 10.1158/0008-5472.CAN-13-2775

    View details for PubMedID 24654231

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


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

    View details for DOI 10.1038/nm.3519

    View details for Web of Science ID 000335710700028

  • An ultrasensitive method for quantitating circulating tumor DNA with broad patient coverage. Nature medicine Newman, A. M., Bratman, S. V., To, J., Wynne, J. F., Eclov, N. C., Modlin, L. A., Liu, C. L., Neal, J. W., Wakelee, H. A., Merritt, R. E., Shrager, J. B., Loo, B. W., Alizadeh, A. A., Diehn, M. 2014; 20 (5): 548-554


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

    View details for DOI 10.1038/nm.3519

    View details for PubMedID 24705333

  • Accuracy of Fluorodeoxyglucose-Positron Emission Tomography Within the Clinical Practice of the American College of Surgeons Oncology Group Z4031 Trial to Diagnose Clinical Stage I Non-Small Cell Lung Cancer ANNALS OF THORACIC SURGERY Grogan, E. L., Deppen, S. A., Ballman, K. V., Andrade, G. M., Verdial, F. C., Aldrich, M. C., Chen, C. L., Decker, P. A., Harpole, D. H., Cerfolio, R. J., Keenan, R. J., Jones, D. R., D'Amico, T. A., Shrager, J. B., Meyers, B. F., Putnam, J. B. 2014; 97 (4): 1142-1148


    Fluorodeoxyglucose-positron emission tomography (FDG-PET) is recommended for diagnosis and staging of non-small cell lung cancer (NSCLC). Meta-analyses of FDG-PET diagnostic accuracy demonstrated sensitivity of 96% and specificity of 78% but were performed in select centers, introducing potential bias. This study evaluates the accuracy of FDG-PET to diagnose NSCLC and examines differences across enrolling sites in the national American College of Surgeons Oncology Group (ACOSOG) Z4031 trial.Between 2004 and 2006, 959 eligible patients with clinical stage I (cT1-2 N0 M0) known or suspected NSCLC were enrolled in the Z4031 trial, and with a baseline FDG-PET available for 682. Final diagnosis was determined by pathologic examination. FDG-PET avidity was categorized into avid or not avid by radiologist description or reported maximum standard uptake value. FDG-PET diagnostic accuracy was calculated for the entire cohort. Accuracy differences based on preoperative size and by enrolling site were examined.Preoperative FDG-PET results were available for 682 participants enrolled at 51 sites in 39 cities. Lung cancer prevalence was 83%. FDG-PET sensitivity was 82% (95% confidence interval, 79 to 85) and specificity was 31% (95% confidence interval, 23% to 40%). Positive and negative predictive values were 85% and 26%, respectively. Accuracy improved with lesion size. Of 80 false-positive scans, 69% were granulomas. False-negative scans occurred in 101 patients, with adenocarcinoma being the most frequent (64%), and 11 were 10 mm or less. The sensitivity varied from 68% to 91% (p=0.03), and the specificity ranged from 15% to 44% (p=0.72) across cities with more than 25 participants.In a national surgical population with clinical stage I NSCLC, FDG-PET to diagnose lung cancer performed poorly compared with published studies.

    View details for DOI 10.1016/j.athoracsur.2013.12.043

    View details for Web of Science ID 000333810300015

    View details for PubMedID 24576597

  • Prevention and management of postoperative air leaks. Annals of cardiothoracic surgery Burt, B. M., Shrager, J. B. 2014; 3 (2): 216-218
  • Chronic cutaneous chest wall fistula and gallstone empyema due to retained gallstones. BMJ case reports Gaster, R. S., Berger, A. J., Ahmadi-Kashani, M., Shrager, J. B., Lee, G. K. 2014; 2014


    We report a case of a 72-year-old man who presented with a persistent pleural effusion and painful abscess in the right lower chest wall 6 months following a laparoscopic cholecystectomy. The patient subsequently developed a chronic cutaneous chest wall fistula requiring a large resection and complex closure. The complication was likely secondary to intraoperative spillage of gallstones. While previous reports describe gallstone spillage in the abdominal cavity as benign, this case illustrates that stones left in the abdominal cavity can potentially lead to significant morbidity. Therefore, stones should be diligently removed from the abdominal cavity when spillage occurs. In addition, it is important that operative notes reflect the occurrence of stone spillage so stones may be suspected when a patient presents with an abdominal or thoracic infection following a cholecystectomy.

    View details for DOI 10.1136/bcr-2013-010159

    View details for PubMedID 25123567

  • miR-1 Induces Growth Arrest and Apoptosis in Malignant Mesothelioma CHEST Xu, Y., Zheng, M., Merritt, R. E., Shrager, J. B., Wakelee, H. A., Kratzke, R. A., Hoang, C. D. 2013; 144 (5): 1632-1643


    We investigated microRNA expression profiles of malignant pleural mesothelioma (MPM) specimens to identify novel microRNA that are potentially involved in the oncogenic transformation of human pleural cells.microRNA microarray transcriptional profiling studies of 25 MPM primary tumors were performed. We used normal pleural from an unmatched patient cohort as normal comparators. To confirm microarray data, we used real-time quantitative PCR. Representative cell lines H513 and H2052 were used in functional analyses of microRNA-1.In addition to several novel MPM-associated microRNAs, we observed that the expression level of microRNA-1 was significantly lower in tumors as compared to normal pleural specimens. Subsequently, pre-mir of microRNA-1 was introduced into MPM cell lines to overexpress this microRNA. Phenotypic changes of these altered cells were assayed. The cellular proliferation rate was significantly inhibited after overexpression of microRNA-1. Early and late apoptosis was increased markedly in microRNA-1-transfected cell lines. Taken together, these data suggested that overexpression of microRNA-1 induced apoptosis in these MPM cell lines, acting as a tumor suppressor. We confirmed our observations by assessing in the transduced MPM cells cell cycle-related genes, pro-apoptotic and anti-apoptotic genes, which all showed coordinated, significant changes characteristic of the apoptotic phenotype.Thus, further investigation and validation of our microRNA database of MPM may elucidate previously unrecognized molecular pathways and/ or mechanisms by identifying novel microRNAs that are involved in malignant transformation. Our study has now found microRNA-1 to be one of these MPM-associated microRNAs, with potential pathogenic and therapeutic significance.

    View details for DOI 10.1378/chest.12-2770

    View details for Web of Science ID 000327143700033

    View details for PubMedID 23828229

  • Lymph Node Evaluation Achieved by Open Lobectomy Compared With Thoracoscopic Lobectomy for N0 Lung Cancer ANNALS OF THORACIC SURGERY Merritt, R. E., Hoang, C. D., Shrager, J. B. 2013; 96 (4): 1171-1177


    Controversy remains regarding the adequacy of the lymph node evaluation achieved by video-assisted thoracic surgery (VATS) lobectomy for lung cancer. This study compared the completeness of the lymph node dissection or sampling for patients undergoing lobectomy by open thoracotomy vs VATS for clinical N0 lung cancer.This study was a retrospective review of 129 patients who underwent lobectomy for clinical N0 lung carcinoma from December 2008 to January 2012.Lobectomy was an open procedure in 69 patients (53.5%) and by VATS in 60 (46.5%). The VATS and open groups were well matched for age (p = 0.50) and forced expiratory volume in 1 second percentage predicted (p = 0.16). The mean pathologic tumor sizes were not significantly different (2.9 ± 0.26 vs 3.4 ± 0.25 cm, respectively; p = 0. 14). The mean number of nodes dissected in the open group was significantly higher (14.7 ± 1.3 vs. 9.9 ± 0.8 nodes; p = 0.003). In the open lobectomy group, 24.6% of the patients were upstaged to pathologic N1 or N2 compared with 10% in the VATS group (p = 0.05). The Kaplan-Meier 3-year survival was similar between the groups.In our hands, significantly more lymph nodes were dissected, and a higher percentage of patients were upstaged to N1/N2, during open lobectomy compared with VATS lobectomy in patients with clinical stage N0 lung cancer. Although this did not translate into improved survival at 3 years, concern is raised about the adequacy of lymph node dissection during VATS lobectomy.

    View details for DOI 10.1016/j.athoracsur.2013.05.04

    View details for Web of Science ID 000325156800016

    View details for PubMedID 23915591

  • Sequential bilateral lung isolation with a single bronchial blocker. A & A case reports Brodsky, J. B., Tzabazis, A., Basarb-Tung, J., Shrager, J. B. 2013; 1 (1): 17-18


    Sequential bilateral lung separation and selective lung collapse can be accomplished with either a double-lumen tube, a single bronchial blocker (BB) that must be repositioned during the operation, or by using 2 BBs, 1 placed in each main bronchus. We provided sequential bilateral lung collapse using a single BB without the need to reposition during surgery.

    View details for DOI 10.1097/ACC.0b013e318291d364

    View details for PubMedID 25611606

  • Liquid chromatography/mass spectrometry methods for measuring dipeptide abundance in non-small-cell lung cancer. Rapid communications in mass spectrometry : RCM Wu, M., Xu, Y., Fitch, W. L., Zheng, M., Merritt, R. E., Shrager, J. B., Zhang, W., Dill, D. L., Peltz, G., Hoang, C. D. 2013; 27 (18): 2091-2098


    Metabolomic profiling is a promising methodology of identifying candidate biomarkers for disease detection and monitoring. Although lung cancer is among the leading causes of cancer-related mortality worldwide, the lung tumor metabolome has not been fully characterized.We utilized a targeted metabolomic approach to analyze discrete groups of related metabolites. We adopted a dansyl [5-(dimethylamino)-1-naphthalene sulfonamide] derivatization with liquid chromatography/mass spectrometry (LC/MS) to analyze changes of metabolites from paired tumor and normal lung tissues. Identification of dansylated dipeptides was confirmed with synthetic standards. A systematic analysis of retention times was required to reliably identify isobaric dipeptides. We validated our findings in a separate sample cohort.We produced a database of the LC retention times and MS/MS spectra of 361 dansyl dipeptides. Interpretation of the spectra is presented. Using this standard data, we identified a total of 279 dipeptides in lung tumor tissue. The abundance of 90 dipeptides was selectively increased in lung tumor tissue compared to normal tissue. In a second set of validation tissues, 12 dipeptides were selectively increased.A systematic evaluation of certain metabolite classes in lung tumors may identify promising disease-specific metabolites. Our database of all possible dipeptides will facilitate ongoing translational applications of metabolomic profiling as it relates to lung cancer. Copyright © 2013 John Wiley & Sons, Ltd.

    View details for DOI 10.1002/rcm.6656

    View details for PubMedID 23943330

    View details for PubMedCentralID PMC3755500

  • Diaphragm muscle atrophy in the mouse after long-term mechanical ventilation MUSCLE & NERVE Tang, H., Lee, M., Khuong, A., Wright, E., Shrager, J. B. 2013; 48 (2): 272-278


    Mechanical ventilation (MV) is a life-saving measure, but full ventilator support causes ventilator-induced diaphragm atrophy (VIDA). Previous studies of VIDA have relied on human biopsies or a rat model. If MV can induce diaphragm atrophy in mice, then mechanistic study of VIDA could be explored via genetic manipulation.We show that 18 hours of MV in mice results in a 15% loss of diaphragm weight and a 17% reduction in fiber cross-sectional area. Important catabolic cascades are activated in this mouse model: transcription of the ubiquitin ligases, atrogin and MuRF1, and the apoptotic marker, Bim, are increased; the marker of autophagy, LC3, is induced at the protein level and shows a punctate distribution in diaphragm muscle fibers.This mouse model recapitulates the key pathophysiological findings of other models of VIDA, and it will enable the genetic manipulation required to fully explore the mechanisms underlying this important process.

    View details for DOI 10.1002/mus.23748

    View details for Web of Science ID 000322158500017

    View details for PubMedID 23813537

  • A Dominant Adenocarcinoma With Multifocal Ground Glass Lesions Does Not Behave as Advanced Disease Late-Breaking Clinical Trial Abstract Session at the 49th Annual Meeting of the Society-of-Thoracic-Surgeons Gu, B., Burt, B. M., Merritt, R. E., Stephanie, S., Nair, V., Hoang, C. D., Shrager, J. B. ELSEVIER SCIENCE INC. 2013: 411–18


    Invasive lung adenocarcinomas increasingly present with synchronous, multifocal, in situ lesions that appear as ground glass opacities (GGOs). The optimal approach in this circumstance (often nonsmokers) remains unclear. We evaluated a general strategy of anatomic resection of the dominant tumor (DT) and wedge resection of accessible ipsilateral GGOs.This is a retrospective review of 39 patients with suspected multifocal in situ adenocarcinomas and 1 DT in a predominantly Caucasian population. Mean follow-up is 30.7 months.Forty-nine percent of patients had no or minimal smoking history; 21% were Asian. The resected DT was pathologically "bronchioloalveolar carcinoma" (26%), minimally invasive adenocarcinoma (5%), adenocarcinoma with bronchioloalveolar features (41%), or moderate well-differentiated adenocarcinoma (28%). The p stage of the DT was IA in 20, IB in 15, and IIA in 4, with mean diameter of 2.6 cm. Thirty-two patients (82%) underwent anatomic resection of the DT; 7 (18%) underwent wedge resection. The mean number of GGOs present initially was 2.7 (range, 1 to 7) with a 5.2-mm mean diameter. An unresected nodule increased in size during follow-up in only 9 patients (23%). The mean diameter growth among these was 3.2 mm, with mean doubling time of 49 months. New GGOs (range, 1 to 8) developed in 16 patients (41%), all of which remained at 7 mm or less. Distant metastasis developed in 2 patients (5.2%); only 1 patient has required intervention for progression of a GGO. The overall survival is 100%.Patients with limited, multifocal, in situ adenocarcinomas and a clinical N0 DT enjoy prolonged survival with generally anatomic resection of the DT and wedge resection of accessible GGOs. These patients should not be considered to harbor T4 or M1a disease.

    View details for DOI 10.1016/j.athoracsur.2013.04.048

    View details for Web of Science ID 000323177800015

    View details for PubMedID 23806231

  • A Rare Population of CD24(+)ITGB4(+)Notch(hi) Cells Drives Tumor Propagation in NSCLC and Requires Notch3 for Self-Renewal CANCER CELL Zheng, Y., de la Cruz, C. C., Sayles, L. C., Alleyne-Chin, C., Vaka, D., Knaak, T. D., Bigos, M., Xu, Y., Hoang, C. D., Shrager, J. B., Fehling, H. J., French, D., Forrest, W., Jiang, Z., Carano, R. A., Barck, K. H., Jackson, E. L., Sweet-Cordero, E. A. 2013; 24 (1): 59-74


    Sustained tumor progression has been attributed to a distinct population of tumor-propagating cells (TPCs). To identify TPCs relevant to lung cancer pathogenesis, we investigated functional heterogeneity in tumor cells isolated from Kras-driven mouse models of non-small-cell lung cancer (NSCLC). CD24(+)ITGB4(+)Notch(hi) cells are capable of propagating tumor growth in both a clonogenic and an orthotopic serial transplantation assay. While all four Notch receptors mark TPCs, Notch3 plays a nonredundant role in tumor cell propagation in two mouse models and in human NSCLC. The TPC population is enriched after chemotherapy, and the gene signature of mouse TPCs correlates with poor prognosis in human NSCLC. The role of Notch3 in tumor propagation may provide a therapeutic target for NSCLC.

    View details for DOI 10.1016/j.ccr.2013.05.021

    View details for Web of Science ID 000321604000010

    View details for PubMedID 23845442

  • An Observational Study of Circulating Tumor Cells and F-18-FDG PET Uptake in Patients with Treatment-Naive Non-Small Cell Lung Cancer PLOS ONE Nair, V. S., Keu, K. V., Luttgen, M. S., Kolatkar, A., Vasanawala, M., Kuschner, W., Bethel, K., Iagaru, A. H., Hoh, C., Shrager, J. B., Loo, B. W., Bazhenova, L., Nieva, J., Gambhir, S. S., Kuhn, P. 2013; 8 (7)


    We investigated the relationship of circulating tumor cells (CTCs) in non-small cell lung cancer (NSCLC) with tumor glucose metabolism as defined by (18)F-fluorodeoxyglucose (FDG) uptake since both have been associated with patient prognosis.We performed a retrospective screen of patients at four medical centers who underwent FDG PET-CT imaging and phlebotomy prior to a therapeutic intervention for NSCLC. We used an Epithelial Cell Adhesion Molecule (EpCAM) independent fluid biopsy based on cell morphology for CTC detection and enumeration (defined here as High Definition CTCs or "HD-CTCs"). We then correlated HD-CTCs with quantitative FDG uptake image data calibrated across centers in a cross-sectional analysis.We assessed seventy-one NSCLC patients whose median tumor size was 2.8 cm (interquartile range, IQR, 2.0-3.6) and median maximum standardized uptake value (SUVmax) was 7.2 (IQR 3.7-15.5). More than 2 HD-CTCs were detected in 63% of patients, whether across all stages (45 of 71) or in stage I disease (27 of 43). HD-CTCs were weakly correlated with partial volume corrected tumor SUVmax (r = 0.27, p-value = 0.03) and not correlated with tumor diameter (r = 0.07; p-value = 0.60). For a given partial volume corrected SUVmax or tumor diameter there was a wide range of detected HD-CTCs in circulation for both early and late stage disease.CTCs are detected frequently in early-stage NSCLC using a non-EpCAM mediated approach with a wide range noted for a given level of FDG uptake or tumor size. Integrating potentially complementary biomarkers like these with traditional patient data may eventually enhance our understanding of clinical, in vivo tumor biology in the early stages of this deadly disease.

    View details for DOI 10.1371/journal.pone.0067733

    View details for Web of Science ID 000321425300025

    View details for PubMedID 23861795

    View details for PubMedCentralID PMC3702496

  • Approach to the patient with multiple lung nodules. Thoracic surgery clinics Shrager, J. B. 2013; 23 (2): 257-266


    It can be difficult to determine whether a patient with more than a single, "solid" lung nodule suspicious for malignancy is suffering from synchronous primary tumors or intrapulmonary metastasis. For this reason, if resection can be performed an aggressive approach is often warranted after demonstrating no mediastinal nodal disease. Increasing evidence suggests that the survival of a patient with a single, invasive lepidic-predominant adenocarcinoma depends on the stage of the invasive tumor, not on the presumed multiple in situ tumors. A suggested clinical approach to each of these types of multifocal tumors, solid and lepidic, is proposed in this article.

    View details for DOI 10.1016/j.thorsurg.2013.01.004

    View details for PubMedID 23566977

  • Determinants of time to opioid cessation post-surgery Ruchelli, G., Clay, D., Schmidt, P., Humphreys, K., Trafton, J., Dirbas, F., Giori, N., Goodman, S., Hoang, C., Huddleston, J., Maloney, W., Merritt, R., Miller, M., Shrager, J., Whyte, R., Mackey, S., Carroll, I. CHURCHILL LIVINGSTONE. 2013: S18–S18
  • An observational study of circulating tumor cells and (18)F-FDG PET uptake in patients with treatment-naive non-small cell lung cancer. PloS one Nair, V. S., Keu, K. V., Luttgen, M. S., Kolatkar, A., Vasanawala, M., Kuschner, W., Bethel, K., Iagaru, A. H., Hoh, C., Shrager, J. B., Loo, B. W., Bazhenova, L., Nieva, J., Gambhir, S. S., Kuhn, P. 2013; 8 (7)


    We investigated the relationship of circulating tumor cells (CTCs) in non-small cell lung cancer (NSCLC) with tumor glucose metabolism as defined by (18)F-fluorodeoxyglucose (FDG) uptake since both have been associated with patient prognosis.We performed a retrospective screen of patients at four medical centers who underwent FDG PET-CT imaging and phlebotomy prior to a therapeutic intervention for NSCLC. We used an Epithelial Cell Adhesion Molecule (EpCAM) independent fluid biopsy based on cell morphology for CTC detection and enumeration (defined here as High Definition CTCs or "HD-CTCs"). We then correlated HD-CTCs with quantitative FDG uptake image data calibrated across centers in a cross-sectional analysis.We assessed seventy-one NSCLC patients whose median tumor size was 2.8 cm (interquartile range, IQR, 2.0-3.6) and median maximum standardized uptake value (SUVmax) was 7.2 (IQR 3.7-15.5). More than 2 HD-CTCs were detected in 63% of patients, whether across all stages (45 of 71) or in stage I disease (27 of 43). HD-CTCs were weakly correlated with partial volume corrected tumor SUVmax (r = 0.27, p-value = 0.03) and not correlated with tumor diameter (r = 0.07; p-value = 0.60). For a given partial volume corrected SUVmax or tumor diameter there was a wide range of detected HD-CTCs in circulation for both early and late stage disease.CTCs are detected frequently in early-stage NSCLC using a non-EpCAM mediated approach with a wide range noted for a given level of FDG uptake or tumor size. Integrating potentially complementary biomarkers like these with traditional patient data may eventually enhance our understanding of clinical, in vivo tumor biology in the early stages of this deadly disease.

    View details for DOI 10.1371/journal.pone.0067733

    View details for PubMedID 23861795

  • Cross-Species Functional Analysis of Cancer-Associated Fibroblasts Identifies a Critical Role for CLCF1 and IL-6 in Non-Small Cell Lung Cancer In Vivo CANCER RESEARCH Vicent, S., Sayles, L. C., Vaka, D., Khatri, P., Gevaert, O., Chen, R., Zheng, Y., Gillespie, A. K., Clarke, N., Xu, Y., Shrager, J., Hoang, C. D., Plevritis, S., Butte, A. J., Sweet-Cordero, E. A. 2012; 72 (22): 5744-5756


    Cancer-associated fibroblasts (CAF) have been reported to support tumor progression by a variety of mechanisms. However, their role in the progression of non-small cell lung cancer (NSCLC) remains poorly defined. In addition, the extent to which specific proteins secreted by CAFs contribute directly to tumor growth is unclear. To study the role of CAFs in NSCLCs, a cross-species functional characterization of mouse and human lung CAFs was conducted. CAFs supported the growth of lung cancer cells in vivo by secretion of soluble factors that directly stimulate the growth of tumor cells. Gene expression analysis comparing normal mouse lung fibroblasts and mouse lung CAFs identified multiple genes that correlate with the CAF phenotype. A gene signature of secreted genes upregulated in CAFs was an independent marker of poor survival in patients with NSCLC. This secreted gene signature was upregulated in normal lung fibroblasts after long-term exposure to tumor cells, showing that lung fibroblasts are "educated" by tumor cells to acquire a CAF-like phenotype. Functional studies identified important roles for CLCF1-CNTFR and interleukin (IL)-6-IL-6R signaling in promoting growth of NSCLCs. This study identifies novel soluble factors contributing to the CAF protumorigenic phenotype in NSCLCs and suggests new avenues for the development of therapeutic strategies.

    View details for DOI 10.1158/0008-5472.CAN-12-1097

    View details for Web of Science ID 000311141300012

    View details for PubMedID 22962265

  • Oxidative stress-responsive microRNA-320 regulates glycolysis in diverse biological systems FASEB JOURNAL Tang, H., Lee, M., Sharpe, O., Salamone, L., Noonan, E. J., Hoang, C. D., Levine, S., Robinson, W. H., Shrager, J. B. 2012; 26 (11): 4710-4721


    Glycolysis is the initial step of glucose catabolism and is up-regulated in cancer cells (the Warburg Effect). Such shifts toward a glycolytic phenotype have not been explored widely in other biological systems, and the molecular mechanisms underlying the shifts remain unknown. With proteomics, we observed increased glycolysis in disused human diaphragm muscle. In disused muscle, lung cancer, and H(2)O(2)-treated myotubes, we show up-regulation of the rate-limiting glycolytic enzyme muscle-type phosphofructokinase (PFKm, >2 fold, P<0.05) and accumulation of lactate (>150%, P<0.05). Using microRNA profiling, we identify miR-320a as a regulator of PFKm expression. Reduced miR-320a levels (to ∼50% of control, P<0.05) are associated with the increased PFKm in each of these diverse systems. Manipulation of miR-320a levels both in vitro and in vivo alters PFKm and lactate levels in the expected directions. Further, miR-320a appears to regulate oxidative stress-induced PFKm expression, and reduced miR-320a allows greater induction of glycolysis in response to H(2)O(2) treatment. We show that this microRNA-mediated regulation occurs through PFKm's 3' untranslated region and that Ets proteins are involved in the regulation of PFKm via miR-320a. These findings suggest that oxidative stress-responsive microRNA-320a may regulate glycolysis broadly within nature.

    View details for DOI 10.1096/fj.11-197467

    View details for Web of Science ID 000310574200031

    View details for PubMedID 22767230

    View details for PubMedCentralID PMC3475252

  • Indications for Surgery in Patients with Localized Pulmonary Infection THORACIC SURGERY CLINICS Merritt, R. E., Shrager, J. B. 2012; 22 (3): 325-?


    Nowadays, antibiotic and antifungal therapy is effective in treating some of the infections that can involve the lung parenchyma in a localized manner, such as bacterial abscess and infection with nonresistant tuberculosis strains. However, other localized pulmonary infections, for example aspergilloma and mucormycosis, are highly resistant to nonsurgical therapy, and in these diseases there are no generally successful options that do not include surgical resection. This article reviews the indications for surgical intervention in the treatment of common infections involving the lung, and also focuses on the general approaches to their management.

    View details for DOI 10.1016/j.thorsurg.2012.05.005

    View details for Web of Science ID 000311863900007

    View details for PubMedID 22789596

  • Prognostic PET F-18-FDG Uptake Imaging Features Are Associated with Major Oncogenomic Alterations in Patients with Resected Non-Small Cell Lung Cancer CANCER RESEARCH Nair, V. S., Gevaert, O., Davidzon, G., Napel, S., Graves, E. E., Hoang, C. D., Shrager, J. B., Quon, A., Rubin, D. L., Plevritis, S. K. 2012; 72 (15): 3725-3734


    Although 2[18F]fluoro-2-deoxy-d-glucose (FDG) uptake during positron emission tomography (PET) predicts post-surgical outcome in patients with non-small cell lung cancer (NSCLC), the biologic basis for this observation is not fully understood. Here, we analyzed 25 tumors from patients with NSCLCs to identify tumor PET-FDG uptake features associated with gene expression signatures and survival. Fourteen quantitative PET imaging features describing FDG uptake were correlated with gene expression for single genes and coexpressed gene clusters (metagenes). For each FDG uptake feature, an associated metagene signature was derived, and a prognostic model was identified in an external cohort and then tested in a validation cohort of patients with NSCLC. Four of eight single genes associated with FDG uptake (LY6E, RNF149, MCM6, and FAP) were also associated with survival. The most prognostic metagene signature was associated with a multivariate FDG uptake feature [maximum standard uptake value (SUV(max)), SUV(variance), and SUV(PCA2)], each highly associated with survival in the external [HR, 5.87; confidence interval (CI), 2.49-13.8] and validation (HR, 6.12; CI, 1.08-34.8) cohorts, respectively. Cell-cycle, proliferation, death, and self-recognition pathways were altered in this radiogenomic profile. Together, our findings suggest that leveraging tumor genomics with an expanded collection of PET-FDG imaging features may enhance our understanding of FDG uptake as an imaging biomarker beyond its association with glycolysis.

    View details for DOI 10.1158/0008-5472.CAN-11-3943

    View details for Web of Science ID 000307354100004

    View details for PubMedID 22710433

    View details for PubMedCentralID PMC3596510

  • Invited commentary. Annals of thoracic surgery Shrager, J. B. 2012; 94 (1): 240-?

    View details for DOI 10.1016/j.athoracsur.2012.04.029

    View details for PubMedID 22734987

  • Prophylaxis and Management of Atrial Fibrillation After General Thoracic Surgery THORACIC SURGERY CLINICS Merritt, R. E., Shrager, J. B. 2012; 22 (1): 13-?


    Atrial fibrillation (AF) commonly affects patients after general thoracic surgery. Postoperative AF increases hospital stay and charges. Effective prophylaxis and treatment is the goal. Calcium channel blockers prevent postoperative AF. Beta blockers are a less viable choice. Amiodarone prophylaxis should be avoided in patients with pulmonary dysfunction or who require pneumonectomy. In management of AF, a brief trial of rate-control agents is appropriate; however, chemical cardioversion with rhythm-control agents should be instituted after 24 hours. High-risk patients with history of stroke or transient ischemic attack, or with two or more risk factors for thromboembolism should receive anticoagulation therapy.

    View details for DOI 10.1016/j.thorsurg.2011.08.016

    View details for Web of Science ID 000311863600003

    View details for PubMedID 22108684

  • Invited commentary. Annals of thoracic surgery Shrager, J. B. 2011; 92 (6): 2005-2006

    View details for DOI 10.1016/j.athoracsur.2011.08.004

    View details for PubMedID 22115210

  • Morbidity and Mortality After Esophagectomy Following Neoadjuvant Chemoradiation ANNALS OF THORACIC SURGERY Merritt, R. E., Whyte, R. I., D'Arcy, N. T., Hoang, C. D., Shrager, J. B. 2011; 92 (6): 2034-2040


    Neoadjuvant chemoradiation (CRT) is an accepted treatment for locally advanced esophageal carcinoma. A survival benefit has not been definitively established, and there is concern that chemoradiation may increase postoperative morbidity and mortality.A retrospective review was made of 138 patients treated for esophageal carcinoma between January 1999 and December 2009. Fifty-four patients who underwent CRT followed by esophagectomy were compared with 84 patients who underwent esophagectomy alone.The chemoradiation and esophagectomy alone cohorts were well matched on all preoperative variables. There was a higher percentage of Ivor Lewis procedures in the esophagectomy alone cohort (82.0%) compared with the CRT cohort (59.3%; p = 0.006). Thirty-five percent of the CRT group underwent transhiatal esophagectomy. Thirty-day mortality was 6.0% (5 of 84) in the esophagectomy alone cohort compared with 1.9% (1 of 54) in the CRT cohort (p = 0.5). Similarly, mean intensive care unit stay (4.7 versus 6.5 days; p = 0.5), ventilator time (2.4 versus 4.2 days; p = 0.5), and length of stay (13.5 versus 17 days; p = 0.2) did not differ significantly between the groups. The overall major complication rates were similar in the CRT and esophagectomy alone cohorts: 57.4% versus 56% (p = 0.98). Multivariate analysis determined that coronary artery disease (p = 0.01; odds ratio 3.5) and transthoracic esophagectomy (p = 0.05; odds ratio 1.4) were predictive of development of postoperative complications. Only cervical anastomotic location (p = 0.04; odds ratio 3.0) was predictive of anastomotic leak on multivariate analysis.Neoadjuvant chemoradiation does not appear to increase postoperative morbidity or mortality after esophagectomy. Major postoperative complications are associated with the transthoracic approach and preoperative coronary artery disease.

    View details for DOI 10.1016/j.athoracsur.2011.05.121

    View details for Web of Science ID 000297333300023

    View details for PubMedID 21945223

  • Intrinsic apoptosis in mechanically ventilated human diaphragm: linkage to a novel Fos/FoxO1/Stat3-Bim axis FASEB JOURNAL Tang, H., Lee, M., Budak, M. T., Pietras, N., Hittinger, S., Vu, M., Khuong, A., Hoang, C. D., Hussain, S. N., Levine, S., Shrager, J. B. 2011; 25 (9): 2921-2936


    Mechanical ventilation (MV) is a life-saving measure in many critically ill patients. However, prolonged MV results in diaphragm dysfunction that contributes to the frequent difficulty in weaning patients from the ventilator. The molecular mechanisms underlying ventilator-induced diaphragm dysfunction (VIDD) remain poorly understood. We report here that MV induces myonuclear DNA fragmentation (3-fold increase; P<0.01) and selective activation of caspase 9 (P<0.05) and Bcl2-interacting mediator of cell death (Bim; 2- to 7-fold increase; P<0.05) in human diaphragm. MV also statistically significantly down-regulates mitochondrial gene expression and induces oxidative stress. In cultured muscle cells, we show that oxidative stress activates each of the catabolic pathways thought to underlie VIDD: apoptotic (P<0.05), proteasomal (P<0.05), and autophagic (P<0.01). Further, silencing Bim expression blocks (P<0.05) oxidative stress-induced apoptosis. Overlapping the gene expression profiles of MV human diaphragm and H₂O₂-treated muscle cells, we identify Fos, FoxO1, and Stat3 as regulators of Bim expression as well as of expression of the catabolic markers atrogin and LC3. We thus identify a novel Fos/FoxO1/Stat3-Bim intrinsic apoptotic pathway and establish the centrality of oxidative stress in the development of VIDD. This information may help in the design of specific drugs to prevent this condition.

    View details for DOI 10.1096/fj.11-183798

    View details for Web of Science ID 000294435200008

    View details for PubMedID 21597002

    View details for PubMedCentralID PMC3157683

  • Benign emptying of the postpneumonectomy space. Annals of thoracic surgery Merritt, R. E., Reznik, S. I., DaSilva, M. C., Sugarbaker, D. J., Whyte, R. I., Donahue, D. M., Hoang, C. D., Smythe, W. R., Shrager, J. B. 2011; 92 (3): 1076-1081


    A fall in the postpneumonectomy fluid level is considered a sign of bronchopleural fistula (BPF) requiring surgical intervention. We have discovered however that in rare asymptomatic patients, this event may not require aggressive surgical treatment.After seeing a case of benign emptying of the postpneumonectomy space (BEPS), we surveyed 28 surgeons to determine its incidence and characteristics.Forty-four cases of BEPS were reported by 23 survey respondents. Among 7 fully documented cases from 4 institutions, we defined the following criteria: the patient must be asymptomatic (no fever, white cell count elevation, or fluid expectoration), negative culture results if fluid sampled (patient not receiving antibiotics), no BPF at bronchoscopy or ventilation scintigraphy scan (or both), and recovery without drainage, or retrospective assessment that the intervention was unnecessary. BEPS occurred between 5 days and 152 days after pneumonectomy (6 cases right pneumonectomy and 1 case left pneumonectomy). Four patients underwent no treatment, 1 patient underwent thoracoscopic exploration (sterile) and closure after antibiotic irrigation, 1 patient underwent thoracoscopic exploration alone, and 1 patient underwent open window thoracostomy (sterile) with eventual closure. In all 7 patients (except the patient who underwent the open window procedure) the space refilled within 8 weeks; no patient experienced a subsequent empyema/BPF. Four patients who met the initial criteria for BEPS went on to experience empyema. The incidence of BEPS appears related to pneumonectomy volume, particularly extrapleural pneumonectomy. Using surgeon volume assumptions, the incidence of BEPS is 0.65%.To our knowledge, BEPS is a previously unreported occurrence. We hypothesize that it results from postoperative intrapleural pressure shifts, with or without a microscopic BPF, that drive fluid out of the pleural space while failing to cause contamination. Awareness of BEPS' existence may allow surgeons to safely avoid open drainage procedures occasionally in patients who experience an asymptomatic fall in fluid level.

    View details for DOI 10.1016/j.athoracsur.2011.04.082

    View details for PubMedID 21871304

  • Consensus definitions to promote an evidence-based approach to management of the pleural space. A collaborative proposal by ESTS, AATS, STS, and GTSC EUROPEAN JOURNAL OF CARDIO-THORACIC SURGERY Brunelli, A., Beretta, E., Cassivi, S. D., Cerfolio, R. J., Detterbeck, F., Kiefer, T., Miserocchi, G., Shrager, J., Singhal, S., Van raemdonck, D., Varela, G. 2011; 40 (2): 291-297


    The present project involved a collective effort agreed by the European Society of Thoracic Surgeons, the American Association for Thoracic Surgery, the Society of Thoracic Surgeons, and the General Thoracic Surgery Club to assemble a joint panel of experts to review the available data and address ambiguous aspects of chest tube definitions and nomenclature. The task force was composed of 11 invited participants, identified for their expertise in the area of chest tube management. The subject was divided in different topics, which were in turn assigned to at least two experts. The draft reports written by the experts on each topic were distributed to the entire expert panel, and comments solicited in advance of the meetings. During the meetings, the drafts were reviewed, discussed, and agreed on by the entire panel. Standardized definitions and nomenclature were proposed for the following topics related to chest tube management: pleural and respiratory mechanics after pulmonary resection; external suction versus no external suction; fixed versus variable suction; objective air leak evaluation; objective fluid drainage evaluation; and chest drain: type, number, and size. A standardized set of definitions and nomenclature were proposed to set a scientifically based framework with which to evaluate existing studies and to more clearly formulate questions, parameters, and outcomes for future studies.

    View details for DOI 10.1016/j.ejcts.2011.05.020

    View details for Web of Science ID 000292690200010

    View details for PubMedID 21757129

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


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

    View details for DOI 10.1097/JTO.0b013e31821517db

    View details for Web of Science ID 000289554100012

    View details for PubMedID 21774104

  • Improved Survival after Pulmonary Metastasectomy for Soft Tissue Sarcoma JOURNAL OF THORACIC ONCOLOGY Predina, J. D., Puc, M. M., Bergey, M. R., Sonnad, S. S., Kucharczuk, J. C., Staddon, A., Kaiser, L. R., Shrager, J. B. 2011; 6 (5): 913-919


    Survival after pulmonary metastasectomy for soft tissue sarcoma (STS) has been lower than in osteosarcoma (14-40% versus 40-50%). With improved patient selection criteria and advanced chemotherapy agents, we hypothesized that survival after metastasectomy for STS has improved in recent years.Retrospective study of 48 patients undergoing pulmonary metastasectomy for STS between 1995 and 2007. Potential predictors of overall survival and disease-free survival (DFS) were examined using the log-rank test or Cox regression. Multivariate analysis was conducted using Cox regression.Overall survival after initial metastasectomy was 67% and 52% at 3 and 5 years, respectively; DFS was 17% and 10% at 3 and 5 years. Univariate analysis indicated that ≤2 pulmonary metastases (p = 0.03), diameter of largest metastasis ≤2 cm (p = 0.09), and the absence of extrapulmonary metastases (p = 0.10) were associated with longer overall survival. Absence of extrapulmonary metastases (p = 0.07) and smaller size of the largest pulmonary metastasis (p = 0.06) were associated with longer DFS. Before 2001, 46.7% of patients received adjuvant chemotherapy versus 72.7% after (p = 0.10). Neither use of chemotherapy nor chemotherapy type was related to overall survival or DFS.Five-year overall survival is substantially higher after pulmonary metastasectomy for STS in our study relative to previously published results (52% versus 14-40%). This improvement does not seem to be the result of greater use of, or newer, chemotherapeutic regimens. Among potential explanations, improved patient selection is the most likely factor.

    View details for DOI 10.1097/JTO.0b013e3182106f5c

    View details for Web of Science ID 000289554100011

    View details for PubMedID 21750417

  • Increased Proteolysis, Myosin Depletion, and Atrophic AKT-FOXO Signaling in Human Diaphragm Disuse AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE Levine, S., Biswas, C., Dierov, J., Barsotti, R., Shrager, J. B., Taitan Nguyen, N., Sonnad, S., Kucharchzuk, J. C., Kaiser, L. R., Singhal, S., Budak, M. T. 2011; 183 (4): 483-490


    Patients on mechanical ventilation who exhibit diaphragm inactivity for a prolonged time (case subjects) develop decreases in diaphragm force-generating capacity accompanied by diaphragm myofiber atrophy.Our objectives were to test the hypotheses that increased proteolysis by the ubiquitin-proteasome pathway, decreases in myosin heavy chain (MyHC) levels, and atrophic AKT-FOXO signaling play major roles in eliciting these pathological changes associated with diaphragm disuse.Biopsy specimens were obtained from the costal diaphragms of 18 case subjects before harvest (cases) and compared with intraoperative specimens from the diaphragms of 11 patients undergoing surgery for benign lesions or localized lung cancer (control subjects). Case subjects had diaphragm inactivity and underwent mechanical ventilation for 18 to 72 hours, whereas this state in controls was limited to 2 to 4 hours.With respect to proteolysis in cytoplasm fractions, case diaphragms exhibited greater levels of ubiquitinated-protein conjugates, increased activity of the 26S proteasome, and decreased levels of MyHCs and α-actin. With respect to atrophic signaling in nuclear fractions, case diaphragms exhibited decreases in phosphorylated AKT, phosphorylated FOXO1, increased binding to consensus DNA sequence for Atrogin-1 and MuRF-1, and increased supershift of DNA-FOXO1 complexes with specific antibodies against FOXO1, as well as increased Atrogin-1 and MuRF-1 transcripts in whole myofiber lysates.Our findings suggest that increased activity of the ubiquitin-proteasome pathway, marked decreases in MyHCs, and atrophic AKT-FOXO signaling play important roles in eliciting the myofiber atrophy and decreases in diaphragm force generation associated with prolonged human diaphragm disuse.

    View details for DOI 10.1164/200910-1487OC

    View details for Web of Science ID 000287568500012

    View details for PubMedID 20833824

  • Invited commentary. Annals of thoracic surgery Shrager, J. B. 2010; 90 (6): 1785-?

    View details for DOI 10.1016/j.athoracsur.2010.07.061

    View details for PubMedID 21095310

  • Should buttresses and sealants be used to manage pulmonary parenchymal air leaks? JOURNAL OF THORACIC AND CARDIOVASCULAR SURGERY Singhal, S., Shrager, J. B. 2010; 140 (6): 1220-1225

    View details for DOI 10.1016/j.jtcvs.2010.06.039

    View details for Web of Science ID 000284149200003

    View details for PubMedID 20951389

  • Should asymptomatic enlarged thymus glands be resected? JOURNAL OF THORACIC AND CARDIOVASCULAR SURGERY Singla, S., Litzky, L. A., Kaiser, L. R., Shrager, J. B. 2010; 140 (5): 977-983


    Patients frequently have an "enlarged thymus" incidentally identified on imaging. We sought to determine whether thymectomy is appropriate in patients with diffusely enlarged thymus glands.A retrospective review was conducted of patients undergoing thymectomy without myasthenia gravis at 1 institution over 15 years.Of 117 patients undergoing thymectomy, 109 patients had complete data. Thirty-six had a gland judged by the surgeon to be diffusely enlarged, and 73 had a discrete mass. Of the 36 diffusely enlarged thymus glands, 18 (50%) occurred in patients with no symptoms referable to the thymus. No patient (0/18; 0%) with an asymptomatic diffusely enlarged thymus gland had a pathologic diagnosis that would have required resection (8 normal; 10 "hyperplasia"). Of the 18 symptomatic patients with diffusely enlarged glands, 4 (22.2%) harbored lymphoma, but none harbored thymoma or other tumor (P < .05; symptomatic vs asymptomatic). Of the 73 patients with discrete masses, 45 (61.6%) were symptomatic, and both the symptomatic and asymptomatic patients had a high rate of pathologic diagnoses that represented an indication for resection (53.3% and 42.8%, respectively, harbored thymoma or other tumor). Of the 25 (of 109) patients initially having a diagnosis of thymic hyperplasia, only 3 (12%) had true follicular hyperplasia on re-review of the pathologic condition. Interestingly, an autoimmune disorder developed in 2 (67%) of these 3 patients on long-term follow-up.Asymptomatic patients with diffusely enlarged thymus glands can be followed up expectantly because they have a negligible incidence of significant thymic disease; symptomatic patients with diffusely enlarged thymus glands may have lymphoma, so biopsy is appropriate. Half of patients with a discrete mass have tumors requiring resection; imaging advances would be useful to better differentiate among patients within this group.

    View details for DOI 10.1016/j.jtcvs.2010.08.005

    View details for Web of Science ID 000283057600017

    View details for PubMedID 20951248

  • Evidence-based suggestions for management of air leaks. Thoracic surgery clinics Merritt, R. E., Singhal, S., Shrager, J. B. 2010; 20 (3): 435-448


    The management of postoperative alveolar air leaks (AALs) continues to challenge thoracic surgeons. AALs increase length of stay and health care costs, and likely lead to other postoperative complications. Staple line buttresses, topical sealants, pleural tents, pneumoperitoneum, and modifications of traditional chest tube management (ie, reduced suction) have all been proposed to help reduce AAL. However, the cost of some of the commercial products being marketed may outweigh their relative effectiveness, and some of these techniques and products have not been adequately studied to date. This article provides a review of the available evidence-based literature that addresses the efficacy of the options currently available to prevent and manage AALs. Management suggestions based on this literature are presented.

    View details for DOI 10.1016/j.thorsurg.2010.03.005

    View details for PubMedID 20619236

  • Mediastinoscopy: Still the Gold Standard 2nd International Biannual Minimally Invasive Thoracic Surgery Summit Shrager, J. B. ELSEVIER SCIENCE INC. 2010: S2084–S2089


    Endobronchial ultrasound (EBUS-TBNA) is emerging as an alternative to mediastinoscopy for mediastinal lymph node evaluation in non-small cell lung cancer. It remains controversial whether EBUS-TBNA is as accurate as mediastinoscopy. Sensitivity appears similar to mediastinoscopy with enlarged nodes, but lower with normal-sized nodes. The false negative rate appears higher than with mediastinoscopy, so nonmalignant EBUS results may be unreliable. Two flawed studies examining costs identify a very small cost benefit to EBUS, which we will question herein. There are scenarios in which EBUS is preferable to mediastinoscopy. However, for routine staging of the upper mediastinum in non-small cell lung cancer, the benefits of EBUS over mediastinoscopy remain unproven.

    View details for DOI 10.1016/j.athoracsur.2010.02.098

    View details for Web of Science ID 000277934200086

    View details for PubMedID 20493986

  • METABOLOMIC PROFILING OF LUNG ADENOCARCINOMA Hoang, C. D., Wu, M., Xu, Y., Peltz, G., Merritt, R., Whyte, R., Shrager, J. LIPPINCOTT WILLIAMS & WILKINS. 2010: S51–S52
  • Adjuvant Cisplatin and Docetaxel for Non-small Cell Lung Cancer The Hospital of the University of Pennsylvania Experience JOURNAL OF THORACIC ONCOLOGY Weiss, J., Eaby, B., Stevenson, J., Kucharczuk, J., Cooper, J., Kaiser, L., Shrager, J., Rengan, R., Langer, C., Evans, T. 2010; 5 (5): 667-672


    Cisplatin and docetaxel (Doc) are commonly used for adjuvant therapy for non-small cell lung cancer based on extrapolation from the metastatic setting. Nevertheless, essentially no data have been published on this regimen in the adjuvant context, leading to controversy, particularly surrounding feasibility.Using a tumor database augmented with chart reviews, we retrospectively evaluated treatment outcomes of all patients receiving postoperative cisplatin (75 mg/m) and Doc (75 mg/m) between August 2003 and November 2008. During this period, this regimen was considered to be the first choice regimen for sufficiently fit patients at the University of Pennsylvania.The database captured 54 patients. Overall, 85.2% received all four planned cycles (83.3% at full dose). Chart review allowed definitive assessment of toxicity in 47 patients. A single patient (2%) died of grade 5 febrile neutropenia. There was no grade 4 toxicity, and 8.5% experienced grade 3 febrile neutropenia. No febrile neutropenia was observed in 26 patients given prophylactic peg-filgrastim. The incidence was 23.8% in the 21 patients not given peg-filgrastim during the first cycle; 6.4% each experienced grade 3 gastritis, anorexia, nausea, and fatigue, and 2.1% experienced grade 3 diarrhea. Median progression-free survival was 17.9 months, and median overall survival has not been reached.Cisplatin and Doc are feasible in the adjuvant setting with superior dose delivery and convenience compared with historic data with cisplatin and vinorelbine.

    View details for DOI 10.1097/JTO.0b013e3181d409f9

    View details for Web of Science ID 000277038200013

    View details for PubMedID 20234321

  • MULTIPLE MICRORNA ARE DYSREGULATED IN MESOTHELIOMA Hoang, C. D., Xu, Y., Zheng, M., Peltz, G., Shrager, J., Kratzke, R. LIPPINCOTT WILLIAMS & WILKINS. 2010: S105–S106
  • Management of Alveolar Air Leaks After Pulmonary Resection ANNALS OF THORACIC SURGERY Singhal, S., Ferraris, V. A., Bridges, C. R., Clough, E. R., Mitchell, J. D., Fernando, H. C., Shrager, J. B. 2010; 89 (4): 1327-1335


    Air leaks are a common problem after pulmonary resection and can be a source of significant morbidity and mortality. Air leaks are associated with prolonged hospital stays, and infectious and cardiopulmonary complications, and they occasionally require reoperation. Despite reasonably robust literature on the topic, the optimal approaches to manage postoperative air leaks remain controversial. We used available literature and expert consensus to formulate suggestions regarding the preferred approaches to both routine and prolonged alveolar air leaks. This review summarizes our findings.

    View details for DOI 10.1016/j.athoracsur.2009.09.020

    View details for Web of Science ID 000275885800068

    View details for PubMedID 20338378

  • Early outcomes after bilateral thoracoscopy versus median sternotomy for lung volume reduction. Innovations (Philadelphia, Pa.) Puc, M. M., Sonnad, S. S., Shrager, J. B. 2010; 5 (2): 97-102


    : A National Emphysema Treatment Trial subanalysis, although finally describing outcomes as "comparable," suggested that bilateral lung volume reduction surgery (LVRS) by video-assisted thoracoscopic surgery (VATS) may be slightly less morbid than by median sternotomy (MS). We report a single surgeon experience using both the MS and VATS approaches to provide additional information on this issue in a setting of uniform patient selection and perioperative management. Our hypothesis was that a VATS approach would provide equivalent or less morbidity than MS despite being applied to a group of patients subjectively selected to be higher risk than those undergoing MS.: Consecutive patients over a 9-year period underwent LVRS by one surgeon by either MS or VATS in a nonrandomized fashion. Thoracoscopy was selected over MS primarily when the surgeon estimated a greater overall risk profile and thus a greater chance of morbidity/mortality in a particular patient.: There were 15 patients in the VATS group and 35 in the MS group. In terms of measures of risk profile, there were no differences between the groups that met statistical significance, but several values trended toward higher risk within the VATS group (eg, age, 63 VATS vs. 59 MS, P = 0.08; moderate pulmonary hypertension, 38% VATS vs. 14% MS, P = 0.11; and residual volume, 241% VATS vs. 226% MS, P = 0.32). With regard to outcomes, operative time was significantly longer in the VATS group (VATS = 155 minutes vs. MS=129 minutes, P = 0.01). All other outcomes, including the incidence of major complications (13.3% VATS vs. 17.1% MS, P = 0.39), were similar between the groups. There was a single death within 90 days (1.9% of entire series; 2.9% of MS group).: In this series, although patients undergoing LVRS by VATS tended to have a higher risk profile, their outcomes were no worse than in those undergoing LVRS by MS. This suggests that the VATS approach to bilateral LVRS may incur slightly less morbidity and thus may be the best option in the most compromised patients who is nonetheless felt will benefit from LVRS.

    View details for DOI 10.1097/IMI.0b013e3181d9277d

    View details for PubMedID 22437355

  • The Society of Thoracic Surgeons Practice Guideline Series: Guidelines for the Management of Barrett's Esophagus With High-Grade Dysplasia ANNALS OF THORACIC SURGERY Fernando, H. C., Murthy, S. C., Hofstetter, W., Shrager, J. B., Bridges, C., Mitchell, J. D., Landreneau, R. J., Clough, E. R., Watson, T. J. 2009; 87 (6): 1993-2002


    The management of Barrett's esophagus with high-grade dysplasia is controversial. The standard of care has traditionally been esophagectomy. However, a number of treatment options aimed at esophageal preservation are increasingly being utilized by many centers. These esophageal-sparing approaches include endoscopic surveillance, mucosal ablation, and endoscopic mucosal resection. In this guideline we review the best evidence supporting these commonly used strategies for high-grade dysplasia to better define management and guide future investigation.

    View details for DOI 10.1016/j.athoracsur.2009.04.032

    View details for Web of Science ID 000266234900072

    View details for PubMedID 19463651

  • Intraoperative and postoperative management of air leaks in patients with emphysema. Thoracic surgery clinics Shrager, J. B., DeCamp, M. M., Murthy, S. C. 2009; 19 (2): 223-?


    Air leaks after pulmonary surgery represent a substantial clinical problem. When they persist beyond a few days, air leaks appear to increase complications and costs. Clearly, emphysema patients are those at greatest risk for developing problematic air leaks. This article, after reviewing what is known about the epidemiology and clinical significance of air leaks, discusses the various techniques that may be employed to avoid the development of problematic air leaks and to manage them when they do occur. It reviews the data available on newer and more traditional options for the prophylaxis and management of air leaks and offers the authors' opinions about the optimal approaches in various clinical situations.

    View details for DOI 10.1016/j.thorsurg.2009.02.004

    View details for PubMedID 19662965

  • Thymoma ANNALS OF THORACIC SURGERY Shrager, J. B. 2009; 87 (1): 339-341
  • Thoracoscopic total parietal pleurectomy for primary spontaneous pneumothorax ANNALS OF THORACIC SURGERY Nathan, D. P., Taylor, N. E., Low, D. W., Raymond, D., Shrager, J. B. 2008; 85 (5): 1825-1827


    Although the management of spontaneous pneumothorax through a thoracotomy traditionally included apical pleurectomy, thoracoscopic treatment of this problem does not generally include pleurectomy. Thoracoscopy in fact allows excellent exposure to perform total parietal pleurectomy, and we hypothesize that including total pleurectomy will reduce recurrences. We describe here the technique of thoracoscopic total parietal pleurectomy and the early outcomes afterward.

    View details for DOI 10.1016/j.athoracsur.2007.11.043

    View details for Web of Science ID 000255319900064

    View details for PubMedID 18442607

  • Rapid disuse atrophy of diaphragm fibers in mechanically ventilated humans NEW ENGLAND JOURNAL OF MEDICINE Levine, S., Nguyen, T., Taylor, N., Friscia, M. E., Budak, M. T., Rothenberg, P., Zhu, J., Sachdeva, R., Sonnad, S., Kaiser, L. R., Rubinstein, N. A., Powers, S. K., Shrager, J. B. 2008; 358 (13): 1327-1335


    The combination of complete diaphragm inactivity and mechanical ventilation (for more than 18 hours) elicits disuse atrophy of myofibers in animals. We hypothesized that the same may also occur in the human diaphragm.We obtained biopsy specimens from the costal diaphragms of 14 brain-dead organ donors before organ harvest (case subjects) and compared them with intraoperative biopsy specimens from the diaphragms of 8 patients who were undergoing surgery for either benign lesions or localized lung cancer (control subjects). Case subjects had diaphragmatic inactivity and underwent mechanical ventilation for 18 to 69 hours; among control subjects diaphragmatic inactivity and mechanical ventilation were limited to 2 to 3 hours. We carried out histologic, biochemical, and gene-expression studies on these specimens.As compared with diaphragm-biopsy specimens from controls, specimens from case subjects showed decreased cross-sectional areas of slow-twitch and fast-twitch fibers of 57% (P=0.001) and 53% (P=0.01), respectively, decreased glutathione concentration of 23% (P=0.01), increased active caspase-3 expression of 100% (P=0.05), a 200% higher ratio of atrogin-1 messenger RNA (mRNA) transcripts to MBD4 (a housekeeping gene) (P=0.002), and a 590% higher ratio of MuRF-1 mRNA transcripts to MBD4 (P=0.001).The combination of 18 to 69 hours of complete diaphragmatic inactivity and mechanical ventilation results in marked atrophy of human diaphragm myofibers. These findings are consistent with increased diaphragmatic proteolysis during inactivity.

    View details for Web of Science ID 000254308400003

    View details for PubMedID 18367735

  • Early changes of lung function and structure in an elastase model of emphysema - a hyperpolarized He-3 MRI study JOURNAL OF APPLIED PHYSIOLOGY Emami, K., Cadman, R. V., Woodburn, J. M., Fischer, M. C., Kadlecek, S. J., Zhu, J., Pickup, S., Guyer, R. A., Law, M., Vahdat, V., Friscia, M. E., Ishii, M., Yu, J., Gefter, W. B., Shrager, J. B., Rizi, R. R. 2008; 104 (3): 773-786


    Early changes of lung function and structure were studied in the presence of an elastase-induced model of emphysema in 35 Sprague-Dawley rats at mild (5 U/100 g) and moderate (10 U/100 g) severities. Lung ventilation was measured on a regional basis (at a planar resolution of 3.2 mm) by hyperpolarized 3He MRI at 5 and 10 wk after model induction. Subsequent to imaging, average alveolar diameter was measured from histological slices taken from the centers of each lobe. Changes of mean fractional ventilation, mean linear intercept, and intrasubject heterogeneity of ventilation were studied during disease progression. Mean fractional ventilation was significantly different between healthy controls (0.23 +/- 0.04) and emphysematous animals at both time points in the 10-unit group (0.06 +/- 0.02 and 0.12 +/- 0.05, respectively). Changes in average alveolar diameter were not statistically observable until the 10th wk between healthy (37 +/- 10 microm) and emphysematous rats (73 +/- 25 and 95 +/- 31 microm, for 5 and 10 units, respectively). Assessment of function-structure correlation suggested that the majority of the decline in fractional ventilation occurred in the first 5 wk, while enlargement of alveolar diameters appeared primarily between the 5th and 10th wk. A thresholding metric, based on the 20th percentile of fractional ventilation over the entire lung, was utilized to detect the onset of the disease with confidence, independent of whether the regional ventilation measurements were normalized with respect to the delivered tidal volume and estimated functional residual capacity of each individual rat.

    View details for DOI 10.1152/japplphysiol.00482.2007

    View details for Web of Science ID 000253822900028

    View details for PubMedID 18063806

  • Extended transcervical thymectomy in the treatment of myasthenia gravis 11th International Conference on Myasthenia Gravis and Related Disorder Khicha, S. G., Kaiser, L. R., Shrager, J. B. WILEY-BLACKWELL. 2008: 336–343


    The ideal operative technique for thymectomy in myasthenia gravis remains controversial. Most surgeons perform thymectomy via median sternotomy, some supplementing this with an even more extensive mediastinal and cervical dissection designed to remove all areas of possible ectopic thymic tissue. We and others have advocated a transcervical approach that is less morbid and costly than sternotomy approaches. The transcervical approach allows a complete extracapsular thymic resection, but it does not address all areas of potential ectopic thymic tissue. We have published our experience with 151 extended transcervical thymectomies (TCT). At mean follow-up of 53 months (complete follow-up in 97%), Kaplan-Meier estimates of complete stable remission were 33% and 35% at 3 and 6 years. If one includes patients who became asymptomatic but remained on low dose, single-drug immunosuppression as complete remissions (CRs), then the CR rates were 43% and 45% at 3 and 6 years. Longer term (mean 83 months) follow-up of the earliest 84 patients in the series showed preserved CR rates. On multivariate analysis, only preoperative Osserman Class (group mean 2.3) was significantly associated with improved CR rate. These results were obtained with a major operative complication rate of 0.7% and minor complication rate of 6.6%, and nearly every operation was performed without the need for overnight hospital admission. We believe that these response rates following TCT are sufficiently similar to those following transsternal techniques of thymectomy to allow us to recommend this less morbid and less costly operation as an eminently reasonable choice in the surgical treatment of myasthenia gravis.

    View details for DOI 10.1196/annals.1405.006

    View details for Web of Science ID 000257139900041

    View details for PubMedID 18567885

  • Complications of video-assisted thoracoscopic lung biopsy in patients with interstitial lung disease ANNALS OF THORACIC SURGERY Kreider, M. E., Hansen-Flaschen, J., Ahmad, N. N., Rossman, M. D., Kaiser, L. R., Kucharczuk, J. C., Shrager, J. B. 2007; 83 (3): 1140-1145


    Current guidelines recommend surgical lung biopsy for diagnosis of interstitial lung diseases (ILDs) in selected patients. To shed light on the risk-benefit ratio for this recommendation, we examined the morbidity and mortality associated with video-assisted thoracoscopic surgical (VATS) lung biopsy in a group of outpatients.A retrospective cohort study was conducted of 68 consecutive ambulatory patients with radiographically apparent interstitial lung disease (ILD) referred for VATS biopsy during a 6-year period. Incidence of postoperative mortality, prolonged air leaks, pneumonias, and re-admissions were calculated. Risk factors for complications of surgery were examined.Three deaths occurred within 60 days after biopsy for a mortality rate of 4.4% (95% confidence interval [CI], 1% to 12%), and 19.1% (95% CI, 11% to 31%) experienced one or more complications of surgery. Risk factors for morbidity included preoperative dependence on oxygen therapy and pulmonary hypertension. The three patients who died had usual interstitial pneumonia on their biopsy specimen and were reintubated postoperatively for acute lung injury. Aggregation of articles published over the past 10 years reporting on surgical lung biopsy for the diagnosis of ILD yielded a postoperative mortality rate of 2% to 4.5%.VATS lung biopsy for diagnosis of ILD, even in ambulatory patients, is not an entirely benign procedure. Biopsy rarely may trigger an acute exacerbation of usual interstitial pneumonitis. The risk of postoperative complications appears to be greatest in those dependent on oxygen and those who have pulmonary hypertension. This information may be used in weighing the risk-benefit ratio of biopsy in individual patients.

    View details for DOI 10.1016/j.athoracsur.2006.10.002

    View details for Web of Science ID 000244648100037

    View details for PubMedID 17307476

  • Cytokine response is lower after lung volume reduction through bilateral thoracoscopy versus sternotomy ANNALS OF THORACIC SURGERY Friscia, M. E., Zhu, J., Kolff, J. W., Chen, Z., Kaiser, L. R., Deutschman, C. S., Shrager, J. B. 2007; 83 (1): 252-256


    Lung volume reduction surgery performed through bilateral video-assisted thoracoscopy (BVATS) was associated in the National Emphysema Treatment Trial with a statistically significant reduction in intensive care unit days, failure to wean, hospital stay, and cost, and earlier recovery compared with median sternotomy. Studies comparing other minimally invasive techniques with "open" procedures, including pulmonary lobectomy, have demonstrated reduced serum proinflammatory mediators postoperatively. We measured these levels after lung volume reduction surgery through BVATS and sternotomy.Serum cytokine levels were measured by radioimmunoassay in 9 consecutive, steroid-free patients undergoing sternotomy and lung volume reduction surgery and 6 undergoing BVATS and lung volume reduction surgery. The groups were not statistically different with respect to age, partial pressure of arterial carbon dioxide, percent forced expiratory volume in 1 second, percent residual volume, percent total lung capacity, diffusion capacity of the lung for carbon monoxide, 6-minute walk, or apical perfusion fraction. Proinflammatory interleukin 6 and interleukin 8 and antiinflammatory interleukin 10 were evaluated preoperatively and postoperatively on days 1, 4, and 5. Clinical data were prospectively collected.There were no major postoperative complications or deaths. Interleukin 6 levels were lower in the BVATS than the sternotomy group (p = 0.016 by repeated measures analysis of variance). Interleukin 8 levels were lower in the BVATS group at most postoperative time points, but there were no significant differences in interleukin 8 or interleukin 10 levels between the sternotomy and BVATS groups at any individual time point or by analysis of variance.Use of a BVATS approach to lung volume reduction surgery is associated with reduced postoperative release of proinflammatory cytokines compared with a sternotomy approach. This may account for the reduction in recovery time and some measures of postoperative morbidity seen with the BVATS approach.

    View details for DOI 10.1016/j.athoracsur.2006.08.012

    View details for Web of Science ID 000242963400041

    View details for PubMedID 17184673

  • Parasternal intercostal muscle remodeling in severe chronic obstructive pulmonary disease JOURNAL OF APPLIED PHYSIOLOGY Levine, S., Nguyen, T., Friscia, M., Zhu, J., Szeto, W., Kucharczuk, J. C., Tikunov, B. A., Rubinstein, N. A., Kaiser, L. R., Shrager, J. B. 2006; 101 (5): 1297-1302


    Studies in experimental animals indicate that chronic increases in neural drive to limb muscles elicit a fast-to-slow transformation of fiber-type proportions and myofibrillar proteins. Since neural drive to the parasternal intercostal muscles (parasternals) is chronically increased in patients with severe chronic obstructive pulmonary diseases (COPDs), we carried out the present study to test the hypothesis that the parasternals of COPD patients exhibit an increase in the proportions of both slow fibers and slow myosin heavy chains (MHCs). Accordingly, we obtained full thickness parasternal muscle biopsies from the third interspace of seven COPD patients (mean +/- SE age: 59 +/- 4 yr) and seven age-matched controls (AMCs). Fiber typing was done by immunohistochemistry, and MHC proportions were determined by SDS-PAGE followed by densitometry. COPD patients exhibited higher proportions of slow fibers than AMCs (73 +/- 4 vs. 51 +/- 3%; P < 0.01). Additionally, COPD patients exhibited higher proportions of slow MHC than AMCs (56 +/- 4 vs. 46 +/- 4%, P < 0.04). We conclude that the parasternal muscles of patients with severe COPD exhibit a fast-to-slow transformation in both fiber-type and MHC proportions. Previous workers have demonstrated that remodeling of the external intercostals, another rib cage inspiratory muscle, elicited by severe COPD is characterized by a slow-to-fast transformation in both fiber types and MHC isoform proportions. The physiological significance of this difference in remodeling between these two inspiratory rib cage muscles remains to be elucidated.

    View details for DOI 10.1152/japplphysiol.01607.2005

    View details for Web of Science ID 000242159300007

    View details for PubMedID 16777998

  • Anterior surgical approaches to the thoracic outlet JOURNAL OF THORACIC AND CARDIOVASCULAR SURGERY Marshall, M. B., Kucharczuk, J. C., Shrager, J. B., Kaiser, L. R. 2006; 131 (6): 1255-1260


    The anatomy of the thoracic outlet is complex, and the optimum surgical approach to pathologic disease at this location is controversial. Although the Dartevelle approach to the apex seems to be a safer and more direct approach, this technique has not been widely adopted in the United States. We have used this approach for pathologic disease at the thoracic outlet and modified it. Our experience is described in this article.A retrospective review was performed on all patients who underwent an anterior approach between December 1997 and May 2003.There were 42 patients who underwent anterior approaches to pathologic disease at the level of the outlet. Diagnosis included apical non-small cell lung cancers (20 patients), osteosarcoma (2 patients), spinal cord compression (5 patients), solitary metastasis (4 patients), and benign lesions (11 patients). There were 22 female and 20 male patients with ages ranging from 26 to 82 years (mean age, 54.6 years). There were 25 complications in 14 patients and 1 in-hospital death. A transmanubrial approach was used in 14 patients, the standard Dartevelle technique was used in 8 patients, and a transclavicular approach with reapproximation of the clavicle was used in 20 patients. Reapproximation failed in 5 patients (3/3 patients who underwent fixation with mini-plates and 2/17 patients with sternal wires).The anterior approach is a useful adjunct to a thoracic surgeon's armamentarium. When a transclavicular approach is optimal, division and reapproximation of the clavicle are feasible. In our experience, reapproximation with wires is superior to plates and screws.

    View details for DOI 10.1016/j.jtcvs.2006.01.044

    View details for Web of Science ID 000238023300011

    View details for PubMedID 16733154

  • Invited commentary. Annals of thoracic surgery Shrager, J. B. 2006; 81 (1): 334-?

    View details for PubMedID 16368395

  • Comparative study of subxiphoid versus video-thoracoscopic pericardial "'window" ANNALS OF THORACIC SURGERY O'Brien, P. K., Kucharczuk, J. C., Marshall, M. B., Friedberg, J. S., Chen, Z., Kaiser, L. R., Shrager, J. B. 2005; 80 (6): 2013-2019


    It remains undefined whether surgical subxiphoid drainage or thoracoscopic pericardial "window" is the optimal operative approach to pericardial effusion. We hypothesized that the true window into the pleural space created by the latter might improve the duration of freedom from recurrent effusion.We conducted a retrospective chart review of indications, preoperative and intraoperative variables, morbidity, recurrence, and survival.Fifty-six patients underwent the subxiphoid procedure and 15 underwent the thoracoscopic procedure. Echocardiographic evidence of tamponade was present before 8 of 10 thoracoscopic procedures (80%) and 43 of 56 subxiphoid procedures (81%) for which descriptions of hemodynamics were available. In addition, non-pericardial procedures were performed in 10 (67%) and 18 (32%) patients, respectively (p = 0.020). Anesthesia time was longer at thoracoscopy (117.1 +/- 32.4 vs 81.1 +/- 25.5 minutes; p < 0.001). Procedural morbidity was higher after thoracoscopy (4 [27%] vs 1 [2%]; p = 0.006), but was generally minor. Hospital mortality tended to be higher after the subxiphoid procedure (7 [13%] vs 0 [0%]; p = 0.332), but none of the deaths was procedure-related. Follow-up was complete for 65 patients (92%). Recurrence occurred in 1 thoracoscopy patient (8%) and 5 subxiphoid patients (10%) (p = 1.000). Mean time to recurrence by Kaplan-Meier analysis trends were longer after thoracoscopy (36.1 vs 11.4 months; p = 0.16), and multivariate analysis identified the thoracoscopic approach as an independent predictor of freedom from recurrence (relative risk, 0.41; p = 0.014).Operative time and minor procedural morbidity are higher with thoracoscopic pericardial window, but long-term control of effusion seemed to be better than after subxiphoid surgical drainage.

    View details for Web of Science ID 000233926800006

    View details for PubMedID 16305836

  • Pain and physical function are similar following axillary, muscle-sparing vs posterolateral thoracotomy CHEST Ochroch, E. A., Gottschalk, A., Augoustides, J. G., Aukburg, S. J., Kaiser, L. R., Shrager, J. B. 2005; 128 (4): 2664-2670


    We set out to determine whether there is a difference in postoperative pain and recovery after the patient undergoes the axillary muscle-sparing incision (ie, muscle-sparing thoracotomy [MT]) vs the modified posterolateral incision (ie, posterolateral thoracotomy [PT]).Analysis of a database originally collected to determine the effect of the timing of epidural analgesia on long-term outcome after thoracotomy.The Hospital of the University of Pennsylvania.Patients presenting for lobectomy, segmentectomy, or bilobectomy.Pain, physical activity, and the extent that pain interfered with activities following major thoracotomy were prospectively assessed with standard questionnaires (ie, the brief pain inventory and the Medical Outcomes Study 36-item short form) on postoperative days 1 to 5, and at postoperative weeks 4, 8, 12, 24, 36, and 48 by a blinded research assistant. Perioperative care was standardized and included patient-controlled thoracic epidural analgesia until thoracostomy tube removal.Eighty-two subjects underwent MT and 38 subjects underwent PT during the 16-month accrual period. There were no significant differences in demographics. Pain reported during hospitalization and after hospital discharge did not differ with respect to incision type (p > or = 0.17). Postoperative physical activity levels were significantly less than those reported preoperatively, with a trend toward better functioning in the MT groups after 8 weeks. Incision type did not predict complications, morbidity, or mortality.When comparing patients who had undergone vertical, axillary, wholly MT to those who had undergone modified serratus muscle-sparing PT, postoperative differences in pain were not apparent. One should not anticipate reduced pain or more rapid overall recovery following MT, at least when epidural analgesia is used aggressively for perioperative pain control.

    View details for Web of Science ID 000232679400112

    View details for PubMedID 16236940

  • Effect of chronic obstructive pulmonary disease on calcium pump ATPase expression in human diaphragm JOURNAL OF APPLIED PHYSIOLOGY Nguyen, T., Rubinstein, N. A., Vijayasarathy, C., Rome, L. C., Kaiser, L. R., Shrager, J. B., Levine, S. 2005; 98 (6): 2004-2010


    We have previously demonstrated that human diaphragm remodeling elicited by severe chronic obstructive pulmonary disease (COPD) is characterized by a fast-to-slow myosin heavy chain isoform transformation. To test the hypothesis that COPD-induced diaphragm remodeling also elicits a fast-to-slow isoform shift in the sarcoendoplasmic reticulum Ca(2+) ATPase (SERCA), the other major ATPase in skeletal muscle, we obtained intraoperative biopsies of the costal diaphragm from 10 severe COPD patients and 10 control subjects. We then used isoform-specific monoclonal antibodies to characterize diaphragm fibers with respect to the expression of SERCA isoforms. Compared with control diaphragms, COPD diaphragms exhibited a 63% decrease in fibers expressing only fast SERCA (i.e., SERCA1; P < 0.001), a 190% increase in fibers containing both fast and slow SERCA isoforms (P < 0.01), and a 19% increase (P < 0.05) in fibers expressing only the slow SERCA isoform (i.e., SERCA2). Additionally, immunoblot experiments carried out on diaphragm homogenates indicated that COPD diaphragms expressed only one-third the SERCA1 content noted in control diaphragms; in contrast, COPD and control diaphragms did not differ with respect to SERCA2 content. The combination of these histological and immunoblot results is consistent with the hypothesis that diaphragm remodeling elicited by severe COPD is characterized by a fast-to-slow SERCA isoform transformation. Moreover, the combination of these SERCA data and our previously reported myosin heavy chain isoform data (Levine S, Nguyen T, Kaiser LR, Rubinstein NA, Maislin G, Gregory C, Rome LC, Dudley GA, Sieck GC, and Shrager JB. Am J Respir Crit Care Med 168: 706-713, 2003) suggests that diaphragm remodeling elicited by severe COPD should decrease ATP utilization by the diaphragm.

    View details for DOI 10.1152/japplphysiol.00767.2004

    View details for Web of Science ID 000229365500006

    View details for PubMedID 15718407

  • Quantitative assessment of emphysema using hyperpolarized He-3 magnetic resonance imaging MAGNETIC RESONANCE IN MEDICINE Spector, Z. Z., Emami, K., Fischer, M. C., Zhu, J., Ishii, M., Vahdat, V., Yu, J., Kadlecek, S., Driehuys, B., Lipson, D. A., Gefter, W., Shrager, J., Rizi, R. R. 2005; 53 (6): 1341-1346


    In this experiment, Sprague-Dawley rats with elastase-induced emphysema were imaged using hyperpolarized (3)He MRI. Regional fractional ventilation r, the fraction of gas replaced with a single tidal breath, was calculated from a series of images in a wash-in study of hyperpolarized gas. We compared the regional fractional ventilation in these emphysematous rats to the regional fractional ventilations we calculated from a previous baseline study in healthy Sprague-Dawley rats. We found that there were differences in the maps of fractional ventilation and its associated frequency distribution between the healthy and emphysematous rat lungs. Fractional ventilation tended to be much lower in emphysematous rats than in normal rats. With this information, we can use data on fractional ventilation to regionally distinguish between healthy and emphysematous portions of the lung. The successful implementation of such a technique on a rat model could lead to work toward the future implementation of this technique in human patients.

    View details for Web of Science ID 000229468200014

    View details for PubMedID 15906306

  • Which patients with stage III non-small cell lung cancer should undergo surgical resection? ONCOLOGIST Patel, V., Shrager, J. B. 2005; 10 (5): 335-344


    The treatment of patients with stage III NSCLC remains controversial. Stage III NSCLC comprises a fairly heterogeneous group of tumors, and furthermore only sparse data from randomized clinical trials exist to guide therapy decisions. This review article proposes a management algorithm for patients with stage III NSCLC that is based upon the currently available data on surgical therapy, chemotherapy, and radiation therapy. By necessity, given the paucity of strong data, a good deal of opinion is offered. The choice to proceed with aggressive, combined modality treatment is presented in light of extent of local disease as well as patient performance status.

    View details for Web of Science ID 000229026000014

    View details for PubMedID 15851792

  • Catamenial pneumothorax: optimal hormonal and surgical management EUROPEAN JOURNAL OF CARDIO-THORACIC SURGERY Marshall, M. B., Ahmed, Z., Kucharczuk, J. C., Kaiser, L. R., Shrager, J. B. 2005; 27 (4): 662-666


    To provide further information addressing the etiology, optimal hormonal management and surgical management in catamenial pneumothorax (CP).We retrospectively analyzed records of all female patients operated on for spontaneous pneumothorax at a university hospital between January 1993 and March 2002.In eight of 24 patients, pneumothoraces were timed with menses. In all, the right side was involved. Seven patients were on hormonal medications pre-operatively and six post-operatively. All six patients taking estrogen/progesterone replacement had recurrences pre-operatively and two of three had recurrences post-operatively while on these medications. No patient suffered a pneumothorax either pre- or post-operatively while taking a gonadotropin releasing hormone agonist (two and three patients, respectively). Intraoperative findings included diaphragmatic implants [5] diaphragmatic fenestrations [4], apical blebs [2] and visceral pleural implants [2]. All pathology was specifically addressed at the time of surgery. Pleural space management included mechanical pleurodesis in seven and pleurectomy with talc insufflation in 1. Follow-up ranged from 27 to 63 months with a mean of 48 months. Three patients developed post-operative recurrences. One was managed without intervention and two required additional procedures.Catamenial pneumothorax is under appreciated, representing up to one-third of women with spontaneous pneumothorax. Hormonal agents that allow for menses are ineffective. Gonadotropin releasing hormone agonists should be considered as part of the pre-operative or post-operative management in high risk patients. Our findings suggest that an additional intervention to augment pleural symphysis at the level of the diaphragm should be performed.

    View details for DOI 10.1016/j.ejcts.2004.12.047

    View details for Web of Science ID 000228319600035

    View details for PubMedID 15784370

  • Hyperpolarized helium-3 MR imaging of pulmonary function RADIOLOGIC CLINICS OF NORTH AMERICA Ishii, M., Fischer, M. C., Emami, K., Alavi, A., Spector, Z. Z., Yu, J. S., Baumgartner, J. E., Itkin, M., Kadlecek, S. J., Zhu, J. L., Bono, M., Gefter, W. B., Lipson, D. A., Shrager, J. B., Rizi, R. R. 2005; 43 (1): 235-?


    Recent advances in HP MR imaging contrast agents have led to novel tests of pulmonary function. Many of these tests show promise in the clinical arena.

    View details for DOI 10.1016/j.rcl.2004.09.010

    View details for Web of Science ID 000225875500017

    View details for PubMedID 15693659

  • A small animal model of regional alveolar ventilation using (HPHe)-He-3 MRI ACADEMIC RADIOLOGY Spector, Z. Z., Emami, K., Fischer, M. C., Zhu, J., Ishii, M., Yu, J., Kadlecek, S., Driehuys, B., Panettieri, R. A., Lipson, D. A., Gefter, W., Shrager, J., Rizi, R. R. 2004; 11 (10): 1171-1179


    The aim of this study was to establish a standardized procedure for the measurement of regional fractional ventilation in a healthy rat model as a baseline for further studies of pulmonary disorder models.The lungs of five healthy male Sprague-Dawley rats were imaged using hyperpolarized helium-3 magnetic resonance imaging. From these images, regional fractional ventilation was calculated and maps generated detailing the distribution of fractional ventilation in the lung. The 1.56 mm x 1.56 mm x 4 mm regions of interest were assigned on 5 cm x 5 cm field of view lung maps. Histograms were also generated showing the frequency distribution of fractional ventilation values. To compare fractional ventilation values between animals, the ventilation procedure was standardized to results from individual pulmonary function tests. Each animal's spontaneous tidal volume, respiratory rate, and inspiration percentage (percent of total respiratory cycle in inspiration) were used in their mechanical ventilation settings.Results were similar among all five healthy rats based on examination of ventilation distribution maps and frequency distribution histograms. Mean (0.13) and standard deviation (0.07) were calculated for fractional ventilation in each animal. However, these values were determined to be influenced by slice selection, and therefore the maps and histograms were favored in analysis of results.This study shows consistent results in healthy rat lungs and will serve as a baseline study for future measurements in emphysematous rat lungs.

    View details for DOI 10.1016/j.acra.2004.08.001

    View details for Web of Science ID 000225110100012

    View details for PubMedID 15530811

  • Lung cancer in transplant recipients - A single-institution experience ARCHIVES OF SURGERY Ahmed, Z., Marshall, M. B., Kucharczuk, J. C., Kaiser, L. R., Shrager, J. B. 2004; 139 (8): 902-906


    That aggressive surgical treatment of lung cancer (LC) is justified by stage-based outcome in immunosuppressed solid organ transplant recipients.Case series.University hospital.Lung cancer developed in 15 patients (0.28%) among a solid organ transplant recipient population of 5400 accrued at our institution over a 25-year period.Smoking prevalence, subtypes and stages of LC represented, operative morbidity, and survival.The mean time from transplantation to the diagnosis of LC was 76 months (range, 9-192 months). Eight patients received kidneys; 3, lungs; and 4, hearts. Only 11 patients (73%) had a smoking history (mean, 66 pack-years). The following carcinomas developed in our patient population: adenocarcinoma, 6 patients; squamous cell, 5; large cell undifferentiated, 2; bronchoalveolar, 1; and small cell, 1. Eight patients (53%) presented with inoperable stage IIIB or IV disease. The remaining patients presented in stages IA (n = 2), IB (n = 1), IIB (n = 2), and IIIA (n = 2); all underwent resection. No major postoperative complications occurred. All patients with stage IIIB or greater disease with or without treatment died quickly (mean survival, 1.4 months; range, 0.33-3.0 months). All patients with stage IIB or less remain alive a mean of 37 months after resection. Patients with stage IIIA survived only a mean of 6.0 months despite resection.Regarding LCs in transplant recipients compared with LCs in the nontransplant population, we find that (1) there is an increased incidence among nonsmokers; (2) death occurs rapidly in unresected patients; (3) resection carries a low morbidity rate; and (4) resection seems to offer a high chance of cure in those with cancers staged IIB or less.

    View details for Web of Science ID 000223118400024

    View details for PubMedID 15302702

  • Myosin gene mutation correlates with anatomical changes in the human lineage NATURE Stedman, H. H., Kozyak, B. W., Nelson, A., Thesier, D. M., Su, L. T., Low, D. W., Bridges, C. R., Shrager, J. B., Minugh-Purvis, N., Mitchell, M. A. 2004; 428 (6981): 415-418


    Powerful masticatory muscles are found in most primates, including chimpanzees and gorillas, and were part of a prominent adaptation of Australopithecus and Paranthropus, extinct genera of the family Hominidae. In contrast, masticatory muscles are considerably smaller in both modern and fossil members of Homo. The evolving hominid masticatory apparatus--traceable to a Late Miocene, chimpanzee-like morphology--shifted towards a pattern of gracilization nearly simultaneously with accelerated encephalization in early Homo. Here, we show that the gene encoding the predominant myosin heavy chain (MYH) expressed in these muscles was inactivated by a frameshifting mutation after the lineages leading to humans and chimpanzees diverged. Loss of this protein isoform is associated with marked size reductions in individual muscle fibres and entire masticatory muscles. Using the coding sequence for the myosin rod domains as a molecular clock, we estimate that this mutation appeared approximately 2.4 million years ago, predating the appearance of modern human body size and emigration of Homo from Africa. This represents the first proteomic distinction between humans and chimpanzees that can be correlated with a traceable anatomic imprint in the fossil record.

    View details for DOI 10.1038/nature02358

    View details for Web of Science ID 000220404300040

    View details for PubMedID 15042088

  • Two commonly used neoadjuvant chemoradiotherapy regimens for locally advanced stage III non-small cell lung carcinoma: Long-term results and associations with pathologic response JOURNAL OF THORACIC AND CARDIOVASCULAR SURGERY Machtay, M., Lee, J. H., Stevenson, J. P., Shrager, J. B., Algazy, K. M., Treat, J., Kaiser, L. R. 2004; 127 (1): 108-113


    We performed this study to determine the outcomes (pathologic response, survival, local-regional control, and toxicity) in patients treated with neoadjuvant chemoradiotherapy and planned operation for stage IIIA non-small cell lung carcinoma.Patients treated from 1993 to 2000 with neoadjuvant chemoradiotherapy and a predetermined plan for subsequent surgical resection for stage III non-small cell lung carcinoma were analyzed. All patients underwent pretreatment evaluation at the university's Multidisciplinary Lung Cancer Center. Most patients (87%) had complete mediastinoscopy staging, and all were believed to be poor candidates for up-front operation because of bulky extent of disease. The radiotherapy program used conventional, 2-dimensionally planned treatment to 45 to 54 Gy in 1.8- to 2-Gy fraction size. Concurrent chemotherapy consisted of etoposide/cisplatin or carboplatin/paclitaxel. Study end points included resectability, pathologic response, local-regional control, survival, and toxicity. An exploratory comparison between pathologic response and long-term survival was performed. An exploratory comparison between older chemotherapy (etoposide/cisplatin) and third-generation chemotherapy (carboplatin/paclitaxel) was also performed.Of 53 patients, 45 (85%) were deemed surgical candidates after induction therapy. Twenty-two (42% of the initial cohort) patients had a major pathologic response to stage 0, I, or II disease. The 5-year actuarial survival was 31%. Major pathologic response was associated with improved survival (48% vs 24%; P =.027). The overall rate of early death potentially related to therapy in this series was 9%; this mostly occurred in patients who underwent right pneumonectomy. There was no difference in efficacy or mortality between etoposide/cisplatin and radiotherapy versus carboplatin/paclitaxel and radiotherapy, although the latter regimen was associated with less grade 3 or higher acute toxicity necessitating interruption or hospitalization during neoadjuvant treatment (P =.02). In-field local control was achieved in 83% of all patients (90% of the patients who underwent resection). Brain metastases as the first site of treatment failure occurred in 23% of all patients.Neoadjuvant concurrent chemoradiation delivers high resectability, major pathologic response rate, and excellent local-regional control, with encouraging long-term survival considering the patient population studied. Major pathologic response correlates with long-term survival. Neoadjuvant carboplatin/paclitaxel and radiotherapy is an appropriate framework on which to add new therapies.

    View details for DOI 10.1016/j.jtcvs.2003.07.027

    View details for Web of Science ID 000188709800018

    View details for PubMedID 14752420

  • Human diaphragm remodeling associated with chronic obstructive pulmonary disease - Clinical implications AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE Levine, S., Nguyen, T., Kaiser, L. R., Rubinstein, N. A., Maislin, G., Gregory, C., Rome, L. C., Dudley, G. A., Sieck, G. C., Shrager, J. B. 2003; 168 (6): 706-713


    Diaphragm remodeling associated with chronic obstructive pulmonary disease (COPD) consists of a fast-to-slow fiber type transformation as well as adaptations within each fiber type. To try to explain disparate findings in the literature regarding the relationship between fiber type proportions and FEV1, we obtained costal diaphragm biopsies on 40 subjects whose FEV1 ranged from 118 to 16% of the predicted normal value. First, we noted that our exponential regression model indicated that changes in FEV1 can account for 72% of the variation in the proportion of Type I fibers. Second, to assess the impact of COPD on diaphragm force generation, we measured maximal specific force generated by single permeabilized fibers prepared from the diaphragms of two patients with normal pulmonary function tests and two patients with severe COPD. We noted that fibers prepared from the diaphragms of severe COPD patients generated a lower specific force than control fibers (p < 0.001) and Type I fibers generated a lower specific force than Type II fibers (p < 0.001). Our finding of an exponential relationship between the proportion of Type I fibers and FEV1 accounts for discrepancies in the literature. Moreover, our single-fiber results suggest that COPD-associated diaphragm remodeling decreases diaphragmatic force generation by adaptations within each fiber type as well as by fiber type transformations.

    View details for DOI 10.1164/rccm.200209-1070OC

    View details for Web of Science ID 000185324600016

    View details for PubMedID 12857719

  • Tracheal trauma. Chest surgery clinics of North America Shrager, J. B. 2003; 13 (2): 291-304


    The etiology, presentation, and management of blunt and penetrating injuries of the trachea has been reviewed. The approach to and outcome following management of more unusual situations such as iatrogenic injuries has also been briefly reviewed. Early recognition of these problems and careful attention to the details of acute management can convert a life-threatening situation into one that can usually be successfully managed by the techniques of tracheal surgery developed and popularized by Dr. Grillo.

    View details for PubMedID 12755314

  • Omentum is highly effective in the management of complex cardiothoracic surgical problems 12th World Congress of the World-Society-of-Cardio-Thoracic-Surgeons Shrager, J. B., Wain, J. C., Wright, C. D., Donahue, D. M., Vlahakes, G. J., Moncure, A. C., Grillo, H. C., Mathisen, D. J. MOSBY-ELSEVIER. 2003: 526–32


    Vascularized, pedicled tissue flaps are often used for cardiothoracic surgical problems complicated by factors that adversely affect healing, such as previous irradiation, established infection, or steroid use. We reviewed our experience with use of the omentum in these situations to provide a yardstick against which results with other vascularized flaps (specifically muscle flaps) could be compared.A retrospective review was undertaken of 85 consecutive patients in whom omentum was used in the chest. In 47 patients (group I), use of omentum was prophylactic to aid in the healing of closures or anastomoses considered to be at high risk for failure. In 32 patients (group II), omentum was used in the treatment of problems complicated by established infection. In 6 patients (group III), omentum was used for coverage of prosthetic chest wall replacements after extensive chest wall resection.Overall, omental transposition was successful in its prophylactic or therapeutic purpose in 88% of these difficult cases (75/85). Success with omentum was achieved for 89% of patients (42/47) in group I, 91% of patients (29/32) in group II, and 67% of patients (4/6) in group III. Three patients (3.5%) had complications of omental mobilization. Four patients (4.7%) died after the operation as a result of failure of the omentum to manage the problem for which it was used.Results with omental transposition compare favorably with published series of similarly challenging cases managed with muscle transposition. Complications of omental mobilization are rare. We believe that its unique properties render the omentum an excellent choice of vascularized pedicle in the management of the most complex cardiothoracic surgical problems.

    View details for DOI 10.1067/mtc.2003.12

    View details for Web of Science ID 000181949800015

    View details for PubMedID 12658194

  • Myosin heavy chain and physiological adaptation of the rat diaphragm in elastase-induced emphysema RESPIRATORY RESEARCH Kim, D. K., Zhu, J. L., Kozyak, B. W., Burkman, J. M., Rubinstein, N. A., Lankford, E. B., Stedman, H. H., Nguyen, T., LEVINE, S., Shrager, J. B. 2003; 4 (1)


    Several physiological adaptations occur in the respiratory muscles in rodent models of elastase-induced emphysema. Although the contractile properties of the diaphragm are altered in a way that suggests expression of slower isoforms of myosin heavy chain (MHC), it has been difficult to demonstrate a shift in MHCs in an animal model that corresponds to the shift toward slower MHCs seen in human emphysema.We sought to identify MHC and corresponding physiological changes in the diaphragms of rats with elastase-induced emphysema. Nine rats with emphysema and 11 control rats were studied 10 months after instillation with elastase. MHC isoform composition was determined by both reverse transcriptase polymerase chain reaction (RT-PCR) and immunocytochemistry by using specific probes able to identify all known adult isoforms. Physiological adaptation was studied on diaphragm strips stimulated in vitro.In addition to confirming that emphysematous diaphragm has a decreased fatigability, we identified a significantly longer time-to-peak-tension (63.9 +/- 2.7 ms versus 53.9 +/- 2.4 ms). At both the RNA (RT-PCR) and protein (immunocytochemistry) levels, we found a significant decrease in the fastest, MHC isoform (IIb) in emphysema.This is the first demonstration of MHC shifts and corresponding physiological changes in the diaphragm in an animal model of emphysema. It is established that rodent emphysema, like human emphysema, does result in a physiologically significant shift toward slower diaphragmatic MHC isoforms. In the rat, this occurs at the faster end of the MHC spectrum than in humans.

    View details for Web of Science ID 000181146600001

    View details for PubMedID 12617755

  • Inspiratory loading does not accelerate dystrophy in mdx mouse diaphragm: implications for regenerative therapy JOURNAL OF APPLIED PHYSIOLOGY Krupnick, A. S., Zhu, J. L., Nguyen, T., Kreisel, D., Balsara, K. R., Lankford, E. B., Clark, C. C., LEVINE, S., Stedman, H. H., Shrager, J. B. 2003; 94 (2): 411-419


    Since the finding that the mdx mouse diaphragm, in contrast to limb muscles, undergoes progressive degeneration analogous to that seen in Duchenne muscular dystrophy, the relationship between the workload on a muscle and the pathogenesis of dystrophy has remained controversial. We increased the work performed by the mdx mouse diaphragm in vivo by tracheal banding and evaluated the progression of dystrophic changes in that muscle. Despite the establishment of dramatically increased respiratory workload and accelerated myofiber damage documented by Evans blue dye, no change in the pace of progression of dystrophy was seen in banded animals vs. unbanded, sham-operated controls. At the completion of the study, more centrally nucleated fibers were evident in the diaphragms of banded mdx mice than in sham-operated mdx controls, indicating that myofiber regeneration increases to meet the demands of the work-induced damage. These data suggest that there is untapped regenerative capacity in dystrophin-deficient muscle and validates experimental efforts aimed at augmenting regeneration within skeletal muscle as a therapeutic strategy in the treatment of dystrophinopathies.

    View details for DOI 10.1152/japplphysiol.00689.2002

    View details for Web of Science ID 000180437600001

    View details for PubMedID 12531909

  • Mediastinal talcoma masquerading as thymoma ANNALS OF THORACIC SURGERY Ahmed, Z., Shrager, J. B. 2003; 75 (2): 568-569


    We report a young woman with a large, calcified anterior mediastinal mass discovered 18 months following a left talc pleurodesis. The lesion was evaluated and treated as the thymoma or teratoma that it appeared to be, with excision by a transcervical approach. Pathologic examination revealed a giant talc granuloma. Awareness of such a possibility following talc pleurodesis may allow surgeons to avoid unnecessary mediastinal exploration, and its occurrence suggests that talc administration simultaneous with mechanical pleurodesis should be avoided.

    View details for Web of Science ID 000180926000057

    View details for PubMedID 12607675

  • Evaluating respiratory muscle adaptations - A new approach AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE LEVINE, S., Nguyen, T., Kaiser, L. R., Shrager, J. B. 2002; 166 (11): 1418-1419

    View details for DOI 10.1164/rccm.2209001

    View details for Web of Science ID 000179590900002

    View details for PubMedID 12450930

  • Benign expectoration of a surgical clip through a pneumonectomy stump JOURNAL OF THORACIC AND CARDIOVASCULAR SURGERY Ahmed, Z., Kaiser, L. R., Shrager, J. B. 2002; 124 (5): 1025-1026

    View details for DOI 10.1067/mtc.2002.124495

    View details for Web of Science ID 000179012300023

    View details for PubMedID 12407389

  • Validating a dipstick method for detecting recent smoking CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION Gariti, P., Rosenthal, D. I., Lindell, K., Hansen-Flaschen, J., Shrager, J., Lipkin, C., Alterman, A. I., Kaiser, L. R. 2002; 11 (10): 1123-1125


    This report evaluates the validity of a new method for verifying self-reported smoking status in patients presenting for pulmonary medicine treatment. A prospective comparison was made between self-reports of smoking status and a new semiquantitative, enzyme-linked, immunosorbent assay-based method testing for the presence of a prime nicotine metabolite, cotinine. Results were validated by gas chromatography/mass spectrometry. Data were collected in an urban, academic, tertiary health care setting. The study included 76 consecutive new patients presenting to participating clinical practices at the Pulmonology or Thoracic Surgery Services. Before taking a smoking history, patients were informed that their urine would be tested onsite for the presence of nicotine using a new method, the NicoMeter, for determining tobacco product exposure, followed by more standard laboratory testing. The level of agreement between the biochemical measurement types was excellent, kappa = 0.777. The new biochemical measurement type used was easy to use. Self-reported smoking status corresponded closely to biochemical testing. However, there was a 5.3-9.5% misclassification of smoking status among the group studied, depending upon the measurement type used. Among 32 lung cancer patients, 15.6%, most likely misrepresented their current smoking status. The NicoMeter appears to be a valid and useful method for confirming self-reported smoking status. Lung cancer patients had a higher rate of inaccurate nonsmoking compared with patients with nonmalignant pulmonary disease. The findings have implications for investigators who accept self-reported smoking status without biochemical verification.

    View details for Web of Science ID 000178634100028

    View details for PubMedID 12376520

  • Transcervical thymectomy for myasthenia gravis achieves results comparable to thymectomy by sternotomy 38th Annual Meeting of the Society-of-Thoracic-Surgeons Shrager, J. B., Deeb, M. E., Mick, R., Brinster, C. J., Childers, H. E., Marshall, M. B., Kucharczuk, J. C., Galetta, S. L., Bird, S. J., Kaiser, L. R. ELSEVIER SCIENCE INC. 2002: 320–26


    It remains controversial whether transcervical thymectomy offers results equivalent to thymectomy by way of a median sternotomy in the treatment of myasthenia gravis. Furthermore, preoperative prognostic factors have not been clearly defined.This study is a retrospective chart review and interview of 78 patients completing transcervical thymectomy for myasthenia gravis between 1992 and 1999.There were 24 men and 54 women. Mean age was 40 years (range, 13 to 78 years). Twelve patients were in Osserman class 1, 25 in class 2, 30 in class 3, and 11 in class 4 (mean, 2.5). There was no perioperative mortality and 6 (7.7%) morbidities. Mean length of stay was 1.5 days and mean follow-up, 54.6 months. The crude cumulative complete remission (asymptomatic off medications for 6 months) rate was 39.7% (n = 31). Only 8 patients (10.3%) failed to improve after transcervical thymectomy. Kaplan-Meier estimates of complete remission were 31% and 43% at 2 and 5 years, respectively. Eight patients with thymoma had a 5-year estimated complete remission rate of 75% in contrast to 43% in 38 patients with thymic hyperplasia and 36% in 32 patients with neither thymoma nor hyperplasia (p = 0.01). Twelve patients with ocular myasthenia had a 5-year estimated complete remission rate of 57%, whereas patients with mild-to-moderate (n = 55) or severe (n = 11) generalized symptoms had 5-year complete remission rates of 43% and 30%, respectively (p = 0.21).Overall, extended transcervical thymectomy offers results that are comparable to those published for the transsternal procedure. Patients with milder disease (including isolated ocular disease) and taking no preoperative immunosuppressive agents appear to experience higher remission rates. In contrast to previous studies, we also find that small thymomas predict better responses to thymectomy.

    View details for Web of Science ID 000177320600006

    View details for PubMedID 12173807

  • Pathological response to preoperative chemoradiation worsens with anemia in non-small cell lung cancer patients Annual Meeting of the Radiological-Society-of-North-America Robnett, T. J., Machtay, M., Hahn, S. M., Shrager, J. B., Freidberg, J. S., Kaiser, L. R. LIPPINCOTT WILLIAMS & WILKINS. 2002: 263–67


    Positive links between hemoglobin level and therapeutic tumor response are well documented in carcinoma of the cervix and the head and neck, but little evidence of such a link exists for lung cancer. We analyzed our series of patients treated with preoperative chemoradiation for stage IIIA non-small cell lung carcinoma.Between June 1992 and February 2000, 41 consecutive patients with clinical stage IIIA (N2, documented by mediastinoscopy or another invasive procedure) non-small cell lung carcinoma received preoperative-intent chemoradiation. The median preoperative radiation dose was 48.6 Gy, and all patients received cisplatin- or paclitaxel-based chemotherapy. Response was graded on a four point scale: (1) progressive disease before surgery and/or technically inoperable; (2) stable disease with resection performed, but specimen containing > 50% viable tumor; (3) partial response with specimen containing < 50% tumor; and (4) complete response or near-complete response: RO resection with no residual carcinoma or pT1NO with only microscopic residual foci. Pretreatment hemoglobin values were correlated with pathological outcome using ANOVA and the non-parametric test for trend across ordered groups.The mean hemoglobin level for groups 1 through 4 was 11.8, 12.1, 12.5, and 13.2 respectively, and the association was statistically significant. If the analysis was limited to patients actually undergoing surgery (eliminating group 1), the association remained significant. The nonparametric test for trend across ordered groups was also significant with and without group 1.Our analysis supports the hypothesis that response to chemoradiation of non-small cell lung carcinoma improves with increasing hemoglobin levels.

    View details for Web of Science ID 000176142200009

    View details for PubMedID 12074326

  • Evolutionary implications of three novel members of the human sarcomeric myosin heavy chain gene family MOLECULAR BIOLOGY AND EVOLUTION Desjardins, P. R., Burkman, J. M., Shrager, J. B., Allmond, L. A., Stedman, H. H. 2002; 19 (4): 375-393


    Sarcomeric myosin heavy chain (MyHC) is the major contractile protein of striated muscle. Six tandemly linked skeletal MyHC genes on chromosome 17 and two cardiac MyHC genes on chromosome 14 have been previously described in the human genome. We report the identification of three novel human sarcomeric MyHC genes on chromosomes 3, 7, and 20, which are notable for their atypical size and intron-exon structure. Two of the encoded proteins are structurally most like the slow-beta MyHC, whereas the third one is closest to the adult fast IIb isoform. Data from pairwise comparisons of aligned coding sequences imply the existence of ancestral genomes with four sarcomeric genes before the emergence of a dedicated smooth muscle MyHC gene. To further address the evolutionary relationships of the distinct sarcomeric and nonsarcomeric rod sequences, we have identified and further annotated human genomic DNA sequences corresponding to 14 class-II MyHCs. An extensive analysis provides a timeline for intron gain and loss, gene contraction and expansion, and gene conversion among genes encoding class-II myosins. One of the novel human genes is found to have introns at positions shared only with the molluscan catchin/MyHC gene, providing evidence for the structure of a pre-Cambrian ancestral gene.

    View details for Web of Science ID 000174967000002

    View details for PubMedID 11919279

  • Suction vs water seal after pulmonary resection - A randomized prospective study CHEST Marshall, M. B., Deeb, M. E., Bleier, J. I., Kucharczuk, J. C., Friedberg, J. S., Kaiser, L. R., Shrager, J. B. 2002; 121 (3): 831-835


    To evaluate whether suction or water seal is superior in the management of chest tubes after pulmonary resection.A prospective, randomized, controlled trial. After an initial, brief period of suction, patients were randomized to water seal or - 20 cm H(2)O suction.University hospital.Sixty-eight patients who underwent wedge resection, segmentectomy, or lobectomy were included in the study. Those patients who underwent reoperative surgery or lung volume reduction surgery were excluded.There were 34 patients in each group. The two groups were evenly matched for age, sex, operation performed, severity of lung disease, and nutritional status. Fifteen patients in each group (44%) had an air leak at the completion of surgery. The duration of the air leak was shorter in the water seal group than in the suction group (mean +/- SEM, 1.50 +/- 0.32 days vs 3.27 +/- 0.80 days, respectively; p = 0.05). The mean times to removal of chest tubes were 3.33 +/- 0.35 days in the water seal group and 5.47 +/- 0.98 days in the suction group (p = 0.06). The length of stapled parenchyma was measured for each patient and averaged 24.9 cm for the water seal group and 18.5 cm for the suction group (p = 0.18). When corrected for the length of staple lines, the duration of air leaks and days with chest tube were dramatically lower in the water seal group (p = 0.02 and p = 0.02, respectively).Placing chest tubes on water seal after a brief period of suction after pulmonary resection shortens the duration of the air leak and likely decreases the time that the chest tubes remain in place. Adoption of this practice may result in lower morbidity and lower hospital costs.

    View details for Web of Science ID 000174446000029

    View details for PubMedID 11888968

  • Bioenergetic adaptation of individual human diaphragmatic myofibers to severe COPD JOURNAL OF APPLIED PHYSIOLOGY Levine, S., Gregory, C., Nguyen, T., Shrager, J., Kaiser, L., Rubinstein, N., Dudley, G. 2002; 92 (3): 1205-1213


    To assess the effect of severe chronic obstructive pulmonary disease (COPD) on the ability of human diaphragmatic myofibers to aerobically generate ATP relative to ATP utilization, we obtained biopsy specimens of the costal diaphragm from seven patients with severe COPD (mean +/- SE; age 56 +/- 1 yr; forced expiratory volume in 1 s 23 +/- 2% predicted; residual volume 267 +/- 30% predicted) and seven age-matched control subjects. We categorized all fibers in these biopsies by using standard techniques, and we carried out the following quantitative histochemical measurements by microdensitometry: 1) succinate dehydrogenase (SDH) activity as an indicator of mitochondrial oxidative capacity and 2) calcium-activated myosin ATPase (mATPase) activity, the ATPase that represents a major portion of ATP consumption by contracting muscle. We noted the following: 1) COPD diaphragms had a larger proportion of type I fibers, a lesser proportion of type IIax fibers, and the same proportion of type IIa fibers as controls. 2) SDH activities of each of the fiber types were higher in COPD than control diaphragms (P < 0.0001); the mean increases (expressed as percent of control values) in types I, IIa, and IIax were 84, 114, and 130%, respectively. 3) COPD elicited no change in mATPase activity of type I and IIa fibers, but mATPase decreased in type IIax fibers (P = 0.02). 4) Mitochondrial oxidative capacity relative to ATP demand (i.e., SDH/mATPase) was higher (P = 0.03) in each of the fiber types in COPD diaphragms than in controls. These results demonstrate that severe COPD elicits an increase in aerobic ATP generating capacity relative to ATP utilization in all diaphragmatic fiber types as well as the previously described fast-to-slow fiber type transformation (Levine S, Kaiser L, Leferovich J, and Tikunov B, N Engl J Med 337: 1799-1806, 1997).

    View details for DOI 10.1152/japplphysiol.00116.2001

    View details for Web of Science ID 000173960100042

    View details for PubMedID 11842060

  • Current presentation and optimal surgical management of sternoclavicular joint infections ANNALS OF THORACIC SURGERY Song, H. K., Guy, T. S., Kaiser, L. R., Shrager, J. B. 2002; 73 (2): 427-431


    Infection of the stemoclavicular joint is unusual, and treatment of this entity has not been standardized. We sought to characterize the current presentation and optimal management of this disease.We retrospectively reviewed the records of the last 7 patients undergoing operation for suppurative infections of the stemoclavicular joint at this institution. Patients were interviewed regarding upper extremity function after formal joint resection.Predisposing factors were common and included diabetes mellitus (n = 2), clavicular fracture (n = 1), human immunodeficiency virus infection (n = 1), immunosuppression (n = 1), and pustular skin disease (n = 1). All patients presented with local symptoms including clavicular mass and tenderness. Diagnosis and evaluation were facilitated by cross-sectional imaging. Organisms isolated included Staphylococcus aureus, group G streptococcus, and Proteus and Propionibacterium species. Antibiotic therapy and simple drainage and debridement were generally ineffective, leading to recurrence of infection in 5 of 6 patients treated initially in this manner. Six patients were treated with resection of the stemoclavicular joint and involved portions of first or second ribs with soft tissue coverage by advancement flap from the ipsilateral pectoralis major muscle. Response to this therapy was excellent, with cure in all patients, no wound complications, and excellent upper extremity function at long-term follow-up.Aggressive surgical management including resection of the sternoclavicular joint and involved ribs with pectoralis flap closure would appear to be the preferred treatment for all but the most minor infections of the sternoclavicular joint. This approach has minimal impact on upper extremity function.

    View details for Web of Science ID 000173624500014

    View details for PubMedID 11845854

  • Sarcomeres are added in series to emphysematous rat diaphragm after lung volume reduction surgery CHEST Shrager, J. B., Kim, D. K., Hashmi, Y. J., Stedman, H. H., Zhu, J. L., Kaiser, L. R., LEVINE, S. 2002; 121 (1): 210-215


    The diaphragm adapts to its shortened state in experimental emphysema primarily by losing sarcomeres in series, thus reducing its optimal operating length. One would expect improved diaphragmatic function after lung volume reduction surgery (LVRS) only if the muscle can readapt to its elevated, lengthened postoperative position by either adding back sarcomeres or lengthening sarcomeres. We used a model of elastase-induced emphysema in rats to test the hypothesis that sarcomere addition occurs following LVRS.A cohort of emphysematous rats was created by the intratracheal instillation of elastase. Five months after the instillation, one group of rats underwent measurement of in situ costal diaphragm length via laparotomy, the determination of optimal muscle fiber operating length (Lo) on stimulated diaphragm strips in vitro, and the measurement of sarcomere length by electron microscopy on strips fixed at Lo. Another group of rats underwent LVRS or sham sternotomy 5 months after the instillation, and 5 months following the operation these animals underwent the same series of diaphragmatic studies.Lo was significantly greater in rats that underwent LVRS than those that underwent sternotomy (mean [+/- SE] Lo after LVRS, 2.50 +/- 0.08 cm; mean Lo after sternotomy, 2.27 +/- 0.06 cm; p = 0.013). There was no significant difference in sarcomere lengths between the two groups (2.95 +/- 0.04 vs 3.04 +/- 0.04 microm, respectively; p = 0.10). Using Lo as the length basis, the mean sarcomere number was calculated to be 8,712 +/- 192 in animals that had undergone LVRS and 7,144 +/- 249 in animals that had undergone sternotomy (p < 0.001).Sarcomere length is not significantly altered but sarcomeres are added in series following LVRS in this experimental model of emphysema/LVRS. It is likely that this sarcomere addition is a prerequisite to the improvement in inspiratory muscle function that has been observed following LVRS in humans.

    View details for Web of Science ID 000173431400035

    View details for PubMedID 11796453

  • Osteogenic sarcoma presenting with lung metastasis ONCOLOGIST Staddon, A. P., Lackman, R., Robinson, K., Shrager, J. B., Warhol, M. 2002; 7 (2): 144-153


    A patient with osteogenic sarcoma presenting with lung metastases is discussed with attention to appropriate diagnosis, staging, and treatment. Multimodality treatment options using chemotherapy, orthopedic surgery and thoracic surgery are presented. Physical medicine and rehabilitation evaluation and treatment are included. Current research options are discussed.

    View details for Web of Science ID 000175213300010

    View details for PubMedID 11961198

  • Risk of death from intercurrent disease is not excessively increased by modern postoperative radiotherapy for high-risk resected non-small-cell lung carcinoma JOURNAL OF CLINICAL ONCOLOGY Machtay, M., Lee, J. H., Shrager, J. B., Kaiser, L. R., Glatstein, E. 2001; 19 (19): 3912-3917


    Some studies report a high risk of death from intercurrent disease (DID) after postoperative radiotherapy (XRT) for non-small-cell lung cancer (NSCLC). This study determines the risk of DID after modern-technique postoperative XRT.A total of 202 patients were treated with surgery and postoperative XRT for NSCLC. Most patients (97%) had pathologic stage II or III disease. Many patients (41%) had positive/close/uncertain resection margins. The median XRT dose was 55 Gy with fraction size of 1.8 to 2 Gy. The risk of DID was calculated actuarially and included patients who died of unknown/uncertain causes. Median follow-up was 24 months for all patients and 62 months for survivors.A total of 25 patients (12.5%) died from intercurrent disease, 16 from confirmed noncancer causes and nine from unknown causes. The 4-year actuarial rate of DID was 13.5%. This is minimally increased compared with the expected rate for a matched population (approximately 10% at 4 years). On multivariate analysis, age and radiotherapy dose were borderline significant factors associated with a higher risk of DID (P =.06). The crude risk of DID for patients receiving less than 54 Gy was 2% (4-year actuarial risk 0%) versus 17% for XRT dose > or = 54 Gy. The 4-year actuarial overall survival was 34%; local control was 84%; and freedom from distant metastases was 37%.Modern postoperative XRT for NSCLC does not excessively increase the risk of intercurrent deaths. Further study of postoperative XRT, particularly when using more sophisticated treatment planning and reasonable total doses, for carefully selected high-risk resected NSCLC is warranted.

    View details for Web of Science ID 000171246200003

    View details for PubMedID 11579111

  • Successful-experience with simultaneous lung volume reduction and cardiac procedures JOURNAL OF THORACIC AND CARDIOVASCULAR SURGERY Shrager, J. B., Kozyak, B. W., Roberts, J. R., Bavaria, J. E., Friedberg, J. S., Kaiser, L. R., Rosengard, B. R. 2001; 122 (1): 196-197

    View details for Web of Science ID 000169837100035

    View details for PubMedID 11436063

  • Expanded indications for transcervical thymectomy in the management of anterior mediastinal masses ANNALS OF THORACIC SURGERY Deeb, M. E., Brinster, C. J., Kucharzuk, J., Shrager, J. B., Kaiser, L. R. 2001; 72 (1): 208-211


    Transcervical thymectomy (TCT) is an accepted though controversial approach for thymectomy in myasthenia gravis (MG). The suggestion of thymoma on computed tomography (CT) has been considered a contraindication to TCT. We sought to determine whether the indications for TCT could be safely expanded to include selected patients with thymomas as well as other types of anterior mediastinal masses.Between January 1992 and September 1999, we performed 121 TCTs: 98 in patients with MG and 23 in patients without MG. The patients' records were retrospectively reviewed.Among the 98 MG patients, 28 had CT scans suspicious for thymoma. Of these, 14 had a thymoma pathologically. These were classified as stage I (5), stage II (8), and stage III (1). Five patients required extension of the incision for completion of the procedure. There have been no thymoma recurrences to date with a mean follow-up of 48 months (range 3 to 96 months). In the 23 patients without MG, 12 had new anterior mediastinal masses, 4 had a history of treated lymphoma, 1 had a history of treated germ cell tumor, and 6 had suspected mediastinal parathyroid adenoma. Diagnostic tissue was obtained in all patients undergoing the procedure for diagnosis, and in 4 of 6 patients, a parathyroid adenoma was successfully resected.Transcervical exploration and thymectomy offers a less invasive approach to the diagnosis and/or definitive treatment of selected anterior mediastinal masses. We suggest that it is appropriate to expand its use to several clinical scenarios beyond the typical indication of thymectomy in MG patients without thymoma.

    View details for Web of Science ID 000169906500049

    View details for PubMedID 11465181

  • Bronchial anastomotic stricture caused by ossification of an intercostal muscle flap ANNALS OF THORACIC SURGERY Deeb, M. E., Sterman, D. H., Shrager, J. B., Kaiser, L. R. 2001; 71 (5): 1700-1702


    We report a case of heterotopic ossification of a pedicled intercostal muscle flap that had been wrapped circumferentially around a bronchial sleeve anastomosis. This ossification caused severe bronchial stenosis and recurrent pneumonias. Stent insertion failed, and the patient ultimately required completion pneumonectomy. We recommended that caution be used when wrapping intercostal muscle around any important lumen.

    View details for Web of Science ID 000168734300065

    View details for PubMedID 11383836

  • Lung volume reduction surgery restores the normal diaphragmatic length-tension relationship in emphysematous rats 80th Annual Meeting of the American-Association-for-Thoracic-Surgery Shrager, J. B., Kim, D. K., Hashmi, Y. J., Lankford, E. B., Wahl, P., Stedman, H. H., LEVINE, S., Kaiser, L. R. MOSBY-ELSEVIER. 2001: 217–24


    Improved respiratory muscle function is a major effect of a lung volume reduction surgery. We studied length adaptation in rat diaphragmatic muscle in an attempt to elucidate the mechanism by which diaphragmatic function improves after this controversial operation.We developed a model of elastase-induced emphysema and bilateral volume reduction through median sternotomy in rats. Five months after emphysema induction, maximum exchangeable lung volume was determined in intubated and anesthetized control animals and animals with emphysema. Costal diaphragmatic length was measured in vivo, and the length at which maximal twitch force is generated was determined on muscle strips in vitro. Also 5 months after elastase administration, another cohort underwent volume reduction or sham sternotomy. Five months after the operation, these animals were similarly studied.Lung volume was increased in emphysematous rats versus control rats (50.9 +/- 1.7 vs 45.4 +/- 1.3 mL, P =.001). Lung volume was decreased in emphysematous animals that had undergone volume reduction versus sham sternotomy (44.7 +/- 0.60 vs 49.4 +/- 1.0 mL, P =.001). In situ diaphragm length (1.99 +/- 0.04 vs 2.24 +/- 0.07 cm, P =.001) and the length at which maximal twitch force is generated (2.25 +/- 0.06 vs 2.48 +/- 0.09 cm, P =.038) were shorter in emphysematous than control animals. After volume reduction, in situ diaphragm length (2.13 +/- 0.06 vs 1.83 +/- 0.02 cm, P <.001) and the length at which maximal twitch force is generated (2.50 +/- 0.08 vs 2.27 +/- 0.06 cm, P =.013) were longer than in animals undergoing sham sternotomy.In this experimental model of emphysema and lung volume reduction surgery, emphysema shortens the length at which maximal twitch force is generated and shifts the diaphragmatic length-tension curve to lower lengths; volume reduction returns the length at which maximal twitch force is generated toward normal and shifts the diaphragmatic length-tension curve back to longer lengths. This restoration toward normal physiology may enable the improvement in diaphragmatic function seen after lung volume reduction surgery. The mechanism by which these length adaptations occur merits further investigation.

    View details for Web of Science ID 000167014300006

    View details for PubMedID 11174726

  • Lobectomy with tangential pulmonary artery resection without regard to pulmonary function ANNALS OF THORACIC SURGERY Shrager, J. B., Lambright, E. S., McGrath, C. M., Wahl, P. M., Deeb, M. E., Friedberg, J. S., Kaiser, L. R. 2000; 70 (1): 234-239


    Non-small cell carcinoma of the lung invading the pulmonary artery (PA) has traditionally been treated by pneumonectomy. Although PA resection and reconstruction (PAR) has begun to gain acceptance, previous series of PAR by the simplest technique of tangential excision and primary repair have been unfavorable. We have maintained a policy of performing PAR preferentially whenever anatomically feasible, and usually this has been possible by tangential excision and primary repair. This study sought to determine if this approach is sound.Retrospective clinical and pathologic review.Thirty-three PARs were performed from 1992 to 1999. The patients, followed 6 to 65 months (mean 25), were aged 36 to 80 years (mean 61), and their tumors were pathologic stage IB (n = 7), IIB (n = 13), IIIA (n = 9), and IIIB (n = 4). The mean preoperative forced expiratory volume in 1 second was 70% predicted. The procedures included 14 bronchial sleeve lobectomies with PAR and 19 simple lobectomies with PAR. The PARs were performed without heparinization and included 19 tangential excisions with primary closure, 11 larger tangential excisions with pericardial patch closure, and 3 sleeve resections. There were no operative deaths and 2 (6.1%) early major complications, all unrelated to the PAR. Thirteen patients (39%) had early minor complications. Four-year Kaplan-Meier survival was 48.3% for stages I/II and 45% for stage III. Ipsilateral, central, intrathoracic recurrence occurred in 3 patients (9.1%).These data are not dramatically different from those reported for standard resections. Although the numbers are small, the results suggest that lobectomy with PAR by tangential excision is an acceptable alternative to pneumonectomy whenever anatomically possible.

    View details for Web of Science ID 000088318100052

    View details for PubMedID 10921714

  • Human skeletal myosin heavy chain genes are tightly linked in the order embryonic-IIa-IId/x-IIb-perinatal-extraocular JOURNAL OF MUSCLE RESEARCH AND CELL MOTILITY Shrager, J. B., Desjardins, P. R., Burkman, J. M., Konig, S. K., Stewart, D. R., Su, L., Shah, M. C., Bricklin, E., Tewari, M., Hoffman, R., Rickels, M. R., Jullian, E. H., Rubinstein, N. A., Stedman, H. H. 2000; 21 (4): 345-355


    Myosin heavy chain (MyHC) is the major contractile protein of muscle. We report the first complete cosmid cloning and definitive physical map of the tandemly linked human skeletal MyHC genes at 17p13.1. The map provides new information on the order, size, and relative spacing of the genes. and it resolves uncertainties about the two fastest twitch isoforms. The physical order of the genes is demonstrated to contrast with the temporal order of their developmental expression. Furthermore, nucleotide sequence comparisons allow an approximation of the relative timing of five ancestral duplications that created distinct genes for the six isoforms. A firm foundation is provided for molecular analysis in patients with suspected primary skeletal myosinopathies and for detailed modelling of the hypervariable surface loops which dictate myosin's kinetic properties.

    View details for Web of Science ID 000089137300005

    View details for PubMedID 11032345

  • Lung volume reduction surgery. Current problems in surgery Shrager, J. B., Kaiser, L. R., Edelman, J. D. 2000; 37 (4): 253-317

    View details for PubMedID 10778395

  • Lymphangioleiomyomatosis: The surgeon's role in diagnosis JOURNAL OF THORACIC AND CARDIOVASCULAR SURGERY Deeb, M., Shrager, J. B., Edelman, J. D., Kaiser, L. 2000; 119 (3): 622-623

    View details for Web of Science ID 000085766600043

    View details for PubMedID 10694627

  • Thoracoscopic lung biopsy - Five commonly asked questions about video-assisted thoracic surgery POSTGRADUATE MEDICINE Shrager, J. B., Kaiser, L. R. 1999; 106 (4): 139-?


    VATS has proved to be an extremely useful diagnostic tool. Perhaps its most frequent application has been in lung biopsy to diagnose indeterminate solitary pulmonary nodules and interstitial infiltrates. In many institutions, VATS procedures have largely replaced previous methods of attempting to establish the nature of a solitary pulmonary nodule. In ambulatory patients with indeterminate infiltrates, VATS techniques have prompted earlier referral to establish a tissue diagnosis, with apparently decreased morbidity. VATS has clearly found a place in the modern practice of thoracic surgery and is likely to play an ever-increasing role in the management of diseases of the chest.

    View details for Web of Science ID 000083166900017

    View details for PubMedID 10533514

  • Bronchopulmonary carcinoid tumors associated with Cushing's syndrome: A more aggressive variant of typical carcinoid JOURNAL OF THORACIC AND CARDIOVASCULAR SURGERY Shrager, J. B., Wright, C. D., Wain, J. C., Torchiana, D. F., Grillo, H. C., Mathisen, D. J. 1997; 114 (3): 367-375


    Our objectives were to delineate the clinicopathologic characteristics of adrenocorticotropin-secreting bronchopulmonary carcinoid tumors causing Cushing's syndrome and to derive from these findings a rational approach to diagnosis and surgical management of this unusual condition.We conducted a retrospective, chart-review analysis of seven consecutive patients treated at the Massachusetts General Hospital over a 16-year period.The patients uniformly had symptoms of marked hypercortisolism, and the underlying lung lesions remained clinically occult for a mean of 24 months. Standard endocrine testing was misleading in 83% of patients, reinforcing the need for an alternative diagnostic strategy based on petrosal sinus catheterization and computed tomography of the chest. Although 72% of the tumors were typical carcinoids by standard criteria, 57% demonstrated microscopic evidence of local invasiveness, and 43% were associated with mediastinal lymph node metastases. Eighty-six percent of patients have been cured by pulmonary resection a mean of 59 months after the operation, but 50% of these required a second operation for resection of involved lymph nodes after an initial relapse.These data suggest that adrenocorticotropin-secreting bronchopulmonary carcinoid tumors represent a distinct, more aggressive subtype of the usual, typical carcinoid. The high rate of lymphatic and local spread demands a surgical approach consisting of anatomic resection and routine mediastinal lymph node dissection.

    View details for Web of Science ID A1997XW44900008

    View details for PubMedID 9305189

  • Treatment of refractory, nonmalignant hydrothorax with a pleurovenous shunt ANNALS OF THORACIC SURGERY Park, S. Z., Shrager, J. B., Allen, M. S., Nagorney, D. M. 1997; 63 (6): 1777-1779


    We present a case of long-term successful application of pleurovenous shunting for the management of pleural effusion. Intractable symptomatic hydrothorax developed as a result of transdiaphragmatic migration of hepatic ascites. After failure of traditional treatment by mechanical pleurodesis, a pleurovenous shunt was inserted. After 1 year of follow-up, the effusion is well controlled, and the shunt remains patent.

    View details for Web of Science ID A1997XH23000055

    View details for PubMedID 9205188



    Surgical thoracoscopy (or pleuroscopy) has historically been underused in the diagnosis and therapy of diseases of the chest. The rapid developments in laparoscopy in recent years caused thoracic surgeons to reconsider the use of endoscopic techniques in surgery of the chest. Advances in video camera technology and the use of digital processing technology so expanded the potential of thoracoscopy that an entirely new set of procedures, called video-assisted thoracic surgery, has emerged. This article reviews situations in which video-assisted procedures have proven useful, the techniques by which these procedures are performed, and the rationale behind using the video-assisted in lieu of the open approach. Video-assisted surgery often allows one to accomplish the same goal as the comparable open procedure but with less morbidity and a shorter hospital stay. With continued development of instrumentation, increasingly complex procedures continue to be accomplished. It is important for radiologists to be aware of these new developments in minimally invasive surgery, as the techniques have major implications for the practice of chest medicine and surgery as a whole. The evolution of the management of the solitary pulmonary nodule is but one example of the way video-assisted thoracic surgery has called into question the traditional approach to diseases of the chest.

    View details for Web of Science ID A1995TA73300017

    View details for PubMedID 7572485



    We describe the case of a 78 year old woman with a severely dysplastic villous adenoma of the duct of Wirsung presenting with abdominal pain, emesis, weight loss, and hyperamylasemia. Abdominal ultrasound, computed tomography, and endoscopic retrograde cholangiopancreatography suggested an intraductal lesion in the head of the pancreas with a dilated distal duct. The patient underwent uncomplicated pancreaticoduodenectomy and has done well. A review of the literature on benign and malignant neoplasms of the main pancreatic duct allows formulation of the typical clinical syndrome, appropriate diagnostic work-up, treatment, and prognosis of patients with these rare lesions. The pancreatic ductal epithelium can present the full spectrum of lesions along the pathogenetic route to malignancy. This is evidence for the presence of an adenoma-to-carcinoma sequence in the pancreas analogous to that which exists in the colon.

    View details for Web of Science ID A1994PM70800002

    View details for PubMedID 7834111



    Promulgated by the Canadian surgeon Arthur Vineberg, internal mammary artery implantation received fairly widespread clinical application during the 1960s, only to be abandoned upon the introduction of coronary artery bypass grafting toward the end of the decade. By 1978, Hurst and Logue's The Heart (4th ed. New York: McGraw-Hill, page 1291) mentioned the procedure only to relate that "indirect myocardial revascularization using the internal thoracic artery is now seldom used." Between the introduction of the operation in 1945 and the mid-1960s, a remarkably hard-fought debate raged over the value of internal mammary artery implantation. Despite the fact that coronary arteriography ultimately demonstrated the viability of Vineberg's concept, for a variety of reasons the operation could not compete with coronary artery bypass grafting, and therefore rapidly fell into disuse. The central role the Vineberg procedure has played in the evolution of coronary revascularization surgery highlights the importance of reviewing the history of its development, application, and eventual abandonment. The Vineberg procedure was, after all, the first intervention documented to increase myocardial perfusion. Recent reports of long-term graft patency and clear patient benefit with internal mammary artery implants reinforce the belief that Vineberg should be given more credit for his work than he has generally received, and that internal mammary artery implantation should not be relegated to the status of a historical curiosity.

    View details for Web of Science ID A1994NL63100069

    View details for PubMedID 7910011



    The X chromosome-linked muscular dystrophic (mdx) mouse lacks the subsarcolemmal protein dystrophin and thus represents a genetic homologue of human Duchenne muscular dystrophy. The present study examined alterations in diaphragm contractile properties and myosin heavy chain (MHC) expression in young (3-4 mo) and old (22-24 mo) control and mdx mice. In young mdx mice, maximum isometric tension (Po) was reduced to 50% of control values. An increase in fibers coexpressing types I (slow) and IIa MHC as well as regenerating fibers expressing embryonic MHC occurred, whereas IIx/b fibers were decreased. In the old mdx group, Po underwent a further reduction to 25% of control, and there was a slowing of twitch kinetics along with markedly increased diaphragm endurance. These changes were associated with an approximate sevenfold increase in type I MHC fibers and virtual elimination of the IIx/b fiber population; there was no detectable embryonic MHC expression. We conclude that the mdx diaphragm responds to progressive muscle degeneration with transition to a slower phenotype associated with reduced power output and augmented muscle endurance. In the setting of progressive muscle fiber destruction, these changes may help preserve contractile function and promote greater survival of remaining muscle fibers by decreasing cellular energy requirements.

    View details for Web of Science ID A1993MA18400030

    View details for PubMedID 8214039



    The protein dystrophin, normally found on the cytoplasmic surface of skeletal muscle cell membranes, is absent in patients with Duchenne muscular dystrophy as well as mdx (X-linked muscular dystrophy) mice. Although its primary structure has been determined, the precise functional role of dystrophin remains the subject of speculation. In the present study, we demonstrate that dystrophin-deficient muscle fibers of the mdx mouse exhibit an increased susceptibility to contraction-induced sarcolemmal rupture. The level of sarcolemmal damage is directly correlated with the magnitude of mechanical stress placed upon the membrane during contraction rather than the number of activations of the muscle. These findings strongly support the proposition that the primary function of dystrophin is to provide mechanical reinforcement to the sarcolemma and thereby protect it from the membrane stresses developed during muscle contraction. Furthermore, the methodology used in this study should prove useful in assessing the efficacy of dystrophin gene therapy in the mdx mouse.

    View details for Web of Science ID A1993KX81600123

    View details for PubMedID 8475120

  • A PCR-BASED ASSAY FOR THE WILD-TYPE DYSTROPHIN GENE TRANSFERRED INTO THE MDX MOUSE MUSCLE & NERVE Shrager, J. B., Naji, A., Kelly, A. M., Stedman, H. H. 1992; 15 (10): 1133-1137


    Myoblast transfer has emerged as a promising treatment for inherited myopathies such as Duchenne muscular dystrophy (DMD). Further development of the technique's therapeutic potential requires an experimental system in which issues of graft rejection can be clearly discriminated from those related to myoblast biology. Here we report the development and initial application of a quantitative assay for myogenic cells bearing a wild-type dystrophin gene following transfer into the mdx mouse. The technique relies upon the ability of a mutagenizing polymerase chain reaction (PCR) primer to create a new restriction site in the amplification production of the wild-type, but not the mdx dystrophin gene. The ratio of host to donor cells can be determined from muscle biopsies as small as 1 mg, regardless of donor H-2 background. This simple technique should allow a number of basic questions related to myoblast and direct gene transfer to be addressed using the mdx mouse model.

    View details for Web of Science ID A1992JN86500011

    View details for PubMedID 1357549


    View details for Web of Science ID A1991GG28300010

    View details for PubMedID 1883127

  • THE MDX MOUSE DIAPHRAGM REPRODUCES THE DEGENERATIVE CHANGES OF DUCHENNE MUSCULAR-DYSTROPHY NATURE Stedman, H. H., Sweeney, H. L., Shrager, J. B., Maguire, H. C., Panettieri, R. A., Petrof, B., Narusawa, M., Leferovich, J. M., Sladky, J. T., Kelly, A. M. 1991; 352 (6335): 536-539


    Although murine X-linked muscular dystrophy (mdx) and Duchenne muscular dystrophy (DMD) are genetically homologous and both characterized by a complete absence of dystrophin, the limb muscles of adult mdx mice suffer neither the detectable weakness nor the progressive degeneration that are features of DMD. Here we show that the mdx mouse diaphragm exhibits a pattern of degeneration, fibrosis and severe functional deficit comparable to that of DMD limb muscle, although adult mice show no overt respiratory impairment. Progressive functional changes include reductions in strength (to 13.5% of control by two years of age), elasticity, twitch speed and fibre length. The collagen density rises to at least seven times that of control diaphragm and ten times that of mdx hind-limb muscle. By 1.5 years of age, similar but less severe histological changes emerge in the accessory muscles of respiration. On the basis of these findings, we propose that dystrophin deficiency alters the threshold for work-induced injury. Our data provide a quantitative framework for studying the pathogenesis of dystrophy and extend the application of the mdx mouse as an animal model.

    View details for Web of Science ID A1991GA22600065

    View details for PubMedID 1865908