Joseph Shrager

All Publications

• JAK inhibition with tofacitinib rapidly increases contractile force in human skeletal muscle. Life science alliance Shrager, J. B., Randle, R., Lee, M., Ahmed, S. S., Trope, W., Lui, N., Poultsides, G., Liou, D., Visser, B., Norton, J. A., Nesbit, S. M., He, H., Kapula, N., Wallen, B., Fatodu, E., Sadeghi, C. A., Konsker, H. B., Elliott, I., Guenthart, B., Backhus, L., Cooke, R., Berry, M., Tang, H. 2024; 7 (11)

  Abstract

  Reduction in muscle contractile force associated with many clinical conditions incurs serious morbidity and increased mortality. Here, we report the first evidence that JAK inhibition impacts contractile force in normal human muscle. Muscle biopsies were taken from patients who were randomized to receive tofacitinib (n = 16) or placebo (n = 17) for 48 h. Single-fiber contractile force and molecular studies were carried out. The contractile force of individual diaphragm myofibers pooled from the tofacitinib group (n = 248 fibers) was significantly higher than those from the placebo group (n = 238 fibers), with a 15.7% greater mean maximum specific force (P = 0.0016). Tofacitinib treatment similarly increased fiber force in the serratus anterior muscle. The increased force was associated with reduced muscle protein oxidation and FoxO-ubiquitination-proteasome signaling, and increased levels of smooth muscle MYLK. Inhibition of MYLK attenuated the tofacitinib-dependent increase in fiber force. These data demonstrate that tofacitinib increases the contractile force of skeletal muscle and offers several underlying mechanisms. Inhibition of the JAK-STAT pathway is thus a potential new therapy for the muscle dysfunction that occurs in many clinical conditions.

  View details for DOI 10.26508/lsa.202402885

  View details for PubMedID 39122555

  View details for PubMedCentralID PMC11316201

• Clinical impact of EGFR and KRAS mutations in surgically treated unifocal and multifocal lung adenocarcinoma. Translational lung cancer research Jiang, J., Berry, M. F., Lui, N. S., Liou, D. Z., Trope, W. L., Backhus, L. M., Shrager, J. B. 2024; 13 (6): 1222-1231

  Abstract

  Epidermal growth factor receptor (EGFR) and Kirsten rat sarcoma (KRAS) are the two most common oncogenic drivers in lung adenocarcinoma, and their roles still need further exploration. Here we aimed to compare the clinical impact of EGFR and KRAS mutations on disease progression in resected unifocal and multifocal lung adenocarcinoma.Clinicopathologic and genomic data were collected for patients who underwent resection of lung adenocarcinoma from 2008 to 2022 at Stanford University Hospital. Retrospective review was performed in 241 patients whose tumors harbored EGFR (n=150, 62.2%) or KRAS (n=91, 37.8%) mutations. Clinical outcome was analyzed with special attention to the natural history of secondary nodules in multifocal cases wherein the dominant tumor had been resected.We confirm that compared with EGFR mutations, patients with KRAS mutations had more smokers, larger tumor size, higher TNM stage, higher positron emission tomography (PET)/computed tomography (CT) standard uptake value max, higher tumor mutation burden, and worse disease-free survival and overall survival on univariate analysis. For patients with multifocal pulmonary nodules, the median follow-up of unresected secondary nodules was 55 months. Secondary nodule progression-free survival (SNPFS) was significantly worse for patients with KRAS mutations than those with EGFR mutations (mean 40.3±6.6 vs. 67.7±6.5 months, P=0.004). Univariate analysis showed tumor size, tumor morphology, pathologic TNM stage, and KRAS mutations were significantly associated with SNPFS, while multivariate analysis showed only KRAS mutations were independently associated with worse SNPFS (hazard ratio 1.752, 95% confidence interval: 1.017-3.018, P=0.043).Resected lung adenocarcinomas with KRAS mutations have more aggressive clinicopathological features and confer worse prognosis than those with EGFR mutations. Secondary pulmonary nodules in multifocal cases with dominant KRAS-mutant tumors have more rapid progression of the secondary nodules.

  View details for DOI 10.21037/tlcr-24-165

  View details for PubMedID 38973951

  View details for PubMedCentralID PMC11225054

• The 2023 American Association for Thoracic Surgery (AATS) Expert Consensus Document: Management of subsolid lung nodules. The Journal of thoracic and cardiovascular surgery Chen, H., Kim, A. W., Hsin, M., Shrager, J. B., Prosper, A. E., Wahidi, M. M., Wigle, D. A., Wu, C. C., Huang, J., Yasufuku, K., Henschke, C. I., Suzuki, K., Tailor, T. D., Jones, D. R., Yanagawa, J. 2024

  Abstract

  Lung cancers that present as radiographic subsolid nodules represent a subtype with distinct biological behavior and outcomes. The objective of this document is to review the existing literature and report consensus among a group of multidisciplinary experts, providing specific recommendations for the clinical management of subsolid nodules.The American Association for Thoracic Surgery Clinical Practice Standards Committee assembled an international, multidisciplinary expert panel composed of radiologists, pulmonologists, and thoracic surgeons with established expertise in the management of subsolid nodules. A focused literature review was performed with the assistance of a medical librarian. Expert consensus statements were developed with class of recommendation and level of evidence for each of 4 main topics: (1) definitions of subsolid nodules (radiology and pathology), (2) surveillance and diagnosis, (3) surgical interventions, and (4) management of multiple subsolid nodules. Using a modified Delphi method, the statements were evaluated and refined by the entire panel.Consensus was reached on 17 recommendations. These consensus statements reflect updated insights on subsolid nodule management based on the latest literature and current clinical experience, focusing on the correlation between radiologic findings and pathological classifications, individualized subsolid nodule surveillance and surgical strategies, and multimodality therapies for multiple subsolid lung nodules.Despite the complex nature of the decision-making process in the management of subsolid nodules, consensus on several key recommendations was achieved by this American Association for Thoracic Surgery expert panel. These recommendations, based on evidence and a modified Delphi method, provide guidance for thoracic surgeons and other medical professionals who care for patients with subsolid nodules.

  View details for DOI 10.1016/j.jtcvs.2024.02.026

  View details for PubMedID 38878052

• What is an Adequate Margin During Sublobar Resection of ≤3cm N0 Subsolid Lung Adenocarcinomas? The Annals of thoracic surgery Kamtam, D. N., Berry, M. F., Lui, N. S., Satoyoshi, M., Elliott, I. A., Liou, D. Z., Guenthart, B., Backhus, L. M., Shrager, J. B. 2024

  Abstract

  Sublobar resection offers non-inferior survival vs. lobectomy for ≤2cm NSCLC and is commonly employed for subsolid tumors. While data exists for solid tumors, the minimum adequate margin of resection for subsolid adenocarcinomas remains unclear.Retrospective review of 1101 adenocarcinoma resections at our institution, 2006-2022.tumors≤3cm with ≥10% radiographic ground glass, excised by sublobar resection.positive nodes, positive or unreported margin. The primary outcome was rate of local recurrence(LR) at multiple thresholds of margin distance. Relationship between margin distance and solid-component size was also explored.194 patients met inclusion criteria. Median(IQR) tumor diameter and margin distance were 12(9-17)mm and 10(5-17)mm, respectively. Median follow-up was 42.5 months. There was a progressive increase in LR with diminishing margin (0.1cm decrements) from 1.5cm to 0.5cm. The difference in the rate of LR between "over"(n=143) and "under"(n=51) was most significant at 0.5cm [8/51(15.7%) vs. 6/143(4.2%),p=0.01] but did not reach α adjusted for multiple comparisons. On Cox regression for LR-free survival (LRFS), margin ≤0.5cm(p=0.19) and %solid component (p=0.14) trended to significance. Combining these using margin-distance-to-solid-component-size ratio, a ratio≤1 did show a significantly higher rate of local recurrence [7(14.3%) vs. 2(2.0%),p=0.009]. Treatment of local recurrences provided at least intermediate-term survival in 87% of recurrences (median post-recurrence follow-up 44 months).During sublobar resection of subsolid lung adenocarcinomas, margin-to-solid-component-size ratio>1.0 appears to be a more reliable factor than margin distance alone to minimize local recurrence. Local recurrence, however, may not impact survival in patients with subsolid adenocarcinomas if timely treatment is administered.

  View details for DOI 10.1016/j.athoracsur.2024.04.018

  View details for PubMedID 38734402

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

  Abstract

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

  View details for DOI 10.1016/j.ijrobp.2024.03.049

  View details for PubMedID 38615887

• We should be considering lung cancer screening for never-smoking Asian-American females. The Journal of thoracic and cardiovascular surgery Kamtam, D. N., Shrager, J. B. 2023

  View details for DOI 10.1016/j.jtcvs.2023.10.020

  View details for PubMedID 37844730

• p53 governs an AT1 differentiation programme in lung cancer suppression. Nature Kaiser, A. M., Gatto, A., Hanson, K. J., Zhao, R. L., Raj, N., Ozawa, M. G., Seoane, J. A., Bieging-Rolett, K. T., Wang, M., Li, I., Trope, W. L., Liou, D. Z., Shrager, J. B., Plevritis, S. K., Newman, A. M., Van Rechem, C., Attardi, L. D. 2023

  Abstract

  Lung cancer is the leading cause of cancer deaths worldwide1. Mutations in the tumour suppressor gene TP53 occur in 50% of lung adenocarcinomas (LUADs) and are linked to poor prognosis1-4, but how p53 suppresses LUAD development remains enigmatic. We show here that p53 suppresses LUAD by governing cell state, specifically by promoting alveolar type 1 (AT1) differentiation. Using mice that express oncogenic Kras and null, wild-type or hypermorphic Trp53 alleles in alveolar type 2 (AT2) cells, we observed graded effects of p53 on LUAD initiation and progression. RNA sequencing and ATAC sequencing of LUAD cells uncovered a p53-induced AT1 differentiation programme during tumour suppression in vivo through direct DNA binding, chromatin remodelling and induction of genes characteristic of AT1 cells. Single-cell transcriptomics analyses revealed that during LUAD evolution, p53 promotes AT1 differentiation through action in a transitional cell state analogous to a transient intermediary seen during AT2-to-AT1 cell differentiation in alveolar injury repair. Notably, p53 inactivation results in the inappropriate persistence of these transitional cancer cells accompanied by upregulated growth signalling and divergence from lung lineage identity, characteristics associated with LUAD progression. Analysis of Trp53 wild-type and Trp53-null mice showed that p53 also directs alveolar regeneration after injury by regulating AT2 cell self-renewal and promoting transitional cell differentiation into AT1 cells. Collectively, these findings illuminate mechanisms of p53-mediated LUAD suppression, in which p53 governs alveolar differentiation, and suggest that tumour suppression reflects a fundamental role of p53 in orchestrating tissue repair after injury.

  View details for DOI 10.1038/s41586-023-06253-8

  View details for PubMedID 37468633

  View details for PubMedCentralID 4231481

• KRAS(G12D) drives lepidic adenocarcinoma through stem-cell reprogramming. Nature Juul, N. H., Yoon, J. K., Martinez, M. C., Rishi, N., Kazadaeva, Y. I., Morri, M., Neff, N. F., Trope, W. L., Shrager, J. B., Sinha, R., Desai, T. J. 2023

  Abstract

  Many cancers originate from stem or progenitor cells hijacked by somatic mutations that drive replication, exemplified by adenomatous transformation of pulmonary alveolar epithelial type II (AT2) cells1. Here we demonstrate a different scenario: expression of KRAS(G12D) in differentiated AT1 cells reprograms them slowly and asynchronously back into AT2 stem cells that go on to generate indolent tumours. Like human lepidic adenocarcinoma, the tumour cells slowly spread along alveolar walls in a non-destructive manner and have low ERK activity. We find that AT1 and AT2 cells act as distinct cells of origin and manifest divergent responses to concomitant WNT activation and KRAS(G12D) induction, which accelerates AT2-derived but inhibits AT1-derived adenoma proliferation. Augmentation of ERK activity in KRAS(G12D)-induced AT1 cells increases transformation efficiency, proliferation and progression from lepidic to mixed tumour histology. Overall, we have identified a new cell of origin for lung adenocarcinoma, the AT1 cell, which recapitulates features of human lepidic cancer. In so doing, we also uncover a capacity for oncogenic KRAS to reprogram a differentiated and quiescent cell back into its parent stem cell en route to adenomatous transformation. Our work further reveals that irrespective of a given cancer's current molecular profile and driver oncogene, the cell of origin exerts a pervasive and perduring influence on its subsequent behaviour.

  View details for DOI 10.1038/s41586-023-06324-w

  View details for PubMedID 37468622

  View details for PubMedCentralID 4013278

• Risk of adenocarcinoma in patients with a suspicious ground-glass opacity: a retrospective review JOURNAL OF THORACIC DISEASE Roy, E., Shrager, J., Benson, J., Trope, W., Bhandari, P., Lui, N., Liou, D., Backhus, L., Berry, M. F. 2022

  View details for DOI 10.21037/jtd-22-583

  View details for Web of Science ID 000869953800001

• Half of Anastomotic Leaks after Esophagectomy are Undetected on Initial Postoperative Esophagram. The Annals of thoracic surgery Elliott, I. A., Berry, M. F., Trope, W., Lui, N. S., Guenthart, B. A., Liou, D. Z., Whyte, R. I., Backhus, L. M., Shrager, J. B. 2022

  Abstract

  The sensitivity of fluoroscopic esophagrams with oral contrast to exclude anastomotic leak after esophagectomy is not well-documented, and the consequences of missing a leak in this setting have not been previously described.We performed a retrospective cohort study of a prospectively maintained institutional database of patients undergoing esophagectomy with esophagogastric anastomosis 2008-2020. Relevant details regarding leaks, management, and outcomes were obtained from the database and formal chart review. Statistical analysis was performed to compare patients with and without leaks, and those with false negative versus positive esophagrams.There were 384 patients who underwent esophagectomy with gastric reconstruction: the majority were Ivor-Lewis (82%), and 51% were wholly or partially minimally-invasive. Using a broad definition of leak, 55 patients (16.7%) developed an anastomotic leak. Twenty-seven of the 55 patients (49%) who ultimately were found to have a leak initially had a negative esophagram (performed on average on postoperative day 6). Those with a negative initial esophagram were more likely to have an uncontained leak (81% vs. 29%, p<0.01), require unplanned readmission (70% vs. 39%, p=0.02), and undergo reoperation (44% vs. 11%, p<0.01).Early postoperative esophagrams intended to evaluate anastomotic integrity have a low sensitivity of 51%, and leaks missed on initial esophagram have greater clinical consequences than those identified on initial esophagram. These findings suggest a high index of suspicion must be maintained even after a normal esophagram and calls into question the common practice of using this test to triage patients for diet advancement.

  View details for DOI 10.1016/j.athoracsur.2022.04.053

  View details for PubMedID 35618049

• Positron emission tomography/computed tomography differentiates resectable thymoma from anterior mediastinal lymphoma. The Journal of thoracic and cardiovascular surgery Byrd, C. T., Trope, W. L., Bhandari, P., Konsker, H. B., Moradi, F., Lui, N. S., Liou, D. Z., Backhus, L. M., Berry, M. F., Shrager, J. B. 2022

  Abstract

  OBJECTIVE: Discrete anterior mediastinal masses most often represent thymoma or lymphoma. Lymphoma treatment is nonsurgical and requires biopsy. Noninvasive thymoma is ideally resected without biopsy, which may potentiate pleural metastases. This study sought to determine if clinical criteria or positron emission tomography/computed tomography could accurately differentiate the 2, guiding a direct surgery versus biopsy decision.METHODS: A total of 48 subjects with resectable thymoma and 29 subjects with anterior mediastinal lymphoma treated from 2006 to 2019 were retrospectively examined. All had pretreatment positron emission tomography/computed tomography and appeared resectable (solitary, without clear invasion or metastasis). Reliability of clinical criteria (age and B symptoms) and positron emission tomography/computed tomography maximum standardized uptake value were assessed in differentiating thymoma and lymphoma using Wilcoxon rank-sum test, chi-square test, and logistic regression. Receiver operating characteristic analysis identified the maximum standardized uptake value threshold most associated with thymoma.RESULTS: There was no association between tumor type and age group (P=.183) between those with thymoma versus anterior mediastinal lymphoma. Patients with thymoma were less likely to report B symptoms (P<.001). The median maximum standardized uptake value of thymoma and lymphoma differed dramatically: 4.35 versus 18.00 (P<.001). Maximum standardized uptake value was independently associated with tumor type on multivariable regression. On receiver operating characteristic analysis, lower maximum standardized uptake value was associated with thymoma. Maximum standardized uptake value less than 12.85 was associated with thymoma with 100.00% sensitivity and 88.89% positive predictive value. Maximum standardized uptake value less than 7.50 demonstrated 100.00% positive predictive value for thymoma.CONCLUSIONS: Positron emission tomography/computed tomography maximum standardized uptake value of resectable anterior mediastinal masses may help guide a direct surgery versus biopsy decision. Tumors with maximum standardized uptake value less than 7.50 are likely thymoma and thus perhaps appropriately resected without biopsy. Tumors with maximum standardized uptake value greater than 7.50 should be biopsied to rule out lymphoma. Lymphoma is likely with maximum standardized uptake value greater than 12.85.

  View details for DOI 10.1016/j.jtcvs.2022.02.055

  View details for PubMedID 35568521

• Rationale and design of a mechanistic clinical trial of JAK inhibition to prevent ventilator-induced diaphragm dysfunction. Respiratory medicine Shrager, J. B., Wang, Y., Lee, M., Nesbit, S., Trope, W., Konsker, H., Fatodu, E., Berry, M. S., Poulstides, G., Norton, J., Burdon, T., Backhus, L., Cooke, R., Tang, H. 2021; 189: 106620

  Abstract

  INTRODUCTION: Ventilator-induced diaphragm dysfunction (VIDD) is an important phenomenon that has been repeatedly demonstrated in experimental and clinical models of mechanical ventilation. Even a few hours of MV initiates signaling cascades that result in, first, reduced specific force, and later, atrophy of diaphragm muscle fibers. This severe, progressive weakness of the critical ventilatory muscle results in increased duration of MV and thus increased MV-associated complications/deaths. A drug that could prevent VIDD would likely have a major positive impact on intensive care unit outcomes. We identified the JAK/STAT pathway as important in VIDD and then demonstrated that JAK inhibition prevents VIDD in rats. We subsequently developed a clinical model of VIDD demonstrating reduced contractile force of isolated diaphragm fibers harvested after 7 vs 1h of MV during a thoracic surgical procedure.MATERIALS AND METHODS: The NIH-funded clinical trial that has been initiated is a prospective, placebo controlled trial: subjects undergoing esophagectomy are randomized to receive 6 preoperative doses of the FDA-approved JAK inhibitor Tofacitinib (commonly used for rheumatoid arthritis) vs. placebo. The primary outcome variable will be the difference in the reduction that occurs in force generation of diaphragm single muscle fibers (normalized to their cross-sectional area), in the Tofacitinib vs. placebo subjects, over 6h of MV.DISCUSSION: This trial represents a first-in-human, mechanistic clinical trial of a drug to prevent VIDD. It will provide proof-of-concept in human subjects whether JAK inhibition prevents clinical VIDD, and if successful, will support an ICU-based clinical trial that would determine whether JAK inhibition impacts clinical outcome variables such as duration of MV and mortality.

  View details for DOI 10.1016/j.rmed.2021.106620

  View details for PubMedID 34655959

• Impact of the Surgical Approach to Thymectomy Upon Complete Stable Remission Rates in Myasthenia Gravis: A Meta-analysis. Neurology Solis-Pazmino, P., Baiu, I., Lincango-Naranjo, E., Trope, W., Prokop, L., Ponce, O. J., Shrager, J. B. 2021

  Abstract

  OBJECTIVES: To determine whether the available operative techniques for thymectomy in myasthenia gravis (MG) confer variable chances for achieving complete stable remission (CSR), we performed a meta-analysis of comparative studies of surgical approaches to thymectomy.METHODS: Meta-analysis of all studies providing comparative data on thymectomy approaches, with CSR reported and minimum 3 years mean follow-up.RESULTS: 12 cohort studies and one randomized clinical trial, containing 1598 patients, met entry criteria. At 3 years, CSR from MG was similar following VATS extended vs. both basic (RR 1.00, p=1.00, 95% CI 0.39-2.58) and extended (RR 0.96, p=0.74, CI: 0.72-1.27) transsternal approaches. CSR at 3 years was also similar following extended transsternal vs. combined transcervical-subxiphoid (RR 1.08, p=0.62, CI: 0.8-1.44) approaches. VATS extended approaches remained statistically equivalent to extended transsternal approaches through 9 years of follow-up (RR 1.51, p=0.05, CI: 0.99-2.30). The only significant difference in CSR rate between a traditional open and a minimally invasive approach was seen at 10 years when comparing the now-abandoned basic (non-sternum-lifting) transcervical approach and the extended transsternal approach (RR 0.4, p=0.01, CI: 0.2-0.8).CONCLUSIONS: A significant difference in the rate of CSR among various surgical approaches for thymectomy in MG was identified only at long-term follow-up, and only between what might be considered the most aggressive approach (extended transsternal thymectomy) and the least aggressive approach (basic transcervical thymectomy). Extended minimally invasive approaches appear to have equivalent CSR rates to extended transsternal approaches and are therefore appropriate in the hands of experienced surgeons.

  View details for DOI 10.1212/WNL.0000000000012153

  View details for PubMedID 33947783

• Cancer diagnoses and survival rise as 65-year-olds become Medicare-eligible. Cancer Patel, D. C., He, H., Berry, M. F., Yang, C. J., Trope, W. L., Wang, Y., Lui, N. S., Liou, D. Z., Backhus, L. M., Shrager, J. B. 2021

  Abstract

  BACKGROUND: A Medicare effect has been described to account for increased health care utilization occurring at the age of 65 years. The existence of such an effect in cancer care, where it would be most likely to reduce mortality, has been unclear.METHODS: Patients aged 61 to 69 years who were diagnosed with lung, breast, colon, or prostate cancer from 2004 to 2016 were identified with the Surveillance, Epidemiology, and End Results database and were dichotomized on the basis of eligibility for Medicare (61-64 vs 65-69 years). With age-over-age (AoA) percent change calculations, trends in cancer diagnoses and staging were characterized. After matching, uninsured patients who were 61 to 64 years old (pre-Medicare group) were compared with insured patients who were 65 to 69 years old (post-Medicare group) with respect to cancer-specific mortality.RESULTS: In all, 134,991 patients were identified with lung cancer, 175,558 were identified with breast cancer, 62,721 were identified with colon cancer, and 238,823 were identified with prostate cancer. The AoA growth in the number of cancer diagnoses was highest at the age of 65 years in comparison with all other ages within the decade for all 4 cancers (P < .01, P < .001, P < .01, and P < .001, respectively). In a comparison of diagnoses at the age of 65 years with those in the 61- to 64-year-old cohort, the greatest difference for all 4 cancers was seen in stage I. In matched analyses, the 5-year cancer-specific mortality was worse for lung (86.3% vs 78.5%; P < .001), breast (32.7% vs 11.0%; P < .001), colon (57.1% vs 35.6%; P < .001), and prostate cancer (16.9% vs 4.8%; P < .001) in the uninsured pre-Medicare group than the insured post-Medicare group.CONCLUSIONS: The age threshold of 65 years for Medicare eligibility is associated with more cancer diagnoses (particularly stage I), and this results in lower long-term cancer-specific mortality for all cancers studied.LAY SUMMARY: Contributing to the current debate regarding Medicare for all, this study shows that the expansion of Medicare would improve cancer outcomes for the near elderly.

  View details for DOI 10.1002/cncr.33498

  View details for PubMedID 33778953

• A molecular cell atlas of the human lung from single-cell RNA sequencing. Nature Travaglini, K. J., Nabhan, A. N., Penland, L., Sinha, R., Gillich, A., Sit, R. V., Chang, S., Conley, S. D., Mori, Y., Seita, J., Berry, G. J., Shrager, J. B., Metzger, R. J., Kuo, C. S., Neff, N., Weissman, I. L., Quake, S. R., Krasnow, M. A. 2020

  Abstract

  Although single-cell RNA sequencing studies have begun to provide compendia of cell expression profiles1-9, it has been difficult to systematically identify and localize all molecularcell types in individual organs to create a full molecular cell atlas. Here, using droplet- and plate-based single-cell RNA sequencing of approximately 75,000 human cells across all lung tissue compartments and circulating blood, combined with a multi-pronged cell annotation approach, we create an extensive cell atlas of the human lung. We define the gene expression profiles and anatomical locations of 58 cell populations in the human lung, including 41 out of 45 previously known cell types and 14 previously unknown ones. This comprehensive molecular atlas identifies the biochemical functions of lung cells and the transcription factors and markers for making and monitoring them; defines the cell targets of circulating hormones and predicts local signalling interactions and immune cell homing; and identifies cell types that are directly affected by lung disease genes and respiratory viruses. By comparing human and mouse data, we identified 17 molecular cell types that have been gained or lost during lung evolution and others with substantially altered expression profiles, revealing extensive plasticity of cell types and cell-type-specific gene expression during organ evolution including expression switches between cell types. This atlas provides the molecular foundation for investigating how lung cell identities, functions and interactions are achieved in development and tissue engineering and altered in disease and evolution.

  View details for DOI 10.1038/s41586-020-2922-4

  View details for PubMedID 33208946

• KEAP1/NFE2L2 mutations to predict local recurrence after radiotherapy but not surgery in localized non-small cell lung cancer. Binkley, M. S., Jeon, Y., Nesselbush, M., Moding, E. J., Nabet, B., Almanza, D. S., Yoo, C., Kurtz, D., Owen, S., Backhus, L., Berry, M. F., Shrager, J. B., Ramchandran, K., Padda, S., Das, M., Neal, J. W., Wakelee, H. A., Alizadeh, A. A., Loo, B. W., Diehn, M. AMER SOC CLINICAL ONCOLOGY. 2020

  View details for Web of Science ID 000560368303348

• Cancer diagnoses and survival rise as 65-year-olds become Medicare eligible. Patel, D. C., He, H., Berry, M. F., Yang, C., Trope, W., Lui, N., Liou, D. Z., Backhus, L., Shrager, J. B. AMER SOC CLINICAL ONCOLOGY. 2020

  View details for Web of Science ID 000560368301130

• Sub-solid lung adenocarcinoma in Asian versus Caucasian patients: different biology but similar outcomes JOURNAL OF THORACIC DISEASE Lui, N. S., Benson, J., He, H., Imielski, B. R., Kunder, C. A., Liou, D. Z., Backhus, L. M., Berry, M. F., Shrager, J. B. 2020; 12 (5): 2161–71

  View details for DOI 10.21037/jtd.2020.04.37

  View details for Web of Science ID 000537461900045

• Paradoxical Motion on Sniff Test Predicts Greater Improvement Following Diaphragm Plication. The Annals of thoracic surgery Patel, D. C., Berry, M. F., Bhandari, P. n., Backhus, L. M., Raees, S. n., Trope, W. n., Nash, A. n., Lui, N. S., Liou, D. Z., Shrager, J. B. 2020

  Abstract

  Diaphragm plication (DP) improves pulmonary function and quality of life for those with diaphragm paralysis/dysfunction. It is unknown whether differing degrees of diaphragm dysfunction as measured by sniff testing impact results after plication.Patients who underwent minimally invasive DP from 2008-2019 were dichotomized based on sniff test results: paradoxical motion (PM) vs. no paradoxical motion (NPM) - the latter including normal/decreased/no motion. Preoperative and postoperative pulmonary function testing (PFT) after DP was compared between the two groups. The impact of diaphragm height index (DHI), a measure of diaphragm elevation, was also assessed.Twenty-six patients underwent preoperative sniff testing, DP, and postoperative PFTs. Including all patients, DP resulted in a 17.8 ± 5.5% (p<0.001) improvement in forced expiratory volume at 1 second (FEV1), a 14.4 ± 5.3% (p<0.001) improvement in forced vital capacity (FVC), and a 4.7 ± 4.6% (p=0.539) improvement in diffusing capacity (DLCO). There were greater improvements in the PM group (n=16) vs. NPM group (n=10) for FEV1 (27.2 ± 6.0% vs. 3.9 ± 6.2%, p=0.017) and FVC (28.1 ± 5.3% vs. -0.5 ± 3.3%, p=0.001). There was no difference in ΔDLCO between groups. There were no differences between patients with PM and NPM in postoperative course/complications. No value for DHI predicted improvement in PFTs following DP.Patients with PM on sniff test have dramatically greater objective improvements in pulmonary function following plication than those without PM. Most patients without PM do not demonstrate improvement in standard PFTs. Improvements in dyspnea require additional study.

  View details for DOI 10.1016/j.athoracsur.2020.07.049

  View details for PubMedID 33031777

• Transcervical Thymectomy is the Most Cost-Effective Surgical Approach in Myasthenia Gravis. The Annals of thoracic surgery Sholtis, C. n., Teymourtash, M. n., Berry, M. n., Backhus, L. n., Bhandari, P. n., He, H. n., Benson, J. n., Wang, Y. Y., Yevudza, E. n., Lui, N. n., Shrager, J. n. 2020

  Abstract

  Extended thymectomy is now proven to improve the course of myasthenia gravis. Retrospective studies demonstrate that several techniques for thymectomy achieve overlapping remission rates. We therefore compared perioperative outcomes and costs among 3 approaches to thymectomy: sternotomy; video/robot assisted; transcervical.To ensure similar study groups, we excluded patients with >4cm or invasive tumors and those who underwent less than an extended thymectomy or concurrent procedures. Hospital costs were collected and analyzed by blinded finance personnel.The final study group consisted of 25 transcervical, 23 video/robotic, and 14 sternotomy subjects. There was a higher incidence of myasthenia gravis in the transcervical and sternotomy groups (p<0.01) and of thymoma in the video/robotic and sternotomy groups (p<0.01). Mean modified Charlson co-morbidity score was higher for sternotomy (2.7±2.1) than transcervical (1.00±.58; p<0.001) and video/robotic (1.13±.97; p=0.001). There was no difference in complication rates between approaches (p=0.83). The cost of transcervical thymectomy was 45% of the cost of sternotomy (p<0.001) and 58% of the cost of video/robotic (p=0.018) approaches; these differences remained highly significant on multivariate analysis. Transcervical thymectomy had shorter mean length of stay (1.2±.5 days) than median sternotomy (4.4±3.5; p<0.001) and video/robot assisted thymectomy (2.6±.96; p=0.045), and "bed cost" was the major contributor to cost difference between the groups.Transcervical thymectomy, which provides overlapping myasthenia gravis remission rates vs. more invasive approaches, is equally safe and far less costly than sternotomy and video/robotic approaches.

  View details for DOI 10.1016/j.athoracsur.2020.01.047

  View details for PubMedID 32135150

• Does size matter? A national analysis of the utility of induction therapy for large thymomas. Journal of thoracic disease Liou, D. Z., Ramakrishnan, D. n., Lui, N. S., Shrager, J. B., Backhus, L. M., Berry, M. F. 2020; 12 (4): 1329–41

  Abstract

  Tumor size of 8 cm or greater is a risk factor for recurrence after thymoma resection, but the role of induction therapy for large thymomas is not well defined. This study tested the hypothesis that induction therapy for thymomas 8 cm and larger improves survival.The use of induction therapy for patients treated with surgical resection for Masaoka stage I-III thymomas in the National Cancer Database between 2006-2013 was evaluated using logistic regression, Kaplan-Meier analysis, and Cox-proportional hazards methods.Of the 1,849 patients who met inclusion criteria, 582 (31.5%) had tumors ≥8 cm. Five-year survival was worse in patients with tumors ≥8 cm compared to smaller tumors [84.6% (95% CI: 81.2-88.1%) vs. 89.4% (95% CI: 87.2-91.7%), P=0.003]. Induction therapy was used in 166 (9.0%) patients overall and was more likely in patients with tumors ≥8 cm [adjusted odds ratio (AOR) 3.257, P<0.001]. Induction therapy was not associated with improved survival in the subset of patients with tumors ≥8 cm in either univariate [80.9% (95% CI: 72.6-90.1%) vs. 85.4% (95% CI: 81.8-89.3%), P=0.27] or multivariable analysis [hazard ratio (HR) 1.54, P=0.10]. Increasing age (HR 1.56/decade, P<0.001) and Masaoka stage III (HR 1.76, P=0.04) were associated with worse survival in patients with tumors ≥8 cm.Survival after thymoma resection is worse for tumors 8 cm or larger compared to smaller tumors and is not improved by induction therapy. Size alone should not be a criterion for using induction therapy prior to thymoma resection.

  View details for DOI 10.21037/jtd.2020.02.63

  View details for PubMedID 32395270

  View details for PubMedCentralID PMC7212162

• mTORC1 underlies age-related muscle fiber damage and loss by inducing oxidative stress and catabolism AGING CELL Tang, H., Inoki, K., Brooks, S. V., Okazawa, H., Lee, M., Wang, J., Kim, M., Kennedy, C. L., Macpherson, P. D., Ji, X., Van Roekel, S., Fraga, D. A., Wang, K., Zhu, J., Wang, Y., Sharp, Z. D., Miller, R. A., Rando, T. A., Goldman, D., Guan, K., Shrager, J. B. 2019; 18 (3)

  View details for DOI 10.1111/acel.12943

  View details for Web of Science ID 000467861100044

• Non-Myasthenia Gravis Immune Syndromes and the Thymus Is There a Role for Thymectomy? THORACIC SURGERY CLINICS Wightman, S. C., Shrager, J. B. 2019; 29 (2): 215-+

  View details for DOI 10.1016/j.thorsurg.2018.12.008

  View details for Web of Science ID 000466617500012

• A national analysis of open versus minimally invasive thymectomy for stage I to III thymoma. The Journal of thoracic and cardiovascular surgery Yang, C. J., Hurd, J. n., Shah, S. A., Liou, D. n., Wang, H. n., Backhus, L. M., Lui, N. S., D'Amico, T. A., Shrager, J. B., Berry, M. F. 2019

  Abstract

  The oncologic efficacy of minimally invasive thymectomy for thymoma is not well characterized. We compared short-term outcomes and overall survival between open and minimally invasive (video-assisted thoracoscopic and robotic) approaches using the National Cancer Data Base.Perioperative outcomes and survival of patients who underwent open versus minimally invasive thymectomy for clinical stage I to III thymoma from 2010 to 2014 in the National Cancer Data Base were evaluated using multivariable Cox proportional hazards modeling and propensity score-matched analysis. Predictors of minimally invasive use were evaluated using multivariable logistic regression. Outcomes of surgical approach were evaluated using an intent-to-treat analysis.Of the 1223 thymectomies that were evaluated, 317 (26%) were performed minimally invasively (141 video-assisted thoracoscopic and 176 robotic). The minimally invasive group had a shorter median length of stay when compared with the open group (3 [2-4] days vs 4 [3-6] days, P < .001). In a propensity score-matched analysis of 185 open and 185 minimally invasive (video-assisted thoracoscopic + robotic) thymectomy, the minimally invasive group continued to have a shorter median length of stay (3 vs 4 days, P < .01) but did not have significant differences in margin positivity (P = .84), 30-day readmission (P = .28), 30-day mortality (P = .60), and 5-year survival (89.4% vs 81.6%, P = .20) when compared with the open group.In this national analysis, minimally invasive thymectomy was associated with shorter length of stay and was not associated with increased margin positivity, perioperative mortality, 30-day readmission rate, or reduced overall survival when compared with open thymectomy.

  View details for DOI 10.1016/j.jtcvs.2019.11.114

  View details for PubMedID 32245668

• The Signaling Network Resulting in Ventilator-induced Diaphragm Dysfunction AMERICAN JOURNAL OF RESPIRATORY CELL AND MOLECULAR BIOLOGY Tang, H., Shrager, J. B. 2018; 59 (4): 417–27

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

  View details for Web of Science ID 000446383600008

• 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

  Abstract

  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 PubMedID 28743420

• Survival and risk factors for progression after resection of the dominant tumor in multifocal, lepidic-type pulmonary adenocarcinoma Gao, R. W., Berry, M. F., Kunder, C. A., Khuong, A. A., Wakelee, H., Neal, J. W., Backhus, L. M., Shrager, J. B. MOSBY-ELSEVIER. 2017: 2092-+

  Abstract

  It remains unclear whether a dominant lung adenocarcinoma that presents with multifocal ground glass opacities (GGOs) should be treated by local therapy. We sought to address survival in this setting and to identify risk factors for progression of unresected GGOs.Retrospective review of 70 patients who underwent resection of a pN0, lepidic adenocarcinoma, who harbored at least 1 additional GGO. Features associated with GGO progression were determined using logistic regression and survival was evaluated using the Kaplan-Meier method.Subjects harbored 1 to 7 GGOs beyond their dominant tumor (DT). Mean follow-up was 4.1 ± 2.8 years. At least 1 GGO progressed after DT resection in 21 patients (30%). In 11 patients (15.7%), this progression prompted resection (n = 5) or stereotactic radiotherapy (n = 6) at mean 2.8 ± 2.3 years. Several measures of the overall tumor burden were associated with GGO progression (all P values < .03) and with progression prompting intervention (all P values < .01). In logistic regression, greater DT size (odds ratio, 1.07; 95% confidence interval, 1.01-1.14) and an initial GGO > 1 cm (odds ratio, 4.98; 95% confidence interval, 1.15-21.28) were the only factors independently associated with GGO progression. Survival was not negatively influenced by GGO progression (100% with vs 80.7% without; P = .1) or by progression-prompting intervention (P = .4).At 4.1-year mean follow-up, 15.7% of patients with unresected GGOs after resection of a pN0 DT underwent subsequent intervention for a progressing GGO. Some features correlated with GGO growth, but neither growth, nor need for an intervention, negatively influenced survival. Thus, even those at highest risk for GGO progression should not be denied resection of a DT.

  View details for PubMedID 28863952

• 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

  Abstract

  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 PubMedID 29109401

• Circulating Tumor DNA Detects Residual Disease and Anticipates Tumor Progression Earlier Than CT Imaging Chaudhuri, A. A., Chabon, J. J., Lovejoy, A. F., Newman, A. M., Stehr, H., Azad, T. D., Zhou, L., Liu, C., Scherer, F., Kurtz, D. M., Esfahani, M. S., Say, C., Carter, J. N., Merriott, D., Dudley, J., Binkley, M. S., Modlin, L., Padda, S. K., Gensheimer, M., West, R. B., Shrager, J. B., Neal, J. W., Wakelee, H. A., Billy, W., Alizadeh, A. A., Diehn, M. ELSEVIER SCIENCE INC. 2017: E4

  View details for DOI 10.1016/j.ijrobp.2017.02.048

  View details for Web of Science ID 000403079100013

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

  Abstract

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

  View details for PubMedID 28899864

• Effect of EGFR Mutations on Survival in Patients following Surgical Resection of Lung Adenocarcinoma Laidlaw, G., Gao, R., Ayers, K., Backhus, L., Berry, M., Shrager, J. ELSEVIER SCIENCE INC. 2017: S751

  View details for Web of Science ID 000413055801500

• 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

  Abstract

  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

• Randomized Trial of Thymectomy in Myasthenia Gravis NEW ENGLAND JOURNAL OF MEDICINE Shrager, J. B. 2016; 375 (20): 2005–6

  View details for PubMedID 28112886

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

  Abstract

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

  View details for DOI 10.1038/nbt.3520

  View details for PubMedID 27018799

• 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

  View details for Web of Science ID 000369727900004

  View details for PubMedCentralID PMC4734839

• Time course and predictive factors for lung volume reduction following stereotactic ablative radiotherapy (SABR) of lung tumors. Radiation oncology Binkley, M. S., Shrager, J. B., Chaudhuri, A., Popat, R., Maxim, P. G., Shultz, D. B., Diehn, M., Loo, B. W. 2016; 11 (1): 40-?

  Abstract

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

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

  View details for PubMedID 26975700

• 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: 1318-1323

  Abstract

  The computed tomographic (CT) appearance of so-called ground glass components within lung adenocarcinomas correlate with noninvasive tumor histology, and solid radiographic components correlate with invasive histology. We hypothesized that T stage might be more accurately applied by considering the solid component nodule diameter rather than total nodule diameter.We identified 74 patients with a solitary lung adenocarcinoma who underwent resection without receiving neoadjuvant therapy. Maximum total diameter and solid diameter of the nodules were measured on CT scans performed within 3 months of surgery. Cox proportional hazard modeling and Kaplan-Meier analyses were performed to determine whether total nodule diameter or solid component diameter was more predictive of overall survival.Thirty-three patients (45 %) had a solid nodule and 41 patients (55 %) had a part-solid nodule. Most patients were white (59 %) and female (69 %), and 42 % had never smoked. Seventy-four percent underwent lobectomy and 23 % sublobar resection. Sixty-six percent had pathologic stage I disease, 22 % stage II, and 12 % stage IIIA. Mean ± SD total and solid nodule diameters were 32.1 ± 17.5 and 24.8 ± 18.0 mm, respectively (p = 0.01). Among patients with part-solid nodules, multivariate modeling incorporating significant univariate predictors of survival (age, gender, procedure, N descriptor) revealed that maximum solid diameter was associated with overall survival (hazard ratio 1.4, p = 0.01), while maximum total diameter was not.In a largely non-Asian cohort undergoing resection for adenocarcinoma, radiographic diameter of the solid component of a part-solid lesion on CT predicts overall survival better than total lesion diameter. These data provide further evidence to support altering the T descriptor for lung adenocarcinoma for part-solid nodules.

  View details for DOI 10.1245/s10434-015-4780-0

  View details for PubMedID 26228108

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

  Abstract

  Alveolar air leaks are a common problem in the daily practice of thoracic surgeons. Prolonged air leak following pulmonary resection is associated with increased morbidity, increased length of hospital stay, and increased costs. This article reviews the evidence for the various intraoperative and postoperative options to prevent and manage postoperative air leak.

  View details for DOI 10.1016/j.thorsurg.2015.07.002

  View details for PubMedID 26515941

• Endobronchial valves in a highly parsed emphysema population LANCET Shrager, J. B. 2015; 386 (9998): 1022–23

  View details for PubMedID 26116486

• The JAK-STAT Pathway Is Critical in Ventilator-Induced Diaphragm Dysfunction. Molecular medicine Tang, H., Smith, I. J., Hussain, S. N., Goldberg, P., Lee, M., Sugiarto, S., Godinez, G. L., Singh, B. K., Payan, D. G., Rando, T. A., Kinsella, T. M., Shrager, J. B. 2015; 20 (1): 579-589

  Abstract

  Mechanical ventilation (MV) is one of the lynchpins of modern intensive-care medicine and is life saving in many critically ill patients. Continuous ventilator support, however, results in ventilation-induced diaphragm dysfunction (VIDD) that likely prolongs patients' need for MV and thereby leads to major associated complications and avoidable intensive care unit (ICU) deaths. Oxidative stress is a key pathogenic event in the development of VIDD, but its regulation remains largely undefined. We report here that the JAK-STAT pathway is activated in MV in the human diaphragm, as evidenced by significantly increased phosphorylation of JAK and STAT. Blockage of the JAK-STAT pathway by a JAK inhibitor in a rat MV model prevents diaphragm muscle contractile dysfunction (by ~85%, p < 0.01). We further demonstrate that activated STAT3 compromises mitochondrial function and induces oxidative stress in vivo, and, interestingly, that oxidative stress also activates JAK-STAT. Inhibition of JAK-STAT prevents oxidative stress-induced protein oxidation and polyubiquitination and recovers mitochondrial function in cultured muscle cells. Therefore, in ventilated diaphragm muscle, activation of JAK-STAT is critical in regulating oxidative stress and is thereby central to the downstream pathogenesis of clinical VIDD. These findings establish the molecular basis for the therapeutic promise of JAK-STAT inhibitors in ventilated ICU patients.

  View details for DOI 10.2119/molmed.2014.00049

  View details for PubMedID 25286450

• Ultrasensitive Detection of Circulating Tumor DNA in Non-Small Cell Lung Cancer by Deep Sequencing Diehn, M., Bratman, S. V., Newman, A. M., Neal, J. W., Wakelee, H. A., Merritt, R. E., Shrager, J. B., Loo, B. W., Alizadeh, A. ELSEVIER SCIENCE INC. 2014: S75

  View details for DOI 10.1016/j.ijrobp.2014.08.315

  View details for Web of Science ID 000346413500167

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

  Abstract

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

  View details for DOI 10.1016/j.ijrobp.2014.05.025

  View details for Web of Science ID 000341456500029

• 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

  Abstract

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

  View details for DOI 10.1038/nm.3519

  View details for PubMedID 24705333

• mTORC1 promotes denervation-induced muscle atrophy through a mechanism involving the activation of FoxO and E3 ubiquitin ligases. Science signaling Tang, H., Inoki, K., Lee, M., Wright, E., Khuong, A., Khuong, A., Sugiarto, S., Garner, M., Paik, J., DePinho, R. A., Goldman, D., Guan, K., Shrager, J. B. 2014; 7 (314): ra18-?

  Abstract

  Skeletal muscle mass and function are regulated by motor innervation, and denervation results in muscle atrophy. The activity of mammalian target of rapamycin complex 1 (mTORC1) is substantially increased in denervated muscle, but its regulatory role in denervation-induced atrophy remains unclear. At early stages after denervation of skeletal muscle, a pathway involving class II histone deacetylases and the transcription factor myogenin mediates denervation-induced muscle atrophy. We found that at later stages after denervation of fast-twitch muscle, activation of mTORC1 contributed to atrophy and that denervation-induced atrophy was mitigated by inhibition of mTORC1 with rapamycin. Activation of mTORC1 through genetic deletion of its inhibitor TSC1 (tuberous sclerosis complex 1) sensitized mice to denervation-induced muscle atrophy and suppressed the kinase activity of Akt, leading to activation of FoxO transcription factors and increasing the expression of genes encoding E3 ubiquitin ligases atrogin [also known as MAFbx (muscle atrophy F-box protein)] and MuRF1 (muscle-specific ring finger 1). Rapamycin treatment of mice restored Akt activity, suggesting that the denervation-induced increase in mTORC1 activity was producing feedback inhibition of Akt. Genetic deletion of the three FoxO isoforms in skeletal muscle induced muscle hypertrophy and abolished the late-stage induction of E3 ubiquitin ligases after denervation, thereby preventing denervation-induced atrophy. These data revealed that mTORC1, which is generally considered to be an important component of anabolism, is central to muscle catabolism and atrophy after denervation. This mTORC1-FoxO axis represents a potential therapeutic target in neurogenic muscle atrophy.

  View details for DOI 10.1126/scisignal.2004809

  View details for PubMedID 24570486

• 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

  Abstract

  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 PubMedID 23806231

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

  Abstract

  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

• 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

  Abstract

  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 PubMedID 22767230

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

  Abstract

  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 PubMedID 22108684

• 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

  Abstract

  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 PubMedID 21597002

• 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

  Abstract

  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

• Endobronchial Valves for Emphysema NEW ENGLAND JOURNAL OF MEDICINE Shrager, J. B. 2011; 364 (4): 382–83

  View details for Web of Science ID 000286592600025

• Extended Transcervical Thymectomy: The Ultimate Minimally Invasive Approach 2nd International Biannual Minimally Invasive Thoracic Surgery Summit Shrager, J. B. ELSEVIER SCIENCE INC. 2010: S2128–S2134

  Abstract

  The ideal operative technique for thymectomy in myasthenia gravis remains controversial. Most surgeons perform thymectomy through median sternotomy; more recently, thoracoscopic and robotic approaches have been described. "Extended transcervical thymectomy" is an out-patient procedure that appears less morbid and costly than other approaches. It allows a complete extracapsular thymic resection. Kaplan-Meier complete stable remission rates after transcervical thymectomy are 33% and 35% at 3 and 6 years (higher including patients remaining on single-drug immunosuppression). The major surgical complication rate is 0.7%. We believe that this less morbid and less costly operation is a very reasonable choice in the surgical treatment of myasthenia gravis.

  View details for DOI 10.1016/j.athoracsur.2010.02.099

  View details for PubMedID 20493996

• 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

  Abstract

  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

• 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-?

  Abstract

  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

• 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

  Abstract

  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

  Abstract

  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

• 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

  Abstract

  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

• 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

  Abstract

  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

• Outcomes after 151 extended transcervical thymectomies for myasthenia gravis 42nd Annual Meeting of the Society-of-Thoracic-Surgeons Shrager, J. B., Nathan, D., Brinster, C. J., Yousuf, O., Spence, A., Chen, Z., Kaiser, L. R. ELSEVIER SCIENCE INC. 2006: 1863–69

  Abstract

  The ideal operative technique for thymectomy in myasthenia gravis (MG) remains controversial. We present the largest series of extended transcervical thymectomy to provide outcomes data to compare with transsternal procedures.A retrospective chart review/interview was made of 164 patients operated upon from 1992 to 2004. Complete remission (CR) was defined as asymptomatic off medication for 6 months or asymptomatic on low-dose single-drug therapy (< or = 10 mg/d prednisone or < or = 150 mg/d azathioprine). A modified Osserman classification based upon the Myasthenia Gravis Foundation of America quantitative disease severity score was employed.The overall complication rate was 7.3%, and nearly all procedures were outpatient. Mean age at surgery was 43 years, and mean preoperative Osserman class was 2.3 (21% class 1; 39% class 2; 28% class 3; 12% class 4). Mean length of follow-up was 53 months. Mean postoperative Osserman class was 1.0. Nineteen percent of patients failed to improve. The crude cumulative CR rate was 37% (n = 58). Kaplan-Meier estimates of CR were 43% and 45% at 3 and 6 years, respectively. On multivariate analysis, only preoperative disease severity was significantly (inversely) associated with Kaplan-Meier CR rates. Longer-term follow-up (83 months) of only the earlier patients shows preserved CR rates (46%).This largest series of extended transcervical thymectomy for MG confirms that the 5-year Kaplan-Meier CR rate is comparable with that obtained after transsternal procedures. Patients with less severe disease have higher CR rates. Complete responses are durable, as the CR rate remains stable with extended follow-up.

  View details for DOI 10.1016/j.athoracsur.2006.05.110

  View details for Web of Science ID 000241497600044

  View details for PubMedID 17062262

• 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

  Abstract

  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

  Abstract

  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

• 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

  Abstract

  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

• Comparison of stages I-II thymoma treated by complete resection with or without adjuvant radiation 39th Annual Meeting of the Society-of-Thoracic-Surgeons Singhal, S., Shrager, J. B., Rosenthal, D. I., LiVolsi, V. A., Kaiser, L. R. ELSEVIER SCIENCE INC. 2003: 1635–41

  Abstract

  Adjuvant radiation after resection of Masaoka stage II thymoma is widely advocated, but the evidence supporting it is controversial. Studies addressing this issue generally report few patients and lump all patients beyond stage I together in the analysis.We retrospectively compared outcomes of stage I and II thymomas treated by resection alone with thymomas treated by resection plus radiation. Histology was re-reviewed to confirm pathologic staging and resection margin status.Between February 1992 and 2002, we performed 167 resections for thymoma. Of these, 70 patients were believed to have tumors in stage IIb or less intraoperatively, and all of these patients underwent complete resection. We reviewed the histopathology of 62 of 70 patients. Thirty thymomas demonstrated less than complete transcapsular microscopic invasion (stage I) and 40 thymomas demonstrated microscopic transcapsular invasion or macroscopic invasion into surrounding fatty tissue (stage II). Forty-seven patients underwent surgery without postoperative mediastinal radiotherapy. Dosages in the 23 radiated patients (3 stage I and 20 stage II) consisted of 45 to 55 Gy. Median follow-up was 70.3 months. Stage II patients who were radiated (n = 20) and those who were not radiated (n = 20) consisted of identical proportions in stages IIa and IIb. Two patients recurred (1 unradiated stage I patient and 1 radiated stage IIb patient). Overall 5-year survival rate was 91%. All who died were free of recurrence at time of death. Log-rank test showed no difference in Kaplan Meier survival curves (p = 0.32) between the radiated and unradiated groups.These data support the contention that margin-negative surgical resection alone is sufficient treatment for both stages I and II thymoma.

  View details for DOI 10.1016/S0003-4975(03)00819-1

  View details for Web of Science ID 000186358600056

  View details for PubMedID 14602300

• 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

  Abstract

  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

• 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

  Abstract

  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

• 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

  Abstract

  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

• 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

  Abstract

  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

  Abstract

  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

• 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

• 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

  Abstract

  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

• DYSTROPHIN PROTECTS THE SARCOLEMMA FROM STRESSES DEVELOPED DURING MUSCLE-CONTRACTION PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Petrof, B. J., Shrager, J. B., Stedman, H. H., Kelly, A. M., Sweeney, H. L. 1993; 90 (8): 3710-3714

  Abstract

  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

  View details for PubMedCentralID PMC46371

• 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

  Abstract

  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

• Greater ipsilateral rectus muscle atrophy after robotic thoracic surgery compared with open and video-assisted thoracoscopic surgery approaches. JTCVS open Wang, Y., Randle, R. J., Bhandari, P., He, H., Trope, W. L., Guenthart, B. A., Guo, H. H., Liou, D. Z., Backhus, L. M., Berry, M. F., Shrager, J. B., Lui, N. S. 2024; 20: 202-209

  Abstract

  Robotic thoracic surgery provides another minimally invasive approach in addition to video-assisted thoracoscopic surgery (VATS) that yields less pain and faster recovery compared with open surgery. However, robotic incisions are generally placed more inferiorly, which may increase the risk of intercostal nerve injury that affects the abdominal wall. We hypothesized that a robotic approach causes greater ipsilateral rectus muscle atrophy compared with open and VATS approaches.The cross-sectional area and density of bilateral rectus abdominis muscles were measured on computed tomography scans in patients who underwent lobectomy in 2018. The differences between the contralateral and ipsilateral muscles were compared between preoperative and 6-month surveillance scans. Changes were compared among the open, VATS, and robotic approaches through a mixed effects model after adjustments of correlation and covariates.Of 99 lobectomies, 25 (25.3%) were open, 56 (56.6%) VATS, and 18 (18.1%) robotic. The difference between the contralateral and ipsilateral rectus muscle cross-sectional area was significantly larger at 6 months after robotic surgery compared with open (31.4% vs 9.5%, P = .049) and VATS (31.4% vs 14.1%, P = .021). There were no significant differences in the cross-sectional area between the open and VATS approach.In this retrospective analysis, there was greater ipsilateral rectus muscle atrophy associated with robotic thoracic surgery compared with open or VATS approaches. These findings should be correlated with clinical symptoms and followed to assess for resolution or persistence.

  View details for DOI 10.1016/j.xjon.2024.05.011

  View details for PubMedID 39296450

  View details for PubMedCentralID PMC11405974

• Impacts of Positive Margins and Surgical Extent on Outcomes after Early-Stage Lung Cancer Resection. The Annals of thoracic surgery Wong, L. Y., Dale, R., Kapula, N., Elliott, I. A., Liou, D. Z., Backhus, L. M., Lui, N. S., Shrager, J. B., Berry, M. F. 2024

  Abstract

  Sublobar resection of early-stage non-small cell lung cancer (NSCLC) is increasingly considered appropriate but may compromise margins compared to lobectomy. This study evaluated resection extent, margin status, and survival for clinical stage I NSCLC patients.Clinical T1-2N0M0 NSCLC patients in the National Cancer Database (2006-2020) treated with primary surgery were compared stratified by margin status. The potential benefit of radiation was explored in subgroup analysis of sublobar resection patients with positive margins.Positive margins occurred in 5,089 (2.8%) of 181,824 patients and were more common in sublobar resections compared to lobectomy (4.3% vs 2.4%,p<0.001). Sublobar resection had the strongest association with positive margins in multivariable analysis (OR 2.06 [95% CI 1.91-2.23],p<0.001). Patients with positive margins were more likely to undergo both adjuvant chemotherapy (16% vs 13%,p<0.001) and radiation (17% vs 1%,p<0.001) but had worse survival in univariate (44.0% 5-year OS vs 69.2%,p<0.001) and multivariable Cox analysis (HR 1.71 [95% CI 1.63-1.78, p<0.001) in the entire cohort, as well as in univariate subset analysis of lobectomy (46.9% vs 70.4%, p<0.001) and sublobar (37.5% vs 64.1%,p<0.001). Postoperative radiation for sublobar patients with positive margins did not improve 5-year OS (36.3% for irradiated patients vs 38.3% for non-irradiated patients,p=0.57), and positive margin sublobar patients treated with radiation had inferior survival to negative margin lobectomy patients.Positive margins occur more frequently after sublobar resection of clinical stage I NSCLC compared to lobectomy. Patients with positive margins have worse survival than complete resection patients and are not rescued by post-operative radiation.

  View details for DOI 10.1016/j.athoracsur.2024.05.032

  View details for PubMedID 38866199

• Interstitial macrophages are a focus of viral takeover and inflammation in COVID-19 initiation in human lung. The Journal of experimental medicine Wu, T. T., Travaglini, K. J., Rustagi, A., Xu, D., Zhang, Y., Andronov, L., Jang, S., Gillich, A., Dehghannasiri, R., Martinez-Colon, G. J., Beck, A., Liu, D. D., Wilk, A. J., Morri, M., Trope, W. L., Bierman, R., Weissman, I. L., Shrager, J. B., Quake, S. R., Kuo, C. S., Salzman, J., Moerner, W. E., Kim, P. S., Blish, C. A., Krasnow, M. A. 2024; 221 (6)

  Abstract

  Early stages of deadly respiratory diseases including COVID-19 are challenging to elucidate in humans. Here, we define cellular tropism and transcriptomic effects of SARS-CoV-2 virus by productively infecting healthy human lung tissue and using scRNA-seq to reconstruct the transcriptional program in "infection pseudotime" for individual lung cell types. SARS-CoV-2 predominantly infected activated interstitial macrophages (IMs), which can accumulate thousands of viral RNA molecules, taking over 60% of the cell transcriptome and forming dense viral RNA bodies while inducing host profibrotic (TGFB1, SPP1) and inflammatory (early interferon response, CCL2/7/8/13, CXCL10, and IL6/10) programs and destroying host cell architecture. Infected alveolar macrophages (AMs) showed none of these extreme responses. Spike-dependent viral entry into AMs used ACE2 and Sialoadhesin/CD169, whereas IM entry used DC-SIGN/CD209. These results identify activated IMs as a prominent site of viral takeover, the focus of inflammation and fibrosis, and suggest targeting CD209 to prevent early pathology in COVID-19 pneumonia. This approach can be generalized to any human lung infection and to evaluate therapeutics.

  View details for DOI 10.1084/jem.20232192

  View details for PubMedID 38597954

• ASO Visual Abstract: Complications of Outpatient Chest Tube Management for Prolonged Air Leaks After Pulmonary Surgery. Annals of surgical oncology Randle, R. J., Bhandari, P., He, H., Berry, M. F., Backhus, L. M., Lui, N. S., Liou, D. Z., Shrager, J. B. 2024

  View details for DOI 10.1245/s10434-024-15405-7

  View details for PubMedID 38743281

• Barriers to Completing Low Dose Computed Tomography Scan for Lung Cancer Screening. Clinical lung cancer Wong, L. Y., Choudhary, S., Kapula, N., Lin, M., Elliott, I. A., Guenthart, B. A., Liou, D. Z., Backhus, L. M., Berry, M. F., Shrager, J. B., Lui, N. S. 2024

  Abstract

  Annual low-dose computed tomography (LDCT) screening has been shown to reduce lung cancer mortality in high-risk individuals by detecting the disease at an earlier stage. This study aims to assess the barriers to completing LDCT in a cohort of patients who were determined eligible for lung cancer screening (LCS).We performed a single institution, mixed methods, cross-sectional study of patients who had a LDCT ordered from July to December 2022. We then completed phone surveys with patients who did not complete LDCT to assess knowledge, attitude, and perceptions toward LCS.We identified 380 patients who met inclusion criteria, including 331 (87%) who completed LDCT and 49 (13%) who did not. Patients who completed a LDCT and those who did not were similar regarding age, sex, race, primary language, household income, body mass index, median pack years, and quit time. Positive predictors of LDCT completion were: meeting USPSTF guidelines (97.9% vs 81.6%), being married (58.3% vs 44.9%), former versus current smokers (55% vs 41.7%), personal history of emphysema (60.4% vs 42.9%), and family history of lung cancer (13.9% vs 4.1%) (all P < .05). Of the patients who participated in the phone survey, only 7% of respondents thought they were high risk for developing lung cancer despite attending a shared decision-making visit and only 10% wanted to re-schedule their LDCT.There exist barriers to completing LDCT even after patients are identified as eligible and complete a shared decision-making visit secondary to knowledge barriers, misperceptions, and patient disinterest.

  View details for DOI 10.1016/j.cllc.2024.04.014

  View details for PubMedID 38749902

• Randomized controlled trials in lung cancer surgery: How are we doing? JTCVS open Wong, L. Y., Li, Y., Elliott, I. A., Backhus, L. M., Berry, M. F., Shrager, J. B., Oh, D. S. 2024; 18: 234-252

  Abstract

  Randomized control trials are considered the highest level of evidence, yet the scalability and practicality of implementing randomized control trials in the thoracic surgical oncology space are not well described. The aim of this study is to understand what types of randomized control trials have been conducted in thoracic surgical oncology and ascertain their success rate in completing them as originally planned.The ClinicalTrials.gov database was queried in April 2023 to identify registered randomized control trials performed in patients with lung cancer who underwent surgery (by any technique) as part of their treatment.There were 68 eligible randomized control trials; 33 (48.5%) were intended to examine different perioperative patient management strategies (eg, analgesia, ventilation, drainage) or to examine different intraoperative technical aspects (eg, stapling, number of ports, port placement, ligation). The number of randomized control trials was relatively stable over time until a large increase in randomized control trials starting in 2016. Forty-four of the randomized control trials (64.7%) were open-label studies, 43 (63.2%) were conducted in a single facility, 66 (97.1%) had 2 arms, and the mean number of patients enrolled per randomized control trial was 236 (SD, 187). Of 21 completed randomized control trials (31%), the average time to complete accrual was 1605 days (4.4 years) and average time to complete primary/secondary outcomes and adverse events collection was 2125 days (5.82 years).Given the immense investment of resources that randomized control trials require, these findings suggest the need to scrutinize future randomized control trial proposals to assess the likelihood of successful completion. Future study is needed to understand the various contributing factors to randomized control trial success or failure.

  View details for DOI 10.1016/j.xjon.2024.01.008

  View details for PubMedID 38690441

  View details for PubMedCentralID PMC11056451

• Complications of Outpatient Chest Tube Management for Prolonged Air Leaks After Pulmonary Surgery. Annals of surgical oncology Randle, R. J., Bhandari, P., He, H., Berry, M. F., Backhus, L. M., Lui, N. S., Liou, D. Z., Shrager, J. B. 2024

  Abstract

  Air leaks are common after pulmonary surgery. Prolonged air leaks (PALs) may persist through discharge and often are managed with one-way valve devices (OWD). We sought to determine the course and complications of patients discharged with OWDs, risk factors for complications, and to evaluate the utility of clamp trials before chest tube (CT) removal.Single-institution, retrospective review of patients discharged with a OWD after pulmonary surgery between 2008 and 2022. Charts were examined for the presence of complications and CT duration. Differences in CT duration were compared by using the Wilcoxon rank-sum test.Sixty-four of 1917 (3.3%) pulmonary surgeries resulted in OWD use. Twelve of 64 (19%) patients discharged with a OWD suffered a complication. Nine of 64 (14%) had a CT-related readmission, and seven of 64 (11%) required PAL intervention. Patients sustaining a complication demonstrated longer CT durations before complication compared with duration in patients without complications, with median days of 13 [IQR 6-21] vs. 7 [IQR 6-12], p = 0.04). Five (7.8%) OWD patients developed an empyema; only one (20%) occurred before a CT duration of 14 days. Sixteen of 64 (25%) patients underwent a clamp trial before CT removal. One of ten (10%) failed even with no air leak present, whereas one of six (17%) failed with a present/questionable air leak.One-way valve device use has a substantial complication rate, and chest tube duration is a risk factor. In-hospital interventions might benefit patients with larger leaks that likely require prolonged OWD use. Because clamp trials occasionally fail, we contend that a clamp trial is the safest course before CT removal.

  View details for DOI 10.1245/s10434-024-15219-7

  View details for PubMedID 38536584

  View details for PubMedCentralID 6026238

• Lepidic-Type Lung Adenocarcinomas: Is It Safe to Observe for Growth Prior to Treating? The Annals of thoracic surgery Wong, L. Y., Elliott, I. A., Liou, D. Z., Backhus, L. M., Lui, N. S., Shrager, J. B., Berry, M. F. 2024

  Abstract

  Lepidic-type adenocarcinomas (LPA) can be multi-focal, and treatment is often deferred until there is observed growth. This study investigated the potential downside of that strategy by evaluating the relationship of nodal involvement with tumor size and survival.The impact of tumor size on lymph node involvement and survival was evaluated for National Cancer Database patients who received surgery without induction therapy as primary treatment for cT1-3N0M0 histologically confirmed LPA from 2006-2019 using logistic regression, Kaplan-Meier, and Cox analyses.Positive nodes occurred in 442 (5.3%) of 8,286 patients. The incidence of having positive nodes approximately doubled with each 1cm increment increase in size. Patients with positive nodes were more likely to have larger tumors (27mm vs 20mm,p<0.001) and clinical T2+ disease (40.7% vs 26.8%,p<0.001) compared to node-negative patients, but tumor size was the only significant independent predictor of having positive nodal disease in logistic regression analysis; this association grew stronger with each incremental centimeter increase in size. Patients with positive nodes were more likely to undergo adjuvant radiation (23.5% vs 1.1%,p<0.001) and chemotherapy (72.9% vs 7.9%,p<0.001), and expectedly had worse survival compared to the node negative group in univariate (5-year overall survival 50.9% vs 81.1%,p<0.001) and multivariable (Hazard ratio 2.56 [95% CI 2.14-3.05],p<0.001) analyses.Nodal involvement is relatively uncommon in early-stage LPAs but steadily increases with tumor size and is associated with dramatically worse survival. This data can be used to inform treatment decisions when evaluating LPA patients.

  View details for DOI 10.1016/j.athoracsur.2024.03.003

  View details for PubMedID 38490310

• The Impact of Immunotherapy Use in Stage IIIA (T1-2N2) NSCLC: A Nationwide Analysis. JTO clinical and research reports Wong, L. Y., Liou, D. Z., Roy, M., Elliott, I. A., Backhus, L. M., Lui, N. S., Shrager, J. B., Berry, M. F. 2024; 5 (3): 100654

  Abstract

  Multiple clinical trials have revealed the benefit of immunotherapy (IO) for NSCLC, including unresectable stage III disease. Our aim was to investigate the impact of IO use on treatment and outcomes of potentially resectable stage IIIA NSCLC in a broader nationwide patient cohort.We queried the National Cancer Database (2004-2019) for patients with stage IIIA (T1-2N2) NSCLC. Treatment and survival were evaluated with descriptive statistics, logistic regression, Kaplan-Meier analysis, and Cox proportional hazards modeling.Overall, 5.5% (3777 of 68,335) of patients received IO. IO use was uncommon until 2017, but by 2019, it was given to 40.1% (1544 of 2308) of stage IIIA patients. The increased use of IO after 2017 was associated with increased definitive chemoradiation treatment (54.2% [6800 of 12,535] from years 2017 to 2019 versus 46.9% [26,251 of 55,914] from 2004 to 2016, p < 0.001) and less use of surgery (18.1% [2266 of 12,535] from years 2017 to 2019 versus 22.0% [12,300 of 55,914] from 2004 to 2016, p < 0.001). IO treatment was associated with significantly better 5-year survival in the entire cohort (36.9% versus 23.4%, p < 0.001) and the subsets of patients treated with chemoradiation (37.2% versus 22.7%, p < 0.001) and surgery (48.6% versus 44.3%, p < 0.001). Pneumonectomy use decreased with increased IO treatment (5.1% of surgical patients [116 of 2266] from years 2017 to 2019 versus 9.2% [1127 of 12,300] from 2004 to 2016, p < 0.001).Increased use of IO was associated with a change in treatment patterns and improved survival for patients with stage IIIA(N2) NSCLC.

  View details for DOI 10.1016/j.jtocrr.2024.100654

  View details for PubMedID 38496376

  View details for PubMedCentralID PMC10941003

• Outcomes of surgery for catastrophic hiatal hernia presentations. Journal of gastrointestinal surgery : official journal of the Society for Surgery of the Alimentary Tract Wong, L., Leipzig, M., Elliott, I. A., Liou, D. Z., Backhus, L. M., Shrager, J. B., Berry, M. F. 2024; 28 (3): 285-286

  View details for DOI 10.1016/j.gassur.2023.12.024

  View details for PubMedID 38445922

• Impact of guideline therapy on survival of patients with stage I-III epithelioid mesothelioma. Journal of thoracic disease Liou, D. Z., Wang, Y., Bhandari, P., Shrager, J. B., Lui, N. S., Backhus, L. M., Berry, M. F. 2023; 15 (12): 6661-6673

  Abstract

  Modern treatment guidelines recommend multimodal therapy with at least chemotherapy and surgery for patients with potentially resectable epithelioid mesothelioma. This study evaluated guideline compliance for patients with stage I-III epithelioid mesothelioma and tested the hypothesis that guideline-concordant therapy improved survival.The National Cancer Database was queried for patients with stage I-III epithelioid malignant pleural mesothelioma between 2004 and 2016. The impact of therapy was evaluated using logistic regression, Kaplan-Meier analysis, Cox-proportional hazards analysis, and propensity-scoring methods.During the study period, guideline-concordant therapy was used in 677 patients (19.1%), and 2,857 patients (80.8%) did not have guideline-concordant therapy. Younger age, being insured, living in a census tract with a higher income, clinical stage, and being treated at an academic or research program were all predictors of receiving guideline-concordant therapy in multivariable analysis. Guideline-concordant therapy yielded improved median survival [24.7 (22.4-26.1) vs. 13.7 (13.2-14.4) months] and 5-year survival [17.7% (14.7-21.3%) vs. 8.0% (7.0-9.3%)] (P<0.001), and continued to be associated with better survival in both multivariable analysis and propensity-matched analysis. In the patients who received guideline therapy, median survival [24.9 (21.9-27.2) vs. 24.5 (21.7-28.1) months] and 5-year survival [14.9% (10.9-20.2%) vs. 20.1% (16.0-25.4%)] was not significantly different between patients who underwent induction (n=304) versus adjuvant (n=373) chemotherapy (P=0.444).Guideline-concordant therapy for potentially resectable epithelioid mesothelioma is associated with significantly improved survival but used in a minority of patients. The timing of chemotherapy with surgery in this study did not have a significant impact on overall survival.

  View details for DOI 10.21037/jtd-23-1334

  View details for PubMedID 38249900

  View details for PubMedCentralID PMC10797401

• Phenotyping EMT and MET cellular states in lung cancer patient liquid biopsies at a personalized level using mass cytometry. Scientific reports Karacosta, L. G., Pancirer, D., Preiss, J. S., Benson, J. A., Trope, W., Shrager, J. B., Sung, A. W., Neal, J. W., Bendall, S. C., Wakelee, H., Plevritis, S. K. 2023; 13 (1): 21781

  Abstract

  Malignant pleural effusions (MPEs) can be utilized as liquid biopsy for phenotyping malignant cells and for precision immunotherapy, yet MPEs are inadequately studied at the single-cell proteomic level. Here we leverage mass cytometry to interrogate immune and epithelial cellular profiles of primary tumors and pleural effusions (PEs) from early and late-stage non-small cell lung cancer (NSCLC) patients, with the goal of assessing epithelial-mesenchymal transition (EMT) and mesenchymal-epithelial transition (MET) states in patient specimens. By using the EMT-MET reference map PHENOSTAMP, we observe a variety of EMT states in cytokeratin positive (CK+) cells, and report for the first time MET-enriched CK+ cells in MPEs. We show that these states may be relevant to disease stage and therapy response. Furthermore, we found that the fraction of CD33+ myeloid cells in PEs was positively correlated to the fraction of CK+ cells. Longitudinal analysis of MPEs drawn 2 months apart from a patient undergoing therapy, revealed that CK+ cells acquired heterogeneous EMT features during treatment. We present this work as a feasibility study that justifies deeper characterization of EMT and MET states in malignant cells found in PEs as a promising clinical platform to better evaluate disease progression and treatment response at a personalized level.

  View details for DOI 10.1038/s41598-023-46458-5

  View details for PubMedID 38065965

  View details for PubMedCentralID 2689101

• Risk of developing subsequent primary lung cancer after receiving radiation for breast cancer. JTCVS open Wong, L., Kapula, N., He, H., Guenthart, B. A., Vitzthum, L. K., Horst, K., Liou, D. Z., Backhus, L. M., Lui, N. S., Berry, M. F., Shrager, J. B., Elliott, I. A. 2023; 16: 919-928

  Abstract

  Background: Radiotherapy (RT) is integral to breast cancer treatment, especially in the current era that emphasizes breast conservation. The aim of our study was to determine the incidence of subsequent primary lung cancer after RT exposure for breast cancer over a time span of 3decades to quantify this risk over time as modern oncologic treatment continues to evolve.Methods: The SEER (Surveillance, Epidemiology, and End Results) database was queried from 1988 to 2014 for patients diagnosed with nonmetastatic breast cancer. Patients who subsequently developed primary lung cancer were identified. Multivariable regression modeling was performed to identify independent factors associated with the development of lung cancer stratified by follow up intervals of 5 to 9years, 10 to 15years, and >15years after breast cancer diagnosis.Results: Of the 612,746 patients who met our inclusion criteria, 319,014 (52%) were irradiated. primary lung cancer developed in 5556 patients (1.74%) in the RT group versus 4935 patients (1.68%) in the non-RT group. In a multivariable model stratified by follow-up duration, the overall HR of developing subsequent ipsilateral lung cancer in the RT group was 1.14 (P=.036) after 5 to 9years of follow-up, 1.28 (P=.002) after 10 to 15years of follow-up, and 1.30 (P=.014) after >15years of follow-up. The HR of contralateral lung cancer was not increased at any time interval.Conclusions: The increased risk of developing a primary lung cancer secondary to RT exposure for breast cancer is much lower than previously published. Modern RT techniques may have contributed to the improved risk profile, and this updated study is important for counseling and surveillance of breast cancer patients.

  View details for DOI 10.1016/j.xjon.2023.10.031

  View details for PubMedID 38204675

• Comparison of failure to rescue in younger versus elderly patients following lung cancer resection. JTCVS open Wang, Y., Kapula, N., Yang, C. J., Manapat, P., Elliott, I. A., Guenthart, B. A., Lui, N. S., Backhus, L. M., Berry, M. F., Shrager, J. B., Liou, D. Z. 2023; 16: 855-872

  Abstract

  Objective: Failure to rescue (FTR), defined as in-hospital death following a major complication, has been increasingly studied in patients who undergo cardiothoracic surgery. This study tested the hypothesis that elderly patients undergoing lung cancer resection have greater rates of FTR compared with younger patients.Methods: Patients who underwent surgery for primary lung cancer between 2011 and 2020 and had at least 1 major postoperative complication were identified using the National Surgical Quality Improvement Program database. Patients who died following complications (FTR) were compared with those who survived in an elderly (80+ years) and younger (<80years) cohort.Results: Of the 2823 study patients, the younger cohort comprised 2497 patients (FTR: n=139 [5.6%]), whereas the elderly cohort comprised 326 patients (FTR: n=39 [12.0%]). Pneumonia was the most common complication in younger (877/2497, 35.1%) and elderly patients (118/326, 36.2%) but was not associated with FTR on adjusted analysis. Increasing age was associated with FTR (adjusted odds ratio [AOR], 1.55 per decade, P<.001), whereas unplanned reoperation was associated with reduced risk (AOR, 0.55, P=.01). Within the elderly cohort, surgery conducted by a thoracic surgeon was associated with lower FTR risk (AOR, 0.29, P=.028).Conclusions: FTR following lung cancer resection was more frequent with increasing age. Pneumonia was the most common complication but not a predictor of FTR. Unplanned reoperation was associated with reduced FTR, as was treatment by a thoracic surgeon for elderly patients. Surgical therapy for complications after lung cancer resection and elderly patients managed by a thoracic specialist may mitigate the risk of death following an adverse postoperative event.

  View details for DOI 10.1016/j.xjon.2023.08.002

  View details for PubMedID 38204720

• The impact of refusing esophagectomy for treatment of locally advanced esophageal adenocarcinoma. JTCVS open Wong, L., Elliott, I. A., Liou, D. Z., Backhus, L. M., Lui, N. S., Shrager, J. B., Berry, M. F. 2023; 16: 987-995

  Abstract

  Objective: Patients with esophageal cancer may be reluctant to proceed with surgery due to high complication rates. This study aims to compare outcomes between eligible surgical candidates who proceeded with surgery versus those who refused surgery.Methods: Characteristics and survival of patients with locally advanced (cT3N0M0, cT1-3N+M0) mid-/distal esophageal adenocarcinoma in the National Cancer Database (2006-2019) who either proceeded with or refused surgery after chemoradiotherapy were evaluated with logistic regression, Kaplan-Meier curves, and Cox proportional hazards methods.Results: Of the 13,594 patients included in the analysis, 595 (4.4%) patients refused esophagectomy. Patients who refused surgery were older, had less distance to travel to their treatment facility, were more likely to have cN0 disease, and were more likely to be treated at a community rather than academic or integrated network program, but did not have significantly different comorbid disease distributions. On multivariable analysis, refusing surgery was independently associated with older age, uninsured, lower income, less distance to a hospital, and treatment in a community program versus an academic/research or integrated network program. Esophagectomy was associated with better survival (5-year survival 40.1% [39.2-41] vs 23.6% [19.9-27.9], P<.001) and was also independently associated with better survival in the Cox model (hazard rate, 0.78 [95% confidence interval, 0.7-0.87], P<.001).Conclusions: The results of this study can inform selected patients with resectable esophageal adenocarcinoma that their survival will be significantly diminished if surgery is not pursued. Many factors associated with refusing surgery are non-clinical and suggest that access to or support for care could influence patient decisions.

  View details for DOI 10.1016/j.xjon.2023.09.006

  View details for PubMedID 38204633

• Impact of hyperthermic intrathoracic chemotherapy (HITHOC) during resection of pleural mesothelioma on patient survival. Journal of thoracic disease Elliott, I. A., He, H., Lui, N. S., Liou, D. Z., Guenthart, B. A., Shrager, J. B., Berry, M. F., Backhus, L. M. 2023; 15 (11): 6140-6150

  Abstract

  Pleural mesothelioma (PM) is rare but portends a poor prognosis. Multimodal treatment, including aggressive surgical resection, may offer the best chance of treatment response and improved survival. Single-center studies suggest that hyperthermic intrathoracic chemotherapy (HITHOC) during surgical resection improves outcomes, but the impact of HITHOC on postoperative morbidity and survival has not been examined on a larger scale.The National Cancer Database was queried for patients undergoing resection for PM from 2006-2017. Patients were excluded if staging or survival data was incomplete. After propensity-score matching, patients who underwent HITHOC were compared to patients who did not (case-control study). Perioperative outcomes and survival were analyzed.The final cohort consisted of 3,232 patients; of these, 365 patients underwent HITHOC. After propensity-score matching, receipt of HITHOC was associated with increased length of stay (12 vs. 7 days, P<0.001) and increased 30-day readmissions (9.9% vs. 4.9%, P=0.007), but decreased 30-day mortality (3.2% vs. 6.0%, P=0.017) and 90-day mortality (7.5% vs. 10.9%). Kaplan-Meier modeling demonstrated that HITHOC was associated with improved survival in the overall cohort (median 20.5 vs. 16.8 months, P=0.001). In multivariable analysis, HITHOC remained associated with improved overall survival [hazard ratio (HR) =0.80; 95% confidence interval (CI): 0.69-0.92; P=0.002], and this persisted in the propensity-matched analysis (HR =0.73; 95% CI: 0.61-0.88; P=0.001).Using a large national database, we describe the impact of HITHOC on survival in patients with PM. Despite observed increased short-term morbidity, in multivariable analysis HITHOC was associated with an overall survival advantage for patients undergoing surgical resection of PM.

  View details for DOI 10.21037/jtd-23-466

  View details for PubMedID 38090290

  View details for PubMedCentralID PMC10713319

• Impact of hyperthermic intrathoracic chemotherapy (HITHOC) during resection of pleural mesothelioma on patient survival JOURNAL OF THORACIC DISEASE Elliott, I. A., He, H., Lui, N. S., Liou, D. Z., Guenthart, B. A., Shrager, J. B., Berry, M. F., Backhus, L. M. 2023

  View details for DOI 10.21037/jtd-23-466

  View details for Web of Science ID 001101361100001

• Outcomes of a Failed Observation Approach for Paraesophageal Hernia Wong, L., Leipzig, M., Elliott, I. A., Lui, N., Liou, D., Backhus, L. M., Shrager, J. B., Berry, M. LIPPINCOTT WILLIAMS & WILKINS. 2023: S483

  View details for Web of Science ID 001094086301454

• Outcomes of a Failed Observation Approach for Paraesophageal Hernia Wong, L., Leipzig, M., Elliott, I. A., Lui, N., Liou, D., Backhus, L. M., Shrager, J. B., Berry, M. LIPPINCOTT WILLIAMS & WILKINS. 2023: S483

  View details for Web of Science ID 001100379000036

• Clinical Impact of EGFR vs KRAS Mutations in Multifocal Lung Adenocarcinoma Jiang, J., Berry, M. F., Lui, N. S., Liou, D. Z., Trope, W. L., Backhus, L. M., Shrager, J. B. ELSEVIER SCIENCE INC. 2023: S484-S485

  View details for Web of Science ID 001098831601318

• The colocatome as a spatial -omic reveals shared microenvironment features between tumour-stroma assembloids and human lung cancer. bioRxiv : the preprint server for biology Bouchard, G., Zhang, W., Li, I., Ilerten, I., Bhattacharya, A., Li, Y., Trope, W., Shrager, J. B., Kuo, C., Tian, L., Giaccia, A. J., Plevritis, S. K. 2023

  Abstract

  Computational frameworks to quantify and compare microenvironment spatial features of in-vitro patient-derived models and clinical specimens are needed. Here, we acquired and analysed multiplexed immunofluorescence images of human lung adenocarcinoma (LUAD) alongside tumour-stroma assembloids constructed with organoids and fibroblasts harvested from the leading edge (Tumour-Adjacent Fibroblasts;TAFs) or core (Tumour Core Fibroblasts;TCFs) of human LUAD. We introduce the concept of the "colocatome" as a spatial -omic dimension to catalogue all proximate and distant colocalisations between malignant and fibroblast subpopulations in both the assembloids and clinical specimens. The colocatome expands upon the colocalisation quotient (CLQ) through a nomalisation strategy that involves permutation analysis and thereby allows comparisons of CLQs under different conditions. Using colocatome analysis, we report that both TAFs and TCFs protected cancer cells from targeted oncogene treatment by uniquely reorganising the tumour-stroma cytoarchitecture, rather than by promoting cellular heterogeneity or selection. Moreover, we show that the assembloids' colocatome recapitulates the tumour-stroma cytoarchitecture defining the tumour microenvironment of LUAD clinical samples and thereby can serve as a functional spatial readout to guide translational discoveries.

  View details for DOI 10.1101/2023.09.11.557278

  View details for PubMedID 37745466

  View details for PubMedCentralID PMC10515823

• The impact of neoadjuvant immunotherapy on perioperative outcomes and survival after esophagectomy for esophageal cancer. JTCVS open Wong, L., Liou, D. Z., Backhus, L. M., Lui, N. S., Shrager, J. B., Berry, M. F. 2023; 14: 547-560

  Abstract

  Objective: Immunotherapy for esophageal cancer is relatively novel but increasingly used. This study evaluated the early use of immunotherapy as an adjunct to neoadjuvant chemoradiotherapy before esophagectomy for locally advanced disease.Methods: Perioperative morbidity (composite of mortality, hospitalization ≥21days, or readmission) and survival of patients with locally advanced (cT3N0M0, cT1-3N + M0) distal esophageal cancer in the National Cancer Database from 2013 to 2020 who underwent neoadjuvant immunotherapy plus chemoradiotherapy or chemoradiotherapy alone followed by esophagectomy were evaluated using logistic regression, Kaplan-Meier curves, Cox proportional hazards methods, and propensity-matched analysis.Results: Immunotherapy was used in 165 (1.6%) of 10,348 patients. Younger age (odds ratio, 0.66; 95% confidence interval, 0.53-0.81; P<.001) predicted immunotherapy use, which slightly delayed time from diagnosis to surgery versus chemoradiation alone (immunotherapy 148 [interquartile range, 128-177] days vs chemoradiation 138 [interquartile range, 120-162] days, P<.001). There were no statistically significant differences between the immunotherapy and chemoradiation groups for the composite major morbidity index (14.5% [24/165] vs 15.6% [1584/10,183], P=.8). Immunotherapy was associated with a significant improvement in median overall survival (69.1months vs 56.3months, P=.005) and 3-year overall survival in univariate analysis (65.6% [95% confidence interval, 57.7-74.5] vs 55.0% [53.9-56.1], P=.005), and independently predicted improved survival in multivariable analysis (hazard ratio 0.68 [95% confidence interval, 0.52-0.89], P=.006). Propensity-matched analysis also showed that immunotherapy use was not associated with increased surgical morbidity (P=.5) but was associated with improved survival (P=.047).Conclusions: Neoadjuvant immunotherapy use before esophagectomy for locally advanced esophageal cancer did not lead to worse perioperative outcomes and shows promising results on midterm survival.

  View details for DOI 10.1016/j.xjon.2023.03.015

  View details for PubMedID 37425457

• Characterization of Epidural Analgesia Interruption and Associated Outcomes After Esophagectomy. The Journal of surgical research Byrd, C. T., Kim, R. K., Manapat, P., He, H., Tsui, B. C., Shrager, J. B., Berry, M. F., Backhus, L. M., Lui, N. S., Liou, D. Z. 2023; 290: 92-100

  Abstract

  Interruption of thoracic epidural analgesia may impact the postoperative course following esophagectomy. This study investigates the incidence and causes of epidural interruption in esophagectomy patients along with associated postoperative outcomes.This single-institution retrospective analysis examined patients undergoing esophagectomy who received a thoracic epidural catheter from 2016 to 2020. Patients were stratified according to whether epidural catheter infusion was interrupted or not postoperatively. Outcomes were compared between the two groups, and predictors of epidural interruption and postoperative complications were estimated using multivariable logistic regression.Of the 168 patients who received a thoracic epidural before esophagectomy, 60 (35.7%) required epidural interruption and 108 (64.3%) did not. Interruption commonly occurred on postoperative day 1 and was due to hypotension 80% of the time. Heart failure (10.0% versus 0.9%, P = 0.009), atrial fibrillation (20.0% versus 3.7%, P = 0.002), preoperative opioid use (30.0% versus 16.7%, P = 0.043), and higher American Society of Anesthesiology classification (88.4% versus 70.4%, P = 0.008) were more prevalent in the epidural interruption cohort. The female gender was associated with epidural interruption on multivariable logistic regression (adjusted odds ratio [AOR] 2.45, P = 0.039). Patients in the epidural interruption cohort had a higher incidence of delirium (30.5% versus 13.9%, P = 0.010), sepsis (13.6% versus 3.7%, P = 0.028), and severe anastomotic leak (18.3% versus 7.4%, P = 0.032). On adjusted analysis, heart disease (AOR 4.26, P = 0.027), BMI <18.5 (AOR 9.83, P = 0.031), and epidural interruption due to hypotension (AOR 3.51, P = 0.037) were associated with severe anastomotic leak.Early epidural interruption secondary to hypotension in esophagectomy patients may be a harbinger of postoperative complications such as sepsis and severe anastomotic leak. Patients requiring epidural interruption due to hypotension should have a low threshold for additional workup and early intervention.

  View details for DOI 10.1016/j.jss.2023.04.009

  View details for PubMedID 37224609

• Surgical Management of Esophageal Perforation: Examining Trends in a Multi-Institutional Cohort. Journal of gastrointestinal surgery : official journal of the Society for Surgery of the Alimentary Tract Wong, L. Y., Leipzig, M., Liou, D. Z., Backhus, L. M., Lui, N. S., Shrager, J. B., Berry, M. F. 2023

  Abstract

  Esophageal perforations historically are associated with significant morbidity and mortality and generally require emergent intervention. The influence of improved diagnostic and therapeutic modalities available in recent years on management has not been examined. This study examined the surgical treatments and outcomes of a modern cohort.Patients with esophageal perforation management in the 2005-2020 American College of Surgeons National Surgical Quality Improvement Program database were stratified into three eras (2005-2009, 2010-2014, and 2015-2020). Surgical management was classified as primary repair, resection, diversion, or drainage alone based on procedure codes. The distribution of procedure use, morbidity, and mortality across eras was examined.Surgical management of 378 identified patients was primary repair (n=193,51%), drainage (n=89,24%), resection (n=70,18%), and diversion (n=26,7%). Thirty-day mortality in the cohort was 9.5% (n=36/378) and 268 patients (71%) had at least one complication. The median length of stay was 15 days. Both morbidity (Era 1 65% [n=42/60] versus Era 2 69% [n=92/131] versus Era 3 72% [n=135/187], p=0.3) and mortality (Era 1 11% [n=7/65] versus Era 2 9% [n=12/131] versus Era 3 10% [n=19/187], p=0.9) did not change significantly over the three defined eras. Treatment over time evolved such that primary repair was more frequently utilized (43% in Era 1 to 51% in Era 3) while diversion was less often performed (13% in Era 1 to 7% in Era 3) (p=0.009).Esophageal perforation management in recent years uses diversion less often but remains associated with significant morbidity and mortality.

  View details for DOI 10.1007/s11605-023-05700-1

  View details for PubMedID 37165161

  View details for PubMedCentralID 7330325

• Organoid modeling of lung-resident immune responses to SARS-CoV-2 infection. Research square Choi, S. S., van Unen, V., Zhang, H., Rustagi, A., Alwahabi, S. A., Santos, A. J., Chan, J. E., Lam, B., Solis, D., Mah, J., Röltgen, K., Trope, W., Guh-Siesel, A., Lin, Z., Beck, A., Edwards, C., Mallajosyula, V., Martin, B. A., Dunn, J. C., Shrager, J., Baric, R. A., Pinsky, B., Boyd, S. D., Blish, C. A., Davis, M. M., Kuo, C. J. 2023

  Abstract

  Tissue-resident immunity underlies essential host defenses against pathogens, but analysis in humans has lacked in vitro model systems where epithelial infection and accompanying resident immune cell responses can be observed en bloc. Indeed, human primary epithelial organoid cultures typically omit immune cells, and human tissue resident-memory lymphocytes are conventionally assayed without an epithelial infection component, for instance from peripheral blood, or after extraction from organs. Further, the study of resident immunity in animals can be complicated by interchange between tissue and peripheral immune compartments. To study human tissue-resident infectious immune responses in isolation from secondary lymphoid organs, we generated adult human lung three-dimensional air-liquid interface (ALI) lung organoids from intact tissue fragments that co-preserve epithelial and stromal architecture alongside endogenous lung-resident immune subsets. These included T, B, NK and myeloid cells, with CD69+CD103+ tissue-resident and CCR7- and/or CD45RA- TRM and conservation of T cell receptor repertoires, all corresponding to matched fresh tissue. SARS-CoV-2 vigorously infected organoid lung epithelium, alongside secondary induction of innate cytokine production that was inhibited by antiviral agents. Notably, SARS-CoV-2-infected organoids manifested adaptive virus-specific T cell activation that was specific for seropositive and/or previously infected donor individuals. This holistic non-reconstitutive organoid system demonstrates the sufficiency of lung to autonomously mount adaptive T cell memory responses without a peripheral lymphoid component, and represents an enabling method for the study of human tissue-resident immunity.

  View details for DOI 10.21203/rs.3.rs-2870695/v1

  View details for PubMedID 37205380

  View details for PubMedCentralID PMC10187413

• ASO Visual Abstract: Impact of Delaying Surgery After Chemoradiation on Outcomes for Locally Advanced Esophageal Squamous Cell Carcinoma. Annals of surgical oncology Wong, L. Y., Liou, D. Z., Vitzthum, L. K., Backhus, L. M., Lui, N. S., Chang, D., Shrager, J. B., Berry, M. F. 2023

  View details for DOI 10.1245/s10434-023-13156-5

  View details for PubMedID 36759429

• Does delaying surgery following induction chemotherapy compromise survival in patients with mesothelioma? JOURNAL OF CANCER METASTASIS AND TREATMENT Wong, L., Baiu, I., Leipzig, M., Titan, A., Liou, D. Z., Lui, N., Berry, M., Shrager, J. B., Backhus, L. 2023; 9

  View details for DOI 10.20517/2394-4722.2023.57

  View details for Web of Science ID 001072777600001

• Impact of Delaying Surgery After Chemoradiation on Outcomes for Locally Advanced Esophageal Squamous Cell Carcinoma. Annals of surgical oncology Wong, L., Liou, D. Z., Vitzthum, L. K., Backhus, L. M., Lui, N. S., Chang, D., Shrager, J. B., Berry, M. F. 2022

  Abstract

  BACKGROUND: Performing selective esophagectomy for locally advanced squamous cell carcinoma may spare patients morbidity, but delayed surgery may infer higher risks. This study evaluated the impact of length of time between chemoradiation and esophagectomy on perioperative outcomes and long-term survival.METHODS: The impact of surgical timing, stratified by surgery performed < 180 and ≥ 180 days from starting radiation, on perioperative outcomes and survival in patients treated with chemoradiation and esophagectomy for cT1N + M0 and cT2-4, any N, M0 squamous cell carcinoma of the mid-distal esophagus in the National Cancer Database (2006-2016) was evaluated with logistic regression, Kaplan-Meier curves, Cox proportional-hazards methods, and propensity-matched analysis.RESULTS: Median time between starting radiation and esophagectomy in 1641 patients was 93 (IQR 81-114) days. Most patients (96.8%, n = 1589) had surgery within 180 days of starting radiation, while 52 patients (3.2%) had delayed surgery. Black race and clinical T stage were associated with delayed surgery. Rates of pathologic upstaging, downstaging, complete response, and positive margins were not significantly different between the groups. Patients with delayed surgery had increased major morbidity as measured by a composite of length of hospital stay, readmission, and 30-day mortality [42.3% (22/52) vs 22.3% (355/1589), p = 0.001]. However, delayed surgery was not associated with a significant difference in survival in both univariate [5-year survival 32.8% (95% CI 21.1-50.7) vs 47.3% (44.7-50.1), p = 0.19] and multivariable analysis [hazard ratio (HR) 1.23 (0.85-1.78), p = 0.26].CONCLUSIONS: Delaying surgery longer than 180 days after starting chemoradiation for esophageal squamous cell carcinoma is associated with worse perioperative outcomes but not long-term survival.

  View details for DOI 10.1245/s10434-022-12980-5

  View details for PubMedID 36572807

• Lobar versus sublobar resection in clinical stage IA primary lung cancer with occult N2 disease. European journal of cardio-thoracic surgery : official journal of the European Association for Cardio-thoracic Surgery Liou, D. Z., Chan, M., Bhandari, P., Lui, N. S., Backhus, L. M., Shrager, J. B., Berry, M. F. 2022

  Abstract

  Sublobar resection is increasingly being utilized for early-stage lung cancers, but optimal management when final pathology shows unsuspected mediastinal nodal disease is unclear. This study tested the hypothesis that lobectomy has improved survival compared to sublobar resection for clinical stage IA tumors with occult N2 disease.The use of sublobar resection and lobectomy for patients in the National Cancer Database who underwent primary surgical resection for clinical stage IA non-small cell lung cancer with pathologic N2 disease between 2010 and 2017 was evaluated using logistic regression. Survival was assessed with Kaplan-Meier analysis, log-rank test, and Cox proportional hazards model.A total of 2,419 patients comprised the study cohort, including 320 sublobar resections (13.2%) and 2,099 lobectomies (86.8%). Older age, female sex, smaller tumour size, and treatment at an academic facility predicted the use of sublobar resection. Patients undergoing lobectomy had larger tumors (2.40 vs 2.05 cm, p < 0.001) and more lymph nodes examined (11 vs 5, p < 0.001). Adjuvant chemotherapy use was similar between the two groups (sublobar 79.4% vs lobectomy 77.4%, p = 0.434). Sublobar resection was not associated with worse survival compared to lobectomy in both univariate (5-year survival 46.6% vs 45.2%, p = 0.319) and multivariable Cox proportional hazards analysis (HR 0.97, p = 0.789).Clinical stage IA non-small cell lung cancer patients with N2 disease on final pathology have similar long-term survival with either sublobar resection or lobectomy. Patients with occult N2 disease after sublobar resection may not require reoperation for completion lobectomy but should instead proceed to adjuvant chemotherapy.

  View details for DOI 10.1093/ejcts/ezac440

  View details for PubMedID 36063054

• Phenotyping Malignant Pleural Effusions with Mass Cytometry: Evidence of EMT and MET States in Late-Stage NSCLC Karacosta, L. G., Pancirer, D., Preiss, J., Shrager, J. B., Sung, A. W., Neal, J. W., Bendall, S. C., Wakelee, H., Plevritis, S. K. ELSEVIER SCIENCE INC. 2022: S577-S578

  View details for Web of Science ID 000858678101493

• Eligibility for Lung Cancer Screening Among Women Receiving Screening for Breast Cancer. JAMA network open Titan, A. L., Baiu, I., Liou, D., Lui, N. S., Berry, M., Shrager, J., Backhus, L. 2022; 5 (9): e2233840

  View details for DOI 10.1001/jamanetworkopen.2022.33840

  View details for PubMedID 36178692

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

  Abstract

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

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

  View details for PubMedID 35748739

• Effect of Perioperative Gabapentin on Postoperative Pain Resolution and Opioid Cessation in a Mixed Surgical Cohort: A Randomized Clinical Trial (vol 153, pg 303, 2018) JAMA SURGERY Hah, J., Mackey, S. C., Schmidt, P. 2022

  View details for DOI 10.1001/jamasurg.2017.4915

  View details for Web of Science ID 000784959200002

• Silver Nitrate-Coated Versus Standard Indwelling Pleural Catheter for Malignant Effusions: The SWIFT Randomized Trial. Annals of the American Thoracic Society Shrager, J. B., Bhatnagar, R., Kearney, C. T., Retzlaff, N. P., Cohen, E., Stanton, A. E., Keyes, C., Wahidi, M. M., Gillespie, C., Rahman, N., Kerry, A. L., Feller-Kopman, D., Nader, D., Akulian, J., Chen, A., Berry, M., Majid, A., Reddy, C., Tremblay, A., Maskell, N. A. 2022

  Abstract

  RATIONALE: Tunneled, indwelling pleural catheters (IPC) have been demonstrated to be an effective method of managing malignant pleural effusions. However, they allow pleurodesis and can therefore be removed in only a subset of patients. A novel, silver-nitrate coated IPC was developed with the intention of creating a rapid, effective chemical pleurodesis to allow more frequent and earlier catheter removal. This study represent the pivotal clinical trial evaluating that catheter vs the standard IPC.OBJECTIVES: To compare the efficacy of a novel silver nitrate-eluting indwelling pleural catheter (SNCIPC) with that of a standard, uncoated catheter.METHODS: The SWIFT trial was a multicentre, parallel-group, randomised, controlled, patient-blind trial. Central randomisation occurred following a computer-generated schedule, stratified by site. Recruitment was from 17 secondary or tertiary-care hospitals in the USA and 3 in the UK and included adult patients with malignant pleural effusion needing drainage, without evidence of lung entrapment or significant loculation. The intervention group underwent insertion of a SNCIPC with maximal fluid drainage, followed by a tapering drainage schedule. The control group received a standard, uncoated catheter. Follow up was until 90 days. The primary outcome measure was pleurodesis efficacy, measured by fluid drainage, at 30 days.RESULTS: 119 patients were randomised. 5 withdrew before receiving treatment, leaving 114 (77 SNCIPC, 37 standard IPC) for intention-to-treat analysis. Mean age was 66 years (SD 11). More patients in the SNCIPC group were in-patients (39% vs 14%, p=0.009). For the primary outcome, pleurodesis rates were 12/37 (32%) in the control group and 17/77 (22%) in the SNCIPC group (rate difference -0.10, 95% CI -0.30-0.09). Median time to pleurodesis was 11 days (IQR 9-23) in the control group and 4 days (IQR 2-15) in the SNCIPC group. No significant difference in treatment-related adverse event rates was noted between groups.CONCLUSIONS: The SNCIPC did not improve pleurodesis efficacy compared to a standard indwelling pleural catheter. This study does not support the wider use of the SNCIPC device. Clinical trial registered with ClinicalTrials.gov (NCT02649894).

  View details for DOI 10.1513/AnnalsATS.202111-1301OC

  View details for PubMedID 35363591

• Reconstructing codependent cellular cross-talk in lung adenocarcinoma using REMI. Science advances Yu, A., Li, Y., Li, I., Ozawa, M. G., Yeh, C., Chiou, A. E., Trope, W. L., Taylor, J., Shrager, J., Plevritis, S. K. 2022; 8 (11): eabi4757

  Abstract

  Cellular cross-talk in tissue microenvironments is fundamental to normal and pathological biological processes. Global assessment of cell-cell interactions (CCIs) is not yet technically feasible, but computational efforts to reconstruct these interactions have been proposed. Current computational approaches that identify CCI often make the simplifying assumption that pairwise interactions are independent of one another, which can lead to reduced accuracy. We present REMI (REgularized Microenvironment Interactome), a graph-based algorithm that predicts ligand-receptor (LR) interactions by accounting for LR dependencies on high-dimensional, small-sample size datasets. We apply REMI to reconstruct the human lung adenocarcinoma (LUAD) interactome from a bulk flow-sorted RNA sequencing dataset, then leverage single-cell transcriptomics data to increase the cell type resolution and identify LR prognostic signatures among tumor-stroma-immune subpopulations. We experimentally confirmed colocalization of CTGF:LRP6 among malignant cell subtypes as an interaction predicted to be associated with LUAD progression. Our work presents a computational approach to reconstruct interactomes and identify clinically relevant CCIs.

  View details for DOI 10.1126/sciadv.abi4757

  View details for PubMedID 35302849

• Textbook outcome after minimally invasive esophagectomy is an important prognostic indicator for predicting long-term oncological outcomes with locally advanced esophageal squamous cell carcinoma. Annals of translational medicine Xu, S. J., Lin, L. Q., Chen, C., Chen, T. Y., You, C. X., Chen, R. Q., Deana, C., Wakefield, C. J., Shrager, J. B., Molena, D., Yang, C. J., Lin, J. H., Chen, S. C. 2022; 10 (4): 161

  Abstract

  The textbook outcome (TO) emerges as a novel prognostic factor in surgical oncology. The present study aimed to evaluate the effect of TO on the risk of death and recurrence in patients with esophageal squamous cell carcinoma (ESCC) after minimally invasive esophagectomy (MIE).The study involved retrospective analysis of 528 patients with ESCC who were subjected to MIE from January 2011 to December 2017. TO included 8 parameters: complete resection; microscopically tumor-negative resection margins (R0); ≥15 lymph nodes removed and examined; no serious postoperative complications; no postoperative intervention; no re-admission to the intensive care unit (ICU); hospital stay ≤21 days; and no readmission ≤30 days. The Cox and logistic regression model were used to analyze the prognostic factors of survival and risk factors for TO.Among the 528 patients with ESCC who were subjected to MIE, 53.2% reached TO. In the case of patients with locally advanced ESCC, 5-year overall survival (OS) was 51.1% (41.2-61.2%) for the TO group but 33.7% (23.7-43.7%) for the non-TO group (HR =0.644, 95% CI: 0.449-0.924, P=0.015). Similarly, 5-year disease-free survival (DFS) was 47.6% (38.0-57.2%) for the TO group but 29.1% (20.1-38.1%) for the non-TO group (HR =0.671, 95% CI: 0.479-0.940, P=0.018). In addition, 5-year recurrence-free survival (RFS) was 62.9% (53.7-72.1%) for the TO group but 39.8% (29.4-50.2%) for the non-TO group (HR =0.606, 95% CI: 0.407-0.902, P=0.012). Multivariate logistic regression analysis further showed that age, American Society of Anesthesiology (ASA) score, intraoperative blood loss, and smoking status acted as independent risk factors for TO. The results of the multivariate analysis assisted in the establishment of a nomogram for the prediction of TO occurrence. This nomogram exhibited satisfactory consistency and prediction ability [area under the receiving operator characteristic (AUROC) =0.717].The present study showed that achieving of TO after MIE improves survival rate and reduce the recurrence rate in patients with locally advanced ESCC. The study further determined the independent factors associated with TO achievement and established a prediction model.

  View details for DOI 10.21037/atm-22-506

  View details for PubMedID 35280418

  View details for PubMedCentralID PMC8908120

• Multi-omics analysis of spatially distinct stromal cells reveals tumor-induced O-glycosylation of the CDK4-pRB axis in fibroblasts at the invasive tumor edge. Cancer research Bouchard, G., Garcia-Marques, F. J., Karacosta, L. G., Zhang, W., Bermudez, A., Riley, N. M., Varma, S., Mehl, L. C., Benson, J. A., Shrager, J. B., Bertozzi, C. R., Pitteri, S. J., Giaccia, A. J., Plevritis, S. K. 2021

  Abstract

  The invasive leading edge represents a potential gateway for tumor metastasis. The role of fibroblasts from the tumor edge in promoting cancer invasion and metastasis has not been comprehensively elucidated. We hypothesize that crosstalk between tumor and stromal cells within the tumor microenvironment (TME) results in activation of key biological pathways depending on their position in the tumor (edge vs core). Here we highlight phenotypic differences between tumor-adjacent-fibroblasts (TAF) from the invasive edge and tumor core fibroblasts (TCF) from the tumor core, established from human lung adenocarcinomas. A multi-omics approach that includes genomics, proteomics, and O-glycoproteomics was used to characterize crosstalk between TAFs and cancer cells. These analyses showed that O-glycosylation, an essential post-translational modification resulting from sugar metabolism, alters key biological pathways including the cyclin-dependent kinase 4 and phosphorylated retinoblastoma protein (CDK4-pRB) axis in the stroma and indirectly modulates pro-invasive features of cancer cells. In summary, the O-glycoproteome represents a new consideration for important biological processes involved in tumor-stroma crosstalk and a potential avenue to improve the anti-cancer efficacy of CDK4 inhibitors.

  View details for DOI 10.1158/0008-5472.CAN-21-1705

  View details for PubMedID 34853070

• Consensus for Thoracoscopic Lower Lobectomy: Essential Components and Targets for Simulation. The Annals of thoracic surgery Erwin, P. A., Lee, A. C., Ahmad, U., Antonoff, M., Arndt, A., Backhus, L., Berry, M., Birdas, T., Cassivi, S. D., Chang, A. C., Cooke, D. T., Crabtree, T., DeCamp, M., Donington, J., Fernandez, F., Force, S., Gaissert, H., Hofstetter, W., Huang, J., Kent, M., Kim, A. W., Lin, J., Martin, L. W., Meyerson, S., Mitchell, J. D., Molena, D., Odell, D., Onaitis, M., Puri, V., Putnam, J., Reddy, R., Schipper, P., Seder, C. W., Shrager, J., Tong, B., Veeramachaneni, N., Watson, T., Whyte, R., Ferguson, M. K. 2021

  Abstract

  BACKGROUND: Despite demonstration of its clear benefits relative to open approaches, a video-assisted thoracic surgery (VATS) technique for pulmonary lobectomy has not been universally adopted. This study aims to overcome potential barriers by establishing the essential components of the operation as well as determining which steps would be most useful for simulation training.METHODS: After randomly selecting experienced thoracic surgeons to participate, an initial list of components to a lower lobectomy was distributed. Feedback was provided by the participants and modifications were made based on anonymous responses in a Delphi process. Components were declared essential once at least 80% of participants came to an agreement. The steps were then rated based upon cognitive and technical difficulty, followed by listing the components most appropriate for simulation.RESULTS: After three rounds of voting, 18 components were identified as essential to performance of a VATS lower lobectomy. The components deemed the most difficult included isolation and division of the basilar and superior segmental branches of the pulmonary artery, isolation and division of the lower lobe bronchus, and the dissection of lymphovascular tissue to expose the target bronchus. The steps determined to be most amenable for simulation included isolation and division of the branches of the pulmonary artery, the lower lobe bronchus, and the inferior pulmonary vein.CONCLUSIONS: Using a Delphi process, a list of essential components for a VATS lower lobectomy was established. Furthermore, three components were identified as most appropriate for simulation-based training, providing insights for future simulation development.

  View details for DOI 10.1016/j.athoracsur.2021.09.033

  View details for PubMedID 34688617

• Induction therapy is not associated with improved survival in large cT4N0 non-small cell lung cancers. The Annals of thoracic surgery Sun, B. J., Bhandari, P., Jeffrey Yang, C., Berry, M. F., Shrager, J. B., Backhus, L. M., Lui, N. S., Liou, D. Z. 2021

  Abstract

  BACKGROUND: The 8th edition staging for non-small cell lung cancer reclassified tumors >7 cm as stage IIIA (T4N0); previously, such tumors without nodal disease were considered stage IIB (T3N0). This study tested the hypothesis that induction chemotherapy for these stage IIIA patients does not improve survival compared to primary surgery.METHODS: The National Cancer Database was queried for non-small cell lung cancer patients with tumor size >7 cm who underwent surgical resection from 2010 - 2015. Patients with clinically node-positive disease or tumor invasion of major structures were excluded. Patients undergoing induction chemotherapy followed by surgery (IC) were compared to patients undergoing primary surgery (PS). Propensity-score matching was performed.RESULTS: In total, 1,610 patients with cT4N0 disease based on tumor size >7 cm and no tumor invasion underwent surgical resection: 1,346 (83.6%) comprised the PS group and 264 (16.4%) the IC group. After propensity-score matching, IC had a higher rate of pN0 (78.4% vs 66.0%, p<0.001) and less lymphovascular invasion (13.9% vs 26.3%, p<0.001), but longer postoperative stay (6 vs 5 days, p<0.001) and higher 30-day mortality (3.5% vs 0%, p=0.002). Median 5-year survival was similar between IC and PS (53.5% vs 62.2%, p=0.075), and IC was not independently associated with survival (HR 1.45, p=0.146).CONCLUSIONS: Patients with cT4N0 non-small cell lung cancer based on tumor size >7 cm and no tumor invasion of major structures have similar overall survival with either IC or PS. IC should not be routinely given for this subset of stage IIIA patients.

  View details for DOI 10.1016/j.athoracsur.2021.07.058

  View details for PubMedID 34425099

• Surgical resection for patients with pulmonary aspergillosis in the national inpatient sample. Journal of thoracic disease Patel, D. C., Bhandari, P., Epstein, D. J., Liou, D. Z., Backhus, L. M., Berry, M. F., Shrager, J. B., Lui, N. S. 2021; 13 (8): 4977-4987

  Abstract

  The role of lung resection in patients with pulmonary aspergillosis is generally reserved for those with localized disease who fail medical management. We used a national database to investigate the influence of preoperative patient comorbidities on inpatient mortality and need for surgery.Patients admitted with pulmonary aspergillosis between 2007 to 2015 were identified in the National Inpatient Sample dataset. Inpatient mortality rates were compared between patients treated medically and surgically. Predictors of mortality, surgical intervention, and non-elective admission were evaluated using multivariable logistic regression.Among a population estimate of 112,998 patients with pulmonary aspergillosis, 107,606 (95.2%) underwent medical management alone and 5,392 (4.8%) underwent surgical resection. Positive predictors for surgery included hemoptysis, and history of lung cancer or chronic pulmonary diseases. Surgically treated patients had a lower inpatient mortality when compared to those treated medically (11.5% vs. 15.1%, P<0.001) in univariate analysis, but this finding did not persist in multivariable analysis (AOR 0.97, P=0.509). The odds of mortality were lower in patients undergoing video assisted thoracoscopic surgery compared to an open approach (AOR 0.77, P=0.001). Among patients treated surgically, mortality was higher in those with a history of lung cancer, solid organ transplantation, liver disease, human immunodeficiency virus infection, hematologic diseases, chronic pulmonary diseases, and those admitted non-electively requiring surgery.In this generalizable study, medical and surgical management of pulmonary aspergillosis were comparable in terms of inpatient mortality. However, non-elective admission and patients with select comorbidities have significantly worse outcomes after surgical intervention.

  View details for DOI 10.21037/jtd-21-151

  View details for PubMedID 34527336

  View details for PubMedCentralID PMC8411153

• Short-term and intermediate-term readmission after esophagectomy. Journal of thoracic disease Wang, Y., Yang, C. J., He, H., Buchan, J. M., Patel, D. C., Liou, D. Z., Lui, N. S., Berry, M. F., Shrager, J. B., Backhus, L. M. 2021; 13 (8): 4678-4689

  Abstract

  The objective of this study was to characterize short- and intermediate-term readmissions following esophagectomy and to identify predictors of readmission in these two groups.Patients who underwent esophagectomy in the National Readmissions Database (2013-2014) were grouped according to whether first readmission was "short-term" (readmitted <30 days) or "intermediate-term" (readmitted 31-90 days) following index admission for esophagectomy. Predictors of readmission were evaluated using multivariable logistic regression modeling.Of the 3,005 patients who underwent esophagectomy, 544 (18.1%) had a short-term readmission and 305 (10.1%) had an intermediate-term readmission. The most frequent reasons for short-term readmission were post-operative infection (7.5%), dysphagia (6.3%) and pneumonia (5.1%). The most common intermediate-term complications were pneumonia (7.2%), gastrointestinal stricture/stenosis (6.9%) and dysphagia (5.9%). In multivariable analysis, being located in a micropolitan area, increasing number of comorbidities and higher severity of illness score were associated with an increased likelihood of having a short-term readmission while being discharged to a facility (as opposed to directly home) was associated with increased likelihood of both short- and intermediate-term readmission (all P<0.05).In this analysis, postoperative infection was the most common reason for short-term readmission. Dysphagia and pneumonia were common reasons for both short- and intermediate-term readmission of patients following esophagectomy. Interventions focused on reducing the risk of postoperative infection and pneumonia may reduce hospital readmissions. Gastrointestinal stricture and dysphagia were associated with increased risk of intermediate readmission and should be examined in the context of morbidity associated with pyloric procedures (e.g., pyloromyotomy) at the time of esophagectomy.

  View details for DOI 10.21037/jtd-21-637

  View details for PubMedID 34527309

  View details for PubMedCentralID PMC8411130

• Short-term and intermediate-term readmission after esophagectomy JOURNAL OF THORACIC DISEASE Wang, Y., Yang, C., He, H., Buchan, J. M., Patel, D. C., Liou, D. Z., Lui, N. S., Berry, M. F., Shrager, J. B., Backhus, L. M. 2021

  View details for DOI 10.21037/jtd-21-637

  View details for Web of Science ID 000682802900001

• Early Discharge after Lobectomy for Lung Cancer does not Equate to Early Readmission. The Annals of thoracic surgery Patel, D. C., Leipzig, M., Jeffrey Yang, C., Wang, Y., Shrager, J. B., Backhus, L. M., Lui, N. S., Liou, D. Z., Berry, M. F. 2021

  Abstract

  BACKGROUND: Enhanced recovery after surgery (ERAS) pathways in several specialties reduce length of stay, but accelerated discharge after thoracic surgery is not well characterized. This study tested the hypothesis that patients discharged on post-operative day 1 (POD1) after lobectomy for lung cancer have an increased risk of readmission.METHODS: Patients who underwent a lobectomy for lung cancer between 2011-2019 in the American College of Surgeons National Surgical Quality Improvement Program database were identified. Readmission rates were compared between patients discharged on postoperative day 1 (POD1) and patients discharged POD 2-6. Early discharge and readmission predictors were evaluated using multivariable logistic regression analysis.RESULTS: Only 854 (3.8%) of 22,585 patients that met inclusion criteria were discharged on POD1, though POD1 discharge rates increased from 2.3% to 8.1% (p< 0.001) from 2011 to 2019. Median hospitalization for POD2-6 patients was 4 days (IQR: 3-5). Patient characteristics associated with a lower likelihood of POD1 discharge were increasing age, smokers, or history of dyspnea, while a minimally invasive approach was the strongest predictor of early discharge (AOR 5.42, p<0.001). Readmission rates were not significantly different for POD1 and POD2-6 groups in univariate analysis (6.0% vs 7.0%, p=0.269). Further, POD1 discharge was not a risk factor for readmission in multivariable analysis (AOR 1.10, p=0.537).CONCLUSIONS: Select patients can be discharged on POD1 after lobectomy for lung cancer without an increased readmission risk, supporting this accelerated discharge target inclusion in lobectomy ERAS protocols.

  View details for DOI 10.1016/j.athoracsur.2021.05.053

  View details for PubMedID 34126077

• Influence of facility volume on long-term survival of patients undergoing esophagectomy for esophageal cancer. The Journal of thoracic and cardiovascular surgery Patel, D. C., Jeffrey Yang, C., He, H., Liou, D. Z., Backhus, L. M., Lui, N. S., Shrager, J. B., Berry, M. F. 2021

  Abstract

  OBJECTIVE: This study investigated the influence of facility volume on long-term survival in patients with esophageal cancer treated with esophagectomy.METHODS: Patients treated with esophagectomy for cT1 3N0 3M0 adenocarcinoma or squamous cell carcinoma of the mid-distal esophagus in the National Cancer Database between 2006 and 2013 were stratified by annual facility esophagectomy volume dichotomized as more/less than both 6 and 20. Patient characteristics associated with facility volume were evaluated using logistic regression, and the influence of facility volume on survival was evaluated with Kaplan-Meier curves, Cox proportional hazards methods, and propensity matched analysis.RESULTS: Of 11,739 patients who had esophagectomy at 1018 facilities where annual volume ranged from 1 to 47.6 cases, 4262 (36.3%) were treated at 44 facilities with annual esophagectomy volume>6 and 1515 (12.9%) were treated at 7 facilities with annual volume>20. Higher volume was associated with significantly better 5-year survival for both annual volume > 6 (47.6% vs 40.2%; P<.001) and annual volume>20 (47.2% vs 42.3%; P<.001), which persisted in propensity matched analyses as well as Cox multivariable analysis (hazard ratio, 0.81; 95% confidence interval, 0.74-0.89; P<.001 for facility volume>6 and hazard ratio, 0.78; 95% confidence interval, 0.65-0.95; P=.01 for facility volume>20). In Cox multivariable analysis that considered facility volume as a continuous variable, higher volume continued to be associated with better survival (hazard ratio, 0.93 per 5 cases; 95% CI, 0.91-0.96; P<.001).CONCLUSIONS: Esophageal cancer patients treated with esophagectomy at higher volume facilities have significantly better long-term survival than patients treated at lower volume facilities.

  View details for DOI 10.1016/j.jtcvs.2021.05.048

  View details for PubMedID 34247867

• A new model using artificial intelligence to predict recurrence after surgical resection of stage I-II non-small cell lung cancer. Lui, N., Wei, N., Trope, W., Nesbit, S., Bhandari, P., Lee, C., Hu, H., Guo, H., Liou, D. Z., Shrager, J. B., Backhus, L., Berry, M. F., Yang, E. LIPPINCOTT WILLIAMS & WILKINS. 2021

  View details for DOI 10.1200/JCO.2021.39.15_suppl.8537

  View details for Web of Science ID 000708120604251

• Investigating gene expression profiles associated with clinical radiation resistance in KEAP1/NFE2L2 wildtype lung cancer. Binkley, M. S., Jeon, Y., Nesselbush, M., Moding, E. J., Nabet, B., Almanza, D., Yoo, C., Kurtz, D. M., Owen, S., Backhus, L. M., Berry, M. F., Shrager, J. B., Ramchandran, K. J., Padda, S. K., Das, M., Neal, J. W., Wakelee, H. A., Alizadeh, A. A., Loo, B. W., Diehn, M. AMER ASSOC CANCER RESEARCH. 2021

  View details for Web of Science ID 000641160600087

• Strong for Surgery: Association Between Bundled Risk Factors and Outcomes After Major Elective Surgery in the VA Population. World journal of surgery Liou, D. Z., Patel, D. C., Bhandari, P., Wren, S. M., Marshall, N. J., Harris, A. H., Shrager, J. B., Berry, M. F., Lui, N. S., Backhus, L. M. 2021

  Abstract

  BACKGROUND: Strong for Surgery (S4S) is a public health campaign focused on optimizing patient health prior to surgery by identifying evidence-based modifiable risk factors. The potential impact of S4S bundled risk factors on outcomes after major surgery has not been previously studied. This study tested the hypothesis that a higher number of S4S risk factors is associated with an escalating risk of complications and mortality after major elective surgery in the VA population.METHODS: The Veterans Affairs Surgical Quality Improvement Program (VASQIP) database was queried for patients who underwent major non-emergent general, thoracic, vascular, urologic, and orthopedic surgeries between the years 2008 and 2015. Patients with complete data pertaining to S4S risk factors, specifically preoperative smoking status, HbA1c level, and serum albumin level, were stratified by number of positive risk factors, and perioperative outcomes were compared.RESULTS: A total of 31,285 patients comprised the study group, with 16,630 (53.2%) patients having no S4S risk factors (S4S0), 12,323 (39.4%) having one (S4S1), 2,186 (7.0%) having two (S4S2), and 146 (0.5%) having three (S4S3). In the S4S1 group, 60.3% were actively smoking, 35.2% had HbA1c>7, and 4.4% had serum albumin<3. In the S4S2 group, 87.8% were smokers, 84.8% had HbA1c>7, and 27.4% had albumin<3. Major complications, reoperations, length of stay, and 30-day mortality increased progressively from S4S0 to S4S3 groups. S4S3 had the greatest adjusted mortality risk (adjusted odds radio [AOR] 2.56, p=0.04) followed by S4S2 (AOR 1.58, p=0.02) and S4S1 (AOR 1.34, p=0.02).CONCLUSION: In the VA population, patients who had all three S4S risk factors, namely active smoking, suboptimal nutritional status, and poor glycemic control, had the greatest risk of postoperative mortality compared to patients with fewer S4S risk factors.

  View details for DOI 10.1007/s00268-021-05979-8

  View details for PubMedID 33598723

• Randomized Phase II Study of 3 Months or 2 Years of Adjuvant Afatinib in Patients With Surgically Resected Stage I-III EGFR-Mutant Non-Small-Cell Lung Cancer JCO PRECISION ONCOLOGY Neal, J. W., Costa, D. B., Muzikansky, A., Shrager, J. B., Lanuti, M., Huang, J., Ramachandran, K. J., Rangachari, D., Huberman, M. S., Piotrowska, Z., Kris, M. G., Azzoli, C. G., Sequist, L., Chaft, J. E. 2021; 5: 325–32

  View details for DOI 10.1200/PO.20.00301

  View details for Web of Science ID 000636554600002

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

  Abstract

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

  View details for DOI 10.1016/j.immuni.2021.02.014

  View details for PubMedID 33691136

• Perioperative Outcomes After Combined Esophagectomy and Lung Resection. The Journal of surgical research Patel, D. C., Bhandari, P., Shrager, J. B., Berry, M. F., Backhus, L. M., Lui, N. S., Liou, D. Z. 2021; 270: 413-420

  Abstract

  The impact of concomitant lung resection during esophagectomy on short-term outcomes is not well characterized. This study tests the hypothesis that lung resection at the time of esophagectomy is not associated with increased perioperative morbidity or mortality.Perioperative outcomes for esophageal cancer patients who underwent esophagectomy alone (EA) were compared to patients who had concurrent esophagectomy and lung resection (EL) using the NSQIP database between 2006-2017. Predictors of morbidity and mortality, including combined surgery, were evaluated using multivariable logistic regression.Among the 6,225 study patients, 6,068 (97.5%) underwent EA and 157 (2.5%) underwent EL. There were no differences in baseline characteristics between the two groups. Operating time for EL was longer than EA (median 416 versus 371 minutes, P < 0.01). Median length of stay was 10 d for both groups. Perioperative mortality was not significantly different between EL and EA patients (5.1% versus 2.8%, P = 0.08). EL patients had higher rates of postoperative pneumonia (22.3% versus 16.2%, P = 0.04) and sepsis (11.5% versus 7.1%, P = 0.03), however major complication rates overall were similar (40.8% versus 35.3%, P = 0.16). Combining lung resection with esophagectomy was not independently associated with increased postoperative morbidity (AOR 1.21 [95% CI 0.87-1.69]) or mortality (AOR 1.63 [95% CI 0.74-3.58]).Concurrent lung resection during esophagectomy is not associated with increased mortality or overall morbidity, but is associated with higher rates of pneumonia beyond esophagectomy alone. Surgeons considering combined lung resection with esophagectomy should carefully evaluate the patient's risk for pulmonary complications and pursue interventions preoperatively to optimize respiratory function.

  View details for DOI 10.1016/j.jss.2021.09.037

  View details for PubMedID 34775148

• Use of a Personalized Multimedia Education Platform Improves Preoperative Teaching for Lung Cancer Patients. Seminars in thoracic and cardiovascular surgery Benson, J. n., Bhandari, P. n., Lui, N. n., Berry, M. n., Liou, D. Z., Shrager, J. n., Ayers, K. n., Backhus, L. M. 2021

  Abstract

  We sought to develop and evaluate a personalized multimedia education (ME) tool for pre-operative patient education to improve patient health knowledge, quality of life and satisfaction with care in thoracic surgery. The ME tool was developed and deployed in outpatient clinic during preoperative teaching for patients undergoing surgical resection for lung cancer for quality improvement. Patients were given an electronic survey prior to preoperative teaching and at initial post-operative visit to assess teaching effectiveness and care satisfaction. Sequential patients received either standard preoperative teaching or teaching using the ME tool. Pre- and postoperative survey responses were compared using independent sample paired t-test and multivariable linear regression modeling for adjustment. The final ME tool was an iPad application that incorporated real-time annotations of 3-dimensional, interactive anatomic diagrams. The tool featured video tours of operations, and radiology image import for annotation by the surgeon. Forty-eight patients were included in this pilot study (standard education (SE) n=26; ME, n=22). ME patients had significantly higher satisfaction scores compared to SE patients with respect to length of education materials, clarity of content, supportiveness of content and willingness to recommend materials to others. There was no difference in length of clinic visit between groups. Both patient and provider input can be used to create an innovative electronic preoperative educational tool that prepares and empowers patients in shared decision-making before surgery. Improvements in health literacy and self-efficacy may be more difficult to achieve but remain important as multimedia teaching tools are further developed.

  View details for DOI 10.1053/j.semtcvs.2021.03.003

  View details for PubMedID 33711462

• Commentary: Progress, or just movement, on thymoma staging? The Journal of thoracic and cardiovascular surgery Shrager, J. B. 2020

  View details for DOI 10.1016/j.jtcvs.2020.11.009

  View details for PubMedID 33293061

• Early Discharge Does Not Equate to Early Return for Patients Undergoing Lobectomy for Lung Cancer: A National Analysis Patel, D. C., Leipzig, M., Yang, C., Wang, Y., Shrager, J. B., Backhus, L. M., Lui, N. S., Liou, D. Z., Berry, M. F. ELSEVIER SCIENCE INC. 2020: S288

  View details for Web of Science ID 000582792300534

• New Information on Talc and Mesothelioma ANNALS OF THORACIC SURGERY Shrager, J. B. 2020; 110 (3): 1099

  View details for Web of Science ID 000565186900061

• Discovery of a novel shared tumor antigen in human lung cancer. Tseng, D., Chiou, S., Yang, X., Reuben, A., Wilhelmy, J., McSween, A., Conley, S., Sinha, R., Nabet, B., Wang, C., Shrager, J. B., Berry, M. F., Backhus, L., Lui, n., Wakelee, H. A., Neal, J. W., Zhang, J., Garcia, K., Mackall, C., Davis, M. AMER SOC CLINICAL ONCOLOGY. 2020

  View details for Web of Science ID 000560368301343

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

  Abstract

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

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

  View details for PubMedID 32269342

• Commentary: Can the esophagus curse a lung transplant? The Journal of thoracic and cardiovascular surgery Shrager, J. B. 2020

  View details for DOI 10.1016/j.jtcvs.2020.02.124

  View details for PubMedID 32417061

• Towards the identification of novel tumor antigens in human lung cancer. Chiou, S., Tseng, D., Wang, C., Reuben, A., Yang, X., Wilhelmy, J., McSween, A., Zhang, J., Shrager, J., Garcia, K., Davis, M. AMER ASSOC CANCER RESEARCH. 2020: 44–45

  View details for Web of Science ID 000518188200060

• Consensus for Thoracoscopic Left Upper Lobectomy-Essential Components and Targets for Simulation. The Annals of thoracic surgery Bryan, D. S., Ferguson, M. K., Antonoff, M. B., Backhus, L. M., Birdas, T. J., Blackmon, S. H., Boffa, D. J., Chang, A. C., Chmielewski, G. W., Cooke, D. T., Donington, J. S., Gaissert, H. A., Hagen, J. A., Hofstetter, W. L., Kent, M. S., Kim, K. W., Krantz, S. B., Lin, J. n., Martin, L. W., Meyerson, S. L., Mitchell, J. D., Molena, D. n., Odell, D. D., Onaitis, M. W., Puri, V. n., Putnam, J. B., Seder, C. W., Shrager, J. B., Soukiasian, H. J., Stiles, B. M., Tong, B. C., Veeramachaneni, N. K. 2020

  Abstract

  Simulation-based training is a valuable component of cardiothoracic surgical education. Effective curriculum development requires consensus on procedural components and focused attention on specific learning objectives. Through use of a Delphi process, we established consensus on the steps of video-assisted thoracoscopic surgery (VATS) left upper lobectomy and identified targets for simulation.Experienced thoracic surgeons were randomly selected for participation. Surgeons voted and commented on the necessity of individual steps comprising VATS left upper lobectomy. Steps with greater than 80% of participants in agreement of their necessity were determined to have established "consensus." Participants voted on the physical or cognitive complexity of each, or both, and chose steps most amenable to focused simulation.Thirty thoracic surgeons responded and joined in the voting process. Twenty operative steps were identified, with surgeons reaching consensus on the necessity of 19. Components deemed most difficult and amenable to simulation included those related to dissection and division of the bronchus, artery, and vein.Through a Delphi process, surgeons with a variety of practice patterns can achieve consensus on the operative steps of left upper lobectomy and agreement on those most appropriate for simulation. This information can be implemented in the development of targeted simulation for VATS lobectomy.

  View details for DOI 10.1016/j.athoracsur.2020.06.152

  View details for PubMedID 33127408

• The role of induction therapy for thymic malignancies: a narrative review. Mediastinum (Hong Kong, China) Patel, D. C., Shrager, J. B., Padda, S. K. 2020; 4: 36

  Abstract

  Advanced thymic epithelial tumors pose a clinical dilemma for surgeons and medical oncologists. Given the prognostic importance of obtaining a complete resection, interventions that improve resectability may have profound implications. The documented chemosensitivity and radiosensitivity of thymic tumors present an opportunity to use these therapies in the neoadjuvant setting to reduce tumor burden and improve the likelihood of achieving a complete resection. The current evidence available is limited to institutional case-series, large retrospective multi-institutional databases, and phase II clinical trials. The primary objective of considering induction therapy should be facilitating a complete resection; other endpoints such as down-staging or pathologic response have not been shown to result in meaningful improvements in long-term outcomes. There are certain high-risk tumor characteristics that may aid clinicians in appropriately selecting patients for induction therapy. The selection of candidates for induction therapy should take place in a multidisciplinary tumor board including medical oncologist, surgeon, and radiation oncologist with experience in managing advanced thymic malignancies. Without randomized controlled trials, it is unlikely the thymic medical community will arrive at a consensus on the utility of induction therapy. This review will summarize the existing literature and provide insight into the role of induction therapy for advanced thymic malignancies.

  View details for DOI 10.21037/med-20-20

  View details for PubMedID 35118304

  View details for PubMedCentralID PMC8794335

• New Information on Talc and Mesothelioma. The Annals of thoracic surgery Shrager, J. B. 2020

  View details for DOI 10.1016/j.athoracsur.2020.02.038

  View details for PubMedID 32224237

• A National Analysis of Treatment Patterns and Outcomes for Patients 80 Years or Older with Esophageal Cancer. Seminars in thoracic and cardiovascular surgery Yang, C. J., Wang, Y. n., Raman, V. n., Patel, D. n., Lui, N. n., Backhus, L. n., Shrager, J. n., Berry, M. F., Liou, D. n. 2020

  Abstract

  The purpose of this study was to evaluate practice patterns and outcomes for patients 80 years or older with esophageal cancer using a nationwide cancer database. Practice patterns for patients 80 years or older with stage I-IV esophageal cancer in the National Cancer Database from 2004-2014 were analyzed. Overall survival associated with different treatment strategies were evaluated using the Kaplan-Meier method and multivariable Cox proportional hazard models. In the study period, 40.5% and 46.2% of patients with stage I adenocarcinoma and squamous cell carcinoma, respectively, did not receive any treatment at all. Less than 11% (196/1,865) of patients with stage I-II disease underwent esophagectomy, even though surgery was associated with a better 5-year survival compared to no treatment (stage I: 47.3% [95% CI 36.2%-57.6%] vs 14.9% [95% CI: 11.2%-19.1%]; stage II: 29.3% [95% CI 20.1%-39.1%] vs 1.2% [95% CI: 0.1%-5.5%]). Of the 1,596 (37.7%) patients with stage III disease who received curative-intent treatment (surgery or chemoradiation), the 5-year survival was significantly better than that of patients who received no treatment (11.9% [95% CI: 9.7%-14.4% vs 4.3% [95% CI: 1.9%-8.3%]). In this national analysis of patients 80 years and older with esophageal cancer, over 40% of patients with stage I disease did not receive treatment. Patients with stage I-III disease had better survival and risks and benefits of treatment for elderly patients should be discussed in a multidisciplinary setting.

  View details for DOI 10.1053/j.semtcvs.2020.09.004

  View details for PubMedID 32977014

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

  Abstract

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

  View details for DOI 10.2147/JPR.S269370

  View details for PubMedID 33239904

  View details for PubMedCentralID PMC7680674

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

  Abstract

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

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

  View details for PubMedID 33071215

• A Mechanistic Clinical Trial of JaK Inhibition to Prevent Ventilator-Induced Diaphragm Dysfunction Shrager, J., Cooke, R., Wang, Y. J., Lee, M. S., Backhus, L., Tang, H. B. AMER THORACIC SOC. 2020

  View details for Web of Science ID 000556393505109

• The Oldest Old: A National Analysis of Outcomes for Patients 90 Years or Older With Lung Cancer. The Annals of thoracic surgery Yang, C. J., Brown, A. B., Deng, J. Z., Lui, N. S., Backhus, L. M., Shrager, J. B., D'Amico, T. A., Berry, M. F. 2019

  Abstract

  BACKGROUND: Most clinicians will encounter patients 90 years or older with non-small cell lung cancer (NSCLC), but evidence that informs treatment decisions for this extremely elderly population is lacking. This study evaluated outcomes associated with treatment strategies for this nonagenarian population.METHODS: Treatment and overall survival for patients 90 years and older with NSCLC in the National Cancer Data Base (2004-2014) were evaluated using logistic regression, the Kaplan-Meier method, and multivariable Cox proportional hazard models.RESULTS: The majority (n = 4152, 57.6%) of the 7205 patients 90 years or older with stage I-IV NSCLC did not receive any therapy. For the entire cohort, receiving treatment was associated with significantly better survival when compared with no therapy (5-year survival, 9.3% [95% confidence interval [CI], 8.0%-10.7%] vs 1.7% [95% CI, 1.2%-2.2%]; multivariable adjusted hazard ratio, 0.53; P < .001). Stage I patients had the most pronounced survival benefit with treatment (median survival, 27.4 months vs 10.0 months with no treatment; P < .001). Among this subset of patients with stage I disease (n= 1430), only 12.7% (n= 182) had surgery and 33% (n= 471) had no therapy. In these stage I patients surgery was associated with significantly better 5-year survival (33.7% [95% CI, 25.4%-42.1%]) than nonoperative therapy (17.1% [95% CI, 13.7%-20.8%]) and no therapy (6.2% [95% CI, 3.8%-9.4%]).CONCLUSIONS: Therapy for nonagenarians with NSCLC is associated with a significant survival benefit but is not used in most patients. Treatment should not be withheld for these "oldest old" patients based on their age alone but should be considered based on stage and patient preferences in a multidisciplinary setting.

  View details for DOI 10.1016/j.athoracsur.2019.09.027

  View details for PubMedID 31757356

• A Single-Cell Resolution Map of EMT and Drug Resistance States for Evaluating NSCLC Clinical Specimens Karacosta, L., Anchang, B., Ignatiadis, N., Kimmey, S., Benson, J., Shrager, J., Sung, A., Neal, J., Wakelee, H., Tibshirani, R., Bendall, S., Plevritis, S. ELSEVIER SCIENCE INC. 2019: S226–S227

  View details for Web of Science ID 000492162201134

• Broad Genomic Profiling of Bronchoalveolar Lavage Fluid in Lung Cancer Nair, V., Hui, A., Chabon, J., Esfahani, M., Stehr, H., Nabet, B., Benson, J., Chaudhuri, A., Zhou, L., Ayers, K., Bedi, H., Ramsey, M., Van Wert, R., Sung, A., Lui, N., Backhus, L., Berry, M., Massion, P., Shrager, J., Alizadeh, A., Diehn, M. ELSEVIER SCIENCE INC. 2019: S747–S748

  View details for Web of Science ID 000492162204084

• Management of Benign Esophageal Perforation in the National Inpatient Sample Lui, N., Bhandari, P., Backhus, L., Liou, D., Shrager, J., Berry, M. F. ELSEVIER SCIENCE INC. 2019: E209

  View details for Web of Science ID 000492749600500

• National Evaluation of Short-Term and Intermediate-Term Readmission after Esophagectomy Yang, C. J., Wang, Y., He, H., Liou, D., Lui, N., Berry, M. F., Shrager, J., Backhus, L. ELSEVIER SCIENCE INC. 2019: S279–S280

  View details for Web of Science ID 000492740900545

• Bone Marrow and Tumor Radiomics at 18F-FDG PET/CT: Impact on Outcome Prediction in Non-Small Cell Lung Cancer. Radiology Mattonen, S. A., Davidzon, G. A., Benson, J., Leung, A. N., Vasanawala, M., Horng, G., Shrager, J. B., Napel, S., Nair, V. S. 2019: 190357

  Abstract

  Background Primary tumor maximum standardized uptake value is a prognostic marker for non-small cell lung cancer. In the setting of malignancy, bone marrow activity from fluorine 18-fluorodeoxyglucose (FDG) PET may be informative for clinical risk stratification. Purpose To determine whether integrating FDG PET radiomic features of the primary tumor, tumor penumbra, and bone marrow identifies lung cancer disease-free survival more accurately than clinical features alone. Materials and Methods Patients were retrospectively analyzed from two distinct cohorts collected between 2008 and 2016. Each tumor, its surrounding penumbra, and bone marrow from the L3-L5 vertebral bodies was contoured on pretreatment FDG PET/CT images. There were 156 bone marrow and 512 tumor and penumbra radiomic features computed from the PET series. Randomized sparse Cox regression by least absolute shrinkage and selection operator identified features that predicted disease-free survival in the training cohort. Cox proportional hazards models were built and locked in the training cohort, then evaluated in an independent cohort for temporal validation. Results There were 227 patients analyzed; 136 for training (mean age, 69 years ± 9 [standard deviation]; 101 men) and 91 for temporal validation (mean age, 72 years ± 10; 91 men). The top clinical model included stage; adding tumor region features alone improved outcome prediction (log likelihood, -158 vs -152; P = .007). Adding bone marrow features continued to improve performance (log likelihood, -158 vs -145; P = .001). The top model integrated stage, two bone marrow texture features, one tumor with penumbra texture feature, and two penumbra texture features (concordance, 0.78; 95% confidence interval: 0.70, 0.85; P < .001). This fully integrated model was a predictor of poor outcome in the independent cohort (concordance, 0.72; 95% confidence interval: 0.64, 0.80; P < .001) and a binary score stratified patients into high and low risk of poor outcome (P < .001). Conclusion A model that includes pretreatment fluorine 18-fluorodeoxyglucose PET texture features from the primary tumor, tumor penumbra, and bone marrow predicts disease-free survival of patients with non-small cell lung cancer more accurately than clinical features alone. © RSNA, 2019 Online supplemental material is available for this article.

  View details for DOI 10.1148/radiol.2019190357

  View details for PubMedID 31526257

• Randomized phase II study of adjuvant afatinib for three months versus two years in patients with resected stage I-III EGFR mutant NSCLC. Chaft, J. E., Costa, D., Muzikansky, A., Shrager, J. B., Lanuti, M., Huang, J., Ramchandran, K., Rangachari, D., Huberman, M., Piotrowska, Z., Kris, M. G., Azzoli, C. G., Sequist, L. V., Neal, J. W. AMER SOC CLINICAL ONCOLOGY. 2019

  View details for Web of Science ID 000487345806385

• 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)

  View details for DOI 10.1001/jamanetworkopen.2019.0168

  View details for Web of Science ID 000465424000048

• 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

  Abstract

  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: ClinicalTrials.gov Identifier: NCT01067144.

  View details for PubMedID 30821824

• Response to comment on "Impact of KRAS mutation subtype and concurrent pathogenic mutations on non-small cell lung cancer outcomes". Lung cancer (Amsterdam, Netherlands) Aredo, J. V., Padda, S. K., Kunder, C. A., Han, S. S., Neal, J. W., Shrager, J. B., Wakelee, H. A. 2019

  View details for DOI 10.1016/j.lungcan.2019.08.020

  View details for PubMedID 31492438

• Rapamycin protects aging muscle. Aging Tang, H. n., Shrager, J. B., Goldman, D. n. 2019

  View details for DOI 10.18632/aging.102176

  View details for PubMedID 31454792

• Talc Pleurodesis: a Medical, Medicolegal, and Socioeconomic Review. The Annals of thoracic surgery Baiu, I. n., Yevudza, E. n., Shrager, J. B. 2019

  Abstract

  Talcum has been used in pleurodesis for over eight decades. Despite a wealth of research, controversy remains over the optimal sclerosant for pneumothorax and pleural effusions. Talc's historical primacy has been challenged due to its potential for pulmonary toxicity, possible carcinogenicity, and recent concerns surrounding availability and legal liability, making an ideal time for a review.This is a systematic review of the talc literature, focused on publications after the year 2000 evaluating mechanism of action, efficacy, side-effect profile, and alternative sclerosants; included is an overview of current socioeconomic and legal controversies.The data support talc as the most effective agent for pleurodesis. There is evidence to suggest that mean particle size has a direct relationship to the side-effect profile and that significant hypoxemic events following talc administration are exceedingly rare using available graded talc preparations. Concerns regarding the development of malignancies following topical talc application remain incompletely resolved but appear related to cosmetic powder preparations that were contaminated with asbestos. Purified talc in the pleural space has not been implicated. Recent difficulties accessing commercial talc preparations have been solved. Although safe and effective talc alternatives do exist, these agents are not as well studied.Talc pleurodesis with modern, purified, graded talc preparations is safe and highly effective. Talc is an inexpensive and accessible option that remains appropriate for pleurodesis despite existing controversies.

  View details for DOI 10.1016/j.athoracsur.2019.08.104

  View details for PubMedID 31593652

• Integrated Bone Marrow and Tumor Radiomics on [18F] FDG Positron Emission Tomography (PET) Augment Stage for Outcome Prediction in Non-Small Cell Lung Cancer Mattonen, S. A., Davidzon, G. A., Benson, J. A., Vasanawala, M., Leung, A. C., Horng, G. S., Shrager, J. B., Napel, S., Nair, V. S. AMER THORACIC SOC. 2019

  View details for Web of Science ID 000466776705345

• The influence of hormone replacement therapy on lung cancer incidence and mortality. The Journal of thoracic and cardiovascular surgery Titan, A. L., He, H. n., Lui, N. n., Liou, D. n., Berry, M. n., Shrager, J. B., Backhus, L. M. 2019

  Abstract

  Data regarding the effects of hormone replacement therapy (HRT) on non-small cell lung cancer (NSCLC) are mixed. We hypothesized HRT would have a protective benefit with reduced NSCLC incidence among women in a large, prospective cohort.We used data from the multicenter randomized Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (1993-2001). Participants were women aged 50 to 74 years followed prospectively for up to 13 years for cancer screening. The influence of HRT on the primary outcome of NSCLC incidence and secondary outcomes of all-cause and disease-specific mortality were assessed with Kaplan-Meier analysis and Cox proportional hazard models adjusting for covariates.In the overall cohort of 75,587 women, 1147 women developed NSCLC after a median follow-up of 11.5 years. HRT use was characterized as 49.4% current users, 17.0% former users, and 33.6% never users. Increased age, smoking, comorbidities, and family history were associated with increased risk of NSCLC. On multivariable analysis, current HRT use was associated with reduced risk of NSCLC compared with never users (hazard ratio, 0.80; 95% confidence interval, 0.70-0.93; P = .009). HRT or oral contraception use was not associated with significant differences in all-cause mortality or disease-specific mortality.These data represent among the largest prospective cohorts suggesting HRT use may have a protective effect on the development of NSCLC among women; the physiological basis of this effect merits further study; however, the results may influence discussion surrounding HRT use in women.

  View details for DOI 10.1016/j.jtcvs.2019.10.070

  View details for PubMedID 31866083

• Mapping lung cancer epithelial-mesenchymal transition states and trajectories with single-cell resolution. Nature communications Karacosta, L. G., Anchang, B. n., Ignatiadis, N. n., Kimmey, S. C., Benson, J. A., Shrager, J. B., Tibshirani, R. n., Bendall, S. C., Plevritis, S. K. 2019; 10 (1): 5587

  Abstract

  Elucidating the spectrum of epithelial-mesenchymal transition (EMT) and mesenchymal-epithelial transition (MET) states in clinical samples promises insights on cancer progression and drug resistance. Using mass cytometry time-course analysis, we resolve lung cancer EMT states through TGFβ-treatment and identify, through TGFβ-withdrawal, a distinct MET state. We demonstrate significant differences between EMT and MET trajectories using a computational tool (TRACER) for reconstructing trajectories between cell states. In addition, we construct a lung cancer reference map of EMT and MET states referred to as the EMT-MET PHENOtypic STAte MaP (PHENOSTAMP). Using a neural net algorithm, we project clinical samples onto the EMT-MET PHENOSTAMP to characterize their phenotypic profile with single-cell resolution in terms of our in vitro EMT-MET analysis. In summary, we provide a framework to phenotypically characterize clinical samples in the context of in vitro EMT-MET findings which could help assess clinical relevance of EMT in cancer in future studies.

  View details for DOI 10.1038/s41467-019-13441-6

  View details for PubMedID 31811131

• Antitumor activity of an engineered decoy receptor targeting CLCF1-CNTFR signaling in lung adenocarcinoma. Nature medicine Kim, J. W., Marquez, C. P., Kostyrko, K. n., Koehne, A. L., Marini, K. n., Simpson, D. R., Lee, A. G., Leung, S. G., Sayles, L. C., Shrager, J. n., Ferrer, I. n., Paz-Ares, L. n., Gephart, M. H., Vicent, S. n., Cochran, J. R., Sweet-Cordero, E. A. 2019

  Abstract

  Proinflammatory cytokines in the tumor microenvironment can promote tumor growth, yet their value as therapeutic targets remains underexploited. We validated the functional significance of the cardiotrophin-like cytokine factor 1 (CLCF1)-ciliary neurotrophic factor receptor (CNTFR) signaling axis in lung adenocarcinoma (LUAD) and generated a high-affinity soluble receptor (eCNTFR-Fc) that sequesters CLCF1, thereby inhibiting its oncogenic effects. eCNTFR-Fc inhibits tumor growth in multiple xenograft models and in an autochthonous, highly aggressive genetically engineered mouse model of LUAD, driven by activation of oncogenic Kras and loss of Trp53. Abrogation of CLCF1 through eCNTFR-Fc appears most effective in tumors driven by oncogenic KRAS. We observed a correlation between the effectiveness of eCNTFR-Fc and the presence of KRAS mutations that retain the intrinsic capacity to hydrolyze guanosine triphosphate, suggesting that the mechanism of action may be related to altered guanosine triphosphate loading. Overall, we nominate blockade of CLCF1-CNTFR signaling as a novel therapeutic opportunity for LUAD and potentially for other tumor types in which CLCF1 is present in the tumor microenvironment.

  View details for DOI 10.1038/s41591-019-0612-2

  View details for PubMedID 31700175

• Cost reduction in video-assisted thoracoscopic lobectomy VIDEO-ASSISTED THORACIC SURGERY Richardson, M. T., Shrager, J. B. 2019; 4

  View details for DOI 10.21037/vats.2018.12.06

  View details for Web of Science ID 000461158100001

• Impact of KRAS mutation subtype and concurrent pathogenic mutations on non-small cell lung cancer outcomes. Lung cancer (Amsterdam, Netherlands) Aredo, J. V., Padda, S. K., Kunder, C. A., Han, S. S., Neal, J. W., Shrager, J. B., Wakelee, H. A. 2019; 133: 144–50

  Abstract

  Concurrent genetic mutations are prevalent in KRAS-mutant non-small cell lung cancer (NSCLC) and may differentially influence patient outcomes. We sought to characterize the effects of KRAS mutation subtypes and concurrent pathogenic mutations on overall survival (OS) and PD-L1 expression, a predictive biomarker for anti-PD-1/PD-L1 immunotherapy.We retrospectively identified patients with KRAS-mutant NSCLC at a single institution and abstracted clinical, molecular, and pathologic data from electronic health records. Cox regression and multinomial logistic regression were used to determine how KRAS mutation subtypes and concurrent pathogenic mutations are associated with OS and tumor PD-L1 expression, respectively.A total 186 patients were included. Common KRAS mutation subtypes included G12C (35%) and G12D (17%). Concurrent pathogenic mutations were identified in TP53 (39%), STK11 (12%), KEAP1 (8%), and PIK3CA (4%). On multivariable analysis, KRAS G12D mutations were significantly associated with poor OS (hazard ratio [HR] 2.43, 95% confidence interval [CI] 1.15-5.16; P = 0.021), as were STK11 co-mutations (HR 2.95, 95% CI 1.27-6.88; P = 0.012). Compared to no (<1%) PD-L1 expression, KRAS G12C mutations were significantly associated with positive yet low (1-49%) PD-L1 expression (odds ratio [OR] 4.94, 95% CI 1.07-22.85; P = 0.041), and TP53 co-mutations with high (≥50%) PD-L1 expression (OR 6.36, 95% CI 1.84-22.02; P = 0.004).KRAS G12D and STK11 mutations confer poor prognoses for patients with KRAS-mutant NSCLC. KRAS G12C and TP53 mutations correlate with a biomarker that predicts benefit from immunotherapy. Concurrent mutations may represent distinct subsets of KRAS-mutant NSCLC; further investigation is warranted to elucidate their role in guiding treatment.

  View details for DOI 10.1016/j.lungcan.2019.05.015

  View details for PubMedID 31200821

• Minimally Invasive Thymectomy and Lung Volume Reduction in a Patient With Myasthenia Gravis ANNALS OF THORACIC SURGERY Salna, M., Kidambi, S., Sampson, J., Shrager, J. B. 2018; 106 (6): E313–E315

  View details for DOI 10.1016/j.athoracsur.2018.04.067

  View details for Web of Science ID 000450312700011

• 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., Zhang, W., Leung, A. C., Kadoch, M., Hoang, C. D., Shrager, J., Quon, A., Rubin, D. L., Plevritis, S. K., Napel, S. 2018; 5

  View details for DOI 10.1038/sdata.2018.202

  View details for Web of Science ID 000447363600001

• 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

  Abstract

  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 PubMedID 30325352

• POSTPARTUM DIAGNOSIS OF CARDIAC PARAGANGLIOMA: A CASE REPORT JOURNAL OF EMERGENCY MEDICINE Berona, K., Joshi, R., Woo, Y., Shrager, J. 2018; 55 (4): E101–E105

  Abstract

  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 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

  View details for DOI 10.1016/j.jtho.2018.08.1447

  View details for Web of Science ID 000454014503110

• 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

  Abstract

  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 PubMedID 30371212

• 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., Shrager, J., Ding, S., Huang, N. F. 2018; 7 (18)

  View details for DOI 10.1161/JAHA.118.009234

  View details for Web of Science ID 000452805400014

• 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

  View details for DOI 10.1016/j.omtm.2018.06.001

  View details for Web of Science ID 000451115100014

• 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

  Abstract

  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 PubMedID 30032829

• Synchronous primary lung adenocarcinomas harboring distinct MET Exon 14 splice site mutations LUNG CANCER Wang, S. Y., Lei, L., Guo, H. H., Shrager, J., Kunder, C. A., Neal, J. W. 2018; 122: 187–91

  View details for DOI 10.1016/j.lungcan.2018.06.019

  View details for Web of Science ID 000440769900030

• GFPT2-Expressing Cancer-Associated Fibroblasts Mediate Metabolic Reprogramming in Human Lung Adenocarcinoma CANCER RESEARCH Zhang, W., Bouchard, G., Yu, A., Shafiq, M., Jamali, M., Shrager, J. B., Ayers, K., Bakr, S., Gentles, A. J., Diehn, M., Quon, A., West, R. B., Nair, V., van de Rijn, M., Napel, S., Plevritis, S. K. 2018; 78 (13): 3445–57

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

  View details for Web of Science ID 000437214300005

• Identifying dynamic EMT states and constructing a proteomic EMT landscape of lung cancer using single cell multidimensional analysis Karacosta, L. G., Anchang, B., Kimmey, S., van de Rijn, M., Shrager, J. B., Bendall, S. C., Plevritis, S. K. AMER ASSOC CANCER RESEARCH. 2018

  View details for DOI 10.1158/1538-7445.AM2018-4997

  View details for Web of Science ID 000468819504024

• Induction therapy for locally advanced distal esophageal adenocarcinoma: Is radiation Always necessary? Liou, D. Z., Backhus, L. M., Lui, N. S., Shrager, J. B., Berry, M. F. MOSBY-ELSEVIER. 2018: 2697–2705

  View details for DOI 10.1016/j.jtcvs.2017.12.136

  View details for Web of Science ID 000432369400117

• 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

  Abstract

  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 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

  Abstract

  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 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

  Abstract

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

  View details for PubMedID 29760045

• 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

  Abstract

  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 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

  Abstract

  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 PubMedID 29191778

• 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-+

  Abstract

  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 PubMedID 29224839

• 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 PubMedID 29128110

• 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

  Abstract

  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 PubMedID 29530567

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

  Abstract

  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 PubMedID 28727543

• 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

  View details for Web of Science ID 000449980300283

• Bioengineered Viral Platform for Intramuscular Passive Vaccine Delivery to Human Skeletal Muscle. Molecular therapy. Methods & clinical development Paulk, N. K., Pekrun, K. n., Charville, G. W., Maguire-Nguyen, K. n., Wosczyna, M. N., Xu, J. n., Zhang, Y. n., Lisowski, L. n., Yoo, B. n., Vilches-Moure, J. G., Lee, G. K., Shrager, J. B., Rando, T. A., Kay, M. A. 2018; 10: 144–55

  Abstract

  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 PubMedID 30101152

• Clinical and Pathological Variables Influencing Noninvasive Detection of Early Stage Lung Cancer Using Circulating Tumor DNA Chabon, J., Chaudhuri, A., Azad, T., Kurtz, D., Stehr, H., Liu, C. L., Martin, J., Merriott, D., Carter, J., Ayers, K., Mansfield, A., Jen, J., Ren, H., West, R., Nair, V., Shrager, J., Neal, J., Wakelee, H., Loo, B., Alizadeh, A., Diehn, M. ELSEVIER SCIENCE INC. 2017: S1851

  View details for DOI 10.1016/j.jtho.2017.09.560

  View details for Web of Science ID 000463860800456

• Comparison of Circulating Tumor DNA Analysis and Surveillance Imaging After Treatment for Localized Lung Cancer Chaudhuri, A. A., Chabon, J. J., Lovejoy, A. F., Newman, A., Stehr, H., Azad, T. D., Carter, J. N., Merriott, D. J., Liu, C. L., Kurtz, D. M., Gensheimer, M. F., Shrager, J. B., Wakelee, H. A., Neal, J. W., Loo, B. W., Alizadeh, A. A., Diehn, M. ELSEVIER SCIENCE INC. 2017: S114

  View details for DOI 10.1016/j.ijrobp.2017.06.269

  View details for Web of Science ID 000411559107060

• 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; 8 (32): 52792-52801

  Abstract

  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 28881771

  View details for PubMedCentralID PMC5581070

• Bioengineered constructs combined with exercise enhance stem cell-mediated treatment of volumetric muscle loss NATURE COMMUNICATIONS Quarta, M., Cromie, M., Chacon, R., Blonigan, J., Garcia, V., Akimenko, I., Hamer, M., Paine, P., Stok, M., Shrager, J. B., Rando, T. A. 2017; 8: 15613

  Abstract

  Volumetric muscle loss (VML) is associated with loss of skeletal muscle function, and current treatments show limited efficacy. Here we show that bioconstructs suffused with genetically-labelled muscle stem cells (MuSCs) and other muscle resident cells (MRCs) are effective to treat VML injuries in mice. Imaging of bioconstructs implanted in damaged muscles indicates MuSCs survival and growth, and ex vivo analyses show force restoration of treated muscles. Histological analysis highlights myofibre formation, neovascularisation, but insufficient innervation. Both innervation and in vivo force production are enhanced when implantation of bioconstructs is followed by an exercise regimen. Significant improvements are also observed when bioconstructs are used to treat chronic VML injury models. Finally, we demonstrate that bioconstructs made with human MuSCs and MRCs can generate functional muscle tissue in our VML model. These data suggest that stem cell-based therapies aimed to engineer tissue in vivo may be effective to treat acute and chronic VML.

  View details for PubMedID 28631758

• 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

  Abstract

  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

  Abstract

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

  View details for DOI 10.1016/j.radonc.2017.03.021

  View details for PubMedID 28460826

• Evolved AAV Capsids for Intramuscular Passive Vaccine Administration to Human Skeletal Muscle Paulk, N. K., Pekrun, K., Charville, G., Maguire-Nguyen, K., Xu, J., Wosczyna, M., Lisowski, L., Lee, G., Shrager, J., Rando, T., Kay, M. A. CELL PRESS. 2017: 96

  View details for Web of Science ID 000401083600200

• Improving care with portfolio of physician-led cancer quality measures at an academic center Porter, J., Smith, A., Winget, M., Rosenthal, E., Seshadri, S., Vetteth, Y., Kiamanesh, E. F., Badwe, A., Advani, R. H., Buyyounouski, M. K., Coutre, S., Dorigo, O., Ganjoo, K. N., Johnston, L. J., Recht, L., Shrager, J. B., Skinner, E. C., Swetter, S. M., Visser, B. C., Blayney, D. W. AMER SOC CLINICAL ONCOLOGY. 2017

  View details for Web of Science ID 000443301600049

• 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

  Abstract

  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 PubMedID 28139704

• 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

  Abstract

  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

• Fdg Pet-CT Suvmax And Circulating Tumor Microemboli Identify Recurrence In Patients With Non-Small Cell Lung Cancer Nair, V. S., Carlsson, F., Carlsson, A., Jamali, M., Keu, K., Vasanawala, M., Shrager, J., Loo, B. W., Horng, G., Kuschner, W., Gambhir, S. S., Kuhn, P. AMER THORACIC SOC. 2017

  View details for Web of Science ID 000400372500266

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

  Abstract

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

  View details for DOI 10.1200/JOP.2017.021139

  View details for PubMedCentralID PMC5880618

• Circulating Tumor DNA Detects Minimal Residual Disease and Predicts Outcome in Localized Lung Cancer Chaudhuri, A., Lovejoy, A., Chabon, J., Newman, A., Stehr, H., Say, C., Carter, J., Zhou, L., West, R., Shrager, J., Neal, J., Wakelee, H., Loo, B., Alizadeh, A., Diehn, M. ELSEVIER SCIENCE INC. 2017: S445

  View details for Web of Science ID 000413055801024

• Using Tissue Gene Expression To Predict Survival Following 'curative' Surgical Resection In Lung Adenocarcinoma Shafiq, M., Zhang, W., Gentles, A., Ayers, K., Nair, V. S., Shrager, J., Hoang, C., Gevaert, O., Napel, S., Plevritis, S. AMER THORACIC SOC. 2017

  View details for Web of Science ID 000400372501537

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

  Abstract

  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 research.clinicaltrials.gov Identifier: NCT01067144.

  View details for PubMedID 29238824

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

  Abstract

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

  View details for DOI 10.1073/pnas.1608461113

  View details for PubMedID 27956614

• Regional Ventilation Predicts Change in Pulmonary Function After Stereotactic Ablative Radiation Therapy of Lung Tumors Binkley, M. S., King, M., Bush, K., Shrager, J. B., Chaudhuri, A. A., Popat, R., Maxim, P. G., Guo, H. H., Diehn, M., Nair, V. S., Loo, B. W. ELSEVIER SCIENCE INC. 2016: E456–E457

  View details for DOI 10.1016/j.ijrobp.2016.06.1776

  View details for Web of Science ID 000387655803435

• 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

  Abstract

  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

  Abstract

  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

• 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

  Abstract

  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

• 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 noninvasive detection of circulating tumor DNA in NSCLC. Newman, A. M., Lovejoy, A. F., Klass, D. M., Kurtz, D., Chabon, J. J., Scherer, F., Stehr, H., Liu, C., Bratman, S., Say, C., Zhou, L., Carter, J. N., West, R. B., Sledge, G. W., Shrager, J. B., Loo, B. W., Neal, J. W., Wakelee, H. A., Alizadeh, A. A., Diehn, M. AMER SOC CLINICAL ONCOLOGY. 2016

  View details for DOI 10.1200/JCO.2016.34.15_suppl.e20500

  View details for Web of Science ID 000404711506257

• AAV Capsid Evolution for Enhanced Antibody Delivery to Human Skeletal Muscle for Use in Next-Generation HIV Vaccines and Muscle Gene Therapies Paulk, N. K., Charville, G., Maguire, K., Pekrun, K., Zhang, Y., Tiffany, M., Vilches-Moure, J., Lee, G., Shrager, J., Rando, T., Kay, M. A. NATURE PUBLISHING GROUP. 2016: S284–S285

  View details for DOI 10.1016/S1525-0016(16)33530-4

  View details for Web of Science ID 000375264200710

• Thoracoscopic Resection of a Symptomatic, Congenital Rib Synostosis. Annals of thoracic surgery Brewer, Z. E., Vokic, N. C., Shrager, J. B. 2016; 101 (4): 1596-1598

  Abstract

  We describe a rare case of a 20-year-old man with a 1½-year history of a symptomatic congenital bridging rib synostosis. A minimally invasive surgical solution was provided, with resolution of symptoms.

  View details for DOI 10.1016/j.athoracsur.2015.06.046

  View details for PubMedID 27000588

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

  Abstract

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

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

  View details for Web of Science ID 000372776500001

  View details for PubMedCentralID PMC4791793

• CRISPR/Cas-mediated genome editing to treat EGFR-mutant lung cancer: a personalized molecular surgical therapy. EMBO molecular medicine Tang, H., Shrager, J. B. 2016; 8 (2): 83-5

  View details for DOI 10.15252/emmm.201506006

  View details for PubMedID 26747090

  View details for PubMedCentralID PMC4734839

• 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

  Abstract

  The computed tomographic (CT) appearance of so-called ground glass components within lung adenocarcinomas correlate with noninvasive tumor histology, and solid radiographic components correlate with invasive histology. We hypothesized that T stage might be more accurately applied by considering the solid component nodule diameter rather than total nodule diameter.We identified 74 patients with a solitary lung adenocarcinoma who underwent resection without receiving neoadjuvant therapy. Maximum total diameter and solid diameter of the nodules were measured on CT scans performed within 3 months of surgery. Cox proportional hazard modeling and Kaplan-Meier analyses were performed to determine whether total nodule diameter or solid component diameter was more predictive of overall survival.Thirty-three patients (45 %) had a solid nodule and 41 patients (55 %) had a part-solid nodule. Most patients were white (59 %) and female (69 %), and 42 % had never smoked. Seventy-four percent underwent lobectomy and 23 % sublobar resection. Sixty-six percent had pathologic stage I disease, 22 % stage II, and 12 % stage IIIA. Mean ± SD total and solid nodule diameters were 32.1 ± 17.5 and 24.8 ± 18.0 mm, respectively (p = 0.01). Among patients with part-solid nodules, multivariate modeling incorporating significant univariate predictors of survival (age, gender, procedure, N descriptor) revealed that maximum solid diameter was associated with overall survival (hazard ratio 1.4, p = 0.01), while maximum total diameter was not.In a largely non-Asian cohort undergoing resection for adenocarcinoma, radiographic diameter of the solid component of a part-solid lesion on CT predicts overall survival better than total lesion diameter. These data provide further evidence to support altering the T descriptor for lung adenocarcinoma for part-solid nodules.

  View details for DOI 10.1245/s10434-015-4780-0

  View details for Web of Science ID 000367288100136

• 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 PubMedID 26536199

• Imaging Based Parameters Associated With Disease Progression of Early-Stage NSCLC Treated With Surgical Resection Wang, A., von Eyben, R., Loo, B. W., Diehn, M., Shrager, J. B., Maxim, P. G., Guo, H. H., Burt, B., Shultz, D. B. ELSEVIER SCIENCE INC. 2015: E414

  View details for DOI 10.1016/j.ijrobp.2015.07.1603

  View details for Web of Science ID 000373215301101

• Time Course and Predictive Factors for Lung Volume Reduction Following Stereotactic Ablative Radiation Therapy (SABR) of Lung Tumors Binkley, M. S., Shrager, J. B., Chaudhuri, A., Popat, R., Maxim, P. G., Shultz, D. B., Diehn, M., Loo, B. W. ELSEVIER SCIENCE INC. 2015: E424

  View details for DOI 10.1016/j.ijrobp.2015.07.1628

  View details for Web of Science ID 000373215301125

• 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

  Abstract

  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 PubMedID 26344908

• Computed Tomography (CT) Characteristics Associated with the Proposed IASLC/ITMIG TNM Pathologic Staging System for Thymoma Padda, S. K., Terrone, D., Khuong, A., Tian, L., Neal, J. W., Riess, J. W., Berry, M., Leung, A. N., Schwartz, E. J., Shrager, J. B., Wakelee, H. A. ELSEVIER SCIENCE INC. 2015: S196

  View details for Web of Science ID 000370365100273

• 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

• Circulating Tumor DNA Concentrations Reflect Metabolic Tumor Volume in NSCLC Modlin, L. A., Bratman, S. V., Newman, A. M., Eclov, N. W., Neal, J. W., Wakelee, H. A., Shrager, J. B., Loo, B. W., Alizadeh, A. A., Diehn, M. ELSEVIER SCIENCE INC. 2014: S812

  View details for DOI 10.1016/j.ijrobp.2014.05.2342

  View details for Web of Science ID 000342331403138

• PRURITUS AS A PARANEOPLASTIC SYMPTOM OF THYMOMA Padda, S., Pagtama, J. Y., Tisch, A. H., Neal, J. W., Riess, J. W., Loo, B. W., Hardy, R., Shrager, J. B., Wakelee, H. A. LIPPINCOTT WILLIAMS & WILKINS. 2014: S240–S241

  View details for Web of Science ID 000344627500044

• COMPUTED TOMOGRAPHY (CT) CHARACTERISTICS ASSOCIATED WITH MASAOKA-KOGA PATHOLOGIC STAGE IN THYMOMA Padda, S., Terrone, D., Khuong, A., Tian, L., Neal, J. W., Riess, J. W., Hoang, C. D., Burt, B. M., Leung, A. N., Shrager, J. B., Wakelee, H. A. LIPPINCOTT WILLIAMS & WILKINS. 2014: S222

  View details for Web of Science ID 000344627500014

• Lung volume reduction after stereotactic ablative radiation therapy of lung tumors: potential application to emphysema. International journal of radiation oncology, biology, physics Binkley, M. S., Shrager, J. B., Leung, A. N., Popat, R., Trakul, N., Atwood, T. F., Chaudhuri, A., Maxim, P. G., Diehn, M., Loo, B. W. 2014; 90 (1): 216-223

  Abstract

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

  View details for DOI 10.1016/j.ijrobp.2014.05.025

  View details for PubMedID 25015205

• Circulating Tumor 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

  Abstract

  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 PubMedID 25157764

• 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

  Abstract

  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

• 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-?

  Abstract

  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

• Noninvasive and ultrasensitive quantitation of circulating tumor DNA by hybrid capture and deep sequencing. Bratman, S., Newman, A. M., To, J., Wynne, J. F., Neal, J. W., Wakelee, H. A., Shrager, J. B., Loo, B. W., Diehn, M., Alizadeh, A. A. AMER SOC CLINICAL ONCOLOGY. 2014

  View details for Web of Science ID 000358613204749

• 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

  Abstract

  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

  Abstract

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

  View details for DOI 10.1038/nm.3519

  View details for Web of Science ID 000335710700028

• 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

  Abstract

  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 PubMedID 24576597

• Prevention and management of postoperative air leaks. Annals of cardiothoracic surgery Burt, B. M., Shrager, J. B. 2014; 3 (2): 216-218

  View details for DOI 10.3978/j.issn.2225-319X.2014.03.03

  View details for PubMedID 24790852

• 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

  Abstract

  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

• Invited commentary. Annals of thoracic surgery Shrager, J. B. 2014; 97 (1): 229-?

  View details for DOI 10.1016/j.athoracsur.2013.08.056

  View details for PubMedID 24384174

• Invited commentary. Annals of thoracic surgery Shrager, J. B. 2014; 97 (1): 266-267

  View details for DOI 10.1016/j.athoracsur.2013.10.024

  View details for PubMedID 24384176

• Stage I Lung Adenocarcinoma Tumor Density And Contour Do Not Predict Circulating Tumor Cell Burden Nair, V. S., Luttgen, M., Keu, K., Jamali, M., Horng, G., Vasanawala, M., Kuschner, W., Shrager, J., Kuhn, P., Gambhir, S. S. AMER THORACIC SOC. 2014

  View details for Web of Science ID 000209838202778

• 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

  Abstract

  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 PubMedID 23828229

• ENERGY METABOLISM IN LUNG ADENOCARCINOMA Hoang, C., Xu, Y., Shi, Z., Lin, Y., Merritt, R. E., Shrager, J., Das, M., Neal, J. W., Wakelee, H. A. LIPPINCOTT WILLIAMS & WILKINS. 2013: S1036–S1037

  View details for Web of Science ID 000339624905063

• VIETNAMESE NON-SMALL CELL LUNG CANCER PATIENTS IN CALIFORNIA: MOLECULAR PROFILES AND CLINICAL CHARACTERISTICS Nguyen, K. H., Das, M., Ramchandran, K., Shrager, J., Merritt, R. E., Hoang, C., Burt, B., Tisch, A., Pagtama, J., Zehnder, J., Berry, G., Wakelee, H. A., Anh-Hoa Nguyen, Neal, J. W. LIPPINCOTT WILLIAMS & WILKINS. 2013: S208–S209

  View details for Web of Science ID 000339624901009

• 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

  Abstract

  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 PubMedID 23915591

• Lung Volume Reduction After Stereotactic Ablative Radiation Therapy of Lung Tumors: Potential Application to Emphysema Binkley, M. S., Shrager, J. B., Trakul, N., Leung, A. N., Popat, R., Atwood, T. F., Maxim, P. G., Diehn, M., Loo, B. W. ELSEVIER SCIENCE INC. 2013: S545–S546

  View details for DOI 10.1016/j.ijrobp.2013.06.1443

  View details for Web of Science ID 000324503602097

• Noninvasive and Ultrasensitive Quantitation of Circulating Tumor DNA by Hybrid Capture and Deep Sequencing Bratman, S. V., Newman, A. M., To, J., Wynne, J. F., Neal, J. W., Wakelee, H., Shrager, J., Loo, B. W., Alizadeh, A. A., Diehn, M. ELSEVIER SCIENCE INC. 2013: S92

  View details for DOI 10.1016/j.ijrobp.2013.06.237

  View details for Web of Science ID 000324503600224

• 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

  Abstract

  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

  Abstract

  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

• 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

  Abstract

  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 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

  Abstract

  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 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)

  Abstract

  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

• FDG-PET avidity negatively impacts survival in pStage I NSCLC in the ACOSOG Z4031 trial. Grogan, E. L., Deppen, S. A., Chen, H., Ballman, K. V., Verdial, F. C., Aldrich, M. C., 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. AMER ASSOC CANCER RESEARCH. 2013

  View details for DOI 10.1158/1538-7445.AM2013-LB-296

  View details for Web of Science ID 000331220601221

• Developing a non-invasive, diagnostic test for stage I non-small cell lung cancer using circulating tumor cells. Luttgen, M. S., Keu, K., Nair, V. S., Horng, G., Vasanawala, M., Kolatkar, A., Carlsson, A., Sabouri, M., Loo, B. W., Shrager, J. B., Iagaru, A., Kuschner, W., Kuhn, P., Gambhir, S. S. AMER ASSOC CANCER RESEARCH. 2013

  View details for DOI 10.1158/1538-7445.AM2013-3485

  View details for Web of Science ID 000331220602190

• 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

  View details for Web of Science ID 000317639400072

• 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)

  Abstract

  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

  View details for PubMedCentralID PMC3702496

• 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

  Abstract

  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 PubMedID 22962265

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

  Abstract

  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 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

  Abstract

  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 PubMedID 22710433

• 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

• Accuracy of FDG-PET to diagnose lung cancer in the ACOSOG Z4031 trial. Grogan, E. L., Deppen, S. A., Ballman, K. V., Andrade, G., Verdail, F. C., Aldrich, M. C., Chen, H., Decker, P. A., Harpole, D., Cerfolio, R., Keenan, R., Jones, D. R., D'Amico, T. A., Shrager, J. B., Meyers, B. F., Putnam, J. B. AMER SOC CLINICAL ONCOLOGY. 2012

  View details for Web of Science ID 000318009802012

• 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

  Abstract

  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 PubMedID 21945223

• 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

  Abstract

  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

• The Society of Thoracic Surgeons Practice Guideline on the Prophylaxis and Management of Atrial Fibrillation Associated With General Thoracic Surgery: Executive Summary ANNALS OF THORACIC SURGERY Fernando, H. C., Jaklitsch, M. T., Walsh, G. L., Tisdale, J. E., Bridges, C. D., Mitchell, J. D., Shrager, J. B. 2011; 92 (3): 1144–52

  View details for DOI 10.1016/j.athoracsur.2011.06.104

  View details for Web of Science ID 000294247400091

  View details for PubMedID 21871327

• 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

  Abstract

  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

• INTEGRATED ANALYSIS OF MICRO-RNAS AND GENES IN MALIGNANT MESOTHELIOMA Hoang, C. D., Gentles, A., Xu, Y., Plevritis, S., Merritt, R. E., Whyte, R. I., Shrager, J. B., Kratzke, R. A. LIPPINCOTT WILLIAMS & WILKINS. 2011: S483–S484

  View details for Web of Science ID 000208855802216

• ENDOBRONCHIAL ULTRASOUND IS HIGHLY EFFECTIVE FOR THE DIAGNOSIS OF LUNG CARCINOMA AND ENABLES EGFR MUTATION ANALYSIS Merritt, R. E., Hoang, C. D., Whyte, R. I., Shrager, J. B. LIPPINCOTT WILLIAMS & WILKINS. 2011: S853–S854

  View details for Web of Science ID 000208855803334

• Proteomic analysis for detection of NSCLC: Results of ACOSOG Z4031. Harpole, D., Ballman, K. V., Oberg, A. L., Whiteley, G., Cerfolio, R., Keenan, R., Jones, D. R., D'Amico, T. A., Shrager, J., Putnam, J. B., Amer Coll Surg Oncology Grp AMER SOC CLINICAL ONCOLOGY. 2011

  View details for DOI 10.1200/jco.2011.29.15_suppl.7003

  View details for Web of Science ID 000208880302143

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

  Abstract

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

  View details for DOI 10.1097/JTO.0b013e31821517db

  View details for PubMedID 21774104

• Clinically relevant interactions between micro-RNAs and genes in malignant mesothelioma characterized by an integrated analysis Hoang, C. D., Gentles, A., Xu, Y., Plevritis, S. K., Merritt, R., Whyte, R., Shrager, J., Kratzke, R. A. AMER ASSOC CANCER RESEARCH. 2011

  View details for DOI 10.1158/1538-7445.AM2011-1149

  View details for Web of Science ID 000209701404109

• 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

  Abstract

  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

  View details for PubMedCentralID PMC3056225

• Endobronchial Valves for Emphysema NEW ENGLAND JOURNAL OF MEDICINE Chang, E. 2011; 364 (4): 382-382

  View details for Web of Science ID 000286592600024

  View details for PubMedID 21268740

• 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

  Abstract

  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

  Abstract

  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

  Abstract

  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 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

  View details for Web of Science ID 000277242900122

• 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

  Abstract

  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

  View details for Web of Science ID 000277242900264

• 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

  Abstract

  : 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

• Adjuvant radiotherapy for completely resected stage II thymoma Berman, A. T., Singhal, S., Su, S., Kucharczuk, J. C., Cooper, J. D., Shrager, J., Kaiser, L. R., Friedberg, J. S., Faerber, J., Evans, T. L., Stevenson, J. P., Langer, C. J., Metz, J. M., Glatstein, E., Hahn, S. M., Rengan, R. LIPPINCOTT WILLIAMS & WILKINS. 2009: S937–S938

  View details for Web of Science ID 000269496002718

• Comparative study of anterior and posterior approaches to superior sulcus tumors Shrager, J. B., Nathan, D., Hoang, C. D., Kurichi, J. E., Kucharczuk, J. C., Kaiser, L. R. LIPPINCOTT WILLIAMS & WILKINS. 2009: S302

  View details for Web of Science ID 000269496000310

• 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

  Abstract

  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

• Spontaneous Chylopericardium: Delineation of the Underlying Anatomic Pathology by CT Lymphangiography ANNALS OF THORACIC SURGERY Itkin, M., Swe, N. M., Shapiro, S. E., Shrager, J. B. 2009; 87 (5): 1595–97

  Abstract

  Primary isolated chylopericardium is a rare condition with little known cause. This is the case of a 22-year-old woman in whom idiopathic chylopericardium developed. A lymphangiogram followed by a computed tomographic scan demonstrated occlusion of the thoracic duct and multiple lymphatic collaterals abutting the pericardial sac. Thoracic duct ligation resulted in the complete cure of the patient's condition. We theorized that the development of the pathologic lymphatic ducts in close proximity to the pericardium resulted in the development of the slowly accumulating chylopericardium.

  View details for DOI 10.1016/j.athoracsur.2008.09.054

  View details for Web of Science ID 000265299100051

  View details for PubMedID 19379917

• Thymoma ANNALS OF THORACIC SURGERY Shrager, J. B. 2009; 87 (1): 339-341

  View details for DOI 10.1016/j.athoracsur.2008.02.013

  View details for PubMedID 19110690

• 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

  Abstract

  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

• 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

  Abstract

  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

• 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

  Abstract

  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

  Abstract

  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

  Abstract

  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

  Abstract

  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

  Abstract

  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

  Abstract

  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

• 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-?

  Abstract

  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

  Abstract

  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

  Abstract

  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

• 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

  Abstract

  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

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

  Abstract

  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

• 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)

  Abstract

  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

  Abstract

  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

  Abstract

  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

  Abstract

  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

  Abstract

  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

  Abstract

  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

  Abstract

  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

• 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

  Abstract

  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

  Abstract

  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

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

  Abstract

  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

• 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

  Abstract

  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

• 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

  Abstract

  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

  Abstract

  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

  Abstract

  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

• 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

  Abstract

  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

• 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-?

  Abstract

  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

• 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

  Abstract

  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

• VIDEO-ASSISTED THORACIC-SURGERY - THE CURRENT STATE-OF-THE-ART AMERICAN JOURNAL OF ROENTGENOLOGY Kaiser, L. R., Shrager, J. B. 1995; 165 (5): 1111-1117

  Abstract

  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

• VILLOUS ADENOMA OF THE MAIN PANCREATIC DUCT - A CLUE TO THE PATHOGENESIS OF PANCREATIC MALIGNANCY SURGICAL ONCOLOGY-OXFORD Shrager, J. B., GREELISH, J., VANARSDALE, C., Furth, E., Daly, J. M. 1994; 3 (4): 203-210

  Abstract

  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

• THE VINEBERG PROCEDURE - THE IMMEDIATE FORERUNNER OF CORONARY-ARTERY BYPASS-GRAFTING ANNALS OF THORACIC SURGERY Shrager, J. B. 1994; 57 (5): 1354-1364

  Abstract

  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

• ADAPTATIONS IN MYOSIN HEAVY-CHAIN EXPRESSION AND CONTRACTILE FUNCTION IN DYSTROPHIC MOUSE DIAPHRAGM AMERICAN JOURNAL OF PHYSIOLOGY Petrof, B. J., Stedman, H. H., Shrager, J. B., Eby, J., Sweeney, H. L., Kelly, A. M. 1993; 265 (3): C834-C841

  Abstract

  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

• 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

  Abstract

  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

• 3 WOMEN AT JOHNS-HOPKINS - PRIVATE PERSPECTIVES ON MEDICAL COEDUCATION IN THE 1890S ANNALS OF INTERNAL MEDICINE Shrager, J. B. 1991; 115 (7): 564-569

  View details for Web of Science ID A1991GG28300010

  View details for PubMedID 1883127