Bio

Clinical Focus


  • Nissen Operation
  • Pleural Diseases
  • VATS Lung Surgery
  • Pancoast Syndrome
  • Pectus Excavatum
  • Cancer > Thoracic Oncology
  • Endobronchial Ultrasound
  • Esophagectomy
  • General Surgery
  • Thoracic Surgery
  • Mesothelioma
  • Transcervical Thymectomy
  • Hyperhidrosis
  • Tracheal Diseases
  • Carcinoma, Non-Small-Cell Lung

Academic Appointments


Administrative Appointments


  • Co-Director, Stanford Cancer Center Tissue Bank (2008 - Present)
  • Member, Stanford Cancer Center (2008 - Present)

Honors & Awards


  • Traveling Fellowship, American Association for Thoracic Surgery (2007-2008)
  • Cecil J. Watson Research Award, Minnesota Medical Foundation and Minneapolis Society of Internal Medicine (2004)
  • Finalist, 6th Annual C. Walton Lillehei Resident Forum Competition, American Association for Thoracic Surgery (2003)
  • The Henry Buchwald Award, Department of Surgery, University of Minnesota (2005)
  • Dr. David Gaviser – Mount Sinai Hospital Surgical Research Award, Department of Surgery, University of Minnesota (2005)
  • Dr. Leslie Zieve Research Award, Veterans Affairs Medical Center, Minneapolis, MN (2002)
  • Cancer and Leukemia Group B Fellow Travel Award, Group Meeting, June 13-16, Washington D.C. (2002)

Professional Education


  • Residency:University of Minnesota School of Medicine (2006) MN
  • Board Certification, Thoracic Surgery, American Board Thoracic Surgery (2009)
  • Fellowship:University of Pennsylvania (2008) PA
  • Board Certification: General Surgery, American Board of Surgery (2007)
  • Internship:UC Davis School of Medicine (1999) CA
  • Medical Education:University of Minnesota School of Medicine (1998) MN

Research & Scholarship

Current Research and Scholarly Interests


In our thoracic oncology laboratory we study the biology of non-small cell lung carcinoma and mesothelioma. We have a focus on translational research aimed at identifying molecular mechanisms of development, progression and/ or metastasis in these solid tumors.

Clinical Trials


  • Molecular Analysis of Thoracic Malignancies Recruiting

    Primary Objective: To collect detailed clinical information on patients with thoracic malignancies via the electronic medical record and a detailed patient questionnaire, collect blood samples, retrieve paraffin embedded tissue if not collected at Stanford, and perform exploratory molecular analysis of tumor tissues.

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

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

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

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

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

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

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  • 4D-CT-based Ventilation Imaging for Adaptive Functional Guidance in Radiotherapy Recruiting

    To determine the appropriate class of deformable image registration algorithm and metric best suited for four-dimensional (4D) CT-based ventilation assessment.

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  • Pulmonary Interstitial Lymphography in Early Stage Lung Cancer Not Recruiting

    Non-small cell lung cancer (NSCLC) is the most deadly cancer in the world. NSCLC annually causes 150,000 deaths in the US and greater than 1 million worldwide. The standard treatment for early stage NSCLC is lobectomy with lymphadenectomy. However, many patients are poor operative candidates or decline surgery. An emerging alternative is Stereotactic Body Radiation Therapy (SBRT). Mounting evidence from Phase I/II studies demonstrates that SBRT offers excellent local control. Most SBRT trials focused on small, peripheral tumors in inoperable patients. Increasingly, clinical trials study SBRT in operable patients, often with larger, central tumors. Using clinical staging, a significant proportion of patients harbor occult nodal metastases when undergoing SBRT to the primary tumor alone. Subgroups of patients carry even higher risk of nodal metastases. These nodal metastases frequently would be removed by surgical intervention. However, SBRT, at present, is only directed at the primary tumor, potentially leading to regional failures in otherwise curable patients. To increase the effectiveness of SBRT for lung tumors, the next logical step is to explore whether the highest risk areas of disease spread can be identified and targeted. Regional failure could be reduced and outcome improved in a significant proportion of patients treated with SBRT if the primary nodal drainage (PND) were identified, targeted and treated in addition to the primary tumor. We propose to conduct a study to determine how well water soluble iodinated contrast material when injected directly into the tumor can be visualized on CT scan and integrated into radiation therapy treatment planning.

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

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

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

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

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

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

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  • Imaging and Biomarkers of Hypoxia in Solid Tumors Recruiting

    To establish PET imaging with the tracer FMISO as an accurate and reliable method for measuring the oxygen content of a tumor and to establish the measurement of secreted markers in blood as an accurate and reliable method for measuring the oxygen content of a tumor.

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

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

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

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Teaching

2013-14 Courses


Postdoctoral Advisees


Publications

Journal Articles


  • 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 Web of Science ID 000327143700033

    View details for PubMedID 23828229

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

    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 Web of Science ID 000325156800016

    View details for PubMedID 23915591

  • 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

  • A Dominant Adenocarcinoma With Multifocal Ground Glass Lesions Does Not Behave as Advanced Disease ANNALS OF THORACIC SURGERY Gu, B., Burt, B. M., Merritt, R. E., Stephanie, S., Nair, V., Hoang, C. D., Shrager, J. B. 2013; 96 (2): 411-418

    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 Web of Science ID 000323177800015

    View details for PubMedID 23806231

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

    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 Web of Science ID 000321604000010

    View details for PubMedID 23845442

  • 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 Web of Science ID 000311141300012

    View details for PubMedID 22962265

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

    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 Web of Science ID 000310574200031

    View details for PubMedID 22767230

  • 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 Web of Science ID 000307354100004

    View details for PubMedID 22710433

  • Non-Small Cell Lung Cancer: Identifying Prognostic Imaging Biomarkers by Leveraging Public Gene Expression Microarray Data-Methods and Preliminary Results RADIOLOGY Gevaert, O., Xu, J., Hoang, C. D., Leung, A. N., Xu, Y., Quon, A., Rubin, D. L., Napel, S., Plevritis, S. K. 2012; 264 (2): 387-396

    Abstract

    To identify prognostic imaging biomarkers in non-small cell lung cancer (NSCLC) by means of a radiogenomics strategy that integrates gene expression and medical images in patients for whom survival outcomes are not available by leveraging survival data in public gene expression data sets.A radiogenomics strategy for associating image features with clusters of coexpressed genes (metagenes) was defined. First, a radiogenomics correlation map is created for a pairwise association between image features and metagenes. Next, predictive models of metagenes are built in terms of image features by using sparse linear regression. Similarly, predictive models of image features are built in terms of metagenes. Finally, the prognostic significance of the predicted image features are evaluated in a public gene expression data set with survival outcomes. This radiogenomics strategy was applied to a cohort of 26 patients with NSCLC for whom gene expression and 180 image features from computed tomography (CT) and positron emission tomography (PET)/CT were available.There were 243 statistically significant pairwise correlations between image features and metagenes of NSCLC. Metagenes were predicted in terms of image features with an accuracy of 59%-83%. One hundred fourteen of 180 CT image features and the PET standardized uptake value were predicted in terms of metagenes with an accuracy of 65%-86%. When the predicted image features were mapped to a public gene expression data set with survival outcomes, tumor size, edge shape, and sharpness ranked highest for prognostic significance.This radiogenomics strategy for identifying imaging biomarkers may enable a more rapid evaluation of novel imaging modalities, thereby accelerating their translation to personalized medicine.

    View details for DOI 10.1148/radiol.12111607

    View details for Web of Science ID 000306660000010

    View details for PubMedID 22723499

  • 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 Web of Science ID 000297333300023

    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

  • Results from a Single Institution Phase II Trial of Concurrent Docetaxel/Carboplatin/Radiotherapy Followed by Surgical Resection and Consolidation Docetaxel/Carboplatin in Stage III Non-Small-Cell Lung Cancer CLINICAL LUNG CANCER Das, M., Donington, J. S., Murphy, J., Kozak, M., Eclov, N., Whyte, R. I., Hoang, C. D., Zhou, L., Le, Q., Loo, B. W., Wakelee, H. 2011; 12 (5): 280-285

    Abstract

    The optimal treatment of locally advanced non-small-cell lung cancer (NSCLC) remains controversial. We hypothesized that using a trimodality approach in selected patients with stage IIIA/IIIB disease would be both feasible and efficacious with reasonable toxicity.We enrolled 13 patients with resectable stage III NSCLC on a prospective phase II trial of trimodality therapy. Induction treatment consisted of weekly docetaxel 20 mg/m(2) and weekly carboplatin at an area under curve (AUC) of 2 concurrent with 45 Gy thoracic radiotherapy. Resection was performed unless felt to be unsafe or if patients had progressive disease. Postoperative consolidation consisted of docetaxel 75 mg/m(2) and carboplatin at an AUC of 6 every 3 weeks for 3 cycles with growth factor support.All patients responded to induction chemoradiotherapy as measured by total gross tumor volume reductions of 43% on average (range, 27%-64%). Twelve patients underwent resection of the tumor and involved nodes, yielding a resectability rate of 92%. The primary endpoint of 2-year overall survival (OS) was 72% (95% confidence interval [CI], 36%-90%), and 2-year progression-free survival (PFS) was 36% (95% CI, 9%-64%). The maximal toxicity observed per patient was grade II in 5 patients (38%); grade III in 7 patients (54%); grade IV in 1 patient (8%); and grade V in none.This trimodality approach resulted in promising outcomes with reasonable toxicity in carefully selected patients with stage III NSCLC at a single institution.

    View details for DOI 10.1016/j.cllc.2011.06.003

    View details for Web of Science ID 000294600800003

    View details for PubMedID 21752720

  • 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 H?O?-treated muscle cells, we identify Fos, FoxO1, and Stat3 as regulators of Bim expression as well as of expression of the catabolic markers atrogin and LC3. We thus identify a novel Fos/FoxO1/Stat3-Bim intrinsic apoptotic pathway and establish the centrality of oxidative stress in the development of VIDD. This information may help in the design of specific drugs to prevent this condition.

    View details for DOI 10.1096/fj.11-183798

    View details for Web of Science ID 000294435200008

    View details for PubMedID 21597002

  • 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 Web of Science ID 000289554100012

    View details for PubMedID 21774104

  • Anterior Mediastinal Masses In: Sellke F, Swanson S, and del Nido PJ (eds.), Sabiston and Spencer Surgery of the Chest (8th Edition) Hoang CD, Kucharczuk J, Shrager JB. 2009: Chapter 40
  • Wedge Gastroplasty and Reinforced Crural Repair: Important Components of Laparoscopic Giant or Recurrent Hiatal Hernia Repair. Journal of Thoracic and Cardiovascular Surgery Whitson BA, Hoang CD, Boettcher AK, Dahlberg PS, Andrade RS, Maddaus MA. 2006; 132 (5): 1196-1202
  • A Gene Profile of Nodal Metastasis: Analysis of Paired Primary Lung and Lymph Node Tumor Cells. Cancer Detection and Prevention Hoang CD, Guillaume TJ, Engel SC, Tawfic SH, Kratzke RA, Maddaus MA. 2005; 29 (6): 509-517
  • Gene Expression Profiling Identifies Matriptase Overexpression in Malignant Mesothelioma. Chest Hoang CD, DCunha J, Casmey CE, Frizelle SP, Maddaus MA, Kratzke RA. 2004; 125 (5): 1843-1852.
  • Expression Profiling of Non-Small-Cell Lung Carcinoma Identifies Metastatic Genotypes Based on Lymph Node Tumor Burden. Journal of Thoracic and Cardiovascular Surgery Hoang CD, DCunha J, Tawfic SH, Gruessner AC, Kratzke RA, Maddaus MA. 2004; 127 (5): 1332-1342.
  • Selective Activation of Insulin Receptor Substrate-1 and -2 in Pleural Mesothelioma Cells is Associated with Distinct Malignant Phenotypes. Cancer Research Hoang CD, Zhang X, Scott PS, Guillaume TJ, Maddaus MA, Yee D, Kratzke RA. 2004; 64 (20): 7479-7485.

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