Herbert Pang

Duke University Medical Center, Durham, North Carolina, United States

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Publications (62)339.38 Total impact

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    ABSTRACT: In early clinical testing, most novel targeted anti-cancer therapies have limited toxicities and limited efficacy, which complicates dose and schedule selection for these agents. Confirmation of target inhibition is critical for rational drug development; however, repeated tumor biopsies are often impractical and peripheral blood mononuclear cells and normal skin are often inadequate surrogates for tumor tissue. Based upon the similarities of tumor and wound stroma, we have developed a clinical dermal granulation tissue model to evaluate novel targeted therapies. A 4mm skin punch biopsy was used to stimulate wound healing and a repeat 5mm punch biopsy was used to harvest the resulting granulation tissue. This assay was performed at pre-treatment and on-treatment evaluating four targeted therapies, bevacizumab, everolimus, erlotinib, and panitumumab, in the context of three different clinical trials. Total and phosphorylated levels VEGFR2, S6RP, and EGFR were evaluated using ELISA-based methodologies. Significant and consistent inhibition of VEGF pathway (using VEGFR2 as the readout) was observed in granulation tissue biopsies from patients treated with bevacizumab and everolimus. Additionally, significant and consistent inhibition of mTOR pathway (using S6RP as the readout) was observed in patients treated with everolimus. Lastly, significant inhibition of EGFR pathway (using EGFR as the readout) was observed in patients treated with panitumumab, but this was not observed in patients treated with erlotinib. Molecular analyses of dermal granulation tissue can be used as a convenient and quantitative pharmacodynamic biomarker platform for multiple classes of targeted therapies. Copyright © 2015, American Association for Cancer Research.
    Clinical Cancer Research 04/2015; DOI:10.1158/1078-0432.CCR-14-2819 · 8.19 Impact Factor
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    ABSTRACT: To evaluate the efficacy of maintenance sunitinib after chemotherapy for small-cell lung cancer (SCLC). The Cancer and Leukemia Group B 30504 trial was a randomized, placebo-controlled, phase II study that enrolled patients before chemotherapy (cisplatin 80 mg/m(2) or carboplatin area under the curve of 5 on day 1 plus etoposide 100 mg/m(2) per day on days 1 to 3 every 21 days for four to six cycles). Patients without progression were randomly assigned 1:1 to placebo or sunitinib 37.5 mg per day until progression. Cross-over after progression was allowed. The primary end point was progression-free survival (PFS) from random assignment for maintenance placebo versus sunitinib using a one-sided log-rank test with α = .15; 80 randomly assigned patients provided 89% power to detect a hazard ratio (HR) of 1.67. One hundred forty-four patients were enrolled; 138 patients received chemotherapy. Ninety-five patients were randomly assigned; 10 patients did not receive maintenance therapy (five on each arm). Eighty-five patients received maintenance therapy (placebo, n = 41; sunitinib, n = 44). Grade 3 adverse events with more than 5% incidence were fatigue (19%), decreased neutrophils (14%), decreased leukocytes (7%), and decreased platelets (7%) for sunitinib and fatigue (10%) for placebo; grade 4 adverse events were GI hemorrhage (n = 1) and pancreatitis, hypocalcemia, and elevated lipase (n = 1; all in same patient) for sunitinib and thrombocytopenia (n = 1) and hypernatremia (n = 1) for placebo. Median PFS on maintenance was 2.1 months for placebo and 3.7 months for sunitinib (HR, 1.62; 70% CI, 1.27 to 2.08; 95% CI, 1.02 to 2.60; one-sided P = .02). Median overall survival from random assignment was 6.9 months for placebo and 9.0 months for sunitinib (HR, 1.28; 95% CI, 0.79 to 2.10; one-sided P = .16). Three sunitinib and no placebo patients achieved complete response during maintenance. Ten (77%) of 13 patients evaluable after cross-over had stable disease on sunitinib (6 to 27 weeks). Maintenance sunitinib was safe and improved PFS in extensive-stage SCLC. © 2015 by American Society of Clinical Oncology.
    Journal of Clinical Oncology 03/2015; 33(15). DOI:10.1200/JCO.2014.57.3105 · 17.88 Impact Factor
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    ABSTRACT: A novel combination of bevacizumab and everolimus was evaluated in refractory colorectal cancer patients in a phase II trial. In this retrospective analysis, plasma samples from 49 patients were tested for over 40 biomarkers at baseline and after one or two cycles of drug administration. Analyte levels at baseline and change on-treatment were correlated with progression-free survival (PFS) and overall survival (OS) using univariate Cox proportional hazard modeling. Multivariable analyses were conducted using Cox modeling. Significant changes in multiple markers were observed following bevacizumab and everolimus treatment. Baseline levels of six markers significantly correlated with PFS and OS, including CRP, Gro-α, IGFBP-1, TF, ICAM-1, and TSP-2 (p<0.05). At C2D1, changes of IGFBP-3, TGFβ-R3, and IGFBP-2 correlated with PFS and OS. Prognostic models were developed for OS and PFS (p=0.0002 and 0.004, respectively). Baseline model for OS consisted of CRP, Gro-α, and TF, while on-treatment model at C2D1 included IGFBP-2, IGFBP-3, and TGFβ-R3. These data demonstrated that multiple biomarkers were significantly modulated in response to bevacizumab and everolimus. Several markers correlated with both PFS and OS. Interestingly, these markers are known to be associated with inflammation and IGF signaling, key modulators of mTOR biology. Copyright © 2015, American Association for Cancer Research.
    Molecular Cancer Therapeutics 02/2015; 14(4). DOI:10.1158/1535-7163.MCT-14-0923-T · 6.11 Impact Factor
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    ABSTRACT: Inhibition of tumor angiogenesis is an effective mechanism to limit tumor growth; dual inhibition may result in additional benefit. Bevacizumab is a monoclonal antibody directed against vascular endothelial growth factor (VEGF), and intetumumab is a fully humanized monoclonal antibody that blocks αv integrins when complexed with β integrins. We evaluated the safety, tolerability, and efficacy of the combination of bevacizumab plus intetumumab in patients with refractory solid tumors. We also explored the effects of these agents on plasma-based biomarkers and wound angiogenesis. Patients with refractory solid tumors, Karnofsky performance status ≥70 %, and adequate organ function were eligible. Plasma samples and wound biopsies were obtained at baseline and on-treatment. Twelve patients were enrolled and received study drug. No tumor responses were noted. Observed toxicities included three cases of transient uveitis likely related to intetumumab and one case of reversible posterior leukoencephalopathy syndrome likely related to bevacizumab. Biomarker analysis revealed changes in soluble endoglin, soluble E-cadherin, and soluble E-selectin as well as PlGF and VEGF-D while on treatment. There was no observed impact of bevacizumab plus intetumumab on the phosphorylated or total levels of paxillin in wound tissue; however, an increase in the ratio of phospho/total paxillin levels was noted. Bevacizumab and intetumumab can be administered safely in combination. Bevacizumab plus intetumumab treatment resulted in changes in the plasma levels of several extracellular matrix interacting proteins and angiogenic factors.
    Cancer Chemotherapy and Pharmacology 12/2014; 75(2). DOI:10.1007/s00280-014-2647-x · 2.57 Impact Factor
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    ABSTRACT: The short-term superiority of video-assisted thoracoscopic surgery lobectomy compared with open lobectomy for early-stage lung cancer has been suggested by single-institution studies. Lack of equipoise limits the feasibility of a randomized study to confirm this. The hypothesis of this study (CALGB 31001) was that VATS lobectomy results in shorter length of hospital stay and fewer complications compared with open lobectomy in stages I and II non-small cell lung cancer in a multi-institutional setting. Five hundred nineteen patients whose tumors had been collected as part of CALGB 140202 (lung cancer tissue bank) were eligible. Propensity-scoring using age, race, sex, performance status, comorbidities, histology, tumor stage, and size as independent variables was used to create a 1:1 matched group of 175 pairs of patients. McNemar's test for binary variables and Wilcoxon signed-rank test for continuous variables were used to assess differences in length of hospital stay, complications, and discharge dispositions between the groups. Comparison of disease-free and overall survival between the two approaches was done using the log-rank test. Probability values of less than 0.05 were considered significant. The matched data on length of hospital stay, complications, and discharge dispositions significantly favored the video-assisted thoracoscopic surgery group. There was no statistically significant difference in survival between the two approaches. This multi-institutional study supports the assertion that thoracoscopic lobectomy results in shorter hospital length of stay, fewer perioperative complications, and greater likelihood of independent home discharge compared with open lobectomy for early-stage lung cancer. Survival was comparable between the two groups. Copyright © 2014 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.
    The Annals of Thoracic Surgery 12/2014; 99(2). DOI:10.1016/j.athoracsur.2014.09.018 · 3.63 Impact Factor
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    ABSTRACT: A proper internal validation is necessary for the development of a reliable and reproducible prognostic model for external validation. Variable selection is an important step for building prognostic models. However, not many existing approaches couple the ability to specify the number of covariates in the model with a cross-validation algorithm. We describe a user-friendly SAS macro that implements a score selection method and a leave-one-out cross-validation approach. We discuss the method and applications behind this algorithm, as well as details of the SAS macro. Copyright © 2014 Elsevier Ltd. All rights reserved.
    Computers in Biology and Medicine 12/2014; 57C:123-129. DOI:10.1016/j.compbiomed.2014.11.015 · 1.46 Impact Factor
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    ABSTRACT: Thyroid hormone (TH) is important for tissue repair because it regulates cellular differentiation. Intrahepatic TH activity is controlled by both serum TH levels and hepatic deiodinases. TH substrate (thyroxine, T4) is converted into active hormone (triidothyronine, T3) by deiodinase 1 (D1), but into inactive hormone (reverse T3, rT3) by deiodinase 3 (D3). Although the relative expressions of D1 and D3 are known to change during liver injury, the cell types and signaling mechanisms involved are unclear. We evaluated the hypothesis that changes in hepatic deiodinases result from repairrelated activation of the Hedgehog pathway in stromal cells. We localized deiodinase expression, assessed changes during injury, and determined how targeted manipulation of Hedgehog signaling in stromal cells impacted hepatic deiodinase expression, TH content, and TH action in rodents. Humans with chronic liver disease were also studied. In healthy liver, hepatocytes strongly expressed D1 and stromal cells weakly expressed D3. During injury, hepatocyte expression of D1 decreased, while stromal expression of D3 increased, particularly in myofibroblasts. Conditionally disrupting Hedgehog signaling in myofibroblasts normalized deiodinase expression. Repairrelated changes in deiodinases were accompanied by reduced hepatic TH content and TH-regulated gene expression. In patients, this was reflected by increased serum rT3. Moreover, decreases in fT3/rT3 and fT4/rT3 distinguished advanced from mild fibrosis, even in individuals with similar serum levels of TSH and fT4. Conclusion: Hedgehog-dependent changes in liver stromal cells drive repair-related changes in hepatic deiodinase expression that promote intrahepatic hypothyroidism, thereby limiting exposure to T3, an important factor for cellular differentiation.
    Endocrinology 08/2014; 155(11):en20141302. DOI:10.1210/en.2014-1302 · 4.64 Impact Factor
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    ABSTRACT: Recent method development has included multi-dimensional genomic data algorithms because such methods have more accurately predicted clinical phenotypes related to disease. This study is the first to conduct an integrative genomic pathway-based analysis with a graph-based learning algorithm. The methodology of this analysis, graph-based semi-supervised learning, detects pathways that improve prediction of a dichotomous variable, which in this study is cancer stage. This analysis integrates genome-level gene expression, methylation, and single nucleotide polymorphism (SNP) data in serous cystadenocarcinoma (OV) and colon adenocarcinoma (COAD). The top 10 ranked predictive pathways in COAD and OV were biologically relevant to their respective cancer stages and significantly enhanced prediction accuracy and area under the ROC curve (AUC) when compared to single data-type analyses. This method is an effective way to simultaneously predict binary clinical phenotypes and discover their biological mechanisms.
    Cancer informatics 07/2014; 13(Suppl 4):1-9. DOI:10.4137/CIN.S13634
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    ABSTRACT: TRC105 is an endoglin-targeting drug that possesses anti-angiogenic and antitumor potential. Analysis of the initial phase I trial of TRC105 demonstrated good tolerability and efficacy in cancer patients. In this report, we analyzed multiple circulating biomarkers at baseline, cycle 2 day 1 (C2D1), and end of study (EOS) for each patient. The baseline level and the fold change from baseline to both C2D1 and EOS for each marker were statistically analyzed. At C2D1, seven markers were significantly downregulated (angiopoietin-2 [Ang-2], insulin-like growth factor-binding protein-3 [IGFBP-3], plasminogen activator inhibitor-1 [PAI-1] total, platelet-derived growth factor [PDGF]-AA, PDGF-BB, thrombospondin-1 [TSP-1], and vascular endothelial growth factor [VEGF]-D). Meanwhile, seven markers were upregulated by C2D1 (E-Cadherin, soluble Endoglin [sEnd], E-Selectin, interleukin-6 [IL-6], osteopontin [OPN], TSP-2, and von Willebrand factor [vWF]). At EOS, seven markers were upregulated including Ang-2, C-reactive protein (CRP), intercellular adhesion molecule-1 (ICAM-1), IGFBP-1, IL-6, TSP-2, and vascular cell adhesion molecule-1 (VCAM-1). A statistical trend was also seen for increases of VEGF-A and placenta growth factor (PlGF) at EOS. Throughout treatment, sEnd levels significantly increased, an observation that was recapitulated in cultured endothelial cells. This is the first report of plasma-based biomarkers in patients receiving TRC105. TRC105 treatment by C2D1 was associated with decreases in several angiogenic factors, including Ang-2, PDGF isoforms, and VEGF isoforms, offering insight into the mechanisms underlying TRC105's anti-angiogenic, antitumor function. Increases in sEnd were the most significant of all observed biomarker changes and may reflect direct drug effects. Additionally, biomarker changes in response to TRC105 are distinct from those seen in patients treated with VEGF-targeting drugs, suggesting the possible utility of combining these two classes of angiogenesis inhibitors in patients.
    Cancer Medicine 06/2014; 3(3). DOI:10.1002/cam4.207
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    ABSTRACT: Purpose To define maximum tolerated dose (MTD), toxicities, and pharmacodynamics of capecitabine, oxaliplatin, bevacizumab, and everolimus in advanced solid tumor patients. Design This was a standard "3 + 3" dose-escalation trial. All subjects received bevacizumab 7.5 mg/kg on day 1 of each cycle. Doses for capecitabine, oxaliplatin and everolimus were modified per dose limiting toxicity (DLT). Baseline and on-treatment plasma biomarkers were analyzed. Archived tumor mRNA levels were evaluated for NRP1, NRP2 and VEGF-A isoforms. Results Twenty-nine patients were evaluable for toxicity and 30 for efficacy. Two DLTs were observed in cohort 1 and one DLT each was observed in cohort -1 and -1b. Grade ≥3 toxicities included neutropenia, hypertension, perforation/fistula/hemorrhage, hypertriglyceridemia, diarrhea, and thromboembolism. Twelve subjects experienced partial response (PR); 12 had stable disease as best response. Three of seven chemorefractory metastatic colorectal cancer (mCRC) subjects experienced PR; 8 of 15 chemonaive mCRC subjects experienced PR. Plasma TβRIII and IL-6 increased on treatment but without correlation to outcome. Increased VEGF165 levels significantly correlated with longer progression free survival. Conclusions Everolimus with full dose capecitabine, oxaliplatin, and bevacizumab had unacceptable toxicity. MTD was: everolimus 5 mg daily; capecitabine 680 mg/m(2) BID days 1-14; oxaliplatin 100 mg/m(2) and bevacizumab 7.5 mg/kg, day 1. Activity was noted in mCRC.
    Investigational New Drugs 04/2014; DOI:10.1007/s10637-014-0089-2 · 2.93 Impact Factor
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    ABSTRACT: Estrogens inhibit stellate cell activation and fibrogenesis. Thus, gender and reproductive states may influence the degree of fibrosis in patients with nonalcoholic steatohepatitis (NASH). To investigate the association between gender, menopause, and the severity of liver fibrosis in patients with NASH, we analyzed 541 adult patients enrolled from our Duke Liver Clinics (n=338) and the Duke Metabolic and Weight Loss Surgery Program (n=203) who had a histologic diagnosis of NASH. Multiple ordinal logistic regression models were used to assess the association between gender, menopause and severity of liver fibrosis. Overall, men, pre-menopausal and post-menopausal women composed 35.1%, 28.4%, and 36.5% of the population, respectively. The mean age was 48 years and 22% had advanced fibrosis. After adjusting for covariates (enrolling site, grades of portal inflammation, and hepatocyte ballooning) and potential confounders (race, body mass index, diabetes/prediabetes, hypertension), adjusted cumulative odd ratio (ACOR) and 95% confidence interval (CI) for greater fibrosis severity was 1.4 [0.9, 2.1] (p=0.17) for post-menopausal women and 1.6 [1.0, 2.5] (p=0.03) for men, having pre-menopausal women as a reference. There was borderline interaction between gender and age group divided by age 50, the average age at menopause in the US (p=0.08): ACOR and 95% CI of having greater fibrosis severity in men compared to women was 1.8 [1.1, 2.9] for patients with age <50 years (p=0.02) and 1.2 [0.7, 2.1] for patients with age ≥ 50 years (p=0.59). Conclusion: Men are at a higher risk of having more severe fibrosis compared to women before menopause, while post-menopausal women have a similar severity of liver fibrosis compared to men. These findings may be explained by the protective effects of estrogen against fibrogenesis. (Hepatology 2013;).
    Hepatology 04/2014; 59(4). DOI:10.1002/hep.26761 · 11.19 Impact Factor
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    Hepatology 02/2014; DOI:10.1002/hep.27038 · 11.19 Impact Factor
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    ABSTRACT: Clinicians rely upon the severity of liver fibrosis to segregate patients with well-compensated nonalcoholic fatty liver disease (NAFLD) into sub-populations at high versus low-risk for eventual liver-related morbidity and mortality. We compared hepatic gene expression profiles in high- and low-risk NAFLD patients to identify processes that distinguish the two groups and hence, might be novel biomarkers or treatment targets. Microarray analysis was used to characterize gene expression in percutaneous liver biopsies from low-risk, "mild" NAFLD patients (fibrosis stage 0-1, n=40) and high risk, "severe" NAFLD patients (fibrosis stage 3-4, n=32). Findings were validated in a second, independent cohort and confirmed by real time PCR and immunohistochemistry. As a group, patients at risk for bad NAFLD outcomes had significantly worse liver injury and more advanced fibrosis (severe NAFLD) than clinically-indistinguishable NAFLD patients with a good prognosis (mild NAFLD). A 64 gene profile reproducibly differentiated severe NAFLD from mild NAFLD, and a 20 gene subset within this profile correlated with NAFLD severity, independent of other factors known to influence NAFLD progression. Multiple genes involved with tissue repair/regeneration and certain metabolism-related genes were induced in severe NAFLD. Ingenuity Pathway Analysis and immunohistochemistry confirmed deregulation of metabolic and regenerative pathways in severe NAFLD, and revealed overlap among the gene expression patterns of severe NAFLD, cardiovascular disease, and cancer. Conclusion: By demonstrating specific metabolic and repair pathways that are differentially activated in livers with severe NAFLD, gene profiling identified novel targets that can be exploited to improve diagnosis and treatment of patients who are at greatest risk for NAFLD-related morbidity and mortality. (Hepatology 2013;).
    Hepatology 02/2014; DOI:10.1002/hep.26661 · 11.19 Impact Factor
  • Herbert Pang, Inyoung Kim, Hongyu Zhao
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    ABSTRACT: Close to three percent of the world’s population suffer from diabetes. Despite the range of treatment options available for diabetes patients, not all patients benefit from them. Investigating how different pathways correlate with phenotype of interest may help unravel novel drug targets and discover a possible cure. Many pathway-based methods have been developed to incorporate biological knowledge into the study of microarray data. Most of these methods can only analyze individual pathways but cannot deal with two or more pathways in a model based framework. This represents a serious limitation because, like genes, individual pathways do not work in isolation, and joint modeling may enable researchers to uncover patterns not seen in individual pathway-based analysis. In this paper, we propose a random effects model to analyze two or more pathways. We also derive score test statistics for significance of pathway effects. We apply our method to a microarray study of Type II diabetes. Our method may eludicate how pathways crosstalk with each other and facilitate the investigation of pathway crosstalks. Further hypothesis on the biological mechanisms underlying the disease and traits of interest may be generated and tested based on this method.
    Statistics in Biosciences 01/2014; DOI:10.1007/s12561-014-9109-1
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    Herbert Pang, Hongyu Zhao
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    ABSTRACT: Cancer biomarker discovery can facilitate drug development, improve staging of patients, and predict patient prognosis. Because cancer is the result of many interacting genes, analysis based on a set of genes with related biological functions or pathways may be more informative than single gene-based analysis for cancer biomarker discovery. The relevant pathways thus identified may help characterize different aspects of molecular phenotypes related to the tumor. Although it is well known that cancer patients may respond to the same treatment differently because of clinical variables and variation of molecular phenotypes, this patient heterogeneity has not been explicitly considered in pathway analysis in the literature. We hypothesize that combining pathway and patient clinical information can more effectively identify relevant pathways pertinent to specific patient subgroups, leading to better diagnosis and treatment. In this article, we propose to perform stratified pathway analysis based on clinical information from patients. In contrast to analysis using all the patients, this more focused analysis has the potential to reveal subgroup-specific pathways that may lead to more biological insights into disease etiology and treatment response. As an illustration, the power of our approach is demonstrated through its application to a breast cancer dataset in which the patients are stratified according to their oral contraceptive use.
    Cancer informatics 01/2014; 13(Suppl 4):73-8. DOI:10.4137/CIN.S13973
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    ABSTRACT: Standard therapy for limited stage small cell lung cancer (L-SCLC) is concurrent chemotherapy and radiotherapy followed by prophylactic cranial radiotherapy. Predictors of post chemoradiotherapy pulmonary toxicity in limited stage (LS) small cell lung cancer (SCLC) patients are not well defined. Current guidelines are derived from non-small cell lung cancer regimens, and do not account for the unique biology of this disease. Therefore, we analyzed patients on three consecutive CALGB LS-SCLC trials treated with concurrent chemotherapy and daily high dose radiotherapy (70 Gy) to determine patient and treatment related factors predicting for post-treatment pulmonary toxicity. Patients treated on CALGB protocols 39808, 30002, 30206 investigating two cycles of chemotherapy followed by concurrent chemotherapy and 70 Gy daily thoracic radiation therapy were pooled. Patient, tumor, and treatment related factors were evaluated to determine predictors of grade 3–5 pulmonary toxicities after concurrent chemoradiotherapy. 100 patients were included. No patient experienced grade 4–5 post-treatment pulmonary toxicity. Patients who experienced post-treatment pulmonary toxicity were more likely to be older (median age 69 vs 60, p = 0.09) and have smaller total lung volumes (2565 cc vs 3530 cc, p = 0.05).). Furthermore,exposure of larger volumes of lung to lower (median V5 = 70%, p = 0.09, median V10 = 63%, p = 0.07), inter-mediate (median V20 = 50, p = 0.04) and high (median V60 = 25%, p = 0.01) doses of radiation were all associated with post-treatment grade 3 pulmonary toxicity, as was a larger mean lung radiation dose(median 31 Gy) p = 0.019. Post-treatment pulmonary toxicity following the completion of 2 cycles of chemotherapy followed by concurrent chemotherapy and high dose daily radiation therapy was uncommon. Care should be taken to minimize mean lung radiation exposure, as well as volumes of low, intermediate and high doses of radiation.
    Lung cancer (Amsterdam, Netherlands) 12/2013; 82(3):436-40. · 3.74 Impact Factor
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    ABSTRACT: Standard therapy for limited stage small cell lung cancer (L-SCLC) is concurrent chemotherapy and radiotherapy followed by prophylactic cranial radiotherapy. Predictors of post chemoradiotherapy pulmonary toxicity in limited stage (LS) small cell lung cancer (SCLC) patients are not well defined. Current guidelines are derived from non-small cell lung cancer regimens, and do not account for the unique biology of this disease. Therefore, we analyzed patients on three consecutive CALGB LS-SCLC trials treated with concurrent chemotherapy and daily high dose radiotherapy (70 Gy) to determine patient and treatment related factors predicting for post-treatment pulmonary toxicity.
    Lung Cancer 12/2013; 82(3):436–440. DOI:10.1016/j.lungcan.2013.10.001 · 3.74 Impact Factor
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    ABSTRACT: Purpose Dasatinib inhibits src family kinases and has anti-angiogenic properties. We conducted a phase I study of dasatinib, capecitabine, oxaliplatin, and bevacizumab (CapeOx/bevacizumab), with an expansion cohort in metastatic colorectal cancer (CRC). Methods Patients were enrolled in a dose escalation cohort to establish the maximum tolerated dose (MTD) and the recommended phase II dose (RP2D). Using a "3 + 3" design, twelve patients with advanced solid tumors received dasatinib (50 mg twice daily or 70 mg daily), capecitabine (850 mg/m(2) twice daily, days 1-14), oxaliplatin (130 mg/m(2) on day 1) and bevacizumab (7.5 mg/kg on day1), every 3 weeks. Ten patients with previously untreated metastatic CRC were then enrolled in an expansion cohort. Activated src (srcact) expression was measured by immunohistochemistry, using an antibody that selectively recognizes the active conformation of src (clone 28). Results Twenty-two patients were enrolled between June 2009 and May 2011. Two DLTs were observed in the 50 mg bid dasatinib cohort, and one DLT was observed in the 70 mg daily dasatinib cohort. The MTD and RP2D for dasatinib was 70 mg daily. The most common treatment-related adverse events were fatigue (20; 91 %) and diarrhea (18; 82 %). Biomarker analysis of srcact expression demonstrated that the overall response rate (ORR) was 75 % (6/8) for patients with high srcact expression (IHC ≥ 2), compared to 0 % (0/8) for patients with low srcact expression (IHC 0 or 1); (p = 0.007). Conclusions The RP2D of dasatinib is 70 mg daily in combination with CapeOx/bevacizumab. High levels of srcact expression may predict those patients most likely to benefit from dasatinib.
    Investigational New Drugs 11/2013; DOI:10.1007/s10637-013-0042-9 · 2.93 Impact Factor
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    ABSTRACT: CALGB80303 was a phase III trial of 602 patients with locally advanced or metastatic pancreatic cancer comparing gemcitabine/bevacizumab vs. gemcitabine/placebo. The study found no benefit in any outcome from the addition of bevacizumab to gemcitabine. Blood samples were collected and multiple angiogenic factors were evaluated and then correlated with clinical outcome in general (prognostic markers) and with benefit specifically from bevacizumab treatment (predictive markers). Plasma samples were analyzed via a novel multiplex ELISA platform for 31 factors related to tumor growth, angiogenesis, and inflammation. Baseline values for these factors were correlated with overall survival using univariate Cox proportional hazard regression models and multivariable Cox regression models with leave-one-out cross validation. Predictive markers were identified using a treatment by marker interaction term in the Cox model. Baseline plasma was available from 328 patients. Univariate prognostic markers for OS were identified including: Ang2, CRP, ICAM-1, IGFBP-1, TSP-2 (all p<0.001). These prognostic factors were found to be highly significant, even after adjustment for known clinical factors. Additional modeling approaches yielded prognostic signatures from multivariable Cox regression. The gemcitabine/bevacizumab signature consisted of IGFBP-1, IL-6, PDGF-AA, PDGF-BB, TSP-2; while the gemcitabine/placebo signature consisted of CRP, IGFBP-1, PAI-1, PDGF-AA, P-selectin (both p<0.0001). Lastly, three potential predictive markers of bevacizumab efficacy were identified: VEGF-D (p<0.01), SDF1 (p<0.05), and Ang2 (p<0.05). This study identified strong prognostic markers for pancreatic cancer patients. Predictive marker analysis indicated that plasma levels of VEGF-D, Ang2, and SDF1 significantly predicted for benefit or lack of benefit from bevacizumab in this population.
    Clinical Cancer Research 10/2013; 19(24). DOI:10.1158/1078-0432.CCR-13-0926 · 8.19 Impact Factor
  • Cancer Research 08/2013; 73(8 Supplement):4707-4707. DOI:10.1158/1538-7445.AM2013-4707 · 9.28 Impact Factor

Publication Stats

495 Citations
339.38 Total Impact Points

Institutions

  • 2009–2015
    • Duke University Medical Center
      • • Department of Biostatistics and Bioinformatics
      • • Department of Immunology
      Durham, North Carolina, United States
  • 2014
    • The University of Hong Kong
      • Li Ka Shing Faculty of Medicine
      Hong Kong, Hong Kong
  • 2009–2014
    • Duke University
      • Department of Medicine
      Durham, North Carolina, United States
  • 2012
    • University of Chicago
      • Department of Medicine
      Chicago, Illinois, United States
  • 2006–2008
    • Yale-New Haven Hospital
      New Haven, Connecticut, United States