Christopher G Wood

University of Texas MD Anderson Cancer Center, Houston, Texas, United States

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Publications (279)1514.17 Total impact

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    ABSTRACT: Adrenocortical carcinoma (ACC) is a rare malignancy with poor prognosis and limited response to chemotherapy. Hepatocyte growth factor (HGF) and its receptor cMET augment cancer growth and resistance to chemotherapy, but their role in ACC has not been examined. In this study, we investigated the association between HGF/cMET expression and cancer hallmarks of ACC. Transcriptomic and immunohistochemical analyses indicated that increased HGF/cMET expression in human ACC samples was positively associated with cancer-related biological processes including proliferation and angiogenesis, and negatively correlated with apoptosis. Accordingly, treatment of ACC cells with exogenous HCG resulted in increased cell proliferation in vitro and in vivo while short hairpin RNA-mediated knockdown or pharmacological inhibition of cMET suppressed cell proliferation and tumor growth. Moreover, exposure of cells to mitotane, cisplatin, or radiation rapidly induced pro-cMET expression and was associated with an enrichment of genes (e.g., CYP450 family) related to therapy resistance further implicating cMET in the anticancer drug response. Together, these data suggest an important role for HGF/cMET signaling in ACC growth and resistance to commonly used treatments. Targeting cMET, alone or in combination with other drugs, could provide a breakthrough in the management of this aggressive cancer. Copyright © 2015, American Association for Cancer Research.
    Cancer Research 08/2015; DOI:10.1158/0008-5472.CAN-14-3707 · 9.28 Impact Factor
  • Cancer Research 08/2015; 75(15 Supplement):836-836. DOI:10.1158/1538-7445.AM2015-836 · 9.28 Impact Factor
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    ABSTRACT: Objective Few studies of renal cell cancer with tumor thrombus have evaluated the risk of recurrence after attempted curative surgery. The objective of this study was to determine predictors of postsurgical recurrence for non-metastatic patients with RCC and venous thrombus.Methods Records from consecutive non-metastatic RCC patients with tumor thrombus treated surgically from 2000 to 2012 at three centers were reviewed. Univariable and multivariable analysis was used to evaluate the association of risk factors for post-surgical recurrence.ResultsA total of 465 non-metastatic patients were identified including patients with thrombus present in: renal vein 257 (55.3%), infrahepatic IVC 144 (31.0%), and suprahepatic IVC 64 (13.8%). Median follow-up was 28.3 months (IQR 12.2-56.4) with metastatic RCC developing in 188 (40.5%) patients.Independent predictors of recurrence included: BMI ≤20 (HR 2.66; 95% CI 1.29-5.49), low pre-operative hemoglobin (HR 1.54; 95% CI 1.07-2.20), perinephric fat invasion (HR 1.51; 95% CI 1.09-2.10), IVC thrombus height (HR 2.64; 95% CI 1.47-4.74), tumor diameter (HR 1.04 95% CI 1.00-1.09), nuclear grade (HR 1.56 95% CI 1.12-2.15), and non-clear cell histology (2.13; 1.30-3.50).Independently predictive variables were used to create a recurrence model for 3 risk groups based on 0, 1-2, or >2 risk factors respectively. Five-year RFS was significantly different in favorable risk (79.1%) compared to intermediate risk (55.1%) or high risk (22.1%) patients, p<0.0001.Conclusions Seven risk factors for recurrence are identified for patients with non-metastatic RCC with thrombus, which can be used to select patients who may benefit from increased surveillance or adjuvant therapy clinical trials.This article is protected by copyright. All rights reserved.
    BJU International 08/2015; DOI:10.1111/bju.13268 · 3.13 Impact Factor
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    ABSTRACT: Several small single-center studies have reported conflicting results on the prognostic value of survivin expression in upper tract urothelial carcinoma (UTUC) following radical nephroureterectomy. We attempted to validate the prognostic utility of survivin using a large multi-institutional cohort. Survivin expression was evaluated by immunohistochemistry in tumor tissue from 732 patients with unilateral, sporadic UTUC treated with radical nephroureterectomy between 1990 and 2008 at 7 centers. Survivin expression was considered altered when at least 10% of the tumor cells stained positive. Associations of altered survivin expression with recurrence-free survival (RFS) and cancer-specific survival (CSS) were evaluated using Cox proportional hazards regression models. Altered survivin expression was observed in 288 (39.3%) tumors and was associated with more advanced pathological tumor stages (P<0.001), lymph node metastases (P<0.001), lymphovascular invasion (P<0.001), tumor necrosis (P = 0.027), and tumor architecture (P<0.001). Median follow-up was 35 (16-64) months. There were 191 (25.4%) patients who experienced disease recurrence, and 165 patients (21.9%) died of the disease. In the univariable analysis, altered survivin expression was significantly associated with worse RFS and CSS (each P<0.001); however, altered survivin expression did not achieve independent predictive status on multivariable models (P = 0.24 and P = 0.53). Similarly, survivin was not independently associated with outcomes in subgroup analyses, including patients with high-grade tumors. In UTUC, altered survivin expression is associated with worse clinicopathological features and worse RFS and CSS. However, it does not appear to be independently associated with cancer outcomes when considering standard prognostic factors. Copyright © 2015 Elsevier Inc. All rights reserved.
    Urologic Oncology 07/2015; DOI:10.1016/j.urolonc.2015.06.016 · 3.36 Impact Factor
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    ABSTRACT: Management of patients with metastatic renal cell carcinoma is challenging and continues to be delivered in a multidisciplinary context. Even with the advent of systemic targeted therapy, complete remission with these new agents is rare using systemic therapy alone. Surgical resection of the primary tumor and metastatic deposits continues to play an important role in managing patients with metastatic renal cell carcinoma when aiming for complete remissions. To date, despite the lack of level 1 evidence, metastasectomy appears to prolong survival and achieve long-term cure in carefully selected patients. This review examines current evidence for the role of metastasectomy in renal cell carcinoma. Studies continue to consistently support a benefit of complete metastasectomy for overall and cancer-specific survival at most sites for resection, with the exception of brain and bone, which tend to perform for symptomatic relief and palliation. Metastasectomy has not yet been examined in a randomized setting. The debate of survival benefit because of selection bias of patients or differences in tumor biology is relevant and has yet to be resolved in the literature. Clearly, careful patient selection remains paramount in optimizing survival benefit from metastasectomy. Patients with isolated surgically resectable metastatic disease, with long disease-free intervals, and with good performance status are likely to benefit the most from metastasectomy.
    Current opinion in urology 06/2015; DOI:10.1097/MOU.0000000000000196 · 2.12 Impact Factor
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    ABSTRACT: Rhabdoid histology in clear-cell renal cell carcinoma is associated with a poor prognosis. The prognosis of patients with clear-cell renal cell carcinoma may also be influenced by molecular alterations. The aim of this study was to evaluate the association between histologic features and salient molecular changes in rhabdoid clear-cell renal cell carcinoma. We macrodissected the rhabdoid and clear-cell epithelioid components from 12 cases of rhabdoid clear-cell renal cell carcinoma. We assessed cancer-related mutations from eight cases using a clinical next-generation exome-sequencing platform. The transcriptome of rhabdoid clear-cell renal cell carcinoma (n=8) and non-rhabdoid clear-cell renal cell carcinoma (n=37) was assessed by RNA-seq and gene expression microarray. VHL (63%) showed identical mutations in all regions from the same tumor. BAP1 (38%) and PBRM1 (13%) mutations were identified in the rhabdoid but not in the epithelioid component and were mutually exclusive in 3/3 cases and 1 case, respectively. SETD2 (63%) mutations were discordant between different histologic regions in 2/5 cases, with mutations called only in the epithelioid and rhabdoid components, respectively. The transcriptome of rhabdoid clear-cell renal cell carcinoma was distinct from advanced-stage and high-grade clear-cell renal cell carcinoma. The diverse histologic components of rhabdoid clear-cell renal cell carcinoma, however, showed a similar transcriptomic program, including a similar prognostic gene expression signature. Rhabdoid clear-cell renal cell carcinoma is transcriptomically distinct and shows a high rate of SETD2 and BAP1 mutations and a low rate of PBRM1 mutations. Driver mutations in clear-cell renal cell carcinoma are often discordant across different morphologic regions, whereas the gene expression program is relatively stable. Molecular profiling of clear-cell renal cell carcinoma may improve by assessing for gene expression and sampling tumor foci from different histologic regions.Modern Pathology advance online publication, 26 June 2015; doi:10.1038/modpathol.2015.68.
    Modern Pathology 06/2015; DOI:10.1038/modpathol.2015.68 · 6.36 Impact Factor
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    ABSTRACT: Objective To evaluate how many patients could have undergone PN instead of RN before and after neoadjuvant axitinib therapy, as assessed by 5 independent urologic oncologists, and to study the variability of inter-observer agreement.Patients and Methods Pre- and post systemic treatment CT scans from 22 patients with ccRCC in a phase II neoadjuvant axitinib trial were reviewed by 5 independent urologic oncologists. RENAL score and Kappa statistics were calculated.ResultsMedian RENAL score changed from 11 pre-treatment to 10 post-treatment, p=0.0017. Five tumors with moderate-complexity pre-treatment remained moderate-complexity post-treatment. Of 17 tumors with high-complexity pre-treatment, 3 became moderate-complexity post-treatment. Overall kappa statistic was 0.611. Moderate-complexity kappa was 0.611 vs. high-complexity kappa of 0.428. Pre-treatment kappa was 0.550 vs. post-treatment of 0.609. After treatment with axitinib, all 5 reviewers agreed that only 5 patients required RN (instead of 8 pre-treatment) and that 10 patients could now undergo PN (instead of 3 pre-treatment). The odds of PN feasibility were 22.8-times higher after treatment with axitinib.Conclusions There is considerable variability in inter-observer agreement on the feasibility of PN in patients treated with neoadjuvant targeted therapy. Although more patients were candidates for PN after neoadjuvant therapy, it remains difficult to identify these patients a priori.This article is protected by copyright. All rights reserved.
    BJU International 06/2015; DOI:10.1111/bju.13188 · 3.13 Impact Factor
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    ABSTRACT: PurposeMetastases to the kidney are a rare entity, historically described in autopsy studies. The primary aim of this study was to describe the presentation, treatment, and outcomes of patients with metastatic tumors to the kidney treated at a tertiary referral center.Patients and Methods We retrospectively identified 151 patients diagnosed with a primary non-renal malignancy with renal metastasis. Clinical, radiographic and pathologic characteristics were assessed. Overall survival (OS) was calculated using Kaplan-Meier methods.ResultsMedian patient age was 56.7 years. The most common presenting symptoms were flank pain (30%), hematuria (16%) and weight loss (12%). Most primary cancers were carcinomas (80.8%). The most common primary tumor sites were lung (43.7%), colorectal (10.6%), ENT (6%), breast (5.3%), soft tissue (5.3%), and thyroid (5.3%). Renal metastases were typically solitary (77.5%). Concordance between radiologist and clinician imaging assessment was 54.0%. Three ablations and 48 nephrectomies were performed. For non-surgical patients, renal metastasis diagnosis was made with FNA or biopsy. Median OS from primary tumor diagnosis was 3.08 years and median OS from time of metastatic diagnosis was 1.13 years. For patients treated with surgery, median OS from primary tumor diagnosis was 4.81 years, and OS from metastatic diagnosis was 2.24 years.Conclusions Metastases to the kidney are a rare entity. Survival appears to be longer in patients who are candidates for, and are treated with surgery. Surgical intervention in carefully selected patients with oligometastatic disease and good performance status should be considered. A multi-disciplinary approach with input from urologists, oncologists, radiologists, and pathologists is needed to achieve the most optimal outcomes for this specific patient population.This article is protected by copyright. All rights reserved.
    BJU International 06/2015; DOI:10.1111/bju.13194 · 3.13 Impact Factor
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    ABSTRACT: Renal cell carcinoma with sarcomatoid dedifferentiation (sRCC) is associated with higher stage of presentation and worse survival. The objective of this study was to examine the clinicopathologic characteristics associated with overall survival (OS), specifically examining the percentage of sarcomatoid component (PSC). We reviewed clinicopathologic data for all nephrectomized patients with confirmed sRCC. Histologic slides were rereviewed by dedicated genitourinary pathologists to ascertain PSC. Patient characteristics were tabulated overall and by disease stage. Cutpoints in the PSC providing a meaningful difference in OS were identified by recursive partitioning analysis (RPA). Factors selected included age group, gender, race, clinical stage, tumor histology, presurgical systemic therapy, lymphovascular invasion, and tumor size. The Kaplan-Meier method and log-rank test were used to assess differences in OS. Among 186 patients with sRCC, 64 (34%) had localized, and 122 (66%) had metastatic disease at presentation. Patients had primarily clear cell histology (73%). Median follow-up was 12.1 months (range: 0.1-242.2mo). Median OS was 12.6 months (95% CI: 10.7-14.9mo). Univariate RPA identified a PSC cutpoint of 10% as prognostically significant. Patients with PSC>10% were at higher risk of death when compared with patients with PSC≤10% (45% vs. 61% 1-y OS; P = 0.04). Multivariate RPA revealed that tumor size, presence of metastatic disease, and PSC were significantly associated with OS. Among 4 identified groups, patients with localized disease and tumor size≤10cm were most likely to be alive at 1 year (89%), and patients with metastatic disease and PSC>40% were least likely to be alive at 1 year (28%; P<0.001). PSC appears to be a prognostic factor in patients with sRCC, with larger percentage of involvement portending a worse survival, especially in patients with metastatic disease. Copyright © 2015 Elsevier Inc. All rights reserved.
    Urologic Oncology 05/2015; DOI:10.1016/j.urolonc.2015.04.011 · 3.36 Impact Factor
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    ABSTRACT: Sunitinib and sorafenib are used widely in the treatment of renal cell carcinoma (RCC). These agents are associated with a significant incidence of cardiovascular (CV) dysfunction and left ventricular ejection fraction (LVEF) declines, observed largely in the metastatic setting. However, in the adjuvant population, the CV effects of these agents remain unknown. We prospectively defined the incidence of cardiotoxicity amongst resected, high-risk RCC patients treated with these agents. Sunitinib, sorafenib, or placebo was administered for up to 12 months in patients with high-risk, resected RCC. LVEF was measured by multi-gated acquisition (MUGA) scans at standard intervals. Additional CV adverse events were reported according to NCI Common Terminology Criteria for Adverse Events (CTCAE). Among 1,943 patients randomized, 1,599 had at least 1 post-baseline MUGA. Within 6 months, 21 patients (1.3%) experienced a cardiac event, defined as an LVEF decline from baseline that was >15% and below the institutional lower limit of normal. Nine of 513 (1.8%) patients were on sunitinib; 7 of 508 (1.4%) on sorafenib; and 5 of 578 (0.9%) on placebo (p=0.28 and 0.56 comparing sunitinib and sorafenib to placebo, respectively). With dose interruption or adjustment, 16 of the 21 recovered their LVEF to >50%. The incidence of symptomatic heart failure, arrhythmia, or myocardial ischemia did not differ among groups. In the adjuvant setting, we prospectively define low incidence of cardiotoxicity with sunitinib and sorafenib. These findings may be related to close CV monitoring, or potentially to fewer CV comorbidities in our non-metastatic population. Copyright © 2015, American Association for Cancer Research.
    Clinical Cancer Research 05/2015; DOI:10.1158/1078-0432.CCR-15-0215 · 8.19 Impact Factor
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    ABSTRACT: Sarcomatoid transformation, wherein an epithelioid carcinomatous tumour component coexists with a sarcomatoid histology, is a predictor of poor prognosis in clear cell renal cell carcinoma (ccRCC). Our understanding of sarcomatoid change has been hindered by the lack of molecular examination. Thus, we sought to characterize molecularly the biphasic epithelioid and sarcomatoid components of sarcomatoid ccRCC and compare them to non-sarcomatoid ccRCC. We examined the transcriptome of the epithelioid and sarcomatoid components of advanced stage sarcomatoid ccRCC (n=43) and non-sarcomatoid ccRCC (n=37) from independent discovery and validation cohorts using the cDNA microarray and RNA-seq platforms. We analyzed DNA copy number profiles, generated using SNP arrays, from patients with sarcomatoid ccRCC (n=10) and advanced non-sarcomatoid ccRCC (n=155). The epithelioid and sarcomatoid components of sarcomatoid ccRCC had similar gene expression and DNA copy number signatures that were, however, distinct from those of high-grade, high-stage non-sarcomatoid ccRCC. Prognostic ccRCC gene expression profiles were shared by the biphasic components of sarcomatoid ccRCC and the sarcomatoid component showed a partial epithelial-to-mesenchymal transition signature. Our genome-scale microarray-based transcript data were validated in an independent set of sarcomatoid and non-sarcomatoid ccRCCs using RNA-seq. Sarcomatoid ccRCC is molecularly distinct from non-sarcomatoid ccRCC, with its genetic programming largely shared by its biphasic morphological components. These data explain why a low percentage of sarcomatoid histology augurs a poor prognosis; suggest the need to modify the pathological grading system; and introduce the potential for candidate biomarkers to detect sarcomatoid change preoperatively without specifically sampling the S component. This article is protected by copyright. All rights reserved.
    05/2015; DOI:10.1002/cjp2.23
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    ABSTRACT: A detailed understanding of renal surgical anatomy is necessary to optimize preoperative planning and operative technique and provide a basis for improved outcomes. To evaluate the literature regarding pertinent surgical anatomy of the kidney and related structures, nephrometry scoring systems, and current surgical strategies for partial nephrectomy (PN). A literature review was conducted. Surgical renal anatomy fundamentally impacts PN surgery. The renal artery divides into anterior and posterior divisions, from which approximately five segmental terminal arteries originate. The renal veins are not terminal. Variations in the vascular and lymphatic channels are common; thus, concurrent lymphadenectomy is not routinely indicated during PN for cT1 renal masses in the setting of clinically negative lymph nodes. Renal-protocol contrast-enhanced computed tomography or magnetic resonance imaging is used for standard imaging. Anatomy-based nephrometry scoring systems allow standardized academic reporting of tumor characteristics and predict PN outcomes (complications, remnant function, possibly histology). Anatomy-based novel surgical approaches may reduce ischemic time during PN; these include early unclamping, segmental clamping, tumor-specific clamping (zero ischemia), and unclamped PN. Cancer cure after PN relies on complete resection, which can be achieved by thin margins. Post-PN renal function is impacted by kidney quality, remnant quantity, and ischemia type and duration. Surgical renal anatomy underpins imaging, nephrometry scoring systems, and vascular control techniques that reduce global renal ischemia and may impact post-PN function. A contemporary ideal PN excises the tumor with a thin negative margin, delicately secures the tumor bed to maximize vascularized remnant parenchyma, and minimizes global ischemia to the renal remnant with minimal complications. In this report we review renal surgical anatomy. Renal mass imaging allows detailed delineation of the anatomy and vasculature and permits nephrometry scoring, and thus precise, patient-specific surgical planning. Novel off-clamp techniques have been developed that may lead to improved outcomes. Copyright © 2015 European Association of Urology. Published by Elsevier B.V. All rights reserved.
    European Urology 04/2015; DOI:10.1016/j.eururo.2015.04.010 · 12.48 Impact Factor
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    ABSTRACT: Surgical resection for renal cell carcinoma (RCC) with suprahepatic inferior vena cava tumor thrombus is associated with significant morbidity, yet there are currently no tools for preoperative prognostic evaluation. Our goal was to develop a preoperative multivariable model for prediction of survival and risk of major complications in patients with suprahepatic thrombi. We identified patients who underwent surgery for RCC with suprahepatic tumor thrombus extension from 2000 to 2013 at 4 tertiary centers. A Cox proportional hazard model was used for analysis of overall survival (OS) and logistic regression was used for major complications within 90 days of surgery (Clavien≥3A). Nomograms were internally calibrated by bootstrap resampling method. A total of 49 patients with level III thrombus and 83 patients with level IV thrombus were identified. During median follow-up of 24.5 months, 80 patients (60.6%) died and 46 patients (34.8%) experienced major complication. Independent prognostic factors for OS included distant metastases at presentation (hazard ratio = 2.52, P = 0.002) and Eastern Cooperative Oncology Group (ECOG) performance status (hazard ratio = 1.84, P<0.0001). Variables associated with increased risk of major complications on univariate analysis included preoperative systemic symptoms, level IV thrombus, and elevated preoperative alkaline phosphatase and aspartate transaminase levels; however, only systemic symptoms (odds ratio = 8.45, P<0.0001) was an independent prognostic factor. Preoperative nomograms achieved a concordance index of 0.72 for OS and 0.83 for major complications. We have developed and internally validated multivariable preoperative models for the prediction of survival and major complications in patients with RCC who have a suprahepatic inferior vena cava thrombus. If externally validated, these tools may aid in patient selection for surgical intervention. Copyright © 2015 Elsevier Inc. All rights reserved.
    Urologic Oncology 04/2015; 193(4):e763-e764. DOI:10.1016/j.juro.2015.02.2234 · 3.36 Impact Factor
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    The Journal of Urology 04/2015; 193(4):e761. DOI:10.1016/j.juro.2015.02.2228 · 3.75 Impact Factor
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    ABSTRACT: Isolated local retroperitoneal recurrence (RPR) after radical nephrectomy (RN) for renal cell carcinoma (RCC) poses a therapeutic challenge. We investigated the outcomes of patients with localized RPR treated with surgical resection. This was a retrospective single-institutional study of 102 patients with RPR treated with surgery from 1990-2014. Demographics, clinical and pathological features, location of RPR, perioperative complications were reported using descriptive statistics. Recurrence free survival (RFS) and cancer-specific survival (CSS) were studied using univariate and multivariate analyses. Median age at RPR diagnosis was 55 years (IQR 49-64). Sixty-two (60.8%) patients were pT3-4 and 20 (19.6%) were pN1. No patients had distant metastatic disease at time of RPR surgery. Median time from nephrectomy to RPR diagnosis was 19 months (IQR 5-38.8). The median size of resected RPR was 4.5cm (IQR 2.7-7). Median follow up after RPR surgery was 32 months (IQR 16-57). Metastatic progression was observed in 60 (58.8%) patients after RPR surgery. Neoadjuvant and salvage systemic therapy were administered in 46 (45.1%) and 48 (47.1%) patients, respectively. On multivariate analysis, pathological nodal stage at original nephrectomy and maximum diameter of RPR were identified as independent risk factors for cancer specific death. Clinico-pathological factors at the time of nephrectomy as well as RPR surgery are important prognosticators. Aggressive surgical resection offers potential cure in a substantial number of patients with RPR with acceptable complications, and still plays a dominant role in the management of isolated locally recurrent RCC. Copyright © 2015 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.
    The Journal of Urology 03/2015; 193(4). DOI:10.1016/j.juro.2015.02.2943 · 3.75 Impact Factor
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    ABSTRACT: We conducted multilevel analyses to identify potential susceptibility loci for renal cell carcinoma (RCC), which may be overlooked in traditional genome-wide association studies (GWAS). A gene set enrichment analysis was performed utilizing a GWAS dataset comprised of 894 RCC cases and 1,516 controls using GenGen, SNP ratio test, and ALIGATOR. The antigen processing and presentation pathway was consistently significant (P = 0.001, = 0.004, and < 0.001, respectively). Versatile gene-based association study approach was applied to the top-ranked pathway and identified the driven genes. By comparing the expression of the genes in RCC tumor and adjacent normal tissues, we observed significant overexpression of HLA genes in tumor tissues, which was also supported by public databases. We sought to validate genetic variants in antigen processing and presentation pathway in an independent GWAS dataset comprised of 1,311 RCC cases and 3,424 control subjects from the National Cancer Institute; one SNP, rs1063355, was significant in both populations (Pmeta-analysis = 9.15 × 10-4, Pheterogeneity = 0.427). Strong correlation indicated that rs1063355 was a cis-expression quantitative trait loci which associated with HLA-DQB1 expression (Spearman's rank r = -0.59, p = 5.61 × 10-6). The correlation was further validated using a public dataset. Our results highlighted the role of immune-related pathway and genes in the etiology of RCC.
    Oncotarget 02/2015; 6(6):4097-109. · 6.63 Impact Factor
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    ABSTRACT: Renal cell carcinoma with sarcomatoid dedifferentiation (sRCC) is an aggressive malignancy associated with a poor prognosis. Although existing literature focuses on patients presenting with metastatic disease, characteristics and outcomes for patients with localized disease are not well described. We aimed to evaluate postnephrectomy characteristics, outcomes, and predictors of survival in patients with sRCC who presented with clinically localized disease. An institutional review board-approved review from 1986 to 2011 identified 77 patients who presented with clinically localized disease, underwent nephrectomy, and had sRCC in their primary kidney tumor. Clinical and pathologic variables were captured for each patient. Overall survival (OS) and recurrence-free survival (RFS) were calculated for all patients and those who had no evidence of disease (NED) following nephrectomy, respectively. Comparisons were made with categorical groupings in proportional hazards regression models for univariable and multivariable analyses. OS for the entire cohort (n = 77) at 2 years was 50%. A total of 56 (77%) patients of the 73 who has NED following nephrectomy experienced a recurrence, with a median time to recurrence of 26.2 months. On multivariable analysis, tumor stage, pathologically positive lymph nodes, and year of nephrectomy were significant predictors of both OS and recurrence-free survival. Limitations include the retrospective nature of this study and relatively small sample size. Long-term survival for patients with sRCC, even in clinically localized disease, is poor. Aggressive surveillance of those who have NED following nephrectomy is essential, and further prospective studies evaluating the benefit of adjuvant systemic therapies in this cohort are warranted. Copyright © 2014 Elsevier Inc. All rights reserved.
    Urologic Oncology 02/2015; 33(4). DOI:10.1016/j.urolonc.2014.11.021 · 3.36 Impact Factor
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    ABSTRACT: Renal cell carcinoma (RCC) is an immunogenic and proangiogenic cancer, and anti-angiogenic therapy is the current mainstay of treatment. RCC patients develop innate or adaptive resistance to anti-angiogenic therapy. There is a need to identify biomarkers which predict therapeutic resistance and guide combination therapy. We assessed the interaction between anti-angiogenic therapy and tumor immune microenvironment, and determined their impact on clinical outcome. Here we found that anti-angiogenic therapy treated RCC primary tumors demonstrated increased infiltration of CD4+ and CD8+ T lymphocytes, which was inversely related to patient overall survival (OS) and progression free survival (PFS). Furthermore, anti-angiogenic therapy treated specimens showed higher infiltration of CD4+FOXP3+ regulatory T cells (Tregs) and enhanced expression of checkpoint ligand programed death-ligand 1 (PD-L1). Both immunosuppressive features were correlated with T lymphocyte infiltration and were negatively related to patient survival. Treatment of RCC cell lines and RCC xenografts in immunodeficient mice with sunitinib also increased tumor PD-L1 expression. This study indicates that anti-angiogenic treatment may both positively and negatively regulate the tumor immune microenvironment. These findings generate hypotheses on resistance mechanisms to anti-angiogenic therapy, and will guide the development of combination therapy with PD-1/PD-L1 blocking agents. Copyright © 2015, American Association for Cancer Research.
    2015 Genitourinary Cancers Symposium of the American Society of Clinical Oncology, J Clin Oncol 33, 2015 (suppl 7; abstr 419); 02/2015
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    ABSTRACT: Variation of mitochondrial DNA copy number (mtDNAcn) in peripheral blood leukocytes (PBLs) has been associated with the risk of various cancers, including renal cell carcinoma (RCC). We assessed the association between mtDNAcn and clear cell RCC (ccRCC) risk in 608 cases and 629 controls frequency-matched on age and gender. Unconditional logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) adjusting for age, gender, BMI, smoking status, history of hypertension, total energy intake and physical activity. Our results suggest an association between low mtDNAcn and ccRCC risk (OR = 1.28, 95% CI: 0.97-1.68, P=0.09). Lower mtDNAcn was associated with increased ccRCC risk in younger individuals (Age<60, OR=1.68, 95% CI: 1.13-2.49, P=0.01), women (OR=1.66, 95% CI: 1.03-2.73, P=0.04), individuals without history of hypertension (OR=1.62, 95% CI: 1.09-2.41, P=0.02) and individuals with low physical activity levels (OR=1.55 95% CI: 1.02-2.37, P=0.05). We observed significant and marginally significant interactions between both age and history of hypertension and mtDNAcn in elevating ccRCC risk (P for interaction=0.04 and 0.07, respectively). Additionally, low mtDNAcn was associated with ccRCC risk in younger individuals with low levels of physical activity [ORs and 95% CI for medium and low physical activity levels respectively, 2.31 (1.18-4.52) and 2.09 (1.17-3.75), p-interaction 0.04]. To our knowledge, this is the first report to investigate the role of mtDNAcn in the clear cell renal cell carcinoma subtype and the first to suggest that this association may be modified by risk factors including age, gender, history of hypertension and physical activity. © The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please email:
    Carcinogenesis 12/2014; 36(2). DOI:10.1093/carcin/bgu248 · 5.27 Impact Factor

Publication Stats

6k Citations
1,514.17 Total Impact Points


  • 2002–2015
    • University of Texas MD Anderson Cancer Center
      • • Department of Urology
      • • Genitourinary Medical Oncology
      • • Department of Epidemiology
      Houston, Texas, United States
  • 2006–2014
    • University of Houston
      Houston, Texas, United States
  • 2010–2013
    • University of Texas Southwestern Medical Center
      • Department of Urology
      Dallas, Texas, United States
    • Peter MacCallum Cancer Centre
      • Peter MacCallum Cancer Center
      Melbourne, Victoria, Australia
  • 2008–2009
    • Keio University
      Edo, Tōkyō, Japan
  • 2003
    • Memorial Sloan-Kettering Cancer Center
      New York, New York, United States
    • University of California, Davis
      • Department of Urology
      Davis, CA, United States