Pheroze Tamboli

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

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Publications (130)564.95 Total impact

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    ABSTRACT: Published experience remains limited for glandular neoplasms of the urachus, especially mucinous cystic tumors. We reviewed 55 glandular urachal neoplasms to evaluate their clinical features and histopathologic spectrum and to devise a classification system for the mucinous cystic forms. Within the 55 cases studied, we observed 2 groups with differing clinical, gross, and histopathologic features. The first group, invasive, noncystic adenocarcinomas (n=24), had clinicopathologic features in accord with the known spectrum of urachal adenocarcinoma (mean age 50 y, female:male ratio 1.7, with recurrence or death from disease in 9/16 cases over a 45 mo mean follow-up). The second group, mucinous cystic tumors (n=31), morphologically resembled mucinous cystic tumors of the ovary and appeared classifiable by the same approach (mean age 47 y, female:male ratio 1.4) and included mucinous cystadenoma (n=4), mucinous cystic tumor of low malignant potential (n=22, including 2 cases with intraepithelial carcinoma), and mucinous cystadenocarcinoma with microscopic (n=4) or frank invasion (n=1). Follow-up information was available for 13 patients with mucinous cystic tumors (mean 41 mo); we observed no local recurrence or distant metastasis. This experience suggests that there is a distinct group of glandular, cystic tumors of the urachus that is classifiable in a manner similar to ovarian neoplasms and that has a favorable prognosis after complete excision. As with cystic neoplasms of other organs, rigorous sampling is recommended to identify potentially small foci of carcinoma that could be missed by inadequate sampling. Accordingly, classification based on methods other than complete surgical excision may be hazardous.
    The American journal of surgical pathology. 08/2014; 38(8):1033-1045.
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    ABSTRACT: We report the case of a 67-year-old female who presented with a large renal mass. Gross examination of the nephrectomy specimen demonstrated a 6-cm renal mass that was invasive into the renal sinus and perinephric fat. Histologic examination revealed two distinct tumor types. The first type had a conventional (clear cell) renal cell carcinoma component that was of low nuclear grade and comprised the minority of the overall tumor. The second type had a high-grade collecting duct carcinoma component with glandular/tubular differentiation and was composed of the majority of the tumor. Immunohistochemical studies demonstrated distinctive patterns of the two tumor types, thus confirming two distinct lineages. Five months postoperatively, the patient developed metastasis to the lungs and right hilar lymph node region. A fine needle aspiration of a lung nodule demonstrated a metastatic, poorly differentiated carcinoma, similar to the collecting duct carcinoma component in the kidney. Collision tumors of the kidney are rare with fewer than ten cases reported in the literature. Our report further expands the spectrum of this rare phenomenon.
    Ai zheng = Aizheng = Chinese journal of cancer 03/2014;
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    ABSTRACT: Gene expression signatures have proven to be useful tools in many cancers to identify distinct subtypes of disease based on molecular features that drive pathogenesis, and to aid in predicting clinical outcomes. However, there are no current signatures for kidney cancer that are applicable in a clinical setting. To generate a signature biomarker for the clear cell renal cell carcinoma (ccRCC) good risk (ccA) and poor risk (ccB) subtype classification that could be readily applied to clinical samples to develop an integrated model for biologically defined risk stratification. A set of 72 ccRCC sample standards was used to develop a 34-gene classifier (ClearCode34) for assigning ccRCC tumors to subtypes. The classifier was applied to RNA-sequencing data from 380 nonmetastatic ccRCC samples from the Cancer Genome Atlas (TCGA), and to 157 formalin-fixed clinical samples collected at the University of North Carolina. Kaplan-Meier analyses were performed on the individual cohorts to calculate recurrence-free survival (RFS), cancer-specific survival (CSS), and overall survival (OS). Training and test sets were randomly selected from the combined cohorts to assemble a risk prediction model for disease recurrence. The subtypes were significantly associated with RFS (p<0.01), CSS (p<0.01), and OS (p<0.01). Hazard ratios for subtype classification were similar to those of stage and grade in association with recurrence risk, and remained significant in multivariate analyses. An integrated molecular/clinical model for RFS to assign patients to risk groups was able to accurately predict CSS above established, clinical risk-prediction algorithms. The ClearCode34-based model provides prognostic stratification that improves upon established algorithms to assess risk for recurrence and death for nonmetastatic ccRCC patients. We developed a 34-gene subtype predictor to classify clear cell renal cell carcinoma tumors according to ccA or ccB subtypes and built a subtype-inclusive model to analyze patient survival outcomes.
    European Urology 02/2014; · 10.48 Impact Factor
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    ABSTRACT: Background Previous studies have shown a modest impact of tyrosine kinase inhibitors on primary renal tumors. Those studies were mostly retrospective and heterogeneous in their eligibility criteria with regard to histology, disease stage, duration of therapy, and time off therapy prior to surgery. Objective To prospectively investigate the safety and efficacy of axitinib in downsizing tumors in patients with nonmetastatic biopsy-proven clear cell renal cell carcinoma (ccRCC). Design, setting, and participants This was a single-institution, single-arm phase 2 clinical trial. Patients with locally advanced nonmetastatic biopsy-proven ccRCC were eligible. Intervention Patients received axitinib 5 mg for up to 12 wk. Axitinib was continued until 36 h prior to surgery. Patient underwent partial or radical nephrectomy after axitinib therapy. Outcome measurements and statistical analysis The primary outcome was objective response rate prior to surgery. Secondary outcomes included safety, tolerability, and quality of life. A dedicated radiologist independently reviewed all computed tomography scans to evaluate for response using Response Evaluation Criteria in Solid Tumors (RECIST). Results and limitations A total of 24 patients were treated. Twenty-two patients continued axitinib for 12 wk; 1 patient continued axitinib for 11 wk and underwent surgery as planned. One patient stopped treatment at 7 wk due to adverse events (AEs). Median reduction of primary renal tumor diameter was 28.3%. Eleven patients experienced a partial response per RECIST; 13 had stable disease. There was no progression of disease while on axitinib. The most common AEs were hypertension, fatigue, oral mucositis, hypothyroidism, and hand-foot syndrome. Postoperatively, 2 grade 3 and 13 grade 2 complications were noted. No grade 4 or 5 complications occurred. Functional Assessment of Cancer Therapy-Kidney Specific Index-15 changed over time, with quality of life worsening while on therapy, but by week 19, it was not statistically different from screening. Limitations include single-arm design and small patient numbers. Conclusions Axitinib was clinically active and reasonably well tolerated in the neoadjuvant setting in patients with locally advanced nonmetastatic ccRCC. Patient summary In this prospective clinical trial, we found that axitinib, when given prior to surgery, results in significant shrinking of kidney cancers. Larger studies are needed prior to further clinical use. Trial registration This clinical trial was registered with clinicaltrials.gov (NCT01263769).
    European Urology 01/2014; · 10.48 Impact Factor
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    ABSTRACT: Purpose: Cytoreductive nephrectomy (CN) remains the standard of care for appropriately selected patients with metastatic renal cell carcinoma (mRCC). Although the role of partial nephrectomy (PN) is well accepted in patients with localized disease, limited data are available regarding PN in the metastatic setting. We sought to identify the indications and outcomes for PN in the setting of mRCC with particular attention to different PN subgroups. Materials and Methods: We analyzed data from a consecutive cohort of 33 patients with mRCC who underwent PN at a single institution between 1996 and 2011. Non-parametric statistics were used to compare PN subgroups. Overall survival (OS) was estimated using Kaplan-Meier method, and survival functions were compared using the log-rank test. Results: Eight patients presented with bilateral synchronous renal masses; 20 with a metachronous contralateral renal mass; and 5 with a unilateral renal mass. Overall, 22 patients (67%) died of disease at a median of 27 months after PN. Patients who underwent PN for a metachronous contralateral renal mass and for a renal mass ≤4cm had the best OS (61 months and 42 months, respectively). Median OS for patients with and without metastatic disease at original diagnosis was 27 and 63 months, respectively (p=0.003). Conclusions: Our findings suggest that the presence of metastasis at original diagnosis and the timing of presentation of the PN index lesion play an important role in survival. These factors should be taken into consideration when determining which patients would benefit from partial nephrectomy in the setting of mRCC.
    The Journal of urology 01/2014; · 3.75 Impact Factor
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    ABSTRACT: Intra-abdominal desmoplastic small round cell tumor (DSRCT) is a rare, aggressive tumor affecting adolescent and young males. DSRCT presenting as a primary renal mass in the absence of visceral or serosal involvement is extremely rare. Herein, we present the pathologic and molecular findings in the case of a young man who presented with a large renal mass without any visceral or serosal involvement. Noticeably, the tumor lacked prominent desmoplastic stroma and only focally expressed cytokeratin, both of which are considered characteristic histologic features for this tumor. Fluorescence in situ hybridization studies using an EWSR1 break-apart probe confirmed the presence of a rearrangement involving the EWSR1 locus and RT-PCR demonstrated the presence of an EWSR1-WT1 fusion transcript associated with the t(11;22) rearrangement, which supported a diagnosis of DSRCT. We also discuss the differential diagnostic considerations faced by the pathologist in the workup of small round cell neoplasms of the kidney.
    Pathology - Research and Practice 01/2014; · 1.21 Impact Factor
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    ABSTRACT: Bone is one of the common sites of metastases from renal cell carcinoma (RCC), however the mechanism by which RCC preferentially metastasize to bone is poorly understood. Homing/retention of RCC cells to bone and subsequent proliferation are necessary steps for RCC cells to colonize bone. To explore possible mechanisms by which these processes occur, we used an in vivo metastasis model in which 786-O RCC cells were injected into SCID mice intracardially, and organotropic cell lines from bone, liver, and lymph node were selected. The expression of molecules affecting cell adhesion, angiogenesis, and osteolysis were then examined in these selected cells. Cadherin-11, a mesenchymal cadherin mainly expressed in osteoblasts, was significantly increased on the cell surface in bone metastasis-derived 786-O cells (Bo-786-O) compared to parental, liver, or lymph node-derived cells. In contrast, the homing receptor CXCR4 was equivalently expressed in cells derived from all organs. No significant difference was observed in the expression of angiogenic factors, including HIF-1α, VEGF, angiopoeitin-1, Tie2, c-MET, and osteolytic factors, including PTHrP, IL-6 and RANKL. While the parental and Bo-786-O cells have similar proliferation rates, Bo-786-O cells showed an increase in migration compared to the parental 786-O cells. Knockdown of Cadherin-11 using shRNA reduced the rate of migration in Bo-786-O cells, suggesting that Cadherin-11 contributes to the increased migration observed in bone-derived cells. Immunohistochemical analysis of cadherin-11 expression in a human renal carcinoma tissue array showed that the number of human specimens with positive cadherin-11 activity was significantly higher in tumors that metastasized to bone than that in primary tumors. Together, these results suggest that Cadherin-11 may play a role in RCC bone metastasis.
    PLoS ONE 01/2014; 9(2):e89880. · 3.53 Impact Factor
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    ABSTRACT: Clear cell papillary renal cell carcinoma (CCPRCC) is a renal neoplasm that has recently received widespread recognition in the literature. There have been several reports of this tumor arising in a sporadic setting and in patients with end-stage renal disease; however, there is limited information available about the clinical, pathologic, and genetic characteristics of this tumor in the setting of Von Hippel-Lindau (VHL) disease. We herein report a series of three patients that developed CCPRCC in this unique clinical setting. The histology and immunohistochemical profile for all three cases was similar to that which has been previously reported for CCPRCC. All tumors were diffusely and strongly positive for Cytokeratin 7, negative for alpha methyl Co-A racemase and showed at least focal staining for CD10. Comparative genomic analysis was performed on tumors from all three patients. One tumor demonstrated monosomy 3 and the other two tumors showed normal chromosomal content. All three patients were alive without evidence of disease progression 5, 3 and 3 years after surgery. CCPRCC represents a distinct tumor type that may occur in the setting of VHL disease and should be considered in the differential diagnosis of extensively cystic renal tumors arising in this clinical setting. Molecular analysis in our series of cases suggests that CCPRCC does indeed represent a unique histologic subtype and must be distinguished from clear cell renal cell carcinoma (CCRCC) due to different biologic potentials. Ancillary studies for accurate classification are recommended due to significant morphologic overlap with CCRCC.
    Human pathology 01/2014; · 3.03 Impact Factor
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    ABSTRACT: We describe the landscape of somatic genomic alterations of 66 chromophobe renal cell carcinomas (ChRCCs) on the basis of multidimensional and comprehensive characterization, including mtDNA and whole-genome sequencing. The result is consistent that ChRCC originates from the distal nephron compared with other kidney cancers with more proximal origins. Combined mtDNA and gene expression analysis implicates changes in mitochondrial function as a component of the disease biology, while suggesting alternative roles for mtDNA mutations in cancers relying on oxidative phosphorylation. Genomic rearrangements lead to recurrent structural breakpoints within TERT promoter region, which correlates with highly elevated TERT expression and manifestation of kataegis, representing a mechanism of TERT upregulation in cancer distinct from previously observed amplifications and point mutations.
    Cancer Cell 12/2013; 26(3):319-330. · 24.76 Impact Factor
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    ABSTRACT: We describe the landscape of somatic genomic alterations of 66 chromophobe renal cell carcinomas (ChRCCs) on the basis of multidimensional and comprehensive characterization, including mtDNA and whole-genome sequencing. The result is consistent that ChRCC originates from the distal nephron compared with other kidney cancers with more proximal origins. Combined mtDNA and gene expression analysis implicates changes in mitochondrial function as a component of the disease biology, while suggesting alternative roles for mtDNA mutations in cancers relying on oxidative phosphorylation. Genomic rearrangements lead to recurrent structural breakpoints within TERT promoter region, which correlates with highly elevated TERT expression and manifestation of kataegis, representing a mechanism of TERT upregulation in cancer distinct from previously observed amplifications and point mutations.
    Cancer Cell. 12/2013; 26(3):319-330.
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    ABSTRACT: ● Despite resection of all visible tumor, RCC may be present within the vein wall of after nephrectomy with thrombectomy, but the significance of positive vein wall margins is unknown. ● The purpose of this study was to evaluate the impact of microscopically positive vascular margins on recurrence and cancer specific survival in RCC patients with venous thrombus PATIENTS AND METHODS: ● All records were reviewed from 1993-2009 at University of Texas MD Anderson Cancer Center of consecutive patients treated surgically for RCC with venous tumor thrombus. ● Patients with metastatic disease, positive soft tissue margins or gross residual disease at time of thrombectomy were excluded. ● Primary outcome measurements were local or systemic disease recurrence, and cancer specific survival. ● Univariate and multivariate analysis was used to evaluate whether microscopically positive vascular margins were associated with RCC recurrence or cancer specific survival after nephrectomy with thrombectomy. ● A total of 256 RCC patients were identified with median follow-up of 36.7 months (IQR 18.4-63.5). Microscopic tumor was present at margin of resection in 47 (18.4%) patients. ● The median recurrence free interval was significantly shorter in patients with positive vascular margins, 22.1 vs. 70.2 months (p=0.009). ● The rate of local recurrence was higher in patients with positive vein margins 12.8% vs. 4.3% (p<0.01). Local recurrence without concomitant systemic recurrence was identified in only 2 of 256 (0.8%) patients. ● Patients with positive vascular margins had significantly worse CSS compared to patients with negative vascular margins, 37.7 vs. 93.0 months (p=0.004). ● After multivariable analysis, positive vascular margins were independently predictive of local recurrence but not systemic recurrence or CSS. ● Complete surgical excision should always be attempted because positive vascular wall margins increase local recurrence rates. ● Invasion of RCC into the vein wall at the resection margin is associated with aggressive tumor biology, and the majority of patients with positive vascular wall margins recur systemically.
    BJU International 10/2013; · 3.05 Impact Factor
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    ABSTRACT: The International Society of Urologic Pathology 2012 Consensus Conference on renal cancer, through working group 3, focused on the issues of staging and specimen handling of renal tumors. The conference was preceded by an online survey of the International Society of Urologic Pathology members, and the results of this were used to inform the focus of confer-ence discussion. On formal voting a Z65% majority was con-sidered a consensus agreement. For specimen handling it was agreed that with radical nephrectomy specimens the initial cut should be made along the long axis and that both radical and partial nephrectomy specimens should be inked. It was recom-mended that sampling of renal tumors should follow a general guideline of sampling 1 block/cm with a minimum of 3 blocks (subject to modification as needed in individual cases). When measuring a renal tumor, the length of a renal vein/caval thrombus should not be part of the measurement of the main tumor mass. In cases with multiple tumors, sampling should include at a minimum the 5 largest tumors. There was a con-sensus that perinephric fat invasion should be determined by examining multiple perpendicular sections of the tumor/peri-nephric fat interface and by sampling areas suspicious for in-vasion. Perinephric fat invasion was defined as either the tumor touching the fat or extending as irregular tongues into the per-inephric tissue, with or without desmoplasia. It was agreed upon that renal sinus invasion is present when the tumor is in direct contact with the sinus fat or the loose connective tissue of the sinus, clearly beyond the renal parenchyma, or if there is in-volvement of any endothelium-lined spaces within the renal si-nus, regardless of the size. When invasion of the renal sinus is uncertain, it was recommended that at least 3 blocks of the tumor-renal sinus interface should be submitted. If invasion is grossly evident, or obviously not present (small peripheral tu-mor), it was agreed that only 1 block was needed to confirm the gross impression. Other recommendations were that the renal vein margin be considered positive only when there is adherent tumor visible microscopically at the actual margin. When a specimen is submitted separately as "caval thrombus," the rec-ommended sampling strategy is to take 2 or more sections to look for the adherent caval wall tissue. It was also recommended that uninvolved renal parenchyma be sampled by including normal parenchyma with tumor and normal parenchyma distant from the tumor. There was consensus that radical nephrectomy specimens should be examined for the purpose of identifying lymph nodes by dissection/palpation of the fat in the hilar area only; however, it was acknowledged that lymph nodes are found in <10% of radical nephrectomy specimens.
    American Journal of Surgical Pathology 10/2013; · 4.87 Impact Factor
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    ABSTRACT: Translocation renal cell carcinoma (tRCC) is a rare subtype of kidney cancer involving the TFEB/TFE3 genes. We aimed to investigate the genomic and epigenetic features of this entity. Experimental design: Cytogenomic analysis was performed with 250K single-nucleotide polymorphism microarrays on 16 tumor specimens and 4 cell lines. LINE-1 methylation, a surrogate marker of DNA methylation, was performed on 27 cases using pyrosequencing. tRCC showed cytogenomic heterogeneity, with 31.2% and 18.7% of cases presenting similarities with clear-cell and papillary RCC profiles, respectively. The most common alteration was a 17q gain in 7 tumors (44%), followed by a 9p loss in 6 cases (37%). Less frequent were losses of 3p and 17p in 5 cases (31%) each. Patients with 17q gain were older (P = 0.0006), displayed more genetic alterations (P < 0.003) and had a worse outcome (P = 0.002) than patients without it. Analysis comparing gene-expression profiling of a subset of tumors bearing 17q gain and those without suggest large scale dosage effects and TP53 haploinsufficiency without any somatic TP53 mutation identified. Cell-line based cytogenetic studies revealed that 17q gain can be related to isochromosome 17 and/or to multiple translocations occurring around 17q breakpoints. Finally, LINE-1 methylation was lower in tRCC tumors from adults compared to tumors from young patients (71.1% vs. 76.7%, P = 0.02). Our results reveal genomic heterogeneity of tRCC with similarities to other renal tumor subtypes and raise important questions about the role of TFEB/TFE3 translocations and other chromosomal imbalances in tRCC biology.
    Clinical Cancer Research 07/2013; · 7.84 Impact Factor
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    ABSTRACT: Genetic changes underlying clear cell renal cell carcinoma (ccRCC) include alterations in genes controlling cellular oxygen sensing (for example, VHL) and the maintenance of chromatin states (for example, PBRM1). We surveyed more than 400 tumours using different genomic platforms and identified 19 significantly mutated genes. The PI(3)K/AKT pathway was recurrently mutated, suggesting this pathway as a potential therapeutic target. Widespread DNA hypomethylation was associated with mutation of the H3K36 methyltransferase SETD2, and integrative analysis suggested that mutations involving the SWI/SNF chromatin remodelling complex (PBRM1, ARID1A, SMARCA4) could have far-reaching effects on other pathways. Aggressive cancers demonstrated evidence of a metabolic shift, involving downregulation of genes involved in the TCA cycle, decreased AMPK and PTEN protein levels, upregulation of the pentose phosphate pathway and the glutamine transporter genes, increased acetyl-CoA carboxylase protein, and altered promoter methylation of miR-21 (also known as MIR21) and GRB10. Remodelling cellular metabolism thus constitutes a recurrent pattern in ccRCC that correlates with tumour stage and severity and offers new views on the opportunities for disease treatment.
    Nature 06/2013; · 38.60 Impact Factor
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    ABSTRACT: Autopsy studies remain an essential tool for understanding the patterns of fungal disease not detected ante mortem with current diagnostic approaches. We collected data concerning the microbiological trends, patient clinical characteristics and sites of involvement for invasive fungal infections (IFIs) identified at autopsy in a single large cancer treatment centre over a 20-year period (1989-2008). The autopsy rate and IFI prevalence both declined significantly during the study period. The prevalence of Aspergillus spp. decreased significantly from the first 15 years of the study (from 0.12 to 0.14 cases per 100 autopsies to 0.07 in 2004-2008; P = 0.04), with only Mucorales accounting for a greater proportion of IFIs over the duration of the study period (0.06 to 0.2 cases per 100 autopsies, P = 0.04). After 2003, moulds accounted for the majority of infections identified at autopsy in the spleen, kidney, heart and gastrointestinal tract. Despite a trend of decreasing prevalence from 1989 to 2004, invasive candidiasis increased in prevalence during later periods 2004-2008 (0.02-0.05 per 100 autopsies) with decreasing kidney, heart and spleen involvement. Despite a declining autopsy rate, these data suggest a decreasing prevalence overall of IFIs with changing patterns of dissemination in patients with haematological malignancies.
    Mycoses 04/2013; · 1.28 Impact Factor
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    ABSTRACT: PURPOSE: We aim to identify tumor-specific alternative splicing events having potential applications in the early detection, diagnosis, prognosis, and therapy of cancers. EXPERIMENTAL DESIGN: We analyzed RNA-seq data on 470 clear cell renal cell carcinomas (ccRCC) and 68 kidney tissues to identify tumor-specific alternative splicing events. We further focused on the FGFR2 isoform switch and characterized ccRCCs expressing different FGFR2 isoforms by integrated analyses using genomic data from multiple platforms and tumor types. RESULTS: We identified 113 top candidate alternatively spliced genes in ccRCC. Prominently, the FGFR2 gene transcript switched from the normal IIIb isoform ("epithelial") to IIIc isoform ("mesenchymal") in nearly 90% of ccRCCs. This switch is kidney-specific since it was rarely observed in other cancers. The FGFR2-IIIb ccRCCs show a transcriptome and methylome resembling those from normal kidney, whereas FGFR2-IIIc ccRCCs possess elevated hypoxic and mesenchymal expression signatures. Clinically, FGFR2-IIIb ccRCCs are smaller in size, of lower tumor grade, and associated with longer patient survival. Gene set enrichment and DNA copy number analyses indicated that FGFR2-IIIb ccRCCs are closely associated with renal oncocytomas and chromophobe RCCs. A re-examination of tumor histology by pathologists identified FGFR2-IIIb tumors as chromophobe RCCs and clear cell papillary RCCs. CONCLUSIONS: FGFR2 IIIb RCCs represent mis-diagnosed ccRCC cases, suggesting FGFR2 isoform testing can be used in the diagnosis of RCC subtypes. The finding of a prevalent isoform switch of FGFR2 in a tissue-specific manner holds promise for the future development of FGFR2-IIIc as a distinct early detection biomarker and therapeutic target for ccRCC.
    Clinical Cancer Research 02/2013; · 7.84 Impact Factor
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    ABSTRACT: Renal cell carcinoma (RCC) is an important contributor to cancer-specific mortality worldwide. Targeted agents that inhibit key subtype-specific signaling pathways have improved survival times and have recently become part of the standard of care for this disease. Accurately diagnosing and classifying RCC on the basis of tumor histology is thus critical. RCC has traditionally been divided into clear-cell and non-clear-cell categories, with papillary RCC forming the most common subtype of non-clear-cell RCC. Renal neoplasms with overlapping histologies, such as tumors with mixed clear-cell and papillary features and hybrid renal oncocytic tumors, are increasingly seen in contemporary practice and present a diagnostic challenge with important therapeutic implications. In this review, we discuss the histologic, immunohistochemical, cytogenetic, and clinicopathologic aspects of these differential diagnoses and illustrate how the classification of RCC has evolved to integrate both the tumor's microscopic appearance and its molecular fingerprint.
    Chinese journal of cancer 12/2012;
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    ABSTRACT: Background Sunitinib is a standard-of-care treatment in advanced clear cell renal cell carcinoma (ccRCC). Retrospective and expanded access data suggest sunitinib has activity in advanced non–clear cell renal cell carcinoma (nccRCC).Objective To prospectively determine the clinical efficacy and safety of sunitinib in patients with advanced nccRCC.Design, setting, and participantsThis is a single-arm phase 2 trial with a two-stage design. Eligibility criteria included pathologically confirmed nccRCC or ccRCC with ≥20% sarcomatoid histology, performance status 0–2, measurable disease, a maximum of two prior systemic therapies, and no prior treatment with tyrosine kinase inhibitors directed against the vascular endothelial growth factor receptors.InterventionPatients received sunitinib 50 mg daily on a 4-wk on, 2-wk off schedule.Outcome measurements and statistical analysisPrimary end points were objective response rate (ORR) and progression-free survival (PFS). Secondary end points were safety and overall survival (OS).Results and limitationsFifty-seven patients were eligible (nccRCC histology: papillary, 27; chromophobe, 5; unclassified, 8; collecting duct or medullary carcinoma, 6; sarcomatoid, 7; and others, 4). Median PFS for 55 evaluable patients was 2.7 mo (95% confidence interval [CI], 1.4–5.4). Two patients with chromophobe and one patient with unclassified histology had a confirmed partial response (5% ORR). Median PFS for patients with papillary histology was 1.6 mo (95% CI, 1.4–5.4). Median PFS for patients with chromophobe histology was 12.7 mo (95% CI, 8.5–NA). Median OS for all patients was 16.8 mo (95% CI, 10.7–26.3). Treatment-emergent adverse events were consistent with sunitinib's mechanism of action. The nonrandomized design and small number of patients are limitations of this study.Conclusions The differential response of chromophobe histology to sunitinib suggests a therapeutically relevant biological heterogeneity exists within nccRCC. The low ORR and short PFS with sunitinib in the other nccRCC subtypes underscore the need to enroll patients with these diverse tumors in clinical trials.
    European Urology 12/2012; 62(6):1013–1019. · 10.48 Impact Factor
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    ABSTRACT: BACKGROUND: There is limited evidence to guide patient selection for cytoreductive nephrectomy (CN) following the diagnosis of metastatic renal cell carcinoma (mRCC). OBJECTIVE: Given the significant variability in oncologic outcomes following surgery, we sought to develop clinically relevant, individualized, multivariable models for the prediction of cancer-specific survival at 6 and 12 mo after CN. The development of this nomogram will better help clinicians select patients for cytoreductive surgery. DESIGN, SETTING, AND PARTICIPANTS: We identified 601 consecutive patients who underwent CN for kidney cancer at a single tertiary cancer center. INTERVENTION: CN for mRCC. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The development cohort was used to select predictive variables from a large group of candidate predictors. The discrimination, calibration, and decision curves were corrected for overfit using 10-fold crossvalidation that included stepwise variable selection. RESULTS AND LIMITATIONS: With a median follow-up of 65 mo (range: 6-199) for the entire cohort, 110 and 215 patients died from kidney cancer at 6 and 12 mo after surgery, respectively. For the preoperative model, serum albumin and serum lactate dehydrogenase were included. Final pathologic primary tumor stage, nodal stage, and receipt of blood transfusion were added to the previously mentioned parameters for the postoperative model. Preoperative and postoperative nomograms demonstrated good discrimination of 0.76 and 0.74, respectively, when applied to the validation data set. Both models demonstrated excellent calibration and a good net benefit over large ranges of threshold probabilities. The retrospective study design is the major limitation of this study. CONCLUSIONS: We have developed models for accurate prediction of cancer-specific survival after CN, using either preoperative or postoperative variables. While these tools need validation in independent cohorts, our results suggest that the models are informative and can be used to aid in clinical decision making.
    European Urology 11/2012; · 10.48 Impact Factor
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    ABSTRACT: Introduction Protein extraction from formalin-fixed paraffin-embedded (FFPE) tissues is challenging due to extensive molecular crosslinking that occurs upon formalin fixation. Reverse-phase protein array (RPPA) is a high-throughput technology, which can detect changes in protein levels and protein functionality in numerous tissue and cell sources. It has been used to evaluate protein expression mainly in frozen preparations or FFPE-based studies of limited scope. Reproducibility and reliability of the technique in FFPE samples has not yet been demonstrated extensively. We developed and optimized an efficient and reproducible procedure for extraction of proteins from FFPE cells and xenografts, and then applied the method to FFPE patient tissues and evaluated its performance on RPPA. Results Fresh frozen and FFPE preparations from cell lines, xenografts and breast cancer and renal tissues were included in the study. Serial FFPE cell or xenograft sections were deparaffinized and extracted by six different protein extraction protocols. The yield and level of protein degradation were evaluated by SDS-PAGE and Western Blots. The most efficient protocol was used to prepare protein lysates from breast cancer and renal tissues, which were subsequently subjected to RPPA. Reproducibility was evaluated and Spearman correlation was calculated between matching fresh frozen and FFPE samples. The most effective approach from six protein extraction protocols tested enabled efficient extraction of immunoreactive protein from cell line, breast cancer and renal tissue sample sets. 85% of the total of 169 markers tested on RPPA demonstrated significant correlation between FFPE and frozen preparations (p < 0.05) in at least one cell or tissue type, with only 23 markers common in all three sample sets. In addition, FFPE preparations yielded biologically meaningful observations related to pathway signaling status in cell lines, and classification of renal tissues. Conclusions With optimized protein extraction methods, FFPE tissues can be a valuable source in generating reproducible and biologically relevant proteomic profiles using RPPA, with specific marker performance varying according to tissue type.
    Proteome Science 09/2012; 10(1). · 2.42 Impact Factor

Publication Stats

3k Citations
564.95 Total Impact Points

Institutions

  • 2000–2014
    • University of Texas MD Anderson Cancer Center
      • • Department of Pathology
      • • Department of Urology
      Houston, Texas, United States
  • 2012
    • University of Texas Southwestern Medical Center
      • Department of Urology
      Dallas, TX, United States
  • 2010–2011
    • University of Wisconsin, Madison
      • Department of Urology
      Madison, MS, United States
    • Dana-Farber Cancer Institute
      Boston, Massachusetts, United States
  • 2008
    • Cedars-Sinai Medical Center
      • Cedars Sinai Medical Center
      Los Angeles, CA, United States
  • 2007
    • McGill University
      • Division of Urology
      Montréal, Quebec, Canada
    • Houston Methodist Hospital
      Houston, Texas, United States
  • 2005
    • Vancouver General Hospital
      Vancouver, British Columbia, Canada
    • University of Nebraska at Omaha
      • Department of Pathology and Microbiology
      Omaha, NE, United States
  • 2003
    • University of Texas Medical Branch at Galveston
      • Department of Internal Medicine
      Galveston, TX, United States
  • 2002
    • University of Wales
      Cardiff, Wales, United Kingdom
  • 1996–2002
    • Henry Ford Hospital
      • Surgery
      Detroit, Michigan, United States
  • 2000–2001
    • Emory University
      Atlanta, Georgia, United States