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1.  Prevalence and Co-Occurrence of Actionable Genomic Alterations in High-Grade Bladder Cancer 
Journal of Clinical Oncology  2013;31(25):3133-3140.
We sought to define the prevalence and co-occurrence of actionable genomic alterations in patients with high-grade bladder cancer to serve as a platform for therapeutic drug discovery.
Patients and Methods
An integrative analysis of 97 high-grade bladder tumors was conducted to identify actionable drug targets, which are defined as genomic alterations that have been clinically validated in another cancer type (eg, BRAF mutation) or alterations for which a selective inhibitor of the target or pathway is under clinical investigation. DNA copy number alterations (CNAs) were defined by using array comparative genomic hybridization. Mutation profiling was performed by using both mass spectroscopy-based genotyping and Sanger sequencing.
Sixty-one percent of tumors harbored potentially actionable genomic alterations. A core pathway analysis of the integrated data set revealed a nonoverlapping pattern of mutations in the RTK-RAS-RAF and phosphoinositide 3-kinase/AKT/mammalian target of rapamycin pathways and regulators of G1-S cell cycle progression. Unsupervised clustering of CNAs defined two distinct classes of bladder tumors that differed in the degree of their CNA burden. Integration of mutation and copy number analyses revealed that mutations in TP53 and RB1 were significantly more common in tumors with a high CNA burden (P < .001 and P < .003, respectively).
High-grade bladder cancer possesses substantial genomic heterogeneity. The majority of tumors harbor potentially tractable genomic alterations that may predict for response to target-selective agents. Given the genomic diversity of bladder cancers, optimal development of target-specific agents will require pretreatment genomic characterization.
PMCID: PMC3753703  PMID: 23897969
Urachal carcinomas occur mostly in the bladder dome, comprising 22 to 35% of vesical adenocarcinomas, and are generally treated by partial cystectomy with en bloc resection of the median umbilical ligament and umbilicus. Detailed pathologic studies with clinical outcome correlation are few.
We reviewed histologic material and clinical data from 24 cases selected from a database of 67 dome-based tumors diagnosed and treated at our institution from 1984 to 2005. Follow-up information was available for all 24 patients.
The mean age at diagnosis was 52 years (range 26-68). 15 patients were male and 9 were female. Location was the dome in 23, and dome and anterior wall in 1. Thirteen cases were pure adenocarcinoma, NOS, 9 were enteric type adenocarcinoma and 2 were adenocarcinoma with focal components of lymphoepithelioma-like carcinoma and urothelial carcinoma with cytoplasmic clearing. Signet ring cell features were focally seen in 2 cases. Cystitis cystica and cystitis glandularis were seen in 4 and 2 cases, respectively. In all instances but one, cystitis cystica/ glandularis was focal and predominantly in the bladder overlying the urachal neoplasm. Urachal remnants were identified in 15 cases: the urachal epithelium was benign urothelial-type in 6 cases and showed adenomatous changes in 9. The overlying bladder urothelium was colonized by adenocarcinoma in 3 cases. In all three, urachal remnants were identified and showed transition from benign to adenomatous epithelium. On immunohistochemistry, these tumors were positive for CK20 and variably positive for CK7 and 34BE12. The majority showed a cytoplasmic membranous staining pattern for beta-catenin, although in 1 case, focal nuclear immunoreactivity was identified.. The Sheldon pathologic stage was pT1 in 0, pT2 in 2, pT3a in 8, pT3b in 11, pT3c in 1, pT4a in 1 and pT4b in 1 patient. One patient had a positive soft tissue margin. The mean follow-up period was 40 months (range 0.3-157.6). Seven of 24 (29%) cases recurred locally. The incidence of local recurrence was higher in patients who underwent a partial cystectomy alone (37.5%) versus those who had a more radical surgery (27%). Distant metastases occurred in 9 (37.5%) patients, 4 of which had no prior local recurrence. Seven patients (29%) died of the disease. All cases with locally recurrent and metastatic disease belonged to stage pT3 or higher.
Pathologic stage is an important prognostic factor in urachal carcinoma. Surface urothelial involvement by carcinoma and presence of cystitis cystica/ glandularis do not necessarily exclude the diagnosis of urachal carcinoma. Immunostains do not unequivocally discriminate a urachal from a colorectal carcinoma, but diffuse positivity for 34BE12 would support, and diffuse nuclear immunoreactivity for beta catenin would militate against, a diagnosis of urachal carcinoma.. Local recurrence may be due to seeding within the distal urothelial tract, particularly in tumors with a configuration that is polypoid and which open into the bladder cavity. The type of surgery performed may have an effect on local recurrence despite negative margins of resection.
PMCID: PMC4225778  PMID: 19252435
3.  Regional lymph node status in patients with bladder cancer found to be pathological stage T0 at radical cystectomy following systemic chemotherapy 
BJU international  2011;108(8 0 2):E272-E277.
To evaluate the effect of preoperative cisplatin-based chemotherapy on the regional lymph nodes of patients with bladder cancer who attain pathological T0 status in the bladder after chemotherapy followed by radical cystectomy.
Patients and Methods
Patients who underwent radical cystectomy at MSKCC for urothelial carcinoma of the bladder were retrospectively reviewed.
Those patients achieving pT0 status after preoperative chemotherapy were identified and classified into two groups, those rendered pT0: (i) after receiving neoadjuvant chemotherapy and (ii) after receiving definitive chemotherapy (defined in this case as chemotherapy given for unresectable or regionally metastatic disease).
These two groups were analyzed separately for lymph node status at cystectomy and regional lymph node recurrence.
Of 169 pT0 patients, 24 patients (14%) had received neoadjuvant chemotherapy whereas 17 patients (10%) had received definitive chemotherapy for unresectable or regionally metastatic disease.
No patient rendered pT0 after neoadjuvant chemotherapy had lymph node involvement at radical cystectomy or recurrence within the regional lymph node template.
Among patients with advanced disease rendered pT0 by definitive chemotherapy 35% had lymph node involvement at radical cystectomy or subsequent recurrence within the dissection template.
Patients achieving pT0 status after receiving neoadjuvant chemotherapy had no evidence of lymph node involvement at cystectomy.
Patients undergoing definitive chemotherapy for advanced disease followed by cystectomy experienced reduced rates of nodal involvement compared to the lymph node-positive rates predicted by preoperative clinical staging. However, there remains a risk of regional lymph node involvement in this group.
PMCID: PMC4319321  PMID: 21320277
carcinoma; transitional cell; bladder; lymph nodes; cystectomy; neoadjuvant
4.  An Epidemiologic and Genomic Investigation Into the Obesity Paradox in Renal Cell Carcinoma 
Obesity increases risk for clear-cell renal cell carcinoma (ccRCC), yet obese patients appear to experience longer survival than nonobese patients. We examined body mass index (BMI) in relation to stage, grade, and cancer-specific mortality (CSM) while considering detection bias, nutritional status, and molecular tumor features.
Data were available from 2119 ccRCC patients who underwent renal mass surgery at Memorial Sloan-Kettering Cancer Center between 1995 and 2012. Logistic regression models produced associations between BMI and advanced disease. Multivariable competing risks regression models estimated associations between BMI and CSM. Somatic mutation, copy number, methylation, and expression data were examined by BMI among a subset of 126 patients who participated in the Cancer Genome Atlas Project for ccRCC using the Kruskal–Wallis or Fisher exact tests. All statistical tests were two-sided.
Obese and overweight patients were less likely to present with advanced-stage disease compared with normal-weight patients (odds ratio [OR] = 0.61, 95% confidence interval [CI] = 0.48 to 0.79 vs OR = 0.65, 95% CI = 0.51 to 0.83, respectively). Higher BMI was associated with reduced CSM in univariable analyses (P < .005). It remained statistically significant after adjustment for comorbidities and albumin level, but it became non-statistically significant after adjusting for stage and grade (P > .10). Genome-wide interrogation by BMI suggested differences in gene expression of metabolic and fatty acid genes, including fatty acid synthase (FASN), consistent with the obesity paradox.
Our findings suggest that although BMI is not an independent prognostic factor for CSM after controlling for stage and grade, tumors developing in an obesogenic environment may be more indolent.
PMCID: PMC3866155  PMID: 24285872
5.  Pilot study of salvage laparoscopic prostatectomy for the treatment of recurrent prostate cancer 
BJU international  2010;108(5):724-728.
To evaluate feasibility, safety and oncological efficacy of salvage laparoscopic radical prostatectomy for pathology-proven biochemical recurrence after primary radiation therapy or cryotherapy for prostate cancer.
This retrospective pilot study examined 15 patients from 2004 to 2010 with biochemical recurrence after external beam radiation therapy (n = 8), brachytherapy (n = 6) or cryotherapy (n = 1). Patients were treated with salvage laparoscopic radical prostatectomy (11 conventional, four robotic-assisted) with bilateral pelvic dissection.
Median duration of surgery was 235 min. None of the following occurred: conversion to open surgery, transfusion, urethrovesical stenosis or perioperative or postoperative mortality. One patient presented with a rectal injury, repaired using uninterrupted sutures and a colostomy. One patient had anastomotic leak treated with prolonged Foley catheterization. Pathological stage was pT2a in three, pT2b in three, pT3a in four, pT3b in three and pT4 in two patients; two patients had nodal metastasis. Within an 8-month median follow-up, 11 patients were disease-free and three had persistent postoperative prostate-specific antigen (PSA) elevation; the remaining patient experienced PSA recurrence after 21 months. Seven patients achieved continence (no pads) by 8.4 months (median), one patient manifested severe incontinence corrected by implanting an artificial sphincter, and seven patients with a 12.6-month mean follow-up continued to need one or two pads per day. Erectile dysfunction was present in five patients before surgery and in 14 patients after surgery.
Salvage laparoscopic radical prostatectomy seems to offer a safe therapeutic alternative for patients failing primary radiation or cryotherapy. However, larger studies with longer-term data are required.
PMCID: PMC4254701  PMID: 21166755
cryotherapy; laparoscopic prostatectomy; prostatic neoplasms; radiotherapy; salvage therapy
6.  Hereditary leiomyomatosis and renal cell carcinoma (HLRCC): a rapid autopsy report of metastatic renal cell carcinoma 
Rapid (“warm”) autopsies of patients with advanced metastatic cancer provide invaluable insight into the natural history, pathobiology, and morphology of advanced and treatment-resistant tumors. Here, we report a rapid autopsy case of a hereditary leiomyomatosis and renal cell carcinoma (HLRCC) patient with advanced metastatic renal cell carcinoma (RCC)—the first such case described for either a primary renal tumor or HLRCC-related cancer. Mutations in the fumarate hydratase (FH) gene underlie HLRCC, a rare syndrome involving cutaneous and uterine leiomyomata and aggressive kidney tumors. Loss of heterozygosity at the wild-type FH gene locus results in profound cellular metabolic derangement, “pseudohypoxic” upregulation of hypoxia-inducible factor 1[alpha] (HIF-1[alpha])-dependent transcription, and aberrant protein succination; these molecular changes drive oncogenesis of kidney tumors in HLRCC patients. The current index patient had a high-grade RCC with classic morphologic features of HLRCC, including large nuclei with prominent eosinophilic nucleoli and perinucleolar clearing. In addition, this patient’s RCC demonstrated extensive sarcomatoid and rhabdoid features—morphologies not previously well described in HLRCC-associated kidney tumors. Here, we report the extent of metastatic dissemination and supplement this unique tumor morphology with mitochondrial enzyme histochemistry and extended immunohistochemical analysis. Tumor cells strongly expressed PAX8, vimentin, CD10, and the HIF target GLUT1 and showed increased nuclear p53 accumulation; the expression of other RCC markers was negative. We also detail microscopic tubular epithelial changes in the grossly uninvolved ipsilateral renal parenchyma and demonstrate sporadic, aberrant upregulation of the HIF targets GLUT1 and CAIX in dysplastic peritumoral tubules.
PMCID: PMC4117250  PMID: 24625422
HLRCC; rapid autopsy; renal cell cancer
Cancer  2010;116(22):5243-5250.
Lymph node counts are a measure of quality assurance and are associated with prognosis for numerous malignancies. To date, investigations of lymph node counts in testis cancer are lacking.
Using the Memorial Sloan-Kettering Testis Cancer Database, we identified 255 patients treated with primary retroperitoneal lymph node dissection (RPLND) for nonseminomatous germ cell tumors (NSGCT) between 1999 and 2008. Features associated with node counts, positive nodes, number of positive nodes, and risk of positive contralateral nodes were evaluated with regression models.
Median (IQR) total node count was 38 (27–53) and was 48 (34 – 61) during the most recent 5 years. Features associated with higher node count on multivariate analysis included high volume surgeon (p=0.034), clinical stage (p=0.036), and more recent year of surgery (p<0.001) while pathologist was not significantly associated with node count (p=0.3). Clinical stage (p<0.001) and total node count (p=0.045) were significantly associated with finding positive nodes on multivariate analysis. The probability of finding positive nodes were 23%, 23%, 31%, and 48% if the total node count was <21, 21 – 40, 41 – 60, and >60, respectively. With a median follow-up of 3.0 years all patients were still alive and 16 patients relapsed while no patient relapsed in the paracaval, interaortocaval, paraaortic, or iliac regions.
Our results suggest that >40 lymph nodes removed at RPLND improves the diagnostic efficacy of the operation. These results will be useful for future trials comparing RPLND, especially when assessing the adequacy of lymph node dissection.
PMCID: PMC4174298  PMID: 20665486
Testicular neoplasms; Lymph nodes; Lymph node excision; Neoplasm staging
Urology  2011;79(2):361-364.
Lymph node counts are a proposed measure of quality assurance for numerous malignancies. Investigation of patient factors associated with lymph node counts are lacking. We sought to determine if body mass index (BMI) is associated with lymph node counts in patients treated with a primary retroperitoneal lymph node dissection (RPLND).
Using the Memorial Sloan-Kettering Testis Cancer Database, we identified 255 patients treated with a primary RPLND for nonseminomatous germ cell tumors (NSGCT) from 1999–2008. The associations between BMI and node counts were evaluated using linear regression models in univariate and multivariable models adjusting for features reported to predict higher node counts (year of surgery, stage, and surgeon volume).
Median BMI (IQR) was 26.1 (23.4 – 28.7) and median (IQR) total node count was 38 (27–53). Median total node count for patients with a BMI <25, 25–<30, and >30 was 35, 42, and 44 nodes, respectively. In a univariate analysis, higher BMI was significantly associated with higher total node counts (coefficient 0.7 nodes for each 1 unit increase in BMI; p=0.026). Features associated with higher node count on multivariate analysis included high volume surgeon (p=0.047), pathologic stage (p=0.017), more recent year of surgery (p<0.001), and higher BMI (p=0.009).
Our results suggest for the first time that BMI is independently associated with higher lymph node counts during a lymph node dissection. If confirmed by others, these results may be important when using lymph node counts as a surrogate for adequacy of a lymph node dissection.
PMCID: PMC4170790  PMID: 22173172
Testicular neoplasms; Lymph nodes; Lymph node excision; Neoplasm staging; Body mass index
The Journal of urology  2009;182(5):2132-2136.
Despite the clear demonstration that different histological subtypes of renal cell carcinoma (RCC) exhibit distinct pathogenesis and genetic alterations, the impact of histology on prognosis remains controversial. We evaluated our experience with tumor histology in patients with localized RCC.
Patients and Methods
We identified 1,863 patients with localized clear cell, papillary, or chromophobe RCC who were treated surgically between 1989 and 2006 at our tertiary care center. Cox proportional hazards regression models were used to evaluate the relationship between tumor histology and outcome-defined as metastasis or death from disease, adjusting for age, sex, operation type, ASA score, TNM stage, and tumor size
Among 1,863 patients, 72% (n=1333) had clear cell histology, 17% (n=310) had papillary RCC, and 12% (n=220) had chromophobe RCC. The median follow-up for patients without an event was 3.4 years. Univariately, patients with clear cell histology had worse clinical outcomes: the 5-year probability of freedom from metastases or death from disease was 86% (95%CI: 84%, 88%), 95% (95% CI: 91%, 97%), and 92% (95% CI: 85%, 96%) for patients with clear cell, papillary, or chromophobe histology, respectively (p < 0.001). On multivariate analysis chromophobe and papillary histology were also significantly associated with better outcome (HR chromophobe 0.40 (95% CI 0.20, 0.80); HR papillary 0.62 (95% CI: 0.34, 1.14); p=0.014).
Clear cell histology seems to be independently associated with worse outcomes in patients undergoing surgical treatment for RCC even after controlling for widely accepted factors influencing prognosis.
PMCID: PMC4169873  PMID: 19758615
renal cell carcinoma; tumor histology; prognosis
10.  The association between statin medication and progression after surgery for localized renal cell carcinoma 
The Journal of urology  2013;191(4):914-919.
Evidence suggests statins may influence pathways of RCC proliferation, though no study has examined the influence of statin medications on progression of RCC in humans.
Materials and Methods
We identified 2608 patients with localized RCC who were treated surgically between 1995–2010 at our tertiary referral center. Competing risks Cox proportional hazards models were used to evaluate the relationship between statin use and time to local recurrence or progression (metastases or death from RCC) and overall survival. Statin use was modeled as a time-dependent covariate as a sensitivity analysis. Models were adjusted for clinical and demographic features.
Of 2608 patients, 699 (27%) were statin users at surgery. Statin users had similar pathological characteristics compared to nonusers. With a median follow-up of 36 months, there were 247 progression events. Statin use was associated with a 33% reduction in the risk of progression after surgery (HR 0.67, 95% CI 0.47–0.96, p=0.028) and an 11% reduction in overall mortality that was not significant (HR 0.89, 95% CI 0.71–1.13, p=0.3). Modeling statin use as time-dependent covariate attenuated the risk reduction in progression to 23% (HR 0.77, p=0.12) and augmented the risk reduction in overall survival (HR 0.71; p=0.002).
In our cohort, statin use was associated with a reduced risk of progression and overall mortality, though this effect was sensitive to method of analysis. If validated in other cohorts, this finding warrants consideration of prospective research on statins in the adjuvant setting.
PMCID: PMC4167747  PMID: 24291547
Kidney neoplasms; hydroxymethylglutaryl-CoA reductase inhibitors; nephrectomy; disease progression; chemoprevention
11.  Tumor Genetic Analyses of Patients with Metastatic Renal Cell Carcinoma and Extended Benefit from mTOR Inhibitor Therapy 
Rapalogs are allosteric mTOR inhibitors and approved agents for advanced kidney cancer. Reports of clonal heterogeneity in this disease challenge the concept of targeted monotherapy, yet a small subset of patients derives extended benefit. Our aim was to analyze such outliers and explore the genomic background of extreme rapalog sensitivity in the context of intratumor heterogeneity.
Experimental Design
We analyzed archived tumor tissue of five RCC patients, who previously achieved durable disease control with rapalogs (median duration 28 months). DNA was extracted from spatially separate areas of primary tumors and metastases. Custom target capture and ultra-deep sequencing was used to identify alterations across 230 target genes. Whole exome sequence analysis was added to investigate genes beyond this original target list.
Five long-term responders contributed 14 specimens to explore clonal heterogeneity. Genomic alterations with activating effect on mTOR signaling were detected in 11 of 14 specimens, offering plausible explanation for exceptional treatment response through alterations in two genes (TSC1, MTOR). In two subjects, distinct yet functionally convergent alterations activated the mTOR pathway in spatially separate sites. In one patient, concurrent genomic events occurred in two separate pathway components across different tumor regions.
Analysis of outlier cases can facilitate identification of potential biomarkers for targeted agents, and we implicate two genes as candidates for further study in this class of drugs. The previously reported phenomenon of clonal convergence can occur within a targetable pathway which might have implications for biomarker development beyond this disease and this class of agents.
PMCID: PMC4140619  PMID: 24622468
12.  TMPRSS2-ERG Rearrangement in Dominant Anterior Prostatic Tumors: Incidence and Correlation with ERG Immunohistochemistry 
Histopathology  2013;63(2):279-286.
To study prostate cancer zonal differences in TMPRSS2-ERG gene rearrangement.
Methods and Results
We examined 136 well-characterized dominant anterior prostatic tumors, including 61 transition zone (TZ) and 75 anterior peripheral zone (PZ) lesions, defined using strict anatomic considerations. TMPRSS2-ERG FISH and ERG protein immunohistochemistry were performed on tissue microarrays. FISH results, available for 56 TZ and 71 anterior PZ samples, were correlated with ERG staining and TZ-associated “clear cell” histology. Fewer TZ cancers (4/56; 7%) were rearranged than anterior PZ cancers (18/71; 25%) [p=0.009]; deletion was the sole mechanism of TZ cancer rearrangement. ERG protein overexpression was present in 4% (2/56; both FISH +) and 30% (21/71; 17 FISH +) of TZ and anterior PZ tumors. “Clear cell” histology was present in 21/56 (38%) TZ and 8/71 (11%) anterior PZ tumors. 7% of cancers with and 21% without this histology had rearrangement, regardless of zonal origin.
TMPRSS2-ERG rearrangement occurs in dominant TZ and anterior PZ prostate cancers, with all rearranged TZ cancers in this cohort showing deletion. ERG immunohistochemistry demonstrated excellent sensitivity (86%) and specificity (96%) for TMPRSS2-ERG rearrangement. TMPRSS2-ERG fusion is rare in TZ tumors and present at a low frequency in tumors displaying “clear cell” histology.
PMCID: PMC3723763  PMID: 23701505
TMPRSS2-ERG rearrangement; transition zone; prostate; cancer; immunohistochemistry
13.  Proposed Morphologic Classification of Prostate Cancer With Neuroendocrine Differentiation 
On July 31, 2013, the Prostate Cancer Foundation assembled a working committee on the molecular biology and pathologic classification of neuroendocrine differentiation in prostate cancer. The committee consisted of genitourinary oncologists, urologists, urological surgical pathologists, basic scientists, and translational researchers, with expertise in this field. It was concluded that the proceedings of the meeting should be reported in 2 manuscripts appealing to different target audiences, one to focus on surgical pathology and the other to review the molecular aspects of this disease. New clinical and molecular data emerging from prostate cancers treated by contemporary androgen deprivation therapies, as well as primary lesions, have highlighted the need for refinement of diagnostic terminology to encompass the full spectrum of neuroendocrine differentiation. It is envisioned that specific criteria associated with the refined diagnostic terminology will lead to clinically relevant pathologic diagnoses that will stimulate further clinical and molecular investigation and identification of appropriate targeted therapies.
PMCID: PMC4112087  PMID: 24705311
small cell carcinoma; Paneth cell like; large cell neuroendocrine carcinoma; carcinoid; prostate adenocarcinonma
14.  Adverse Outcomes in Clear Cell Renal Cell Carcinoma with Mutations of 3p21 Epigenetic Regulators BAP1 and SETD2: a Report by MSKCC and the KIRC TCGA Research Network 
To investigate the impact of newly identified chromosome 3p21 epigenetic tumor suppressors PBRM1, SETD2, and BAP1 on cancer specific survival (CSS) of 609 clear cell renal cell carcinoma (ccRCC) patients from two distinct cohorts.
Patients and Methods
Select sequencing on 3p tumor suppressors of 188 patients who underwent resection of primary ccRCC at the Memorial Sloan-Kettering Cancer Center (MSKCC) was performed to interrogate the genotype-phenotype associations. These findings were compared to analyses of the genomic and clinical dataset from our non-overlapping The Cancer Genome Atlas (TCGA) cohort of 421 primary ccRCC patients.
3p21 tumor suppressors are frequently mutated in both the MSKCC (PBRM1, 30.3%; SETD2, 7.4%; BAP1, 6.4%) and the TCGA (PBRM1, 33.5%; SETD2, 11.6%; BAP1, 9.7%) cohorts. BAP1 mutations are associated with worse CSS in both cohorts (MSKCC, p=0.002, HR 7.71 (2.08–28.6); TCGA, p=0.002, HR 2.21 (1.35–3.63)). SETD2 are associated with worse CSS in the TCGA cohort (p=0.036, HR 1.68 (1.04–2.73)). On the contrary, PBRM1 mutations, the second most common gene mutations of ccRCC, have no impact on CSS.
The chromosome 3p21 locus harbors three frequently mutated ccRCC tumor suppressor genes. BAP1 and SETD2 mutations (6–12%) are associated with worse CSS, suggesting their roles in disease progression. PBRM1 mutations (30–34%) do not impact CSS, implicating its principal role in the tumor initiation. Future efforts should focus on therapeutic interventions and further clinical, pathologic and molecular interrogation of this novel class of tumor suppressors.
PMCID: PMC3708609  PMID: 23620406
15.  Immunoexpression status and prognostic value of mammalian target of rapamycin and hypoxia-induced pathway members in papillary cell renal cell carcinomas☆ 
Human pathology  2012;43(12):2129-2137.
Dysregulation of the mammalian target of rapamycin and hypoxia-induced pathways has been consistently identified in clear cell renal cell carcinomas. However, experience with non–clear cell renal cell carcinoma subtypes is scant. In this study, we evaluated the immunohistochemical expression of upstream (PTEN and phosphorylated AKT) and downstream (phosphorylated S6 and 4EBP1) effectors of the mammalian target of rapamycin pathway, as well as related cell-cycle proteins (p27 and c-MYC), and a member of the hypoxia-induced pathway (HIF-1α) in 54 patients with papillary renal cell carcinoma treated by nephrectomy. PTEN was lower in tumor than in normal kidney, and loss of PTEN expression was found in 48% of the patients. In tumor tissues, phosphorylated S6, 4EBP1, and HIF-1α were higher than in normal kidney. Conversely, scores of p27 were lower in tumor than in normal kidney. Finally, scores of c-MYC and phosphorylated AKT were similar in tumor and in normal kidney. Overall mortality and cancer-specific mortality were 24% and 11%, respectively. Tumor progression was observed in 17% of the patients. None of the tested biomarkers predicted cancer-specific mortality or tumor progression. As expected, patients with high T-stage tumors had higher hazard ratios for cancer-specific mortality (hazard ratio, 6.9) and tumor progression (hazard ratio, 6.7). Patients with higher Fuhrman grades also had higher risks for cancer-specific mortality (hazard ratio, 11.4) and tumor progression (hazard ratio, 4.5). In summary, our study provides evidence of dysregulation of the mammalian target of rapamycin and hypoxia-induced pathways in papillary renal cell carcinoma. Immunohistochemistry for members of the mammalian target of rapamycin pathway and for HIF-1α lacked prognostic significance in our cohort.
PMCID: PMC4029100  PMID: 22542128
Papillary renal cell carcinoma; mTOR; PTEN; AKT; S6; 4EBP1; HIF-1α
Urology  2010;77(2):368-372.
Recent observations suggest that surgeon volume is associated with lymph node counts during retroperitoneal lymph node dissection (RPLND). We report our contemporary single-surgeon experience with lymph node counts during primary RPLND for nonseminomatous germ cell tumors (NSGCT).
Using the Memorial Sloan-Kettering Testis Cancer Database, we identified 124 consecutive patients treated with primary RPLND by a single experienced surgeon for NSGCT between 2004 and 2008. Predictors of positive nodes and number of positive nodes were evaluated with logistic and linear regression models adjusting for year of surgery and clinical stage.
Positive lymph nodes were observed in 37 (30%) while 87 (70%) patients were pN0. Mean total node count was 51 (SD= 23) during the 5 year study period. Mean node counts for the paracaval, interaortocaval, and paraaortic regions were 8 (SD= 6), 17 (SD= 9), and 26 (SD= 15), respectively. In a multivariate analysis, higher total node count was significantly associated with finding positive nodes (odds ratio 1.02 for each additional node counted; p=0.037) and finding multiple positive nodes (coefficient 0.04 for each additional node counted; p=0.004). Year of surgery (p<0.001) was associated with higher total node counts, while clinical stage and pathologist were not (p>0.5 for each).
The average total node count for a primary RPLND by an experienced surgeon is approximately 50 nodes with nearly half of the nodes originating in the paraaortic region. These results will be useful when assessing the adequacy of lymph node dissections for testis, renal, and upper tract urothelial malignancies.
PMCID: PMC4012337  PMID: 21109294
Testicular neoplasms; Lymph node excision; Neoplasm staging; Retroperitoneal space; Lymph nodes
17.  Epigenetic expansion of VHL-HIF signal output drives multi-organ metastasis in renal cancer 
Nature medicine  2012;19(1):50-56.
Inactivation of the von Hippel-Lindau tumor suppressor (VHL) is an archetypical tumor-initiating event in clear cell renal carcinoma (ccRCC), leading to the activation of hypoxia-inducible transcription factors (HIFs). However, VHL mutation status in ccRCC is not correlated with clinical outcome. Here we show that during ccRCC progression, cancer cells exploit diverse epigenetic alterations to empower a branch of the VHL-HIF pathway for metastasis, and the strength of this activation is associated with poor clinical outcome. By analyzing metastatic subpopulations of VHL-deficient ccRCC cells, we discovered an epigenetically altered VHL-HIF response specific to metastatic ccRCC. Focusing on the two most prominent pro-metastatic VHL-HIF target genes, we show that liberation from PRC2-dependent repressive histone methylation (H3K27me3) activates HIF-driven CXCR4 expression in support of chemotactic cell invasion, whereas loss of DNA methylation enables HIF-driven CYTIP expression to protect cancer cells from death cytokine signals. Thus, metastasis in ccRCC is based on an epigenetically expanded output of the tumor-initiating pathway.
PMCID: PMC3540187  PMID: 23223005
18.  TMPRSS2-ERG gene fusion is not associated with outcome in patients treated by prostatectomy 
Cancer research  2009;69(4):1400-1406.
A significant number of prostate cancers have been shown to have recurrent chromosomal rearrangements resulting in the fusion of the androgen regulated TMPRSS2 promoter to a member of the ETS transcription factor family, most commonly ERG. This results in ERG overexpression which may have a direct causal role in prostate tumorigenesis or progression. However, the clinical significance of the rearrangement is unclear and, in particular, relationship to outcome has been inconsistent in recent reports. We analyzed TMPRSS2-ERG gene rearrangement status by fluorescence in situ hybridization (FISH) in 521 cases of clinically localized surgically treated prostate cancer with 95 months median follow-up and also in 40 unmatched metastases. 42% of primary tumors and 40% of metastases had rearrangements. 11% had copy number increase (CNI) of the TMPRRS2-ERG region. Rearrangement alone was associated with lower grade, but not with stage, biochemical recurrence, metastases or death. CNI with and without rearrangement was associated with high grade and advanced stage. Further, a subgroup of cancers with CNI and rearrangement by deletion, with two or more copies of the deleted locus, tended to be more clinically aggressive. DNA index assessment revealed that the majority of tumors with CNI of TMPRSS2-ERG had generalized aneuploidy/ tetraploidy in contrast to tumors without TMPRSS2-ERG CNI, which were predominantly diploid. We therefore conclude that translocation of TMPRSS2-ERG is not associated with outcome and the aggressive clinical features associated with CNI of chromosome 21 reflect generalized aneuploidy and are not due to CNI specifically of rearranged TMPRSS2-ERG.
PMCID: PMC3676271  PMID: 19190343
TMPRSS2; ERG; fusion; prostate; outcome
19.  Clinical and Pathologic Impact of Select Chromatin Modulating Tumor Suppressors in Clear Cell Renal Cell Carcinoma 
European urology  2012;63(5):848-854.
Historically, VHL was the only frequently mutated gene in clear cell renal cell carcinoma (ccRCC), with conflicting clinical relevance. Excitingly, recent sequencing efforts identified several novel, frequent mutations of histone modifying and chromatin remodeling genes in ccRCC, including PBRM1, SETD2, BAP1 and KDM5C. Intriguingly, PBRM1, SETD2 and BAP1 are located in close proximity to VHL within a commonly lost (~90%) 3p locus. To date the clinical and pathologic significance of mutations in these novel candidate tumor suppressors is unknown.
To determine the frequency of and render the first clinical and pathologic outcome associated with mutations of these novel candidate tumor suppressors in ccRCC.
Design, Setting, and Participants
Targeted sequencing was performed in 185 ccRCC and matched normal tissues from a single institute. Pathologic features, baseline patient characteristics and follow-up data were recorded.
Statistical Analysis
The linkage between mutations and clinical and pathologic outcomes was interrogated with Fisher’s exact test (for stage and Fuhrman nuclear grade) and the permutation log-rank test (for cancer specific survival).
Results and Limitations
PBRM1, BAP1, SETD2 and KDM5C are mutated at 29%, 6%, 8% and 8%, respectively. Tumors with mutations in PBRM1 or any of BAP1, SETD2 or KDM5C (19%) are more likely to present with stage 3+ diseases, p=0.01 and p=0.001, respectively. Small tumors (<4cm) with PBRM1 mutations are more likely to exhibit stage 3 pathologic features (OR 6.4, p=0.001). BAP1 mutations tend to occur in Fuhrman Grade 3–4 tumors (p=0.052) and associate with worse cancer specific survival (p=0.01). Clinical outcome data is limited by the number of events.
Most mutations of chromatin modulators discovered in ccRCC are loss-of-function, which associate with advanced stage, grade, and possibly worsened cancer specific survival. Further studies validating the clinical impact of these novel mutations and future development of therapeutics remedying these tumor suppressors are warranted.
PMCID: PMC3615105  PMID: 23036577
Chromatin; Histone; Mutation; Outcome; Renal Cell Carcinoma
20.  Sarcomatoid-variant Renal Cell Carcinoma Treatment Outcome and Survival in Advanced Disease 
Sarcomatoid variant is a spindle cell phenotype of renal cell carcinoma (RCC), which is associated with a poor prognosis. We reviewed outcomes of systemic therapy for metastatic, sarcomatoid-variant RCC.
Clinical features, treatment outcome, and survival were evaluated in 63 patients with sarcomatoid-variant metastatic RCC (47 clear cell, 16 nonclear cell). Initial systemic treatment included antiangiogenesis-targeted therapy (n=34), cytokines (n=20), and chemotherapy (n=9).
Five of 63 patients (8%) achieved an objective response to the first systemic treatment: 1 (5%) to cytokine and 4 (12%) to sunitinib-targeted therapy. Median progression-free survival for 63 patients was 3 months (95% confidence interval), and median overall survival was 10 months (95% confidence interval). The median progression-free survival for patients treated with sunitinib versus all others was 4.4 months versus 2 months (P=0.03), and 3 months for patients with clear-cell histology versus 1.6 months for nonclear-cell histology (P=0.004).
Metastatic sarcomatoid-variant RCC was associated with a poor response to systemic therapy. Sunitinib treatment resulted in a modest response rate, but studies to characterize the underlying tumor biology of sarcomatoid-variant RCC, to assess outcome to targeted agents, and to develop novel treatment strategies are warranted.
PMCID: PMC3661202  PMID: 21127411
metastatic; sarcomatoid; renal cell carcinoma; sunitinib; targeted therapy
The Journal of urology  2008;179(5):1811-1817.
To compare in a non-randomized prospective fashion the oncological, functional and morbidity outcomes after laparoscopic (LRP) and retropubic (RRP) radical prostatectomy.
Material and Methods
Between January, 2003 and December, 2005, 1430 consecutive men with clinically localized prostate cancer, underwent radical prostatectomy, 612 LRP and 818 RRP. Surgical approach was selected by the patient. Preoperative staging, respective surgical techniques, pathologic examination and follow-up were uniform. Functional outcome was measured by patient-completed health related quality of life questionnaire.
Positive surgical margin rates (11%) and freedom from progression (median followup: 18 months) were comparable between LRP and RRP (hazard ratio (HR) 0.99 for LRP vs RRP, p=0.9).
We found no significant association between operation type and time to postoperative potency (HR 1.04 for LRP vs. RRP; 95% C.I. 0.74, 1.46; p=0.8). LRP patients were less likely to become continent than RRP patients. (HR 0.56 for LRP vs. RRP; 95% C.I. 0.44, 0.70; p<0.0005).
LRP was associated with lesser blood loss (315 ml (SD186) vs. 1267 ml (SD 660)), and overall transfusion rate (3% vs. 49%). No significant difference was noted in cardiovascular, thrombo-embolic and urinary complications. Emergency room visits and readmissions were higher after LRP (15% vs. 11% and 4.6% vs. 1.2% respectively).
In our institution and during the study period, LRP and RRP provided comparable oncological efficacy. LRP was associated with less blood loss and transfusion rate, and higher postoperative hospital visits and readmission rate. While the recovery of potency was equivalent, that of continence was superior after RRP.
PMCID: PMC3622224  PMID: 18353387
prostate neoplasm; pathology; laparoscopy; surgery
22.  Phase II trial of sunitinib in patients with metastatic non-clear cell renal cell carcinoma 
Investigational New Drugs  2010;30(1):335-340.
Sunitinib is associated with a robust objective response rate in patients with metastatic clear cell renal cell carcinoma (RCC). The primary objective of this phase II clinical trial was to assess the overall response rate for sunitinib in patients with papillary metastatic RCC as well as other non-clear cell histologies. A Simon 2-stage design was used to determine the number of papillary metastatic RCC patients for enrollment, and allowed for descriptive response data for other non-clear cell histologies. Twenty-three patients were enrolled, including 8 with papillary renal cell carcinoma (RCC) and the remainder with other non-clear cell histologies (unclassified in 5 patients). All patients received 50 mg of oral sunitinib in cycles of 4 weeks followed by 2 weeks of rest (4/2). The trial was stopped early because of slow accrual; no responses were observed in the 8 patients with papillary RCC. In the 22 evaluable patients, best response to sunitinib included a partial response in 1 patient with unclassified RCC, stable disease in 15, and progression in 6. The median progression-free survival was 5.5 months (95% CI, 2.5–7.1) in all 23 patients, and 5.6 months for the 8 papillary patients (95% CI, 1.4–7.1). The robust objective responses sunitinib had produced in clear cell RCC could not be demonstrated in this study comprised of patients with non-clear cell histologies.
PMCID: PMC3257373  PMID: 20711632
Papillary renal cell carcinoma; Non-clear cell renal cell carcinoma; Sunitinib; Phase II trial
23.  Immunoexpression Status and Prognostic Value of mTOR and Hypoxia-induced Pathway Members in Primary and Metastatic Clear Cell Renal Cell Carcinomas 
The need for effective targeted therapies for renal cell carcinomas (RCC) has fueled the interest for understanding molecular pathways involved in the oncogenesis of kidney tumors. Aiming to analyze the expression status and prognostic significance of mTOR and hypoxia-induced pathway members in patients with clear cell RCC (ccRCC) tissue microarrays were constructed from 135 primary and 41 metastatic ccRCC. Immunoexpression levels were compared and correlated with clinicopathologic parameters and outcome. PTEN levels were significantly lower in primary and metastatic ccRCC compared to benign tissues (P<0.001). Levels of phos-AKT, phos-S6, and 4EBP1 were higher in metastatic ccRCC (P≤0.001). For phos-S6 and 4EBP1, levels were higher in primary ccRCC compared to benign tissues (P<0.001). c-MYC levels were higher in metastatic ccRCC (P<0.0001) and incremental p27 levels were observed in benign, primary ccRCC, and metastatic ccRCC (P<0.0001). HIF-1α levels were significantly higher in primary and metastatic ccRCC compared to benign tissues (P<0.0001). In primary ccRCC, levels of all mTOR and hypoxia-induced pathway members were significantly associated with pT stage (P≤0.036), p27 levels with Fuhrman grade (P=0.031), and 4EBP1, p27, and HIF-1α levels with tumor size (P≤0.025). Tumor size, HIF-1α and phos-S6 levels were associated with disease-specific survival (P≤0.032) and tumor progression (P≤0.043). In conclusion, both mTOR and hypoxia-induced pathways were activated in primary and metastatic ccRCC. PTEN loss seems to be an early event during tumorigenesis. Tumor size, HIF-1α and phos-S6 expression were found to be independent predictors of both DSS and tumor progression in primary ccRCC.
PMCID: PMC3505672  PMID: 21881486
clear cell renal cell carcinoma; mammalian target of rapamycin pathway; hypoxia-induced pathway; PTEN; AKT; S6; 4EBP1; c-MYC; p27; HIF-1α; prognosis
24.  Xp11 Translocation Renal Cell Carcinoma (RCC): Extended Immunohistochemical Profile Emphasizing Novel RCC Markers 
Xp11 translocation renal cell carcinoma (RCC) harbor various TFE3 gene fusions, and are known to underexpress epithelial immunohistochemical (IHC) markers such as cytokeratin and EMA relative to usual adult type RCC; however, their profile in reference to other IHC markers that are differentially expressed in other subtypes of RCC has not been systematically assessed. Few therapeutic targets have been identified in these aggressive cancers. We created 2 tissue microarrays (TMA) containing five 1.4-mm cores from each of 21 Xp11 translocation RCC (all confirmed by TFE3 IHC, 6 further confirmed by genetics), 7 clear cell RCC (CCRCC), and 6 papillary RCC (PRCC). These TMA were labeled for a panel of IHC markers. In contrast to earlier published data, Xp11 translocation RCC frequently expressed renal transcription factors PAX8 (16/21 cases) and PAX2 (14/21 cases), whereas only 1 of 21 cases focally expressed MiTF and only 5 of 21 overexpressed p21. Although experimental data suggest otherwise, Xp11 translocation RCC did not express WT-1 (0/21 cases). Although 24% of Xp11 translocation RCC expressed HIF-1α (like CCRCC), unlike CCRCC CA IX expression was characteristically only focal (mean 6% cell labeling) in Xp11 translocation RCC. Other markers preferentially expressed in CCRCC or PRCC, such as HIG-2, claudin 7, and EpCAM, yielded inconsistent results in Xp11 translocation RCC. Xp11 translocation RCC infrequently expressed Ksp-cadherin (3/21 cases) and c-kit (0/21 cases), markers frequently expressed in chromophobe RCC. Using an H-score that is the product of intensity and percentage labeling, Xp11 translocation RCC expressed higher levels of phosphorylated S6, a measure of mTOR pathway activation (mean H score = 88), than did CCRCC (mean H score = 54) or PRCC (mean H score = 44). In conclusion, in contrast to prior reports, Xp11 translocation RCC usually express PAX2 and PAX8 but do not usually express MiTF. Although they may express HIF-1α, they only focally express the downstream target CA IX. They inconsistently express markers associated with other RCC subtypes, further highlighting the lack of specificity of the latter markers. TFE3 and Cathepsin K remain the most sensitive and specific markers of these neoplasms. Elevated expression of phosphorylated S6 in Xp11 translocation RCC suggests the mTOR pathway as an attractive potential therapeutic target for these neoplasms.
PMCID: PMC3449149  PMID: 20679884
TFE3; renal cell carcinoma; biomarker
25.  Prognostic Impact of Muscular Venous Branch Invasion in Localized Renal Cell Carcinoma 
The Journal of urology  2010;185(1):37-42.
Beginning with the 2002 AJCC staging system, renal sinus muscular venous branch invasion has prognostic equivalence with renal vein invasion (RVI) in renal cell carcinoma. To validate this presumed equivalence, we compared patients with isolated MVBI to those with RVI and to those without any confirmed vascular invasion.
From routine cataloging at Memorial Sloan-Kettering Cancer Center, we identified 500 patients who underwent partial or radical nephrectomy from 2003 to 2008. After excluding patients with metastasis or non-cortical RCC pathology, 85 patients with MVBI (+) were identified. Patients with pT1-2 MVBI (−) (n = 259) or RVI (+) (n = 71) disease served as comparison groups. A multivariable Cox model was used to control for tumor characteristics, using the Kattan RCC nomogram.
In multivariable analysis, the risk of recurrence in the pT1-2 MVBI (−) group was lower than in the MVBI (+) group (HR 0.06, 95% CI 0.02–0.18; p <0.001). Patients with RVI (+) had similar recurrence rates to those with MVBI (+) (HR 0.80, 95% CI 0.39–1.65; p = 0.6). Overall survival rates were higher in the MVBI (−) group than in the other groups.
Patients with MVBI have inferior outcomes compared to those with pT1-2 disease. This confirms the adverse prognosis of MVBI and supports pathologic upstaging. The prognosis of MVBI is similar to that of RVI, although we can’t exclude the possibility of a difference. Our findings underscore the importance of close patient follow-up and careful pathologic assessment of the nephrectomy specimen.
PMCID: PMC3437930  PMID: 21074196
renal cell carcinoma; muscular venous branch invasion; vascular; prognosis; TNM stage

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