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1.  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
2.  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
3.  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
4.  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
6.  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
7.  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
Pelvic lymph node (LN) metastasis is a well-recognized route of prostate cancer spread. However, the relationship between topography and pathologic features of primary prostatic cancers and patterns of pelvic LN metastasis has not been well studied. We reviewed original slides of radical prostatectomies and pelvic LN dissections from 125 patients with LN metastasis and recorded total # of LN excised / laterality of positive LN, as well as localization, staging parameters, lymphovascular invasion and tumor volume of primary tumors.
LN Quantity and Distribution
14.6 (mean) and 13 (median) LN were resected. 76 (61%), 33 (26%) and 16 (13%) cases had 1, 2 and > 2 positive LN, while 58, 44 and 20 cases had LN metastasis on the right (R), left (L), and bilaterally.
Pathologic Features
86% (108/125) and 37% (46/125) demonstrated extraprostatic extension and seminal vesicle invasion, while 64% showed lymphovascular invasion. Mean and median total tumor volume was 6.39 and 3.92 cc, with ≥ 50% and ≥ 90% Gleason patterns 4/5 in 105 (84%) and 73 (58%) cases, respectively.
Correlation with Dominant Tumor Location
Dominant lesions on RP: 50 R lobe, 44 L lobe, 31 bilateral. 15/50 (30%) R lobe and 18/44 (41%) L lobe dominant tumors had LN metastasis on the contralateral side. Only 4% (5/125) of cases were associated with anterior dominant tumors. 30–40% of LN metastases occur contralateral to the dominant tumor. LN metastasis is overwhelmingly associated with high grade, high stage and large volume disease. LN positivity is rarely associated with anterior dominant tumors.
PMCID: PMC3414911  PMID: 21107093
prostate; pelvic lymph node; topography; anterior tumor; lymphovascular invasion
9.  TMPRSS2-ERG gene fusion is associated with low Gleason scores and not with high grade morphologic features 
TMPRSS2-ERG gene rearrangement is seen in about half of clinically-localized prostate cancers, yet controversy exists regarding its prognostic implications. Similarly, the relationship of TMPRSS2-ERG fusion to Gleason score and morphology remains uncertain. We assigned Gleason scores and recorded morphologic features for 521 clinically-localized prostate cancers sampled in triplicate and arrayed in 8 tissue microarray blocks. Fluorescence in situ hybridization was performed to delineate TMPRSS2-ERG aberrations. Using maximum Gleason score, based on 3 core evaluation, and overall Gleason score, based on prostatectomy sections, Fisher’s exact test was performed for tumors with TMPRSS2-ERG translocation/deletion, copy number increase (≥3) of the TMPRSS2-ERG region without translocation/deletion, and copy number increase and concomitant translocation/deletion. 217 (41%) translocation/deletion and 30 (5.9%) copy number increase alone cases were detected. Among 217 translocation/deletion cases, 32 had translocation/deletion with copy number increase. 237, 200, and 75 cancers had maximum core-specific Gleason score of 6, 7, and 8–10, respectively. Tumors with translocation/deletion tended toward lower Gleason scores than those without (p=0.002) with similar results for overall Gleason score (p=0.02); Copy number increase cases tended toward higher Gleason scores than those without (p<0.001). Gleason score 8–10 tumors demonstrated lower odds of translocation/deletion (OR 0.38; 95%CI 0.21–0.68) and higher odds of copy number increase alone (OR 7.33; 95%CI 2.65–20.31) or copy number increase + translocation/deletion (OR 3.03; 95%CI 1.12–8.15) relative to Gleason score < 7 tumors. No significant difference in TMPRSS2-ERG incidence was observed between patients with and without cribriform glands, glomerulations, signet ring cells, or intraductal cancer (p=0.821, 0.095, 0.132, 0.375). TMPRSS2-ERG gene fusion is associated with lower core-specific and overall Gleason scores and not with high grade morphologies. Conversely, TMPRSS2-ERG copy number increase, with or without rearrangement, is associated with higher Gleason score. These findings indicate that translocation/deletion of TMPRSS2-ERG is not associated with histologic features of aggressive prostate cancer.
PMCID: PMC3413944  PMID: 20562851
TMPRSS2; ERG; fusion; prostate cancer; Gleason score; morphology
10.  Genomic Deregulation during Renal Cell Carcinoma Metastasis Implements a Myofibroblast-Like Gene Expression Program 
Cancer Research  2010;70(23):9682-9692.
Clear cell renal cell carcinoma (RCC) is the most common and invasive adult kidney cancer. The genetic and biological mechanisms that drive metastatic spread of RCC remain largely unknown. We have investigated the molecular signatures and underlying genomic aberrations associated with RCC metastasis, using an approach that combines a human xenograft model, expression profiling of RNA, DNA and microRNA (miRNA), functional verification, and clinical validation. We show that increased metastatic activity is associated with acquisition of a myofibroblast-like signature in both tumor cell lines and in metastatic tumor biopsies. Our results also show that the mesenchymal trait did not provide an invasive advantage to the metastatic tumor cells. We further show that some of the constituents of the mesenchymal signature, including the expression of the well characterized myofibroblastic marker S100A4, are functionally relevant. Epigenetic silencing and miRNA-induced expression changes accounted for the change in expression of a significant number of genes, including S100A4, in the myofibroblastic signature; however, DNA copy number variation did not affect the same set of genes. These findings provide evidence that widespread genetic and epigenetic alterations can lead directly to global deregulation of gene expression and contribute to the development or progression of RCC metastasis culminating in a highly malignant myofibroblast-like cell with a mesenchymal phenotype.
PMCID: PMC3281492  PMID: 20952505
11.  Molecular genetics of testicular germ cell tumors 
Testicular germ cell tumors (TGCT) are the most common malignancy in young men. While most TGCT are potentially curable, approximately 5% of patients with TGCT may develop chemoresistance and die from the disease. This review article summarizes current knowledge in genetics underlying the development, progression and chemoresistance of TGCT. Most post-pubertal TGCT originate from intratubular germ cell neoplasia unclassified (IGCNU), which are transformed fetal gonocytes. Development of IGCNU may involve aberrantly activated KITLG/KIT pathway and overexpression of embryonic transcription factors such as NANOG and POU5F1, which leads to suppression of apoptosis, increased proliferation, and accumulation of mutations in gonocytes. Invasive TGCT consistently show gain of chromosome 12p, typically isochromosome 12p. Single gene mutations are uncommon in TGCT. KIT, TP53, KRAS/NRAS, and BRAF are genes most commonly mutated in TGCT and implicated in their pathogenesis. Different histologic subtypes of TGCT possess different gene expression profiles that reflect different directions of differentiation. Their distinct gene expression profiles are likely caused by epigenetic regulation, in particular DNA methylation, but not by gene copy number alterations. Resistance of TGCT to chemotherapy has been linked to karyotypic aberrations, single-gene mutations, and epigenetic regulation of gene expression in small-scale studies. The study of TGCT genetics could ultimately translate into development of new molecular diagnostic and therapeutic modalities for these tumors and improve the care of patients with these malignancies.
PMCID: PMC3304567  PMID: 22432056
Pathology; genetics; testis; germ cell tumor
12.  Somatic mutation of Fibroblast Growth Factor Receptor-3 (FGFR3) defines a distinct morphologic subtype of high-grade urothelial carcinoma 
The Journal of pathology  2011;224(2):270-279.
FGFR3 mutations are common in low grade urothelial carcinoma and represent a potential therapeutic target in this disease. Their incidence and functional role in high grade urothelial carcinoma (HGUC), which displays an increased propensity for recurrence and muscularis propria invasion, is less well defined. We developed a mass spectrometry based genotyping assay to define the incidence of FGFR3 mutations in a large clinically annotated set of urothelial carcinomas. FGFR3 mutations were found in 17% of HGUC versus 84% of low-grade lesions. Retrospective pathologic review of the class of FGFR3 mutant HGUC revealed unique histologic features characterized by a bulky, exophytic component with branching papillary architecture as well as irregular nuclei with a koilocytoid appearance. The predictive value of this histologic appearance was confirmed using a prospective set of 49 additional HGUC. Prospective histologic review was able to correctly predict for the presence of an FGFR3 mutation in 13 of 24 HGUC specimens that exhibited the distinct morphology (54%). All 25 specimens lacking the defined histologic features were FGFR3 wild-type for a negative predictive value of 100%. Macrodissection of individual tumors confirmed the presence of the FGFR3 mutant allele in non-invasive and invasive, low and high-grade regions of individual tumors and in the lymph node metastases of patients whose tumors possessed the characteristic morphologic signature, suggesting that FGFR3 mutations are not restricted to the more clinically indolent regions of HGUCs. These data suggest that histologic screening of HGUC followed by confirmatory genotyping can be used to enrich for the population of HGUC most likely to harbor activating mutations in the FGFR3 receptor tyrosine kinase. Histologic review could thus aid in the development of targeted inhibitors of FGFR3 by facilitating the identification of the subset of patients most likely to harbor activating mutations in the FGFR3 gene.
PMCID: PMC3235805  PMID: 21547910
fibroblast growth factor receptor-3; FGFR3; urothelial carcinoma; morphology
13.  An exploratory study of endorectal MRI and spectroscopy of the prostate as pre-operative predictive biomarkers of biochemical relapse after radical prostatectomy 
The Journal of urology  2010;184(6):2320-2327.
Radical prostatectomy (RP)has significant side effects. Pre-operative information which could predict the long-term outcome of RP would be valuable to both patient and physician. The purpose of this study was to determine whether pre-treatment endorectal MRI/MRSI has the potential to predict biochemical recurrence (BCR) after RP.
Materials and Methods
130 of 202 patients who had endorectal MRI/MRSI from January 2000 to December 2002 followed by RP satisfied all inclusion criteria and were included in the analysis. MRI and MRSI factors with potential predictive capability were compared to BCR data. These included MRI risk score based on local extent of disease, and MRSI index lesion characteristics including the number of voxels and degree of metabolic abnormality (MRSI grade). Associations between MRI and MRSI variables and time-to-BCR were evaluated using Cox Proportional Hazards regression, adjusting for known predictors of BCR such as stage, grade, and PSA.
Within a median followup period of 68 months, there were 26 biochemical failures. MRI risk score, MRSI index lesion volume and presence of high grade voxels each correlated with time-to-BCR. In a model which combined clinical parameters, MRI score, MRSI lesion volume and the presence of at least one high grade voxel, the MRSI variables remained significant whereas the MRI score dropped out.
MRSI index lesion volume and the presence of high grade MRSI voxels correlate with time-to-BCR after radical prostatectomy even when adjusted for clinical data. These results suggest pre-operative predictive utility for endorectal MRI/MRSI in patients considering radical prostatectomy.
PMCID: PMC3074584  PMID: 20952035
MRI; spectroscopy; prostate; cancer; recurrence
14.  Predicting Post-External-beam Radiation Therapy PSA Relapse of Prostate Cancer Using Pre-treatment MRI 
To investigate whether pre-treatment endorectal magnetic resonance imaging (MRI) findings can predict biochemical relapse in patients with clinically localized prostate cancer (PCa) treated with external-beam radiation therapy (EBRT).
Patients and Methods
Between January 2000 and January 2002, 224 patients (median age 69 years, range 45-82) with biopsy-proven PCa underwent endorectal MRI before high-dose (≥ 81 Gy) EBRT. The value of multiple clinical and MRI variables in predicting PSA relapse at 5 years was determined using univariate and multivariate stepwise Cox regression. Clinical variables included pre-treatment PSA, clinical T-stage, Gleason score, use of neoadjuvant hormonal therapy and radiation dose. MRI variables, derived from retrospective consensus readings by two radiologists, measured intraprostatic and extraprostatic tumor burden.
After median follow-up of 67 months, 37 patients (16.5%) developed PSA relapse. The significant predictors of PSA relapse in univariate analysis were pre-treatment PSA, clinical T-stage, and multiple MRI variables including MRI TN-stage score; extracapsular extension (ECE) status; number of sextants involved by ECE, all lesions, or index (dominant) lesion; apical involvement; and diameter and volume of index lesion. Pretreatment PSA and ECE status were the only significant independent predictors upon multivariate analysis (P< 0.05 for both). ECE status was associated with the highest hazard ratio of 3.04; 5-year PSA relapse rates were 7% for no ECE, 20% for unilateral ECE, and 48% for bilateral ECE.
MRI findings can be used to predict post-EBRT PSA relapse, with ECE status on MRI and pre-treatment PSA being significant independent predictors of this endpoint.
PMCID: PMC2891893  PMID: 20133067
MR imaging; prostate cancer; external beam radiation therapy; biochemical recurrence; extracapsular extension
15.  High level of SOX9 in the prostate contributes to increased proliferation and can cooperate with PTEN loss to accelerate neoplasia formation 
Cancer research  2010;70(3):979-987.
Developmental pathways have been shown to be important in the initiation and progression of cancer in various tissues. We showed that the transcription factor SOX9 is expressed in the epithelia of the mouse embryonic prostate and is required for proper prostate development. We have performed an in vivo investigation into the role of SOX9 in prostate cancer in mouse and human. Studies on Pten and Nkx3.1 mutant mice show that cells with an increased level of SOX9 appear within the epithelia at the early stages of prostate neoplasia and this high expression correlates with all stages of neoplastic progression. Using genetically modified mice we show that overexpression of SOX9 in prostate epithelia leads to an increase in cell proliferation without inducing hyperplasia. In mice that were heterozygous for the conditional mutant allele of Pten, overexpression of SOX9 gave rise to an earlier induction of high-grade prostate intraepithelial neoplasia. Consistent with this role, loss of Sox9 in prostate epithelia led to a decrease in proliferating cells in normal and in homozygous Pten mutant mice with prostate neoplasia. Analysis of a cohort of 880 human prostate cancer samples showed that SOX9 expression is associated with increasing Gleason grades and higher Ki67 staining. These studies identify SOX9 as part of a developmental pathway that is reactivated in prostate neoplasia where it is involved in regulating proliferation and suggests it can contribute to carcinogenesis in specific genetic contexts.
PMCID: PMC3083842  PMID: 20103652
Previous studies have proposed that the morphologic spectrum of prostatic glands of variable size with tall columnar cells displaying basally-oriented nuclei and clear to pale pink cytoplasm (TZ-LOOK) is characteristic of the well- to moderately-differentiated component of transition zone (TZ) tumors. However, the specificity of these findings has not been well studied. In a recent report, we identified dominant peripheral zone (PZ) and TZ tumors situated anterior to the prostatic urethra. Currently, we evaluate the histopathologic features of 215 dominant tumors, including 63 TZ and 73 anterior PZ lesions and an additional cohort of 79 posterior PZ tumors, in radical prostatectomy specimens, to identify the prevalence of this morphology in tumors of different zonal origin. Each dominant tumor was assigned a TZ-LOOK extent score of 0 to 4, with 0 = no such morphology, 1 = 1-25%, 2 = 26-50%, 3 = 51-75%, and 4 = >75%. Overall, 121/215 (56%) tumors showed some degree of this histology, including 56 of 63 (89%) TZ tumors and 65 of 152 (43%) PZ tumors (p< 0.0001). 37 of 215 (17%) lesions had scores of 3-4, with 31 (84%) of these being of TZ origin. However, only 31/63 (49%) TZ tumors had >50% TZ-LOOK. Among PZ tumors, 6/152 (4%) had predominant (>50%) TZ-LOOK morphology, yet 23/152 (15%) of all PZ tumors and 23/65 (35%) of PZ tumors displaying any degree of TZ-LOOK had scores of 2-3 (>25%; non-focal). In tumors of both zones with predominant (scores 3-4; > 50%) TZ-LOOK histology, darker glands of usual acinar adenocarcinoma were often seen at the periphery. Conversely, in tumors with non-predominant TZ-LOOK (scores 1-2; ≤ 50%), these glands were frequently admixed with small glands bearing dark cytoplasm. In this series, we demonstrate that some degree of TZ-LOOK morphology is twice as frequent in dominant TZ tumors than in PZ tumors. Tumors demonstrating > 50% of this histology are very likely of TZ origin, but this scenario occurs in only half of TZ tumors. Importantly, the TZ-LOOK is non-focal in up to 35% of PZ tumors exhibiting any degree of this morphology. Given this lack of specificity, caution should be exercised in assigning zone of origin based on this histologic appearance, especially in limited samples such as prostate needle biopsy.
PMCID: PMC3010973  PMID: 18769336
prostate; transition zone; peripheral zone; radical prostatectomy
17.  Tumor associated endothelial expression of B7-H3 predicts survival in ovarian carcinomas 
B7-H3 and B7x are members of the B7 family of immune regulatory ligands that are thought to attenuate peripheral immune responses through co-inhibition. Previous studies have correlated their overexpression with poor prognosis and decreased tumor-infiltrating lymphocytes in various carcinomas including uterine endometrioid carcinomas, and mounting evidence supports an immuno-inhibitory role in ovarian cancer prognosis. We sought to examine the expression of B7-H3 and B7x in 103 ovarian borderline tumors and carcinomas and study associations with clinical outcome. Using immunohistochemical tissue microarray analysis on tumor specimens, we found that 93 and 100% of these ovarian tumors express B7-H3 and B7x, respectively, with expression found predominantly on cell membranes and in cytoplasm. In contrast, only scattered B7-H3- and B7x-positive cells were detected in non-neoplastic ovarian tissues. B7-H3 was also expressed in the endothelium of tumor-associated vasculature in 44% of patients, including 78% of patients with high-stage tumors (FIGO stages III and IV), nearly all of which were high-grade serous carcinomas, and 26% of patients with low-stage tumors (FIGO stages I and II; P<0.001), including borderline tumors. Analysis of cumulative survival time and recurrence incidence revealed that carcinomas with B7-H3-positive tumor vasculature were associated with a significantly shorter survival time (P=0.02) and a higher incidence of recurrence (P=0.03). The association between B7-H3-positive tumor vasculature and poor clinical outcome remained significant even when the analysis was limited to the high-stage subgroup. These results show that ovarian borderline tumors and carcinomas aberrantly express B7-H3 and B7x, and that B7-H3-positive tumor vasculature is associated with high-grade serous histological subtype, increased recurrence and reduced survival. B7-H3 expression in tumor vasculature may be a reflection of tumor aggressiveness and has diagnostic and immunotherapeutic implications in ovarian carcinomas.
PMCID: PMC2976590  PMID: 20495537
B7; co-inhibition; co-stimulation; endothelium; ovarian cancer; serous carcinoma; T cell; tumor vasculature
18.  Identification and Validation of a Gene Expression Signature That Predicts Outcome in Adult Men With Germ Cell Tumors 
Journal of Clinical Oncology  2009;27(31):5240-5247.
Germ cell tumor (GCT) is the most common malignancy in young adult men. Currently, patients are risk-stratified on the basis of clinical presentation and serum tumor markers. The introduction of molecular markers could improve outcome prediction.
Patients and Methods
Expression profiling was performed on 74 nonseminomatous GCTs (NSGCTs) from cisplatin-treated patients (ie, training set) and on 34 similarly treated patients with NSGCTs (ie, validation set). A gene classifier was developed by using prediction analysis for microarrays (PAM) for the binary end point of 5-year overall survival (OS). A predictive score was developed for OS by using the univariate Cox model.
In the training set, PAM identified 140 genes that predicted 5-year OS (cross-validated classification rate, 60%). The PAM model correctly classified 90% of patients in the validation set. Patients predicted to have good outcome had significantly longer survival than those with poor predicted outcome (P < .001). For the OS end point, a 10-gene model had a predictive accuracy (ie, concordance index) of 0.66 in the training set and a concordance index of 0.83 in the validation set. Dichotomization of the samples on the basis of the median score resulted in significant differences in survival (P = .002). For both end points, the gene-based predictor was an independent prognostic factor in a multivariate model that included clinical risk stratification (P < .01 for both).
We have identified gene expression signatures that accurately predict outcome in patients with GCTs. These predictive genes should be useful for the prediction of patient outcome and could provide novel targets for therapeutic intervention.
PMCID: PMC3651602  PMID: 19770384
Cancer research  2008;68(15):6054-6058.
B7x is the newest member of the B7-CD28 family and is thought to dampen immune responses via negative costimulation. Tumor expression of B7x was recently described in renal cell carcinoma (RCC) and was associated with poor outcome. We developed an assay to detect serum soluble B7x (sB7x) and investigated 101 patients with clear cell RCC who underwent nephrectomy between 2003 and 2007. For controls, we obtained serum from 101 sex-matched blood donors within the same age range. Following an Enzyme-Linked Immunosorbent Assay for sB7x, detectable levels (>0.1ng/ml) of sB7x were observed in 53 RCC patients compared with 18 controls (p
PMCID: PMC2918370  PMID: 18676826
Carcinoma; renal cell; Tumor markers; biological; T lymphocytes; Lymphocyte activation
To evaluate whether pretreatment magnetic resonance imaging (MRI)/MR spectroscopic imaging (MRSI) findings and molecular markers in surgical specimens correlate with each other and with pretreatment clinical variables (biopsy Gleason score, clinical stage, and prostate-specific antigen level) and whether they contribute incremental value in predicting prostate cancer recurrence.
Experimental Design
Eighty-eight prostate cancer patients underwent MRI/MRSI before radical prostatectomy; imaging findings were scored on a scale of 1 to 7 (no tumor seen—lymph node metastasis). Ki-67, phospho-Akt, and androgen receptor expression in surgical specimens were assessed by immunohistochemistry. To examine correlations between markers and imaging scores, Spearman's correlation was used. To test whether markers and imaging scores differed by clinical stage or Gleason score, Wilcoxon's rank sum test was used. To examine time to recurrence, the methods of Kaplan-Meier were used. Cox proportional hazards models were built and their concordance indices (C-indices) were calculated to evaluate prediction of recurrence.
All markers correlated moderately strongly with MRI/MRSI score (all correlation coefficients >0.5). Markers and MRI/MRSI score were strongly associated with clinical stage and biopsy Gleason score (P < 0.01 for all). At last follow-up, 27 patients had recurrence. C-indices for MRI/MRSI score and all markers were associated with time to recurrence and ranged from 0.78 to 0.89. A Cox model combining all clinical predictors had a C-index of 0.89; the C-index increased to 0.95 when MRI/MRSI score was added and to 0.97 when markers were also added.
MRI/MRSI findings and molecular markers correlated well with each other and contributed incremental value to clinical variables in predicting prostate cancer recurrence.
PMCID: PMC2811524  PMID: 19435838
The question of whether magnetic resonance spectroscopic imaging (MRSI) can be used to predict the Gleason score has been recently examined at our institution (1) and higher Gleason grade was associated with higher R=(choline+creatine)/citrate values. We wish to quantify this correlation by calculating as a function of R the probability that a particular voxel has a pathologic Gleason score ≥4+3, with sextant biopsy BxG and lesion volume V as cofactors.
Methods and Materials
The data consist of MRSI ratios R stratified by patient, lesion (contiguous abnormal voxels), voxels, biopsy and pathologic Gleason, and lesion volume. The data were analyzed using a logistic model.
For both low- and high-Gleason biopsy lesions, the probability of pathologic Gleason score ≥4+3 increases with lesion volume. At low values of R a lesion volume of at least 15–20 voxels is needed to reach a probability of success of 80%; the biopsy result helps reduce the prediction uncertainty. At larger MRS ratios (R>6) the biopsy result becomes essentially uninformative, once the lesion volume is >12 voxels. With the exception of low values of R, for lesions with low-Gleason score at biopsy, the MRS ratios serve primarily as a selection tool for assessing lesion volumes.
In patients with biopsy Gleason score ≥4+3, high MRSI tumor volume and (Cho+Cr)/Cit may justify the initiation of voxel-specific dose escalation. This is an example of biologically-motivated focal treatment for which IMRT and especially brachytherapy are ideally suited.
PMCID: PMC2692099  PMID: 18990509
prostate cancer; focal treatment; magnetic resonance spectroscopic imaging; Gleason grade
The Journal of urology  2009;181(5):2033-2036.
We evaluated our experience with renal cortical tumors to determine if tumor size is associated with malignant histology and/or nuclear grade.
Materials and Methods
We identified 2,675 patients treated surgically at Memorial Sloan-Kettering for renal cell carcinoma (RCC) or a benign tumor between 1989 and 2007. Histologic subtype and tumor size were obtained from our kidney cancer database and logistic regression analyses were performed.
Among the 2,675 tumors, 311 (12%) were benign while 2,364 (88%) were RCC. The odds ratio for association of malignancy with tumor size was 1.16 (95% CI 1.11–1.22; p<0.001), indicating that each 1cm increase in tumor size was associated with a 16% increase in the odds of malignancy. The percentage of benign tumors decreased from 38% for those less than 1 cm to 7% for tumors 7 cm or greater. For patients with clear cell RCC, each 1 cm increase in tumor size increased the odds of a high grade (Fuhrman grade 3–4) compared with a low grade (Fuhrman grade 1–2) tumor by 25% (odds ratio 1.25, 95% CI 1.21–1.30; p<0.001). For this subset, the percentage of high grade tumors increased from 0% for tumors <1cm to 59% for tumors >7cm.
Our results confirm previous observations suggesting that the risk of malignancy and risk of high grade tumors increases with tumor size. Patients with small renal masses have a low risk for harboring a high-grade clear cell malignancy which may be useful during initial consultation.
PMCID: PMC2734327  PMID: 19286217
Carcinoma, renal cell; Kidney neoplasms; Neoplasm staging; Histology
Cancer  2009;115(2):303-310.
Models are available to accurately predict biochemical recurrence (BCR) following radical prostatectomy (RP). Since not all patients experiencing BCR will progress to metastatic disease, it is appealing to determine post-operatively which patients are likely to manifest systemic disease.
The study cohort consisted of 881 patients undergoing RP between 1985 and 2003. Clinical failure (CF) was defined as metastases, a rising PSA in a castrate state, or death from prostate cancer. The cohort was randomized into training and validation sets. The accuracy of four models to predict clinical outcome within five years of RP were compared: “post-operative BCR nomogram” and “Cox regression CF model” based on standard clinical and pathologic parameters, and two CF “systems pathology” models which integrate clinical and pathologic parameters with quantitative histomorphometric and immunofluorescent biomarker features (“systems pathology models #1 and #2”).
When applied to the validation set, the concordance index for the post-operative BCR nomogram was 0.85, Cox regression CF model 0.84, systems pathology model #1 0.81, and systems pathology model #2 0.85.
Models predicting either biochemical recurrence or clinical failure following radical prostatectomy exhibit similarly high levels of accuracy since standard clinical and pathologic variables appear to be the primary determinants of both outcomes. Patients and clinicians interested in predicting clinical failure can recalibrate standard biochemical recurrence models to estimate the likelihood of systemic disease. It is possible that introducing current or novel biomarkers found to be uniquely associated with disease progression may further enhance the accuracy of the systems pathology-based platform.
PMCID: PMC2740715  PMID: 19025977
prostate cancer; radical prostatectomy; metastases; death; prediction
The past several years have seen unprecedented advances in the application of various therapeutic strategies for the treatment of patients with renal cancer. The availability of active immunotherapy, anti-angiogenic therapy and targeted therapy for this disease has brought front and center issues related to choosing the appropriate treatment for particular patient populations. It is increasingly evident that the most promising treatment selection strategies will incorporate identifying specific features of the tumor itself. In order to facilitate this move toward personalized medicine, it is critically important to establish some standard principles for renal cancer tissue collection, preparation and analysis for translational research studies.
In this article we identify and discuss some critical issues related to tissue-based kidney cancer research. We focus on five major areas: 1) surgical and image-guided techniques for tissue collection 2) quality control of specimen collection, processing, storage and review 3) issues related to analysis of paraffin embedded tissues 4) genomic studies 5) assessment of reproducibility of assays across institutions. In addition, some practical implementation strategies are proposed.
While many of the topics discussed are specific for renal cancer, several are also relevant to tissue based biomarker investigations in a broad array of malignancies.
PMCID: PMC2586673  PMID: 18559586
Renal; Cancer; Biomarkers; Tissue; Standard Operating Procedures
The Journal of urology  2008;179(4):1368-1373.
We report local control outcomes, as assessed by posttreatment biopsies in patients who underwent 3-dimensional conformal radiotherapy for clinically localized prostate cancer. In addition, we report the influence of local tumor control on long-term distant metastases and cause specific survival outcomes.
Materials and Methods
Posttreatment prostate biopsies were performed in 339 patients who underwent 3-dimensional conformal radiotherapy for clinically localized prostate cancer. The histological outcome of prostate biopsy was classified as positive—prostatic adenocarcinoma without typical radiation induced changes or negative—no evidence of carcinoma or severe treatment effect. Median followup in this group of 339 patients was 10 years after the completion of treatment and 6.25 years after posttreatment biopsy.
Overall biopsy outcomes in these patients were positive in 32%, severe treatment effect in 21% and negative in 47%. A higher radiation dose in the intermediate and high risk subgroups was associated with a lower incidence of positive biopsy. Of patients at intermediate risk who received a dose of 75.6 or greater 24% had a positive biopsy compared to 42% who received 70.2 Gy or less (p = 0.03). In the high risk group positive treatment biopsies were noted in 51% of patients who received 70.2 Gy or less, 33% of those who received 75.6 Gy and 15% of those who received 81 Gy or greater (70.2 or less vs 75.6 Gy p = 0.07 and 75.6 vs 81 Gy or greater p = 0.05). Short course neoadjuvant androgen deprivation therapy before 3-dimensional conformal radiotherapy had a significant impact on the posttreatment biopsy outcome. Of patients who did not receive androgen deprivation therapy 42% had a positive biopsy compared to 16% who received androgen deprivation therapy (p <0.0001). Patients with negative and severe treatment effect biopsies had similar 10-year prostate specific antigen relapse-free survival outcomes that were markedly different from outcomes in those with positive treatment biopsies. Multivariate analysis indicated that the strongest predictor of biochemical failure was posttreatment biopsy status (positive vs severe treatment effect or negative p <0.001), followed by pretreatment prostate specific antigen (p = 0.05) and clinical T stage (p = 0.09). Similarly multivariate analysis revealed that a positive posttreatment biopsy was one of the strongest predictors of distant metastasis and prostate cancer death in this cohort of patients.
As assessed by posttreatment prostate biopsies, local control is improved with higher radiation doses. Long-term biochemical outcomes in patients with posttreatment biopsies demonstrating severe treatment effect changes were not different than those in patients with negative biopsies. We also noted that local tumor control was associated with a decrease in distant metastases and prostate cancer mortality, further highlighting the importance of achieving optimal tumor control in patients with clinically localized disease.
PMCID: PMC2646887  PMID: 18289585
prostate; biopsy; mortality; radiotherapy; neoplasm metastasis

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