Victor E Reuter

University of Otago, Taieri, Otago Region, New Zealand

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Publications (478)2428.43 Total impact

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    ABSTRACT: Given the bone tropism of prostate cancer, conventional imaging modalities poorly identify or quantify metastatic disease. (89)Zr-huJ591 positron emission tomography (PET) imaging was performed in patients with metastatic prostate cancer to analyze and validate this as an imaging biomarker for metastatic disease. The purpose of this initial study was to assess safety, biodistribution, normal organ dosimetry, and optimal imaging time post-injection for lesion detection.
    European journal of nuclear medicine and molecular imaging 08/2014; · 5.11 Impact Factor
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    ABSTRACT: Cisplatin-based chemotherapy is the standard of care for patients with muscle invasive urothelial carcinoma. Pathologic downstaging to pT0/pTis after neoadjuvant cisplatin-based chemotherapy is associated with improved survival, although molecular determinants of cisplatin response are incompletely understood. We performed whole exome sequencing on pre-treatment tumor and germline DNA from 50 patients with muscle invasive urothelial carcinoma who received neoadjuvant cisplatin-based chemotherapy followed by cystectomy (25 pT0/pTis "responders", 25 pT2+ "non-responders") to identify somatic mutations that occurred preferentially in responders. ERCC2, a nucleotide excision repair gene, was the only significantly mutated gene enriched in the cisplatin responders compared with non-responders (q < 0.01). Expression of representative ERCC2 mutations in an ERCC2-deficient cell line failed to rescue cisplatin and UV sensitivity compared to wild-type ERCC2. Lack of normal ERCC2 function may contribute to cisplatin sensitivity in urothelial cancer and somatic ERCC2 mutation status may inform cisplatin-containing regimen usage in muscle invasive urothelial carcinoma.
    Cancer Discovery 08/2014; · 10.14 Impact Factor
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    ABSTRACT: Members of the International Society of Urological Pathology (ISUP) participated in a half-day consensus conference to discuss guidelines and recommendations regarding best practice approaches to use of immunohistochemistry (IHC) in differential diagnostic situations in urologic pathology, including bladder, prostate, testis and, kidney lesions. Four working groups, selected by the ISUP leadership, identified several high-interest topics based on common or relevant challenging diagnostic situations and proposed best practice recommendations, which were discussed by the membership. The overall summary of the discussions and the consensus opinion forms the basis of a series of articles, one for each organ site. This Special Article summarizes the overall recommendations made by the four working groups. It is anticipated that this ISUP effort will be valuable to the entire practicing community in the appropriate use of IHC in diagnostic urologic pathology.
    The American journal of surgical pathology. 08/2014; 38(8):1017-1022.
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    ABSTRACT: Urothelial carcinoma of the bladder (UCB) is genomically heterogeneous, with frequent alterations in genes regulating chromatin state, cell cycle control, and receptor kinase signaling. To identify prognostic genomic markers in high-grade UCB, we used capture-based massively parallel sequencing to analyze 109 tumors. Mutations were detected in 240 genes, with 23 genes mutated in ≥5% of cases. The presence of a recurrent phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha (PIK3CA) mutation was associated with improved recurrence-free survival (RFS) (hazard ratio [HR]: 0.35; p=0.014) and improved cancer-specific survival (CSS) (HR: 0.35; p=0.040) in patients treated with radical cystectomy (RC). In multivariable analyses controlling for pT and pN stages, PIK3CA mutation remained associated with RFS (HR: 0.39; p=0.032). The most frequent alteration, TP53 mutation (57%), was more common in extravesical disease (69% vs 32%, p=0.005) and lymph node-positive disease (77% vs 56%, p=0.025). Patients with cyclin-dependent kinase inhibitor 2A (CDKN2A)-altered tumors experienced worse RFS (HR: 5.76; p<0.001) and worse CSS (HR: 2.94; p=0.029) in multivariable analyses. Mutations in chromatin-modifying genes were highly prevalent but not associated with outcomes. In UCB patients treated with RC, PIK3CA mutations are associated with favorable outcomes, whereas TP53 and CDKN2A alterations are associated with poor outcomes. Genomic profiling may aid in the identification of UCB patients at highest risk following RC.
    European urology. 08/2014;
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    ABSTRACT: Primary renal neoplasms comprise multiple distinct entities, some of which are well understood and others that are not. It is not uncommon for some of these entities to have overlapping morphologic features. Their clinical behavior is varied, ranging from highly malignant to benign, and metastatic renal cell carcinoma oftentimes enters into the differential diagnosis of tumors of unknown primary. In this age of personalized medicine, identifying biomarkers that can better predict clinical outcome and response to therapy is a pressing need. In 2013 the International Society of Urological Pathology held a meeting in which best practices recommendations on the use of immunohistochemical markers in urologic malignancies were discussed. In this review we make recommendations regarding immunohistochemical markers that are best suited to aid in establishing a diagnosis of renal primary, panels of antibodies that are most useful in classifying renal tumors, and the current status of prognostic and predictive biomarkers. Although no prognostic or predictive marker and set of markers have yet to be validated, ongoing research suggests that this fact is likely to change in the near future.
    The American journal of surgical pathology. 08/2014; 38(8):e35-e49.
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    ABSTRACT: Primary prostate cancer is the most common malignancy in men but has highly variable outcomes, highlighting the need for biomarkers to determine which patients can be managed conservatively. Few large prostate oncogenome resources currently exist that combine the molecular and clinical outcome data necessary to discover prognostic biomarkers. Previously, we found an association between relapse and the pattern of DNA copy number alteration (CNA) in 168 primary tumors, raising the possibility of CNA as a prognostic biomarker. Here we examine this question by profiling an additional 104 primary prostate cancers and updating the initial 168 patient cohort with long-term clinical outcome. We find that CNA burden across the genome, defined as the percentage of the tumor genome affected by CNA, was associated with biochemical recurrence and metastasis after surgery in these two cohorts, independent of the prostate-specific antigen biomarker or Gleason grade, a major existing histopathological prognostic variable in prostate cancer. Moreover, CNA burden was associated with biochemical recurrence in intermediate-risk Gleason 7 prostate cancers, independent of prostate-specific antigen or nomogram score. We further demonstrate that CNA burden can be measured in diagnostic needle biopsies using low-input whole-genome sequencing, setting the stage for studies of prognostic impact in conservatively treated cohorts.
    Proceedings of the National Academy of Sciences of the United States of America. 07/2014;
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    ABSTRACT: Metastatic solid tumors are almost invariably fatal. Patients with disseminated small-cell cancers have a particularly unfavorable prognosis with most succumbing to their disease within two years. Here, we report on the genetic and functional analysis of an outlier curative response of a patient with metastatic small cell cancer to combined checkpoint kinase 1 (Chk1) inhibition and DNA damaging chemotherapy. Whole-genome sequencing revealed a clonal hemizygous mutation in the Mre11 complex gene RAD50 that attenuated ATM signaling which in the context of Chk1 inhibition contributed, via synthetic lethality, to extreme sensitivity to irinotecan. As Mre11 mutations occur in a diversity of human tumors, the results suggest a tumor-specific combination therapy strategy whereby checkpoint inhibition in combination with DNA damaging chemotherapy is synthetically lethal in tumor but not normal cells with somatic mutations that impair Mre11 complex function.
    Cancer Discovery 06/2014; · 10.14 Impact Factor
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    ABSTRACT: A previous study noted frequent B-RAF mutations among European patients with cisplatin-resistant but not cisplatin-sensitive germ cell tumors (GCT). We sought to validate this finding by assessing for these mutations among GCT patients at our center. Patients and Methods: Adolescent and adult patients with GCT who received cisplatin-based chemotherapy and had tumor tissue available were eligible for participation. Response to cisplatin was reviewed to determine sensitivity and resistance. Tumor DNA was extracted and subjected to Sequenom analysis to detect hotspot alterations in FGFR3, AKT1, PIK3CA, KRAS, HRAS, NRAS, and BRAF with Sanger Sequencing for confirmation. Nine GCT cell lines with varying degrees of cisplatin sensitivity and resistance were also assayed by Sequenom. Seventy (24 cisplatin-sensitive; 46 cisplatin-resistant) of 75 patients had tumors with sufficient quality DNA to perform Sequenom. Nineteen mutations were detected among 16 (23%) patients but no BRAF mutations were identified. Similarly, none of the cell lines harbored BRAF mutations. FGFR3 was the most frequent mutation, identified in 13% of both sensitive and resistant samples. All other mutations were exclusive to resistant cases (3 KRAS, 3 AKT1, 3 PIK3CA, 1 HRAS). BRAF mutations are rare in American GCT patients, including those with cisplatin-resistance. However, other potentially targetable mutations occur in over 25% of cisplatin-resistant patients. FGFR3, AKT1 and PIK3CA mutations are all reported for the first time in GCT. Whereas FGFR3 mutations occurred with equal frequency in both sensitive and resistant GCT, mutations in AKT1 and PIK3CA were observed exclusively in cisplatin-resistant tumors.
    Clinical Cancer Research 05/2014; · 7.84 Impact Factor
  • The American journal of surgical pathology 05/2014; · 4.06 Impact Factor
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    ABSTRACT: To determine whether the Gyrus ACMI plasma kinetic bipolar device (Gyrus ACMI, Southborough, MA) improves pathologic specimen preservation and clinical outcomes compared to standard monopolar electrocautery. In our prospective study, 83 patients underwent monopolar or bipolar transurethral resection of bladder tumors between April 2006 and February 2007 at Memorial Sloan-Kettering Cancer Center. Dedicated genitourinary oncology pathologists blinded to resection type and assessed pathologic features including stage and grade, presence of muscularis propria, fragment size, presence and thickness of thermal artifacts within the specimen, layer of tissue most affected, severity of tissue distortion, and diagnostic impact of thermal artifacts. Clinical outcomes including, perforation, obturator reflex, need for muscle paralysis, a catheter, or admission, were recorded. Clinical and pathologic outcomes between resection modality were compared. There were no significant thermal artifacts in 9/38 (23.7 %) and 11/45 (24.4 %) monopolar and bipolar specimens, respectively. The layer of bladder tissue most affected by thermal artifacts was readable in 18/38 (47.4 %) monopolar and 27/45 (60.0 %) bipolar specimens. Tissue distortion from thermal artifacts led to areas within 11/38 (28.9 %) monopolar and 7/45 (15.6 %) bipolar specimens being unreadable. Ultimately, thermal artifacts caused moderate diagnostic difficulty in 2/38 (5.3 %) specimens of the monopolar group and severe diagnostic difficulty in 1/45 (2.2 %) bipolar specimens. Clinically, there was no major difference between resection methods. Plasma kinetic bipolar equipment appears to cause less tissue distortion and has the potential to facilitate staging and grading of bladder tumors. No differences in clinical outcomes were appreciated between resection methods. If these results can be repeated in larger studies, the bipolar device represents a small advancement in transurethral resection.
    International Urology and Nephrology 05/2014; · 1.33 Impact Factor
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    ABSTRACT: On July 31, 2013, the Prostate Cancer Foundation assembled a working committee on the molecular biology and pathologic classification of neuroendocrine (NE) differentiation in prostate cancer. 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 NE differentiation. The classification system consists of: Usual prostate adenocarcinoma with NE differentiation; 2) Adenocarcinoma with Paneth cell NE differentiation; 3) Carcinoid tumor; 4) Small cell carcinoma; 5) Large cell NE carcinoma; and 5) Mixed NE carcinoma - acinar adenocarcinoma. The article also highlights "prostate carcinoma with overlapping features of small cell carcinoma and acinar adenocarcinoma" and "castrate-resistant prostate cancer with small cell cancer-like clinical presentation". 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.
    The American journal of surgical pathology 04/2014; · 4.06 Impact Factor
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    ABSTRACT: 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 1α (HIF-1α)-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.
    The American journal of surgical pathology 04/2014; 38(4):567-77. · 4.06 Impact Factor
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    ABSTRACT: 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. 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.
    Clinical Cancer Research 03/2014; · 7.84 Impact Factor
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    ABSTRACT: Renal cell carcinomas (RCCs) harboring the t(6;11)(p21;q12) translocation were first described in 2001 and recently recognized by the 2013 International Society of Urological Pathology Vancouver Classification of Renal Neoplasia. Although these RCCs are known to label for melanocytic markers HMB45 and Melan A and the cysteine protease cathepsin K by immunohistochemistry (IHC), a comprehensive IHC profile has not been reported. We report 10 new t(6;11) RCCs, all confirmed by break-apart TFEB fluorescence in situ hybridization. A tissue microarray containing 6 of these cases and 7 other previously reported t(6;11) RCCs was constructed and immunolabeled for 21 different antigens. Additional whole sections of t(6;11) RCC were labeled with selected IHC markers. t(6;11) RCC labeled diffusely and consistently for cathepsin K and Melan A (13 of 13 cases) and almost always at least focally for HMB45 (12 of 13 cases). They labeled frequently for PAX8 (14 of 23 cases), CD117 (10 of 14 cases), and vimentin (9 of 13 cases). A majority of cases labeled at least focally for cytokeratin Cam5.2 (8 of 13 cases) and CD10 and RCC marker antigen (10 of 14 cases each). In contrast to a prior study's findings, only a minority of cases labeled for Ksp-cadherin (3 of 19 cases). The median H score (product of intensity score and percentage labeling) for phosphorylated S6, a marker of mTOR pathway activation, was 101, which is high relative to most other RCC subtypes. In summary, IHC labeling for PAX8, Cam5.2, CD10, and RCC marker antigen supports classification of the t(6;11) RCC as carcinomas despite frequent negativity for broad-spectrum cytokeratins and EMA. Labeling for PAX8 distinguishes the t(6;11) RCC from epithelioid angiomyolipoma, which otherwise shares a similar immunoprofile. CD117 labeling is more frequent in the t(6;11) RCC compared with the related Xp11 translocation RCC. Increased pS6 expression suggests a possible molecular target for the uncommon t(6;11) RCCs that metastasize.
    The American journal of surgical pathology 03/2014; · 4.06 Impact Factor
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    ABSTRACT: To report cancer-specific outcomes of micropapillary NMIBC. The records of 36 patients restaged within three months of initial micropapillary NMIBC diagnosis were retrospectively reviewed. Early radical cystectomy ([RC] within a three-month landmark after restaging transurethral resection of bladder tumor [TURBT]), or conservative management (intravesical Bacillus Calmette-Guérin, surveillance, or deferred RC) was offered according to surgeon and patient preference. Cumulative incidence of cancer-specific mortality (CSM) and metastasis was estimated using Kaplan-Meier methods. Differences in cumulative incidence of CSM and metastasis between groups were tested using the log rank test. Median patient age was 68 (interquartile range [IQR] 63, 77) years. Male-to-female ratio was 3:1. At restaging, all patients had ≤cT1 disease. Fifteen (42%) patients underwent early RC; 21 (58%) conservative management. Median follow-up time from landmark for cancer-specific survivors was 3.1 years (IQR 1.1, 5.9). Five-year cumulative incidence of CSM was 17% in the early RC group and 25% in the conservative management group, with an absolute difference of 7% (95% confidence interval [CI]: -26%, 41%; p = 0.8). The 5-year cumulative incidence of metastasis was 21% and 34%, respectively, with an absolute difference of 13% (95% CI: -23%, 49%; p = 0.9). The extent of the micropapillary component was not significantly associated with CSM (p = 0.4) or metastasis (p = 0.9). Using proper selection criteria, including patient and pathologic factors, certain patients with cT1 micropapillary UC managed conservatively were not found to have significantly worse outcomes compared to patients undergoing early radical cystectomy.
    The Journal of urology 03/2014; · 4.02 Impact Factor
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    ABSTRACT: To improve the overall accuracy of diagnosis in needle biopsies of renal masses, especially small renal masses (SRMs), using fluorescence in situ hybridization (FISH). To develop a renal cortical neoplasm classification decision tree based on genomic alterations detected by FISH. Ex vivo fine needle aspiration (FNA) biopsies of 122 resected renal cortical neoplasms were subjected to FISH using a series of seven probe sets to assess gain or loss of 10 chromosomes and rearrangement of the 11q13 locus. Using specimen (nephrectomy)-histology as the gold standard, a genomic aberration based-decision tree was generated to classify specimens. The diagnostic potential of the decision tree was assessed by comparing the FISH-based classification and biopsy-histology to specimen-histology. Of the 114 biopsies diagnostic by either method, a higher diagnostic yield was achieved by FISH (92%, 96%) than histology alone (82%, 84%) in the 65 biopsies from SRMs (<4cm) and 49 from larger masses respectively. An optimized decision tree was constructed based on aberrations detected in eight chromosomes, by which the maximum concordance of classification achieved by FISH was 79%, irrespective of mass size. In SRMs, the overall sensitivity of diagnosis by FISH compared to histopathology, was improved for benign oncocytoma, comparable for chromophobe renal cell carcinoma subtype, and less for clear cell and papillary subtypes. Diagnostic accuracy of classification of needle biopsy specimens (from SRMs) increased from 80% obtained by histology alone to 94% upon combining histology and FISH. The current study lends support for a role of a novel FISH assay developed by us to assist in the yield and accuracy of diagnosis of renal cortical neoplasms in needle biopsies, in particular to help guide clinical management of patients with SRMs that were non-diagnostic by histology.
    BJU International 01/2014; · 3.05 Impact Factor
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    ABSTRACT: Hereditary leiomyomatosis and renal cell carcinoma (HLRCC) syndrome is an autosomal dominant disorder in which germline mutations of fumarate hydratase (FH) gene confer an increased risk of cutaneous and uterine leiomyomas and renal cancer. HLRCC-associated renal cancer is highly aggressive and frequently presents as a solitary mass. We reviewed the clinicopathologic features of 9 patients with renal tumors presenting as sporadic cases but who were later proven to have FH germline mutations. Histologically, all tumors showed mixed architectural patterns, with papillary as the dominant pattern in only 3 cases. Besides papillary, tubular, tubulopapillary, solid, and cystic elements, 6 of 9 tumors contained collecting duct carcinoma-like areas with infiltrating tubules, nests, or individual cells surrounded by desmoplastic stroma. Prominent tubulocystic carcinoma-like component and sarcomatoid differentiation were identified. Although all tumors exhibited the proposed hallmark of HLRCC (large eosinophilic nucleolus surrounded by a clear halo), this feature was often not uniformly present throughout the tumor. Prior studies have shown that a high level of fumarate accumulated in HLRCC tumor cells causes aberrant succination of cellular proteins by forming a stable chemical modification, S-(2-succino)-cysteine (2SC), which can be detected by immunohistochemistry. We thus explored the utility of detecting 2SC by immunohistochemistry in the differential diagnosis of HLRCC tumors and other high-grade renal tumors and investigated the correlation between 2SC staining and FH molecular alterations. All confirmed HLRCC tumors demonstrated diffuse and strong nuclear and cytoplasmic 2SC staining, whereas all clear cell (184/184, 100%), most high-grade unclassified (93/97, 96%), and the large majority of "type 2" papillary (35/45, 78%) renal cell carcinoma cases showed no 2SC immunoreactivity. A subset of papillary (22%) and rare unclassified (4%) tumors showed patchy or diffuse cytoplasmic staining without nuclear labeling, unlike the pattern seen with confirmed HLRCC tumors. Sequencing revealed no germline or somatic FH alterations in 14 tumors that either exhibited only cytoplasmic 2SC staining (n=5) or were negative for 2SC (n=9), despite their HLRCC-like morphologic features. Our results emphasize the pivotal role of pathologic examination in the diagnosis of HLRCC patients and indicate immunohistochemical detection of 2SC as a useful ancillary tool in the differentiation of HLRCC renal tumors from other high-grade renal cell carcinomas.
    The American journal of surgical pathology 01/2014; · 4.06 Impact Factor
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    ABSTRACT: Purpose: To evaluate pathologic variables of testicular sex cord–stromal tumors (TSCST), management options, and clinical outcomes. Methods: We performed a retrospective review of 48 patients with TSCST treated at Memorial Sloan-Kettering Cancer Center between 1997 and 2012. Clinical outcomes were compared based on treatment and previously described pathologic factors associated with metastatic potential. Results: Of 48 patients, 37 underwent surveillance without retroperitoneal lymph node dissection, 34 having 0 high-risk features and 3 having 1 high-risk feature. Median follow-up was 14.5 months (IQR 6.9 – 32.5 months); no patients experienced recurrence. Retroperitoneal lymph node dissection was performed in 11 patients, 6 with clinical stage 1 disease and ≥2 high-risk features who underwent early dissection, 2 with clinical stage IIa disease at diagnosis who underwent early dissection, 3 with clinical stage 1 disease and ≥2 high-risk features were observed by outside clinicians but were referred to our institution for retroperitoneal disease. Six patients with clinical stage 1 disease underwent early dissection, 4 had no evidence of disease with median follow-up of 6.6 years, 2 recurred and died of disease. Of the 2 patients with IIa disease at diagnosis, neither relapsed. Of the 3 patients with delayed dissections all 3 relapsed and 1 died of disease. Conclusions: Patients with TSCST and ≤1 high-risk feature can be safely observed without retroperitoneal lymph node dissection, though longer follow-up is needed. Given lack of effective alternative treatments, early retroperitoneal lymph node dissection for patients with ≥2 high-risk features or clinical stage IIa disease may be beneficial.
    The Journal of urology 01/2014; · 4.02 Impact Factor
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    ABSTRACT: Purpose: Several recently reported recurrent genomic alterations in clear cell renal cell carcinoma (ccRCC) are linked to pathological and clinical outcomes. We determined if any of the recurrent cancer gene mutations or copy number alterations identified in the Cancer Genome Atlas (TCGA) ccRCC dataset could add to the predictive accuracy of the current prognostic models. Materials and Methods: 413 patients who underwent nephrectomy/partial nephrectomy with whole exome, copy number array analyses, and clinical variables were interrogated. Sixty-five recurrent genomic alterations were identified based on prevalence and combined into 35 alterations including 12 cancer gene mutations. The genomic markers were modeled using the elastic-net algorithm with preoperative variables (tumor size + age) and in the postoperative setting using the externally validated Mayo Clinic stage, size, grade, and necrosis (SSIGN) prognostic scoring system. These models were subjected to internal validation using bootstrap. Results: The median follow up for survivors was 45 months. Several markers correlated with adverse cancer-specific survival (CSS) and time to recurrence (TTR) on univariate analysis. However, most lost significance when controlling for tumor size +/- age in the preoperative models or SSIGN score in the postoperative setting. The addition of multiple genomic markers selected by the elastic-net algorithm failed to substantially add to the predictive accuracy of any of the preoperative or postoperative models for CSS or TTR. Conclusions: While recurrent copy number alterations and cancer gene mutations are biologically significant, they do not appear to improve the predictive accuracy of existing clinical CSS or TTR models in ccRCC.
    The Journal of urology 01/2014; · 4.02 Impact Factor
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    ABSTRACT: We describe the landscape of somatic genomic alterations of 66 chromophobe renal cell carcinomas (ChRCCs) on the basis of multidimensional and comprehensive characterization, including mtDNA and whole-genome sequencing. The result is consistent that ChRCC originates from the distal nephron compared with other kidney cancers with more proximal origins. Combined mtDNA and gene expression analysis implicates changes in mitochondrial function as a component of the disease biology, while suggesting alternative roles for mtDNA mutations in cancers relying on oxidative phosphorylation. Genomic rearrangements lead to recurrent structural breakpoints within TERT promoter region, which correlates with highly elevated TERT expression and manifestation of kataegis, representing a mechanism of TERT upregulation in cancer distinct from previously observed amplifications and point mutations.
    Cancer Cell. 12/2013; 26(3):319-330.

Publication Stats

18k Citations
2,428.43 Total Impact Points


  • 2014
    • University of Otago
      Taieri, Otago Region, New Zealand
  • 1987–2014
    • Memorial Sloan-Kettering Cancer Center
      • • Department of Pathology
      • • Department of Surgery
      • • Genitourinary Oncology Service
      • • Department of Radiology
      • • Urology Service
      • • Laboratory of Cancer Genetics
      • • Department of Medicine
      New York City, New York, United States
  • 2003–2012
    • Johns Hopkins Medicine
      • Department of Pathology
      Baltimore, MD, United States
    • University of Michigan
      • Department of Urology
      Ann Arbor, MI, United States
  • 2011
    • Autonomous University of Barcelona
      Cerdanyola del Vallès, Catalonia, Spain
    • Queen Mary, University of London
      • Centre for Molecular Oncology
      London, ENG, United Kingdom
  • 2010
    • University of São Paulo
      San Paulo, São Paulo, Brazil
    • Brigham and Women's Hospital
      • Department of Medicine
      Boston, MA, United States
    • Credit Valley Hospital
      Mississauga, Ontario, Canada
  • 2008–2010
    • University of California, Los Angeles
      • Department of Epidemiology
      Los Angeles, CA, United States
    • Winthrop University Hospital
      • Division of Surgical Pathology
      Mineola, New York, United States
    • University of Chicago
      • Department of Pathology
      Chicago, IL, United States
  • 1995–2010
    • Cornell University
      • Department of Medicine
      Ithaca, NY, United States
  • 2009
    • Universidad Nacional de Asunción
      San Lorenzo del Campo Grande, Central, Paraguay
    • Columbia University
      New York City, New York, United States
  • 2007
    • Johns Hopkins University
      • Department of Pathology
      Baltimore, MD, United States
  • 2006
    • University of London
      Londinium, England, United Kingdom
  • 2002
    • Weill Cornell Medical College
      • Department of Urology
      New York City, New York, United States
  • 2001
    • Vanderbilt University
      • Division of Urologic Surgery
      Nashville, MI, United States
  • 2000
    • Indiana University-Purdue University Indianapolis
      • Department of Pathology and Laboratory Medicine
      Indianapolis, IN, United States
  • 1990–1998
    • Miles Memorial Hospital
      Damariscotta, Maine, United States
  • 1997
    • Henry Ford Hospital
      Detroit, Michigan, United States
  • 1996
    • University of California, San Francisco
      • Department of Urology
      San Francisco, CA, United States
  • 1994
    • Gracie Square Hospital, New York, NY
      New York City, New York, United States