Publications by authors named "Eugene J Pietzak"

38 Publications

Inherited Germline Cancer Susceptibility Gene Variants in Individuals with Non-Muscle-Invasive Bladder Cancer.

Clin Cancer Res 2022 Jul 14. Epub 2022 Jul 14.

Memorial Sloan Kettering Cancer Center, New York, NY, United States.

Purpose: Identification of inherited germline variants can guide personalized cancer screening, prevention, and treatment. Pathogenic and likely pathogenic (P/LP) germline variants in cancer predisposition genes are frequent among patients with locally advanced or metastatic urothelial carcinoma, but their prevalence and significance in patients with non-muscle invasive bladder cancer (NMIBC), the most common form of urothelial carcinoma, is understudied.

Experimental Design: Germline analysis was conducted on paired tumor/normal sequencing results from two distinct cohorts of patients initially diagnosed with NMIBC. Associations between clinicopathologic features and clinical outcomes with the presence of P/LP germline variants in ≥76 hereditary cancer predisposition genes were analyzed.

Results: A similar frequency of P/LP germline variants were seen in our two NMIBC cohorts (12% [12/99] vs. 8.7% [10/115], p=0.4). In the combined analysis, P/LP germline variants were found only in patients with high-grade NMIBC (22/163), but none of the 46 patients with low-grade NMIBC (13.5% vs. 0%, p=0.005). Fifteen (9.2%) patients with high-grade NMIBC had P/LP variants in DNA damage response (DDR) genes, most within the nucleotide excision repair (ERCC2/3) and homologous recombination repair (BRCA1, NBN, RAD50) pathways. Contrary to prior reports in NMIBC patients not receiving BCG, P/LP germline variants were not associated with worse recurrence-free or progression-free survival in patients treated with BCG.

Conclusions: Our results support offering germline counseling and testing for all patients with high-grade bladder cancer, regardless of the initial tumor stage. Therapeutic strategies that target impaired DNA repair may benefit patients with high-grade NMIBC.
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http://dx.doi.org/10.1158/1078-0432.CCR-22-1006DOI Listing
July 2022

Clinical and Genomic Characterization of Bladder Carcinomas With Glandular Phenotype.

JCO Precis Oncol 2022 06;6:e2100392

Genitourinary Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY.

Purpose: To compare oncologic outcomes and genomic alteration profiles in patients with bladder and urachal adenocarcinoma, urothelial carcinoma (UC) with glandular differentiation, and UC, not otherwise specified (NOS) undergoing surgical resection, with emphasis on response to systemic therapy.

Methods: We identified patients with bladder cancer with glandular variants who underwent surgical resection at Memorial Sloan Kettering from 1995 to 2018 (surgical cohort) and/or patients who had tumor sequencing using a targeted next-generation sequencing platform (genomics cohort). Pathologic complete and partial response rates to neoadjuvant chemotherapy (NAC) and recurrence-free and cancer-specific survival were measured. Alteration frequencies between histologic subtypes were compared.

Results: Thirty-seven patients with bladder adenocarcinoma, 46 with urachal adenocarcinoma, 84 with UC with glandular differentiation, and 1,049 with UC, NOS comprised the surgical cohort. Despite more advanced disease in patients with bladder and urachal adenocarcinoma, no significant differences in recurrence or cancer-specific survival by histology were observed after adjusting for stage. In patients with UC with glandular differentiation, NAC resulted in partial (≤ pT1N0) and complete (pT0N0) responses in 28% and 17%, respectively. Bladder and urachal adenocarcinoma genomic profiles resembled colorectal adenocarcinoma with frequent , , and alterations while the genomic profile of UC with glandular differentiation more closely resembled UC, NOS. Limitations include retrospective nature of analysis and small numbers of nonurothelial histology specimens.

Conclusion: The genomic profile of bladder adenocarcinomas resembled colorectal adenocarcinomas, whereas UC with glandular differentiation more closely resembled UC, NOS. Differences in outcomes among patients with glandular bladder cancer variants undergoing surgical resection were largely driven by differences in stage. Cisplatin-based NAC demonstrated activity in UC with glandular differentiation, suggesting NAC should be considered for this histologic variant.
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http://dx.doi.org/10.1200/PO.21.00392DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9249273PMC
June 2022

() Copy Number Changes (Gain) & Response to Immune Checkpoint Blockade Therapy in Carcinomas of the Urinary Tract.

Bladder Cancer 2021 13;7(4):395-400. Epub 2021 Dec 13.

Department of Pathology, Memorial Sloan Kettering Cancer Center.

Background: Immune checkpoint inhibitors are an important therapeutic option for urothelial carcinoma, but durable responses are achieved in a minority of patients. Identifying pre-treatment biomarkers that may predict response to these therapies or who exhibit intrinsic resistance, is of paramount importance.

Objective: To explore the prevalence of copy number alteration in urothelial carcinoma and correlate with response to immune checkpoint inhibitors.

Methods: We analyzed a cohort of 1050 carcinomas of the bladder and upper urinary tract that underwent targeted next generation sequencing, prospectively. We assessed PD-L1 protein expression, copy number status (next generation sequencing/FISH), and detailed treatment response.

Results: We identified 9 tumors with amplification and 9 tumors with deletion. PD-L1 protein expression was the highest in amplified tumors. Of the 9 patients whose tumors harbored amplification, 6 received immunotherapy with 4 deriving clinical benefit, and two achieving durable response. Of the 9 patients whose tumors had copy number losses, 4 received immunotherapy with 3 experiencing disease progression.

Conclusions: copy number alterations may serve as potential biomarkers of response to immunotherapy in urothelial carcinoma patients, if validated in larger cohorts.
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http://dx.doi.org/10.3233/blc-201532DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8782437PMC
December 2021

Identification of a Novel Inflamed Tumor Microenvironment Signature as a Predictive Biomarker of Bacillus Calmette-Guérin Immunotherapy in Non-Muscle-Invasive Bladder Cancer.

Clin Cancer Res 2021 08 11;27(16):4599-4609. Epub 2021 Jun 11.

Department of Surgery (Urology Service), Memorial Sloan Kettering Cancer Center, New York, New York.

Purpose: Improved risk stratification and predictive biomarkers of treatment response are needed for non-muscle-invasive bladder cancer (NMIBC). Here we assessed the clinical utility of targeted RNA and DNA molecular profiling in NMIBC.

Experimental Design: Gene expression in NMIBC samples was profiled by NanoString nCounter, an RNA quantification platform, from two independent cohorts ( = 28, = 50); targeted panel sequencing was performed in a subgroup ( = 50). Gene signatures were externally validated using two RNA sequencing datasets of NMIBC tumors ( = 438, = 73). Established molecular subtype classifiers and novel gene expression signatures were assessed for associations with clinicopathologic characteristics, somatic tumor mutations, and treatment outcomes.

Results: Molecular subtypes distinguished between low-grade Ta tumors with FGFR3 mutations and overexpression (UROMOL-class 1) and tumors with more aggressive clinicopathologic characteristics (UROMOL-classes 2 and 3), which were significantly enriched with TERT promoter mutations. However, UROMOL subclasses were not associated with recurrence after bacillus Calmette-Guérin (BCG) immunotherapy in two independent cohorts. In contrast, a novel expression signature of an inflamed tumor microenvironment (TME) was associated with improved recurrence-free survival after BCG. Expression of immune checkpoint genes (PD-L1/PD-1/CTLA-4) was associated with an inflamed TME, but not with higher recurrence rates after BCG. FGFR3 mutations and overexpression were both associated with low immune signatures.

Conclusions: Assessment of the immune TME, rather than molecular subtypes, is a promising predictive biomarker of BCG response. Modulating the TME in an immunologically "cold" tumor warrants further investigation. Integrated transcriptomic and exome sequencing should improve treatment selection in NMIBC.
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http://dx.doi.org/10.1158/1078-0432.CCR-21-0205DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8416390PMC
August 2021

Pathological and oncological outcomes in patients with sarcomatoid differentiation undergoing cystectomy.

BJU Int 2022 04 24;129(4):463-469. Epub 2021 May 24.

Urology Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA.

Objective: To evaluate whether urothelial carcinoma (UC) with sarcomatoid differentiation is associated with a lower pathological response rate to neoadjuvant chemotherapy (NAC) and worse oncological outcomes compared to UC without variant histology among patients undergoing radical cystectomy.

Patients And Methods: Patients with UC undergoing cystectomy from 1995 to 2018 at the Memorial Sloan Kettering Cancer Centre were identified. Patients with sarcomatoid differentiation at transurethral resection (TUR) or cystectomy, and patients without variant histology were selected. Downstaging from ≥cT2 to ≤pT1N0 defined partial response and pT0N0 defined complete response. Recurrence-free, cancer-specific and overall survival were modelled.

Results: We identified 131 patients with sarcomatoid differentiation and 1722 patients without variant histology, of whom 25 with sarcomatoid histology on biopsy and 313 without variant histology received NAC. Those with sarcomatoid differentiation presented with higher consensus tumour stage (94% ≥T2 vs 62%; P < 0.001) and were, therefore, more likely to receive NAC (29% vs 18%; P = 0.003). We found no evidence to support a difference in partial (24% vs 31%) or complete (20% vs 24%) response between patients with sarcomatoid histology and those with pure UC at TUR (P = 0.6). Among patients with sarcomatoid differentiation, 5-year recurrence-free survival was 55% (95% confidence interval [CI] 41-74) among patients receiving NAC and 40% (95% CI 31-52) among patients undergoing cystectomy alone (P = 0.1). Adjusting for stage, nodal involvement, margin status and receipt of NAC, sarcomatoid differentiation was associated with worse recurrence-free (hazard ratio [HR] 1.82, 95% CI 1.39-2.39), disease-specific (HR 1.66, 95% CI 1.23-2.22), and overall survival (HR 1.37, 95% CI 1.06-1.78).

Conclusions: Sarcomatoid differentiation was associated with higher stage at presentation and independently associated with worse survival. Given similar pathological response rates if sarcomatoid differentiation is detected at initial resection, and greater survival among patients receiving NAC, treatment with NAC appears warranted. Other drivers of the poor outcomes of this histology must be investigated.
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http://dx.doi.org/10.1111/bju.15428DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8522172PMC
April 2022

Germ Cell Tumor Molecular Heterogeneity Revealed Through Analysis of Primary and Metastasis Pairs.

JCO Precis Oncol 2020 30;4. Epub 2020 Oct 30.

Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY.

Purpose: Although primary germ cell tumors (GCTs) have been extensively characterized, molecular analysis of metastatic sites has been limited. We performed whole-exome sequencing and targeted next-generation sequencing on paired primary and metastatic GCT samples in a patient cohort enriched for cisplatin-resistant disease.

Patients And Methods: Tissue sequencing was performed on 100 tumor specimens from 50 patients with metastatic GCT, and sequencing of plasma cell-free DNA was performed for a subset of patients.

Results: The mutational landscape of primary and metastatic pairs from GCT patients was highly discordant (68% of all somatic mutations were discordant). Whereas genome duplication was common and highly concordant between primary and metastatic samples, only 25% of primary-metastasis pairs had ≥ 50% concordance at the level of DNA copy number alterations (CNAs). Evolutionary-based analyses revealed that most mutations arose after CNAs at the respective loci in both primary and metastatic samples, with oncogenic mutations enriched in the set of early-occurring mutations versus variants of unknown significance (VUSs). pathway alterations were identified in nine cisplatin-resistant patients and had the highest degree of concordance in primary and metastatic specimens, consistent with their association with this treatment-resistant phenotype.

Conclusion: Analysis of paired primary and metastatic GCT specimens revealed significant molecular heterogeneity for both CNAs and somatic mutations. Among loci demonstrating serial genetic evolution, most somatic mutations arose after CNAs, but oncogenic mutations were enriched in the set of early-occurring mutations as compared with VUSs. Alterations in were clonal when present and shared among primary-metastasis pairs.
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http://dx.doi.org/10.1200/PO.20.00166DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7608584PMC
October 2020

Modeling biological and genetic diversity in upper tract urothelial carcinoma with patient derived xenografts.

Nat Commun 2020 04 24;11(1):1975. Epub 2020 Apr 24.

Urology Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA.

Treatment paradigms for patients with upper tract urothelial carcinoma (UTUC) are typically extrapolated from studies of bladder cancer despite their distinct clinical and molecular characteristics. The advancement of UTUC research is hampered by the lack of disease-specific models. Here, we report the establishment of patient derived xenograft (PDX) and cell line models that reflect the genomic and biological heterogeneity of the human disease. Models demonstrate high genomic concordance with the corresponding patient tumors, with invasive tumors more likely to successfully engraft. Treatment of PDX models with chemotherapy recapitulates responses observed in patients. Analysis of a HER2 S310F-mutant PDX suggests that an antibody drug conjugate targeting HER2 would have superior efficacy versus selective HER2 kinase inhibitors. In sum, the biological and phenotypic concordance between patient and PDXs suggest that these models could facilitate studies of intrinsic and acquired resistance and the development of personalized medicine strategies for UTUC patients.
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http://dx.doi.org/10.1038/s41467-020-15885-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7181640PMC
April 2020

A New Twist to an Old Tale: Immunotherapy in Non-muscle-invasive Bladder Cancer.

Eur Urol Oncol 2018 08 24;1(3):199-201. Epub 2018 Jul 24.

Genitourinary Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Department of Medicine, Weill Cornell Medical College, New York, NY, USA.

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http://dx.doi.org/10.1016/j.euo.2018.07.001DOI Listing
August 2018

Genomic landscape of inverted urothelial papilloma and urothelial papilloma of the bladder.

J Pathol 2019 07 22;248(3):260-265. Epub 2019 Apr 22.

Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.

Inverted urothelial papilloma (IUP) and urothelial papilloma (UP) are rare urothelial neoplasms that typically follow a benign clinical course. Oncogenic mutations in FGFR3, HRAS, and the TERT promoter have been reported in these entities but no comprehensive molecular analysis has been performed. We sought to characterize the genomic landscape of IUP and UP using whole-exome and targeted next-generation sequencing. In IUP, 10 of 11 tumors harbored oncogenic hotspot mutations in HRAS and the remaining tumor had an oncogenic KRAS mutation. None of the IUP tumors harbored TERT promoter or FGFR3 mutations. In UP, 8 of 11 tumors had oncogenic KRAS mutations and two had oncogenic HRAS mutations. One UP tumor had oncogenic mutations in FGFR3, PIK3CA, and the TERT promoter, and arose in a patient with recurrent non-invasive papillary urothelial carcinomas. In contrast to urothelial carcinoma, the APOBEC mutational signature was not present in any IUP and UP tumors, and oncogenic alterations in chromatin remodeling genes were uncommon in both IUP and UP. The current study suggests that IUP and UP are driven primarily by RAS pathway activation and lack the more common genomic features of urothelial cancers. Copyright © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
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http://dx.doi.org/10.1002/path.5261DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6579631PMC
July 2019

Clonal Relatedness and Mutational Differences between Upper Tract and Bladder Urothelial Carcinoma.

Clin Cancer Res 2019 02 23;25(3):967-976. Epub 2018 Oct 23.

Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York.

Purpose: To investigate genomic differences between urothelial carcinomas of the upper tract (UTUC) and bladder (UCB), with a focus on defining the clonal relatedness of temporally distinct tumors.

Experimental Design: We prospectively sequenced tumors and matched germline DNA using targeted next-generation sequencing methods. The cohort included 195 UTUC patients and 454 UCB patients. For a subgroup of 29 patients with UTUC and a history of a subsequent UCB, both tumors were analyzed to assess their clonal relatedness.

Results: With the progression to higher UTUC clinical state, there were fewer alterations in the RTK/RAS pathway but more alterations in TP53/MDM2. Compared with UCB, and were less frequently altered in UTUC (26% vs. 46%, 3% vs. 20%, 8% vs. 19%, respectively; < 0.001), whereas and were more frequently altered (40% vs. 26%, 12% vs. 4%, respectively; < 0.001). On the basis of an integrated analysis of tumor mutational burden, MSIsensor score and mutational signature, 7.2% of UTUC tumors were classified as MSI-high/MMR-deficient (MSI-H/dMMR). The risk of bladder recurrence after UTUC was significantly associated with mutations in and . Comparison of UCB with corresponding UTUC tumors from the same patient supports their clonal relatedness.

Conclusions: UTUC and UCB exhibit significant differences in the prevalence of common genomic alterations. In individual patients with a history of both tumors, UCB and UTUC were always clonally related. Genomic characterization of UTUC provides information regarding the risk of bladder recurrence and can identify tumors associated with Lynch syndrome.
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http://dx.doi.org/10.1158/1078-0432.CCR-18-2039DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6359971PMC
February 2019

Genomic Differences Between "Primary" and "Secondary" Muscle-invasive Bladder Cancer as a Basis for Disparate Outcomes to Cisplatin-based Neoadjuvant Chemotherapy.

Eur Urol 2019 02 2;75(2):231-239. Epub 2018 Oct 2.

Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Genitourinary Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.

Background: Cisplatin-based neoadjuvant chemotherapy (NAC) followed by radical cystectomy (RC) is the standard of care for patients with muscle-invasive bladder cancer (MIBC). It is unknown whether this treatment strategy is appropriate for patients who progress to MIBC after treatment for prior noninvasive disease (secondary MIBC).

Objective: To determine whether clinical and genomic differences exist between primary and secondary MIBC treated with NAC and RC.

Design, Setting, And Participants: Clinicopathologic outcomes were compared between 245 patients with clinical T2-4aN0M0-stage primary MIBC and 43 with secondary MIBC treated with NAC and RC at Memorial Sloan Kettering Cancer Center (MSKCC) from 2001 to 2015. Genomic differences were assessed in a retrospective cohort of 385 prechemotherapy specimens sequenced by whole-exome or targeted exon capture by the Cancer Genome Atlas or at MSKCC. Findings were confirmed in an independent validation cohort of 94 MIBC patients undergoing prospective targeted exon sequencing at MSKCC.

Outcome Measurements And Statistical Analysis: Pathologic response rates, recurrence-free survival (RFS), bladder cancer-specific survival (CSS), and overall survival (OS) were measured. Differences in somatic genomic alteration rates were compared using Fisher's exact test and the Benjamini-Hochberg false discovery rate method.

Results And Limitations: Patients with secondary MIBC had lower pathologic response rates following NAC than those with primary MIBC (univariable: 26% vs 45%, multivariable: odds ratio=0.4 [95% confidence interval=0.18-0.84] p=0.02) and significantly worse RFS, CSS, and OS. Patients with secondary MIBC treated with NAC had worse CSS compared with cystectomy alone (p=0.002). In a separate genomic analysis, we detected significantly more likely deleterious somatic ERCC2 missense mutations in primary MIBC tumors in both the discovery (10.9% [36/330] vs 1.8% [1/55], p=0.04) and the validation (15.7% [12/70] vs 0% [0/24], p=0.03) cohort.

Conclusions: Patients with secondary MIBC treated with NAC had worse clinical outcomes than similarly treated patients with primary MIBC. ERCC2 mutations predicted to result in increased cisplatin sensitivity were enriched in primary versus secondary MIBC. Prospective validation is still needed, but given the lack of clinical benefit with cisplatin-based NAC in patients with secondary MIBC, upfront RC or enrollment in clinical trials should be considered.

Patient Summary: A retrospective cohort study of patients with "primary" and "secondary" muscle-invasive bladder cancer (MIBC) treated with chemotherapy before surgical removal of the bladder identified lower response rates and shorter survival in patients with secondary MIBC. Tumor genetic sequencing of separate discovery and validation cohorts revealed that chemotherapy-sensitizing DNA damage repair gene mutations occur predominantly in primary MIBC tumors and may underlie the greater sensitivity of primary MIBC to chemotherapy. Prospective validation is still needed, but patients with secondary MIBC may derive greater benefit from upfront surgery or enrollment in clinical trials rather than from standard chemotherapy.
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http://dx.doi.org/10.1016/j.eururo.2018.09.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6339572PMC
February 2019

Histologic and Oncologic Outcomes Following Liver Mass Resection With Retroperitoneal Lymph Node Dissection in Patients With Nonseminomatous Germ Cell Tumor.

Urology 2018 Aug 25;118:114-118. Epub 2018 Apr 25.

Urology Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY. Electronic address:

Objective: To evaluate the oncologic outcomes and histologic concordance of postchemotherapy residual liver mass resection with postchemotherapy retroperitoneal lymph node dissection (PC-RPLND).

Methods: Retrospective review of our prospectively maintained germ cell tumor (GCT) surgical database identified patients with nonseminomatous GCT who underwent both postchemotherapy residual liver mass resection and PC-RPLND between 1990 and 2015.

Results: A total of 36 patients were identified, of whom 29 (81%) presented with a liver mass at initial diagnosis and 17 (47%) received second-line chemotherapy before liver resection. Teratoma was found in 8 (22%) and 5 (14%) of PC-RPLND and liver resection specimens, respectively. Viable GCT was found in 5 (14%) and 4 (11%) of PC-RPLND and liver resection specimens, respectively. Histologic discordance was observed in 4 of 19 patients (21%; 95% confidence interval [CI] 6.1%-46%); in all cases, liver resection specimens contained teratoma or viable GCT while PC-RPLND revealed only fibrosis or necrosis. At 3 years after surgical intervention, the Kaplan-Meier estimated probability of cancer-specific survival was 75% (95% CI 55%-85%) and the probability of progression-free survival was 75% (95% CI 56%-87%).

Conclusion: In this contemporary cohort, clinically significant discordance was observed between the histology of metastatic liver masses and that of retroperitoneal lymph nodes. The benefit of postchemotherapy liver mass resection for patients with advanced nonseminomatous GCT is supported by favorable survival outcomes. Until more reliable predictors of postchemotherapy histology exist, complete surgical resection of all sites of residual disease should be performed whenever feasible.
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http://dx.doi.org/10.1016/j.urology.2018.04.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7001858PMC
August 2018

Tumor Evolution and Drug Response in Patient-Derived Organoid Models of Bladder Cancer.

Cell 2018 04;173(2):515-528.e17

Department of Medicine, Columbia University Medical Center, New York, NY 10032, USA; Department of Genetics and Development, Columbia University Medical Center, New York, NY 10032, USA; Department of Urology, Columbia University Medical Center, New York, NY 10032, USA; Department of Systems Biology, Columbia University Medical Center, New York, NY 10032, USA; Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, NY 10032, USA. Electronic address:

Bladder cancer is the fifth most prevalent cancer in the U.S., yet is understudied, and few laboratory models exist that reflect the biology of the human disease. Here, we describe a biobank of patient-derived organoid lines that recapitulates the histopathological and molecular diversity of human bladder cancer. Organoid lines can be established efficiently from patient biopsies acquired before and after disease recurrence and are interconvertible with orthotopic xenografts. Notably, organoid lines often retain parental tumor heterogeneity and exhibit a spectrum of genomic changes that are consistent with tumor evolution in culture. Analyses of drug response using bladder tumor organoids show partial correlations with mutational profiles, as well as changes associated with treatment resistance, and specific responses can be validated using xenografts in vivo. Our studies indicate that patient-derived bladder tumor organoids represent a faithful model system for studying tumor evolution and treatment response in the context of precision cancer medicine.
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http://dx.doi.org/10.1016/j.cell.2018.03.017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5890941PMC
April 2018

Genomic Profile of Urothelial Carcinoma of the Upper Tract from Ureteroscopic Biopsy: Feasibility and Validation Using Matched Radical Nephroureterectomy Specimens.

Eur Urol Focus 2019 05 1;5(3):365-368. Epub 2018 Feb 1.

Department of Surgery, Urology Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA. Electronic address:

Urothelial carcinoma of the upper tract (UTUC) presents specific challenges regarding accurate staging and tumor sampling. We aimed to assess the feasibility of applying next-generation sequencing to biopsy specimens and gauged the concordance of their genetic profiles with matched radical nephroureterectomy (RNU) specimens. Of the 39 biopsy specimens collected, 36 (92%) had adequate material for sequencing using a hybridization-based exon capture assay (MSK-IMPACT). The most frequently altered genes across the patient cohort were consistent with the urothelial carcinoma-associated alterations identified in a cohort of 130 RNU specimens previously sequenced at our center, including mutations in the TERT promoter (64%), hotspot activating mutations in FGFR3 (64%), and frequent mutations in chromatin remodeling genes. For 12 patients, a matching tumor sample from a subsequent RNU was sequenced. We found a high level of concordance between matched biopsy and RNU specimens, up to 92% for the likely pathogenic alterations. PATIENT SUMMARY: We evaluated the feasibility of genomic characterization of tumor tissue collected at the time of ureteroscopic biopsy and found high concordance with subsequent radical nephroureterectomy specimens. Molecular characterization of urothelial carcinoma of the upper tract biopsies could guide treatment decision-making and identify high-risk patients who could benefit from neoadjuvant chemotherapy and low-risk patients who could benefit from conservative or organ-sparing strategies.
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http://dx.doi.org/10.1016/j.euf.2018.01.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7583604PMC
May 2019

Male Neobladder.

Urol Clin North Am 2018 Feb;45(1):37-48

Urology Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA. Electronic address:

Successful outcome with orthotopic neobladders begins in the preoperative phase with appropriate patient selection and extensive patient counseling. Meticulous attention to surgical and oncological principles is required to optimize neobladder outcomes. Long-term follow-up is needed not only for oncological purposes but also to monitor for the late complications, such as ureterointestinal strictures, renal deterioration, infections, and voiding dysfunction.
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http://dx.doi.org/10.1016/j.ucl.2017.09.003DOI Listing
February 2018

Incidence and Effect of Thromboembolic Events in Radical Cystectomy Patients Undergoing Preoperative Chemotherapy for Muscle-invasive Bladder Cancer.

Clin Genitourin Cancer 2017 Aug 10. Epub 2017 Aug 10.

Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY.

Background: We evaluated the incidence and effect of thromboembolic events (TEEs) in patients with muscle-invasive bladder cancer treated with preoperative chemotherapy (POC) and radical cystectomy (RC) with pelvic lymph node dissection (PLND).

Patients And Methods: We performed a retrospective review of all patients who had undergone POC followed by RC plus PLND for muscle-invasive bladder cancer from June 2000 to January 2013 (n = 357). The chemotherapy type (neoadjuvant vs. induction), incidence and timing of TEE diagnosis (preoperatively vs. ≤ 90 days postoperatively), and effect of TEEs on clinical outcomes were recorded.

Results: Overall, 79 patients (22%; 95% confidence interval [CI], 18%-27%) experienced a TEE: 57 (16%) occurred during POC and 22 (6.2%) were diagnosed postoperatively. Forty patients (11%; 95% CI, 8.1%-15%) required an inferior vena cava filter. We found no significant differences in neoadjuvant versus induction chemotherapy and the risk of TEEs (difference, 3.3%; 95% CI, -5% to 12%; P = .5). No significant difference were found in the rates of POC completion according to the presence of a TEE (difference, 1.0%; 95% CI, -11% to 13%; P = .9). The occurrence of TEE did not significantly affect other perioperative outcomes. The risk of recurrence and overall survival were not associated with TEE on multivariable analysis.

Conclusion: We found a high incidence of TEEs (22%) in patients undergoing POC before RC plus PLND, with a 16% incidence in the preoperative period. TEEs in the POC setting leads to invasive procedures; however, we did not find a significant effect on POC completion or postoperative complication risk. Further research is required to determine whether preventative TEE measures during POC can improve clinical outcomes.
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http://dx.doi.org/10.1016/j.clgc.2017.07.022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6053335PMC
August 2017

Prognostic Value of TERT Alterations, Mutational and Copy Number Alterations Burden in Urothelial Carcinoma.

Eur Urol Focus 2019 03 10;5(2):201-204. Epub 2017 Aug 10.

Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA. Electronic address:

Point mutations in the TERT gene promoter occur at high frequency in multiple cancers, including urothelial carcinoma (UC). However, the relationship between TERT promoter mutations and UC patient outcomes is unclear due to conflicting reports in the literature. In this study, we examined the association of TERT alterations, tumor mutational burden per megabase (Mb), and copy number alteration (CNA) burden with clinical parameters and their prognostic value in a cohort of 398 urothelial tumors. The majority of TERT mutations were located at two promoter region hotspots (chromosome 5, 1 295 228 C>T and 1 295 250 C>T). TERT alterations were more frequently present in bladder tumors than in upper tract tumors (73% vs 53%; p=0.001). ARID1A, PIK3CA, RB1, ERCC2, ERBB2, TSC1, CDKN1A, CDKN2A, CDKN2B, and PTPRD alterations showed significant co-occurrence with TERT alterations (all p<0.0025). TERT alterations and the mutational burden/Mb were independently associated with overall survival (hazard ratio[HR] 2.31, 95% confidence interval [CI] 1.46-3.65; p<0.001; and HR 0.96, 95% CI 0.93-0.99; p=0.002), disease-specific survival (HR 2.23, 95% CI 1.41-3.53; p<0.001; and HR 0.96, 95% CI 0.93-0.99; p=0.002), and metastasis-free survival (HR 1.63, 95% CI 1.05-2.53; p=0.029; and HR 0.98, 95% CI 0.96-1.00; p=0.063) in multivariate models. PATIENT SUMMARY: The majority of TERT gene mutations that we detected in urothelial carcinoma are located at two promoter hotspots. Urothelial tumors with TERT alterations had worse prognosis compared to tumors without TERT alterations, whereas tumors with a higher mutational burden had more favorable outcome compared to tumors with low mutational burden.
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http://dx.doi.org/10.1016/j.euf.2017.07.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5809230PMC
March 2019

The Impact of Plasmacytoid Variant Histology on the Survival of Patients with Urothelial Carcinoma of Bladder after Radical Cystectomy.

Eur Urol Focus 2019 01 27;5(1):104-108. Epub 2017 Jun 27.

Urology Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA. Electronic address:

Background: The clinical significance of the plasmacytoid variant (PCV) in urothelial carcinoma (UC) is currently lacking.

Objective: To compare clinical outcomes of patients with any PCV with that of patients with pure UC treated with radical cystectomy (RC).

Design, Setting, And Participants: We identified 98 patients who had pathologically confirmed PCV UC and 1312 patients with pure UC and no variant history who underwent RC at our institution between 1995 and 2014.

Outcome Measurements And Statistical Analysis: Univariable and multivariable Cox regression and Cox proportional hazards regression to determine if PCV was associated with overall survival (OS).

Results And Limitations: Patients with PCV UC were more likely to have advanced tumor stage (p=0.001), positive lymph nodes (p=0.038), and receive neoadjuvant chemotherapy than those with pure UC (46% vs 22%, p<0.0001). The rate of positive soft tissue surgical margins was over five times greater in the PCV UC group compared with the pure UC group (21% vs 4.1%, respectively, p<0.0001). Median OS for the pure UC versus the PCV patients were 8 yr and 3.8 yr, respectively. On univariable analysis, PCV was associated with an increased risk of overall mortality (hazard ratio=1.34, 95% confidence interval: 1.02-1.78, p=0.039). However, on multivariable analysis adjusted for age, sex, neoadjuvant chemotherapy received, lymph node status, pathologic stage, and soft margin status, the association between PCV and OS was no longer significant (hazard ratio=1.06, 95% confidence interval: 0.78, 1.43, p=0.7). This retrospective study is limited by the lack of pathological reanalysis, and the impact of other concurrent mixed histology cannot be determined in this study.

Conclusions: Patients with PCV features have a higher disease burden at RC compared with those with pure UC. However, PCV was not an independent predictor of survival after RC on multivariable analysis, suggesting that PCV histology should not be used as an independent prognostic factor.

Patient Summary: Plasmacytoid urothelial carcinoma is a rare and aggressive form of bladder cancer. Patients with plasmacytoid urothelial carcinoma had worse adverse pathologic features, but this was not associated with worse overall mortality when compared with patients with pure urothelial carcinoma.
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http://dx.doi.org/10.1016/j.euf.2017.06.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6485953PMC
January 2019

Next-generation Sequencing of Nonmuscle Invasive Bladder Cancer Reveals Potential Biomarkers and Rational Therapeutic Targets.

Eur Urol 2017 12 3;72(6):952-959. Epub 2017 Jun 3.

Urology Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA. Electronic address:

Background: Molecular characterization of nonmuscle invasive bladder cancer (NMIBC) may provide a biologic rationale for treatment response and novel therapeutic strategies.

Objective: To identify genetic alterations with potential clinical implications in NMIBC.

Design, Setting, And Participants: Pretreatment index tumors and matched germline DNA from 105 patients with NMIBC on a prospective Institutional Review Board-approved protocol underwent targeted exon sequencing analysis in a Clinical Laboratory Improvement Amendments-certified clinical laboratory.

Outcome Measurements And Statistical Analysis: Comutation patterns and copy number alterations were compared across stage and grade. Associations between genomic alterations and recurrence after intravesical bacillus Calmette-Guérin (BCG) were estimated using Kaplan-Meier and Cox regression analyses.

Results And Limitations: TERT promoter mutations (73%) and chromatin-modifying gene alterations (69%) were highly prevalent across grade and stage, suggesting these events occur early in tumorigenesis. ERBB2 or FGFR3 alterations were present in 57% of high-grade NMIBC tumors in a mutually exclusive pattern. DNA damage repair (DDR) gene alterations were seen in 30% (25/82) of high-grade NMIBC tumors, a rate similar to MIBC, and were associated with a higher mutational burden compared with tumors with intact DDR genes (p<0.001). ARID1A mutations were associated with an increased risk of recurrence after BCG (hazard ratio=3.14, 95% confidence interval: 1.51-6.51, p=0.002).

Conclusions: Next-generation sequencing of treatment-naive index NMIBC tumors demonstrated that the majority of NMIBC tumors had at least one potentially actionable alteration that could serve as a target in rationally designed trials of intravesical or systemic therapy. DDR gene alterations were frequent in high-grade NMIBC and were associated with increased mutational load, which may have therapeutic implications for BCG immunotherapy and ongoing trials of systemic checkpoint inhibitors. ARID1A mutations were associated with an increased risk of recurrence after BCG therapy. Whether ARID1A mutations represent a predictive biomarker of BCG response or are prognostic in NMIBC patients warrants further investigation.

Patient Summary: Analysis of frequently mutated genes in superficial bladder cancer suggests potential targets for personalized treatment and predictors of treatment response, and also may help develop noninvasive tumor detection tests.
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http://dx.doi.org/10.1016/j.eururo.2017.05.032DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6007852PMC
December 2017

The Impact of Blue Light Cystoscopy on the Diagnosis and Treatment of Bladder Cancer.

Authors:
Eugene J Pietzak

Curr Urol Rep 2017 May;18(5):39

Division of Urology, Department of Surgery, University of Pennsylvania Health System, 3rd Floor, West Pavilion, 3400 Civic Center Boulevard, Philadelphia, PA, USA.

Photodynamic diagnostic technique with blue light cystoscopy (BLC) takes advantage of the preferential uptake and accumulation of protoporphyrins in neoplastic tissue which emit a red fluorescence when illuminated with blue light (360-450 nm wavelengths). This allows enhanced visualization of small papillary tumors and flat carcinoma in situ lesions that might have been missed on white light cystoscopy (WLC). There is compelling evidence that the ability of BLC to detect these additional tumors translates into improved recurrence rates compared to WLC. However, the impact of BLC with regard to progression rates and in patients who are managed with intravesical therapy is not yet known. Further work is required to optimize the integration of BLC into clinical practice, but the future for BLC appears promising.
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http://dx.doi.org/10.1007/s11934-017-0685-8DOI Listing
May 2017

Editorial Comment.

Urology 2017 04 26;102:162. Epub 2016 Dec 26.

Division of Urology, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY.

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http://dx.doi.org/10.1016/j.urology.2016.08.064DOI Listing
April 2017

Editorial Comment.

Urology 2017 Jan 7;99:173. Epub 2016 Nov 7.

Division of Urology, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY.

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http://dx.doi.org/10.1016/j.urology.2016.04.062DOI Listing
January 2017

Genetic Determinants of Cisplatin Resistance in Patients With Advanced Germ Cell Tumors.

J Clin Oncol 2016 11 30;34(33):4000-4007. Epub 2016 Sep 30.

Aditya Bagrodia, Byron H. Lee, William Lee, Eugene K. Cha, Gopa Iyer, Eugene J. Pietzak, Sizhi Paul Gao, Emily C. Zabor, Irina Ostrovnaya, Samuel D. Kaffenberger, Aijazuddin Syed, Maria E. Arcila, Raju S. Chaganti, Ritika Kundra, Jana Eng, Joseph Hreiki, Michael F. Berger, Dean F. Bajorin, Manjit S. Bains, Nikolaus Schultz, Victor E. Reuter, Joel Sheinfeld, George J. Bosl, Hikmat A. Al-Ahmadie, David B. Solit, Darren R. Feldman, Memorial Sloan Kettering Cancer Center; John P. Sfakianos, Icahn School of Medicine at Mount Sinai; Gopa Iyer, Michael F. Berger, Dean F. Bajorin, Manjit S. Bains, Victor E. Reuter, Joel Sheinfeld, George J. Bosl, Hikmat A. Al-Ahmadie, David B. Solit, Darren R. Feldman, Weill Cornell Medical College; and Vladimir Vacic, Kanika Arora, Dayna M. Oschwald, New York Genome Center, New York, NY.

Purpose Owing to its exquisite chemotherapy sensitivity, most patients with metastatic germ cell tumors (GCTs) are cured with cisplatin-based chemotherapy. However, up to 30% of patients with advanced GCT exhibit cisplatin resistance, which requires intensive salvage treatment, and have a 50% risk of cancer-related death. To identify a genetic basis for cisplatin resistance, we performed whole-exome and targeted sequencing of cisplatin-sensitive and cisplatin-resistant GCTs. Methods Men with GCT who received a cisplatin-containing chemotherapy regimen and had available tumor tissue were eligible to participate in this study. Whole-exome sequencing or targeted exon-capture-based sequencing was performed on 180 tumors. Patients were categorized as cisplatin sensitive or cisplatin resistant by using a combination of postchemotherapy parameters, including serum tumor marker levels, radiology, and pathology at surgical resection of residual disease. Results TP53 alterations were present exclusively in cisplatin-resistant tumors and were particularly prevalent among primary mediastinal nonseminomas (72%). TP53 pathway alterations including MDM2 amplifications were more common among patients with adverse clinical features, categorized as poor risk according to the International Germ Cell Cancer Collaborative Group (IGCCCG) model. Despite this association, TP53 and MDM2 alterations predicted adverse prognosis independent of the IGCCCG model. Actionable alterations, including novel RAC1 mutations, were detected in 55% of cisplatin-resistant GCTs. Conclusion In GCT, TP53 and MDM2 alterations were associated with cisplatin resistance and inferior outcomes, independent of the IGCCCG model. The finding of frequent TP53 alterations among mediastinal primary nonseminomas may explain the more frequent chemoresistance observed with this tumor subtype. A substantial portion of cisplatin-resistant GCTs harbor actionable alterations, which might respond to targeted therapies. Genomic profiling of patients with advanced GCT could improve current risk stratification and identify novel therapeutic approaches for patients with cisplatin-resistant disease.
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http://dx.doi.org/10.1200/JCO.2016.68.7798DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5477828PMC
November 2016

Neoadjuvant Treatment of High-Risk, Clinically Localized Prostate Cancer Prior to Radical Prostatectomy.

Curr Urol Rep 2016 May;17(5):37

Urology Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY, 10065, USA.

Multimodal strategies combining local and systemic therapy offer the greatest chance of cure for many with men with high-risk prostate cancer who may harbor occult metastatic disease. However, no systemic therapy combined with radical prostatectomy has proven beneficial. This was in part due to a lack of effective systemic agents; however, there have been several advancements in the metastatic and castrate-resistant prostate cancer that might prove beneficial if given earlier in the natural history of the disease. For example, novel hormonal agents have recently been approved for castration-resistant prostate cancer with some early phase II neoadjuvant showing promise. Additionally, combination therapy with docetaxel-based chemohormonal has demonstrated a profound survival benefit in metastatic hormone-naïve patients and might have a role in eliminating pre-existing ADT-resistant tumor cells in the neoadjuvant setting. The Cancer and Leukemia Group B (CALGB)/Alliance 90203 trial has finished accrual and should answer the question as to whether neoadjuvant docetaxel-based chemohormonal therapy provides an advantage over prostatectomy alone. There are also several promising targeted agents and immunotherapies under investigation in phase I/II trials with the potential to provide benefit in the neoadjuvant setting.
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http://dx.doi.org/10.1007/s11934-016-0592-4DOI Listing
May 2016

Simplification of the Fuhrman grading system for renal cell carcinoma.

Can J Urol 2015 Dec;22(6):8069-73

Division of Urology, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania, USA.

Introduction: The Fuhrman grading system (FGS) is the most widely utilized pathological classification and predictor of renal cell carcinoma (RCC) prognosis. The aim of this study was to test the prognostic ability of a simplified two-tier FGS.

Materials And Methods: We reviewed the data of 509 patients with clear cell RCC who underwent radical or partial nephrectomy between January 1994 and April 2007. The conventional four-tier (I, II, III, IV) FGS was compared to a simplified two-tier FGS in which grades I and II were combined (low grade) and grades III and IV were combined (high grade). Cancer-specific survival (CSS) was calculated for each patient. Univariate and multivariate analyses were used in combination with area under the curve (AUC) of receiver operating characteristic curves to compare prognostic accuracies between grading schemes.

Results: Median follow up was 81.6 months. Using the conventional FGS, the 5 year CSS for Fuhrman grades I, II, III, and IV were 74.1%, 76.0%, 57.3%, and 40.7%, respectively (p < 0.001). Using the simplified two-tier FGS, the 5 year CSS for low grade and high grade were 75.5% and 54.7%, respectively (p < 0.001). Both FGSs achieved independent predictor status in multivariate analyses. Prognostic accuracy of multivariate models between the two FGSs had nearly identical AUCs, with a c-statistic of 0.769 and 0.716 for the two-tier and conventional systems, respectively.

Conclusions: Our findings indicate that the simplified FGS performs similarly to the conventional system. The use of this simplified system may promote greater continuity of pathological interpretation as well as provide a more simplified approach for clinician utilization.
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December 2015

Reply.

Urology 2015 Nov 26;86(5):973. Epub 2015 Sep 26.

Division of Urology, Department of Surgery, Hospital of the University of Pennsylvania, Philadelphia, PA.

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http://dx.doi.org/10.1016/j.urology.2015.05.044DOI Listing
November 2015

Single instillation of mitomycin C plus bacillus Calmette-Guérin (BCG) versus BCG alone in high grade non-muscle invasive bladder cancer.

Can J Urol 2015 Aug;22(4):7876-81

Department of Urology, NYU Langone Medical Center, New York, New York, USA.

Introduction: This study sought to determine if the addition of perioperative mitomycin C (MMC) to treatment with bacillus Calmette-Guérin (BCG) after transurethral resection (TURBT) is superior to TURBT plus BCG alone in high grade non-muscle invasive bladder cancer (NMIBC).

Materials And Methods: Data for 719 patients diagnosed with NMIBC at the University of Pennsylvania Health System between 1977 and 2009 was reviewed retrospectively. Of these patients, 120 had high grade disease and were treated with either BCG alone or with a single instillation of 40 mg of MMC perioperatively in addition to BCG and were thus included in our study. The primary endpoints of this study included recurrence-free survival, overall and disease-free survival as assessed via Kaplan-Meier analysis.

Results: Of the 120 patients identified who received treatment for high grade NMIBC, 97 were treated with BCG alone and 23 received a single instillation of perioperative MMC in addition to BCG. There were no statistically significant differences noted in demographic or pathologic variables. Patients were followed for a median of 4.5 years and a maximum of 21.8 years, with no differences demonstrated in recurrence-free survival (p = 0.75), overall survival (p = 0.93) or disease-free survival (p = 0.76). Both lack of lymphovascular invasion and BCG maintenance therapy reached significance as independent predictors of recurrence-free survival (p = 0.19 and p = 0.28).

Conclusions: While our study indicates that perioperative MMC likely offers little benefit in regards to recurrence or survival in high grade NMIBC, at this point in time, a larger scale, randomized, controlled trial is needed to adequately address this question.
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August 2015

Heavy Cigarette Smoking and Aggressive Bladder Cancer at Initial Presentation.

Urology 2015 Nov 17;86(5):968-72. Epub 2015 Jul 17.

Division of Urology, Department of Surgery, Hospital of the University of Pennsylvania, Philadelphia, PA.

Objective: To identify the impact of smoking intensity on tumor characteristics at the time of initial bladder cancer diagnosis.

Methods: We retrospectively reviewed our institution's prospective database of patients diagnosed with bladder cancer from 1987 to 2009. Only patients with urothelial cell carcinoma and recorded tobacco history were included. Patients were stratified by tobacco history into nonsmokers, light smokers (≤ 30 pack-years), and heavy smokers (> 30 pack-years). An additional analysis was performed looking at patients meeting National Lung Cancer Screening Trial (NLCST) criteria (55- to 74-year-old patients with ≥ 30 pack-years smoking history and < 15 years since smoking cessation). Clinicopathologic characteristics of the initial bladder tumor at time of diagnosis were analyzed.

Results: We identified 197 (26.6%) nonsmokers, 251 (33.9%) light smokers, and 292 (39.5%) heavy smokers. Males were more likely to be heavy smokers (44.5% vs 23.6%, P ≤ .01). Compared with nonsmokers and light smokers, the initial tumors in heavy smokers were more likely to be high grade with a more advanced clinical stage. Heavy smokers were more likely to present with muscle-invasive bladder cancer (MIBC) at initial diagnosis. When compared to nonsmokers, the odds ratio for presenting with MIBC was 1.18 (95% confidence interval = 0.68-2.1) for light smokers and 1.38 (95% confidence interval = 1.06-1.8) for heavy smokers. Of 793 patients with adequate information for analysis, 184 (23.2%) met NLCST criteria. Those meeting NLCST criteria were most likely to be male, to present with gross hematuria, and to have initial tumors that were high grade and muscle invasive. NLCST criteria eligibility remained associated with MIBC on multivariate analysis.

Conclusion: Heavy smokers and patients meeting NLCST criteria are more likely to have high-grade tumors with detrusor muscle invasion at initial presentation.
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http://dx.doi.org/10.1016/j.urology.2015.05.040DOI Listing
November 2015
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