Publications by authors named "Bernard H Bochner"

205 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

Uretero-enteric stricture outcomes: secondary analysis of a randomised controlled trial comparing open versus robot-assisted radical cystectomy.

BJU Int 2022 Jun 13. Epub 2022 Jun 13.

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

Objectives: To analyse the risk of uretero-enteric anastomotic stricture in patients randomised to open (ORC) or robot-assisted radical cystectomy (RARC) with extracorporeal urinary diversion.

Patients And Methods: We included 118 patients randomised to RARC (n = 60) or ORC (n = 58) at a single, high-volume institution from March 2010 to April 2013. Urinary diversion was performed by experienced open surgeons. Stricture was defined as non-malignant obstruction on imaging, corroborated by clinical status, and requiring procedural intervention. The risk of stricture within 1 year was compared between groups using Fisher's exact test.

Results: In all, 58 and 60 patients were randomised to RARC and ORC, respectively. We identified five strictures, all in the ORC group. In patients with ≥1 year of follow-up, the increase in risk of stricture from open surgery was 9.3% (95% confidence interval 1.5%, 17%). Of the five strictures, three were managed endoscopically while two required open revision. There was no evidence that perioperative Grade 3-5 complications were associated with development of a stricture (P = 1) and no evidence of a difference in 24-month estimated glomerular filtration rate between arms (P = 0.15).

Conclusions: In this study at a high-volume centre, RARC with extracorporeal urinary diversion achieved excellent ureteric anastomotic outcomes. Purported increased risk of stricture is not a reason to avoid RARC. Future research should examine the impact of different surgical techniques and operator experience on the risk of stricture, especially as more intracorporeal diversions are performed.
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http://dx.doi.org/10.1111/bju.15825DOI Listing
June 2022

Long-term Outcomes of Local and Metastatic Small Cell Carcinoma of the Urinary Bladder and Genomic Analysis of Patients Treated With Neoadjuvant Chemotherapy.

Clin Genitourin Cancer 2022 May 11. Epub 2022 May 11.

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

Introduction: Small cell carcinoma of the bladder (SCCB) is a rare variant of bladder cancer with poor outcomes. We evaluated long-term outcomes of nonmetastatic (M0) and metastatic (M1) SCCB and correlated pathologic response with genomic alterations of patients treated with neoadjuvant chemotherapy (NAC).

Patients And Methods: Clinical history and pathology samples from SCCB patients diagnosed at our institution were reviewed.

Results: One hundred and ninety-nine SCCB patients were identified. (M0: 147 [74%]; M1: 52 [26%]). Among M0 patients, 108 underwent radical cystectomy (RC) (NAC: 71; RC only: 23; adjuvant chemotherapy: 14); 14 received chemoradiotherapy; the rest received chemotherapy alone or no cancer-directed therapy. RC-only patients had a median follow-up of 9.1 years, and median disease-free survival (DFS) and overall survival (OS) were 1.1 and 1.2 years, respectively. NAC patients had pathologic response (
Conclusion: M0 SCCB is chemo-sensitive and patients have excellent long-term survival following response to NAC. Patients with M1 disease have poor survival despite systemic therapy. Loss-of-function mutations of ERCC2 were associated with pathologic complete response to NAC.
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http://dx.doi.org/10.1016/j.clgc.2022.05.005DOI Listing
May 2022

Neoadjuvant Atezolizumab With Gemcitabine and Cisplatin in Patients With Muscle-Invasive Bladder Cancer: A Multicenter, Single-Arm, Phase II Trial.

J Clin Oncol 2022 04 28;40(12):1312-1322. Epub 2022 Jan 28.

Memorial Sloan Kettering Cancer Center, New York, NY.

Purpose: Neoadjuvant gemcitabine and cisplatin (GC) followed by radical cystectomy (RC) is standard for patients with muscle-invasive bladder cancer (MIBC). On the basis of the activity of atezolizumab (A) in metastatic BC, we tested neoadjuvant GC plus A for MIBC.

Methods: Eligible patients with MIBC (cT2-T4aN0M0) received a dose of A, followed 2 weeks later by GC plus A every 21 days for four cycles followed 3 weeks later by a dose of A before RC. The primary end point was non-muscle-invasive downstaging to < pT2N0.

Results: Of 44 enrolled patients, 39 were evaluable. The primary end point was met, with 27 of 39 patients (69%) < pT2N0, including 16 (41%) pT0N0. No patient with < pT2N0 relapsed and four (11%) with ≥ pT2N0 relapsed with a median follow-up of 16.5 months (range: 7.0-33.7 months). One patient refused RC and two developed metastatic disease before RC; all were considered nonresponders. The most common grade 3-4 adverse event (AE) was neutropenia (n = 16; 36%). Grade 3 immune-related AEs occurred in five (11%) patients with two (5%) requiring systemic steroids. The median time from last dose of chemotherapy to surgery was 7.8 weeks (range: 5.1-17 weeks), and no patient failed to undergo RC because of AEs. Four of 39 (10%) patients had programmed death-ligand 1 (PD-L1)-positive tumors and were all < pT2N0. Of the patients with PD-L1 low or negative tumors, 23 of 34 (68%) achieved < pT2N0 and 11 of 34 (32%) were ≥ pT2N0 ( = .3 for association between PD-L1 and < pT2N0).

Conclusion: Neoadjuvant GC plus A is a promising regimen for MIBC and warrants further study. Patients with < pT2N0 experienced improved relapse-free survival. The PD-L1 positivity rate was low compared with published data, which limits conclusions regarding PD-L1 as a predictive biomarker.
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http://dx.doi.org/10.1200/JCO.21.01485DOI Listing
April 2022

Association of Biochemically Verified Post-Diagnosis Smoking and Nonmuscle-Invasive Bladder Cancer Recurrence Risk.

J Urol 2022 06 27;207(6):1200-1206. Epub 2022 Jan 27.

Memorial Sloan Kettering Cancer Center, New York, New York.

Purpose: Our goal was to determine the association between biochemically verified post-diagnosis smoking exposure and nonmuscle-invasive bladder cancer (NMIBC) recurrence risk.

Materials And Methods: We conducted a prospective study of 354 NMIBC patients with a smoking history undergoing care between 2015 and 2018. Patients contributed at least 2 biospecimens during followup which were tested for cotinine to determine biochemically verified post-diagnosis smoking exposure (yes/no). Our primary endpoint was time to first recurrence after study start date. We examined whether post-diagnosis smoking exposure was associated with recurrence risk in multivariable Cox proportional hazards models that accounted for demographics, clinicopathological variables, time since diagnosis and pack-years.

Results: Patients were predominantly White, male and had a median age of 68 years. Most patients had Ta disease (62%) and tumors of high grade (68%). Intravesical bacillus Calmette-Guérin was given to 63% of the cohort. Patients were followed for a median of 3.6 years since study start. Post-diagnosis smoking exposure was detected in 22% of patients, and 38.7% (137) of patients experienced a recurrence during followup. In multivariable models, only bacillus Calmette-Guérin treatment and prior recurrence rate were significantly associated with recurrence. There was no association between post-diagnosis smoking exposure and recurrence risk (HR: 0.73, 95% CI: 0.45-1.20).

Conclusions: In a cohort of patients with predominantly high risk NMIBC, post-diagnosis smoking exposure was not associated with NMIBC recurrence. However, smoking cessation support remains a critical component of cancer care given that the benefits of quitting extend far beyond NMIBC recurrence.
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http://dx.doi.org/10.1097/JU.0000000000002449DOI Listing
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

Health-related Quality of Life for Patients Undergoing Radical Cystectomy: Results of a Large Prospective Cohort.

Eur Urol 2022 Mar 8;81(3):294-304. Epub 2021 Oct 8.

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

Background: Radical cystectomy (RC) has the potential for profound changes to health-related quality of life (HRQOL).

Objective: To evaluate a broad range of HRQOL outcomes in a large RC cohort.

Design, Setting, And Participants: A single-center prospective study enrolled RC patients from 2008 to 2014. We collected 14 separate patient-reported outcome measures at the presurgical visit and at 3, 6, 12, 18, and 24 mo after RC.

Outcome Measurements And Statistical Analysis: To visualize the patterns of recovery over time across domains, we used generalized estimating equations (GEEs) with nonlinear terms. Given substantial differences in patient selection for the type of urinary diversion, we separately modeled longitudinal HRQOL within conduit and continent diversion groups. The mean pre-RC scores were compared to illustrate the baseline HRQOL differences between diversion groups.

Results And Limitations: The analyzed cohort included 411 patients (n = 205 ileal conduit, n = 206 continent diversion). At baseline, patients receiving continent diversion reported better mean physical (p < 0.001), urinary (p = 0.006), and sexual function (p < 0.001), but lower social function (p = 0.015). After RC, GEE modeling showed physical function scores decreasing 5/100 points by 6 mo, and subsequently stabilizing or returning to baseline. By 12 mo, social function improved by 10/100 points among continent diversions, while remaining stable among ileal conduits. Global quality of life exceeded baseline scores by 6 mo. Sexual function scores were low before RC, with limited recovery. Psychosocial domains were stable or improved, except for 10/100-point worsening of body image among ileal conduits.

Conclusions: RC patients reported favorable HRQOL recovery within 24 mo in most areas other than body image (ileal conduits) and sexual function (both). Importantly, large measurable decreases in scores were not reported by 3 mo after RC. These contemporary outcomes and the excellent locoregional control provided by RC further support it as the gold standard therapy for high-risk bladder cancer.

Patient Summary: We review quality of life in the 24 mo following radical cystectomy. Large decreases in health-related quality of life were not reported, with most areas returning to, or exceeding, baseline, except for sexual function and body image.
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http://dx.doi.org/10.1016/j.eururo.2021.09.018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8891075PMC
March 2022

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

Natural history, response to systemic therapy, and genomic landscape of plasmacytoid urothelial carcinoma.

Br J Cancer 2021 03 21;124(7):1214-1221. Epub 2021 Jan 21.

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

Background: Plasmacytoid urothelial carcinoma (PUC) is a rare, aggressive histologic variant of urothelial cancer characterised by a diffuse growth pattern and CDH1 mutation. We studied the efficacy of preoperative platinum-based chemotherapy in nonmetastatic PUC and immune checkpoint inhibitors (ICIs) in advanced PUC.

Methods: Cases of nonmetastatic PUC and advanced PUC treated with ICIs at our institution were identified. Outcomes were compared to those of a published cohort of patients with urothelial carcinoma not otherwise specified.

Results: We identified 81 patients with nonmetastatic PUC. Of the patients with localised disease who underwent neoadjuvant chemotherapy, pathologic complete response and downstaging rates were 12 and 21%, respectively. Pathologic downstaging was not associated with significant improvement in clinical outcomes. Up to 18% of localised disease and 28% of locally advanced cases had unresectable disease at the time of surgery. ICI-treated advanced PUC (N = 21) had progression-free and overall survival of 4.5 and 10.5 months, respectively, and a 38% response rate. FGFR3 and DNA damage response gene alterations were observed in 3 and 15% of cases, respectively.

Conclusions: PUC is associated with high disease burden and poor chemosensitivity. Increased awareness and recognition of this disease variant will allow for new treatment strategies.
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http://dx.doi.org/10.1038/s41416-020-01244-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8007750PMC
March 2021

Examining the Accuracy of Self-Reported Smoking-Related Exposure among Recently Diagnosed Nonmuscle Invasive Bladder Cancer Patients.

J Urol 2021 May 24;205(5):1321-1325. Epub 2020 Dec 24.

Memorial Sloan Kettering Cancer Center, New York, New York.

Purpose: Cigarette smoking is a risk factor for developing nonmuscle invasive bladder cancer, and continued smoking exposure after diagnosis may increase the likelihood of adverse clinical outcomes. We compare self-reported vs biochemically verified nicotine exposure to determine the accuracy of self-report among recently diagnosed nonmuscle invasive bladder cancer patients.

Materials And Methods: This cross-sectional analysis consisted of 517 nonmuscle invasive bladder cancer patients who contributed a urine or saliva specimen the same day as self-reporting their smoking, use of e-cigarettes, nicotine replacement therapy and whether they lived with a smoker. Cotinine, the primary metabolite of nicotine, was used as an objective biomarker of recent nicotine exposure.

Results: The prevalence of high, low and no cotinine exposure was 13%, 54% and 33%, respectively. Overall, 7.3% of patients (38/517) reported being a current cigarette smoker, while 13% (65/517) had cotinine levels consistent with active smoking exposure. Of these 65 patients 27 denied current smoking, resulting in a sensitivity of self-reported current smoking of 58%. After considering other sources of nicotine exposure such as e-cigarettes, cigars, nicotine replacement therapy and living with a smoker, the sensitivity was higher, at 82%. Nearly all patients with low cotinine denied any smoking-related exposure.

Conclusions: Our findings suggest either biochemical verification with cotinine or additional questions about other sources of nicotine are needed to accurately identify nonmuscle invasive bladder cancer patients who have smoking-related exposures. Accurate classification of active and passive smoking exposure is essential to allow clinicians to advise cessation and help researchers estimate the association between post-diagnosis smoking-related exposure and nonmuscle invasive bladder cancer recurrence risk.
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http://dx.doi.org/10.1097/JU.0000000000001571DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9262154PMC
May 2021

Fibroblast Growth Factor Receptor 3 Alteration Status is Associated with Differential Sensitivity to Platinum-based Chemotherapy in Locally Advanced and Metastatic Urothelial Carcinoma.

Eur Urol 2020 12 1;78(6):907-915. Epub 2020 Aug 1.

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

Background: Alterations in fibroblast growth factor receptor 3 (FGFR3) occur in ∼15% of muscle-invasive bladder cancers (MIBCs) and metastatic urothelial carcinomas (mUCs).

Objective: To determine the association between FGFR3 status and response to platinum-based chemotherapy in patients with MIBC or mUC.

Design, Setting, And Participants: The authors conducted a retrospective review and comparison of patients having (1) MIBC treated with neoadjuvant chemotherapy (NAC), (2) mUC treated with first-line platinum-based chemotherapy (M1 cohort), and (3) MIBC who were from The Cancer Genome Atlas (TCGA).

Intervention: Platinum-based chemotherapy.

Outcome Measurements And Statistical Analysis: Pathologic response, recurrence-free (RFS) or progression-free (PFS) survival, and overall survival (OS) were compared between patients with FGFR3 alteration (FGFR3alt) and those without it (FGFR3wild type [FGFR3wt]) in the three cohorts.

Results And Limitations: Nine of 72 NAC patients (13%) had FGFR3alt, of whom none had pathologic complete response and three had residual non-MIBC (carcinoma in situ, n = 1; pT1, n = 2). FGFR3alt was associated with shorter RFS (hazard ratio, 2.74; p = 0.044) but not OS. Among TCGA patients who underwent adjuvant chemotherapy (n = 74), FGFR3alt patients had shorter RFS as well. Conversely, among chemotherapy-naive TCGA patients, FGFR3alt was associated with longer RFS and OS. In the M1 cohort (FGFR3alt, n = 27; FGFR3wt, n = 81), FGFR3alt was associated with higher rates of pulmonary metastases and nonregional lymphadenopathy. Despite lower response rates among FGFR3alt patients (37% vs 49%; p = 0.056), PFS and OS were not significantly different from FGFR3wt patients.

Conclusions: FGFR3 status is associated with lower responses to platinum-based chemotherapy, which may prompt exploration of nonchemotherapeutic approaches for perioperative management of FGFR3alt urothelial cancers.

Patient Summary: Approximately 15% of bladder cancers harbor mutations in the fibroblast growth factor receptor 3 (FGFR3) gene. Our findings suggest that FGFR3 mutations might be associated with lower responses and shorter time to recurrence among patients with muscle-invasive bladder cancer who received perioperative platinum-based chemotherapy. FGFR3 status does not significantly impact response to chemotherapy among those with metastatic urothelial cancers.
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http://dx.doi.org/10.1016/j.eururo.2020.07.018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8215618PMC
December 2020

Reply by Authors.

J Urol 2020 10 23;204(4):684. Epub 2020 Jul 23.

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

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http://dx.doi.org/10.1097/JU.0000000000001071.03DOI Listing
October 2020

Reply by Authors.

J Urol 2020 08 8;204(2):259. Epub 2020 Jul 8.

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

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http://dx.doi.org/10.1097/JU.0000000000001006.02DOI Listing
August 2020

Goal-directed versus Standard Fluid Therapy to Decrease Ileus after Open Radical Cystectomy: A Prospective Randomized Controlled Trial.

Anesthesiology 2020 08;133(2):293-303

From the Department of Anesthesiology and Critical Care Medicine, Anesthesiology Service (V.A.-C., A.C.P., M.F.) the Department of Epidemiology and Biostatistics (K.S.T.) the Department of Surgery, Urology Service (G.D., H.W.H., B.H.B., E.K.C., T.F.D., S.M.D.), Memorial Sloan Kettering Cancer Center, New York, New York the Departments of Urology (G.D., H.W.H., B.H.B., E.K.C., S.M.D.) Anesthesiology (A.C.P., M.F.), Weill Cornell Medical College, New York, New York.

Background: Postoperative ileus is a common complication of intraabdominal surgeries, including radical cystectomy with reported rates as high as 32%. Perioperative fluid administration has been associated with improvement in postoperative ileus rates, but it is difficult to generalize because earlier studies lacked standardized definitions of postoperative ileus and other relevant outcomes. The hypothesis was that targeted individualized perioperative fluid management would improve postoperative ileus in patients receiving radical cystectomy.

Methods: This is a parallel-arm, double-blinded, single-center randomized trial of goal-directed fluid therapy versus standard fluid therapy for patients undergoing open radical cystectomy. The primary outcome was postoperative ileus, and the secondary outcome was complications within 30 days post-surgery. Participants were at least 21 yr old, had a maximum body mass index of 45 kg/m and no active atrial fibrillation. The intervention in the goal-directed therapy arm combined preoperative and postoperative stroke volume optimization and intraoperative stroke volume variation minimization to guide fluid administration, using advanced hemodynamic monitoring.

Results: Between August 2014 and April 2018, 283 radical cystectomy patients (142 goal-directed fluid therapy and 141 standard fluid therapy) were included in the analysis. Postoperative ileus occurred in 25% (36 of 142) of patients in the goal-directed fluid therapy arm and 21% (30 of 141) of patients in the standard arm (difference in proportions, 4.1%; 95% CI, -5.8 to 13.9; P = 0.418). There was no difference in incidence of high-grade complications between the two arms (20 of 142 [14%] vs. 23 of 141 [16%]; difference in proportions, -2.2%; 95% CI, -10.6 to 6.1; P = 0.602), with the exception of acute kidney injury, which was more frequent in the goal-directed fluid therapy arm (56% [80 of 142] vs. 40% [56 of 141] in the standard arm; difference in proportions, 16.6%; 95% CI, 5.1 to 28.1; P = 0.005; P = 0.170 after adjustment for multiple testing).

Conclusions: Goal-directed fluid therapy may not be an effective strategy for lowering the risk of postoperative ileus in patients undergoing open radical cystectomy.
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http://dx.doi.org/10.1097/ALN.0000000000003367DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8320377PMC
August 2020

Primary urethral cancer: treatment patterns and associated outcomes.

BJU Int 2020 09 4;126(3):359-366. Epub 2020 Jun 4.

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

Objectives: To evaluate treatment patterns and associated outcomes of patients with urethral cancer.

Patients And Methods: After obtaining institutional review board approval we identified 165 patients treated for primary urethral cancer between 1956 and 2017. Treatment included monotherapy (surgery or radiation), dual therapy (surgery+radiation, surgery+chemotherapy, or chemotherapy+radiation) or triple therapy (surgery+radiation+chemotherapy). Rates of different treatments were described by treatment year. The association between treatment type and outcomes was evaluated with multivariable Cox regression models, adjusting for disease characteristics.

Results: The study cohort included 74 men and 91 women, with a median age of 61 years. Common histologies were squamous cell (36%), urothelial (27%) and adenocarcinoma (25%). At presentation, 72% of patients had invasive disease, 24% had nodal involvement, and 5% had metastases. Treatment included monotherapy (57%), dual therapy (21%), and triple therapy (10%). The use of monotherapy decreased over time, while rates of dual therapy remained consistent, and rates of triple therapy increased. The median follow-up was 4.7 years. Estimated 5-year local recurrence-free, disease-specific and overall survival were 51%, 48% and 41%, respectively. Monotherapy was associated with decreased local recurrence-free survival after adjusting for stage, histology, sex and year of treatment (P = 0.017). There was no evidence that treatment type was associated with distant recurrence, cancer-specific or overall survival.

Conclusions: We found preliminary evidence that multimodal therapy, more commonly used in recent years, was of benefit in patients with primary urethral cancer. This finding should be confirmed in further studies involving multiple centres because of the low incidence of the disease.
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http://dx.doi.org/10.1111/bju.15095DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7483343PMC
September 2020

Trends in Management and Outcomes among Patients with Urothelial Carcinoma Undergoing Radical Cystectomy from 1995 to 2015: The Memorial Sloan Kettering Experience.

J Urol 2020 10 15;204(4):677-684. Epub 2020 Apr 15.

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

Purpose: We evaluated trends in oncologic characteristics and outcomes as well as perioperative management among patients undergoing radical cystectomy at Memorial Sloan Kettering from 1995 to 2015.

Materials And Methods: We retrospectively reviewed our institutional database to analyze changes in disease recurrence probability, cancer specific and all cause mortality, incidence of muscle invasive bladder cancer, use of perioperative chemotherapy, rate of positive soft tissue surgical margins and lymph node yield.

Results: In 2,740 patients with nonmetastatic urothelial carcinoma undergoing radical cystectomy from 1995 to 2015 the 5-year probability of disease recurrence decreased from a peak of 42% in 1997 to 34% in 2013 (p=0.045), while the 5-year probability of cancer specific mortality likewise declined from 36% in 1997 to 24% in 2013 (p=0.009). The incidence of nonmuscle invasive disease before radical cystectomy did not change, comprising 30% to 35% of patients across the study period. Use of neoadjuvant chemotherapy rose significantly as 57% of patients with muscle invasive bladder cancer from 2010 to 2015 received it. We observed a corresponding rise in complete pathological response (pT0) at radical cystectomy, as well as decreasing positive soft tissue surgical margins (10% to 2.5%) and rising lymph node yield (7 to 24) from 1995 to 2015.

Conclusions: During a 21-year period outcomes after radical cystectomy at our institution improved significantly, as the probability of recurrence and cancer specific mortality decreased. Increasing use of neoadjuvant chemotherapy, rising pT0 rates, decreased positive soft tissue surgical margins and increasing lymph node yields likely contributed, suggesting that optimized surgical and perioperative care led to improved cancer outcomes in patients undergoing radical cystectomy.
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http://dx.doi.org/10.1097/JU.0000000000001071DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7483392PMC
October 2020

Neoadjuvant Gemcitabine-Cisplatin Plus Radical Cystectomy-Pelvic Lymph Node Dissection for Muscle-invasive Bladder Cancer: A 12-year Experience.

Clin Genitourin Cancer 2020 10 6;18(5):387-394. Epub 2020 Mar 6.

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

Introduction: The aim of this study was to determine drug delivery/toxicity, and pathologic/surgical outcomes of patients with muscle-invasive bladder cancer (MIBC) receiving neoadjuvant gemcitabine-cisplatin (GC) plus radical cystectomy-pelvic lymph node dissection (RC-PLND).

Patients And Methods: Chemotherapy and surgical/pathologic outcomes were retrospectively analyzed with 5-year survival follow-up at a referral center. Post-neoadjuvant chemotherapy (NAC) pathologic endpoints included complete response (pT0N0), residual non-MIBC (pTa/Tis/T1N0), and ≥ MIBC (≥ pT2 and/or N+). Associations of pathologic/surgical findings with overall survival (OS), disease-free survival (DFS), and surgical management with RC-PLND were analyzed (Cox regression).

Results: Clinical T2a-T4aN0M0 MIBC patients (n = 154) from January 2000-October 2012 received GC plus RC-PLND. Patients (n = 117; 76%) received GC × 4 and 136 (88%) GC × 3. Five-year OS was 61% (95% confidence interval [CI], 53-71). Median number of resected lymph nodes (LNs) was 19. Down-staging was observed as follows: pT0N0: 21%; pTa/Tis/T1N0: 25%, with similar 5-year OS (85% and 89%, respectively). Five-year OS for < pT2 versus ≥ pT2 residual disease was 87% (95% CI, 78%-98%) versus 38% (95% CI, 27%-53%); P < .001. Post-NAC stage ≥ pT2 (HR, 6.79; 95% CI, 2.63-17.53; P < .001), positive LN (HR, 3.64; 95% CI, 1.84-7.19; P < .001), and positive margins (HR, 4.15; 95% CI, 1.68-10.25; P = .002) were associated with increased risk of all-cause death (multivariable analysis). An HR of 0.97 (95% CI, 0.94-1.00) was observed for each additional node removed, but this effect was not statistically significant (P = .056).

Conclusions: Neoadjuvant GC achieves meaningful pathologic responses. Patients with ≥ pT2 residual disease, positive margins, or positive LN post-chemotherapy have inferior survival.
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http://dx.doi.org/10.1016/j.clgc.2020.02.014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8375301PMC
October 2020

Late Recurrences Following Radical Cystectomy Have Distinct Prognostic and Management Considerations.

J Urol 2020 09 7;204(3):460-465. Epub 2020 Apr 7.

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

Purpose: Disease recurrence after radical cystectomy generally occurs within 2 years and has a poor prognosis. Less well defined are the outcomes in patients who experience a late recurrence (more than 3 years after radical cystectomy). We report our institutional experience with late recurrences and describe the relationships between time to recurrence, management strategies and survival.

Materials And Methods: The study cohort comprised 2,315 patients who underwent radical cystectomy for urothelial carcinoma at our center between 2000 and 2014, of whom 617 had a recurrence. Median followup for survivors was 2.6 years after recurrence (IQR 0.95-4.5). For the study we considered disease recurrence as recurrences outside the urinary tract. We compared baseline characteristics and post-recurrence management between those with recurrence 3 or less and more than 3 years after radical cystectomy.

Results: A total of 58 patients with late recurrence had significantly lower consensus T stage and lower frequency of nodal involvement. The average 1-year bladder cancer death rate from the time of recurrence declined from 66% to 50% to 33% for patients with recurrence times of 6 months, 2 years, and 5 years after radical cystectomy, respectively. For patients who survived at least 1 year after recurrence, the estimated survival at 5 years after recurrence was 45% for those with late recurrence and 21% for patients who had an early recurrence. Local consolidative therapy (metastasectomy or radiation) was more common in patients with late recurrence (19% vs 3.6%, p <0.0001). Cancer specific survival in early recurring cases was significantly worse than in late recurring cases in the subset receiving local consolidation (p=0.02).

Conclusions: The prolonged lifespan of patients experiencing a late recurrence after radical cystectomy can be leveraged to individualize management. There is strong rationale for investigating the role of metastasectomy in the management of late recurrences.
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http://dx.doi.org/10.1097/JU.0000000000001028DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8532564PMC
September 2020

Diagnostic Performance of Vesical Imaging Reporting and Data System for the Prediction of Muscle-invasive Bladder Cancer: A Systematic Review and Meta-analysis.

Eur Urol Oncol 2020 06 19;3(3):306-315. Epub 2020 Mar 19.

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

Context: A noninvasive multiparametric magnetic resonance imaging (MRI)-based scoring system for predicting muscle-invasive bladder cancer (MIBC), the "Vesical Imaging Reporting and Data System" (VI-RADS), was recently developed by an international multidisciplinary panel. Since then, a few studies evaluating the value of VI-RADS for predicting MIBC have been published.

Objective: To review the diagnostic performance of VI-RADS for the prediction of MIBC.

Evidence Acquisition: PubMed and EMBASE databases were searched up to November 10, 2019. We included diagnostic accuracy studies using VI-RADS to predict MIBC using cystectomy or transurethral resection as the reference standard. Methodological quality was evaluated with Quality Assessment of Diagnostic Accuracy Studies-2. Sensitivity and specificity were pooled and plotted using hierarchical summary receiver operating characteristics (HSROC) modeling. Meta-regression analyses were done to explore heterogeneity.

Evidence Synthesis: Six studies (1770 patients) were included. Pooled sensitivity and specificity were 0.83 (95% confidence interval [CI] 0.70-0.90) and 0.90 (95% CI 0.83-0.95), and the area under the HSROC curve was 0.94 (95% CI 0.91-0.95). Heterogeneity was present among the studies (Q = 29.442, p <  0.01; I = 87.93%, and 90.99% for sensitivity and specificity). Meta-regression analyses showed that the number of patients (>205 vs ≤205), magnetic field strength (3 vs 1.5 T), T2-weighted image slice thickness (3 vs 4 mm), and VI-RADS cutoff score (≥3 vs ≥4) were significant factors affecting heterogeneity (p ≤  0.03).

Conclusions: VI-RADS shows good sensitivity and specificity for determining MIBC. Technical factors associated with MRI acquisition and cutoff scores need to be taken into consideration as they may affect performance.

Patient Summary: A recently established noninvasive magnetic resonance imaging-based scoring system shows good diagnostic performance in detecting muscle-invasive bladder cancer.
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http://dx.doi.org/10.1016/j.euo.2020.02.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7293940PMC
June 2020

Ileal conduit or orthotopic neobladder: selection and contemporary patterns of use.

Curr Opin Urol 2020 05;30(3):415-420

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

Purpose Of Review: The orthotopic neobladder and ileal conduit are the two most commonly utilized urinary diversions among patients undergoing radical cystectomy. Although orthotopic diversion offers several advantages, only 20% of patients nationally receive this diversion, with decreasing utilization over time. The purpose of this article is to review advantages of each diversion type and considerations in patient selection, review trends in diversion utilization and perioperative and functional outcomes, and examine recent studies evaluating methods of optimizing diversion selection and patient satisfaction and outcomes.

Recent Findings: Decreasing utilization of orthotopic diversion has coincided with the increasing utilization of minimally invasive surgical techniques. A multicentre robotic series demonstrated a higher incidence of high-grade complications with intracorporeal diversion, reflecting the learning-curve associated with this technique. Patient satisfaction with urinary diversion is associated with informed decision-making and goal alignment. Ongoing quality of life studies is aiming to identify predictors of patient satisfaction with the selected urinary diversion and may help guide patient counselling.

Summary: Given the potential advantages of orthotopic diversion, its decreasing use is a concerning trend. Elucidating patient goals and informed decision-making are critical to patient satisfaction. A patient-centred approach should be used when selecting the type of urinary diversion for a given patient.
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http://dx.doi.org/10.1097/MOU.0000000000000738DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8261790PMC
May 2020

Utility of Routine Preoperative F-Fluorodeoxyglucose Positron Emission Tomography/Computerized Tomography in Identifying Pathological Lymph Node Metastases at Radical Cystectomy.

J Urol 2020 Aug 5;204(2):254-259. Epub 2020 Mar 5.

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

Purpose: We determined the diagnostic performance of F-FDG (fluorodeoxyglucose) positron emission tomography/computerized tomography for detecting nodal metastases in patients with muscle invasive urothelial bladder cancer before radical cystectomy.

Materials And Methods: Preoperative F-FDG positron emission tomography/computerized tomography scans (208) were retrospectively reviewed. Scans were routinely performed in 185 patients with muscle invasive urothelial bladder cancer between August 2012 and February 2017, all of whom underwent radical cystectomy and pelvic lymph node dissection. Analyses were stratified by clinical node involvement and chemotherapy status. The diagnostic performance of F-FDG positron emission tomography/computerized tomography was assessed according to sensitivity, specificity, positive predictive value and negative predictive value.

Results: Lymph node metastases at time of pelvic lymph node dissection were present in 21.8% of those without suspicious nodes on computerized tomography (clinically node negative) and 52.6% of those with suspicious nodes on computerized tomography (clinically node positive). Median metastatic focus size was 5 mm. In clinically node negative cases F-FDG positron emission tomography/computerized tomography rarely detected nodal metastases (sensitivity 7% to 23%). In clinically node positive cases negative F-FDG positron emission tomography/computerized tomography was useful in ruling out lymph node metastases (sensitivity 92% to 100%). This study was limited by its mixed population and focus on pelvic nodal metastases only.

Conclusions: F-FDG positron emission tomography/computerized tomography appears to be most useful for better characterization of enlarged nodes identified by computerized tomography. Routine preoperative F-FDG positron emission tomography/computerized tomography has limited utility in clinically node negative cases.
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http://dx.doi.org/10.1097/JU.0000000000001006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8477436PMC
August 2020
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