Nima Almassi

HSD3B1 and Response to a Nonsteroidal CYP17A1 Inhibitor in Castration-Resistant Prostate Cancer

Importance The HSD3B1 (1245C) germline variant encodes for a gain-of-function missense in 3&bgr;-hydroxysteroid dehydrogenase isoenzyme 1 (3&bgr;HSD1) that results in increased dihydrotestosterone synthesis from extragonadal precursors and is predictive of more rapid progression to castration-resistant prostate cancer (CRPC). Objective To determine whether the HSD3B1 (1245C) genotype is predictive of clinical response to extragonadal androgen ablation with nonsteroidal 17&agr;-hydroxylase/17,20-lyase (CYP17A1) inhibition in men with metastatic CRPC. Design, Setting, and Participants An observational study of men with metastatic CRPC treated with ketoconazole between June 1998 and December 2012 was conducted at the University of California, San Francisco. Exposures Extragonadal androgen ablation with the nonsteroidal CYP17A1 inhibitor ketoconazole among men with metastatic CRPC. Main Outcomes and Measures The primary end points of analysis were duration of ketoconazole therapy and time to disease progression stratified by HSD3B1 genotype. Disease progression was defined as either biochemical or radiographic progression, using the Prostate Cancer Working Group 3 and Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 definitions, respectively. Kaplan-Meier analysis was used to estimate time on therapy and time to disease progression. A log-rank test for trend was used to compare outcomes by HSD3B1 genotype. Results A total of 90 men (median [interquartile range] age, 61.5 [55.3-67.0] years) with metastatic CRPC were included in the analysis, with sufficient data to determine duration of ketoconazole therapy and time to disease progression in 88 and 81 patients, respectively. The median duration of therapy increased with the number of inherited HSD3B1 (1245C) variant alleles: 5.0 months (95% CI, 3.4-10.4) for 0 variant alleles; 7.5 months (95% CI, 4.9-19.2) for 1; and 12.3 months (95% CI, 1.8-not reached) for 2 (overall comparison for trend, P = .01). Median progression-free survival also increased with number of HSD3B1 (1245C) variant alleles inherited: 5.4 months (95% CI, 3.7-7.5) for 0 variant alleles; 9.7 months (95% CI, 5.6-32.9) for 1; and 15.2 months (95% CI, 7.8-not reached) for 2 (overall comparison for trend, P = .03). Conclusions and Relevance Inheritance of the HSD3B1 (1245C) variant allele, which is a predictive biomarker of resistance to castration, is also a predictive biomarker of sensitivity to extragonadal androgen ablation with a nonsteroidal CYP17A1 inhibitor. These findings signal a possible pathway of treatment stratification for patients with prostate cancer.

Intermediate-Term Outcomes for Men with Very Low/Low and Intermediate/High Risk Prostate Cancer Managed by Active Surveillance

Purpose: We compare intermediate term clinical outcomes among men with favorable risk and intermediate/high risk prostate cancer managed by active surveillance. Materials and Methods: A total of 635 men with localized prostate cancer have been on active surveillance since 2002 at a high volume academic hospital in the United States. Median followup is 50.5 months (IQR 31.1–80.3). Time to event analysis was performed for our clinical end points. Results: Of the cohort 117 men (18.4%) had intermediate/high risk disease. Overall 5 and 10‐year all cause survival was 98% and 94%, respectively. Cumulative metastasis‐free survival at 5 and 10 years was 99% and 98%, respectively. To date no cancer specific deaths had been observed. Overall freedom from intervention was 61% and 49% at 5 and 10 years, respectively. Overall cumulative freedom from failure of active surveillance, defined as metastasis or biochemical failure after local therapy with curative intent, was 97% and 91% at 5 and 10 years, respectively. Of the men 21 (9.9%) experienced biochemical failure after deferred treatment and the 5‐year progression‐free probability was 92%. Compared to men with favorable risk disease those with intermediate/high risk cancer experienced no difference in metastases, surveillance failure or curative intervention. However, patients at higher risk were at significantly increased risk for all cause mortality, likely reflecting patient selection factors. These conclusions may be limited by the small number of events and the duration of our study. Conclusions: Patients with localized prostate cancer who are on active surveillance demonstrated a low rate of active surveillance failure, prostate cancer specific mortality and metastases regardless of baseline risk.

Association of HSD3B1 Genotype With Response to Androgen-Deprivation Therapy for Biochemical Recurrence After Radiotherapy for Localized Prostate Cancer.

Importance The variant HSD3B1 (1245C) allele enhances dihydrotestosterone synthesis and predicts resistance to androgen-deprivation therapy (ADT) for biochemically recurrent prostate cancer after prostatectomy and for metastatic disease. Whether this is true after radiotherapy is unknown. Objective To determine whether the HSD3B1 (1245C) allele predicts worse clinical outcomes from ADT for biochemical recurrence after radiotherapy. Design, Setting, and Participants The Prostate Clinical Research Information System at Dana-Farber Cancer Institute was used to identify the study cohort, which included men treated with ADT for biochemical recurrence after primary radiotherapy between 1996 and 2013. We retrospectively determined HSD3B1 genotype. Main Outcomes and Measures Time to progression, time to metastasis, and overall survival according to genotype. Demographic and treatment characteristics were evaluated for confounders. Multivariable analyses were performed to adjust for known prognostic factors. Results A total of 218 eligible men were identified, of whom 213 (98%) were successfully genotyped. Of these, 97 of 213 (46%), 96 of 213 (45%) and 20 of 213 (9%) carried 0, 1, and 2 variant alleles. Overall variant allele frequency was 136 of 426 alleles (32%). Median patient age (interquartile range) was 69 (63-74), 72 (65-78), and 69 (65-77) years for 0, 1, and 2 variant alleles (P = .03). Demographic and treatment factors were otherwise similar. During a median follow-up of 7.9 years, median time to progression was 2.3 years (95% CI, 1.6-3.1 years) with 0 variant alleles, 2.3 years (95% CI, 1.5-3.3 years) with 1 variant allele, and 1.4 years (95% CI, 0.7-3.3 years) with 2 variant alleles (P = .68). Median time to metastasis diminished with the number of variant alleles inherited: 7.4 (95% CI, 6.7-9.7), 5.8 (95% CI, 4.9-6.5), and 4.4 (95% CI, 3.0-5.7) years, with inheritance of 0, 1, and 2 variant alleles, respectively (P = .03). Median OS was 7.7 (95% CI, 6.7-10.3), 6.9 (95% CI, 5.8-8.4), and 7.2 (95% CI, 3.8-7.9) years with inheritance of 0, 1, and 2 variant alleles, respectively (P = .31). On multivariable analysis with 0 variant alleles as the reference, the adjusted hazard ratio for metastasis was 1.19 (95% CI, 0.74-1.92) (P = .48) for 1 variant allele and 2.01 (95% CI, 1.02-3.97) (P = .045) for 2 variant alleles. Multivariable analysis did not demonstrate significant differences in TTP or OS. Conclusions and Relevance In this study, the HSD3B1 (1245C) allele was associated with more rapid development of metastases in men treated with ADT for biochemical recurrence after primary radiation therapy for prostate cancer. Notably, 105 of 213 men (49%) had received prior ADT, and 119 of 213 (56%) received an androgen receptor antagonist during salvage treatment, both of which may attenuate the effect of the variant allele.

Preoperative Prediction and Postoperative Surgeon Assessment of Volume Preservation Associated with Partial Nephrectomy: Comparison with Measured Volume Preservation

OBJECTIVE To evaluate whether surgeons can predict the percent parenchymal mass that will be preserved by partial nephrectomy (PN) based on preoperative imaging, which could have potential utility for preoperative surgical planning and patient counseling. The proportion of preserved viable parenchyma following PN is the primary determinant of functional recovery. However, direct measurement of parenchymal volume preservation (VP) can be complex and time consuming. MATERIALS AND METHODS For patients managed with PN at our institution (2007-2014), we randomly selected 45 with a third in each of low, intermediate, or high R.E.N.A.L. complexity groups. All patients had recorded postoperative surgeon assessment of volume preservation (SAVP) and measured VP based on preoperative or postoperative computed tomography. Nine clinical providers predicted VP based solely on review of preoperative imaging while blinded to SAVP and measured VP. Clinical experience of the providers ranged from medical students to experienced urologic surgeons. RESULTS Median age was 66 years, median tumor size was 4.0 cm, and median R.E.N.A.L. was 8. Median measured VP was 81% (interquartile range of 74-89%). Preoperative prediction of VP correlated poorly with measured VP among the different surgeons (mean correlation coefficient, R = 0.34, range = 0.24-0.40). Surgeon experience provided minimal incremental improvement. Correlation between R.E.N.A.L. and measured VP was also marginal (R = 0.43). In contrast, correlation between postoperative SAVP and measured VP was much more robust (R = 0.75, P <.001). CONCLUSION Preoperative prediction of VP and R.E.N.A.L. score correlated poorly with measured VP for patients managed with PN. In contrast, postoperative SAVP provided a relatively reliable estimate of VP, and should be considered an acceptable substitute in most clinical circumstances.

Comparative Cost-Effectiveness Analysis of Modified 1-Layer versus Formal 2-Layer Vasovasostomy Technique

PURPOSE Approximately 2% to 6% of men undergoing vasectomy will ultimately have it reversed. Cost is a major consideration for patients and providers with regard to vasovasostomy. Opportunities for cost savings for vasectomy reversal lie in the reduction of variable costs, namely operative time and materials used. In this study we determine the cost benefits of a modified 1-layer vasovasostomy compared to a formal 2-layer vasovasostomy. MATERIALS AND METHODS A retrospective analysis was performed of a single surgeon experience of vasectomy reversals performed from 2010 to 2015. The cohort consisted of men who underwent bilateral vasovasostomy using a formal 2-layer or modified 1-layer technique. The primary end points of the analysis were total operative time; number, cost and type of suture used; and patency/postoperative semen analysis. Bivariate analysis was performed for these continuous variables using the Wilcoxon rank test and the chi-square test was used for categorical variables. RESULTS Of the 106 men who underwent bilateral vasovasostomy 81.1% (86) had a formal and 18.9% (20) had a modified 1-layer repair. The modified 1-layer closure resulted in a significantly shorter operative time, lower microsuture cost and lower overall operative cost compared to formal repair (all p <0.05). There were no statistically significant differences in semen parameters between the 2 techniques at the first postoperative visit. CONCLUSIONS The modified 1-layer vasovasostomy resulted in shorter operative times and lower costs compared to formal repair without compromising postoperative patency. In this era of cost containment the modified repair provides the opportunity to perform vasectomy reversal at a lower cost to patients and providers.

Intraoperative Ultrasound-Guided Removal of Retained Mini Sling Anchor Causing Vaginal Pain: A Case Report.

Since the introduction of the tension-free vaginal tape, the surgical management of female stress urinary incontinence has undergone a dramatic shift toward synthetic midurethral slings (MUSs). The evolution of the MUS has led to the development of the single incision mini sling (SIMS), a minimally invasive procedure that can be performed under local anesthesia. Complications arising after SIMS placement parallel those of the traditional MUS, including pelvic pain, dyspareunia, and mesh erosion. The patient in this case presented with persistent pelvic pain due to a retained SIMS anchor after having previously undergone SIMS placement and subsequent transvaginal exploration with mesh removal. We report the use of intraoperative ultrasound for identification and removal of the retained SIMS anchor.

Feasibility of Cisplatin-Based Neoadjuvant Chemotherapy in Muscle-Invasive Bladder Cancer Patients With Diminished Renal Function

Micro‐Abstract A retrospective analysis assessed chemotherapy tolerability and outcomes of patients with glomerular filtration rate (GFR) < 60 mL/min who received cisplatin‐based neoadjuvant chemotherapy for muscle‐invasive bladder cancer. Patients with impaired GFR had more treatment discontinuations and modifications relative to normal GFR patients, but most completed intended treatment cycles. For carefully selected patients with impaired GFR, cisplatin‐based chemotherapy remains a treatment option. Background: Cisplatin‐based neoadjuvant chemotherapy (NAC) before radical cystectomy is the standard of care in muscle‐invasive bladder cancer. There are limited data regarding chemotherapy tolerability and outcomes for patients with low glomerular filtration rate (GFR) who receive cisplatin‐based NAC. Patients and Methods: A retrospective analysis of patients who received cisplatin‐based NAC at Cleveland Clinic (2005‐2016) was undertaken. Patients with pre‐NAC GFR < 60 mL/min by either Cockcroft‐Gault (CG) or Modification of Diet in Renal Disease (MDRD) formula were compared to patients with GFR ≥ 60 mL/min for NAC tolerability, pathologic complete and partial response (pPR), and the ability to undergo radical cystectomy. Results: Thirty patients with low GFR (34‐59 mL/min) and 94 patients with normal GFR (≥ 60 mL/min) were identified. Low GFR patients were older (median, 71 vs. 65 years), but other demographic and transurethral resection of bladder tumor characteristics were comparable. Low GFR patients more frequently had early NAC discontinuation (30% vs. 13%), NAC modifications (delays, dose reduction, or discontinuation, 66% vs. 40%), and cisplatin‐based NAC administered in split doses (37% vs. 16%). No differences in NAC tolerability or outcomes were noted among low GFR patients receiving split‐dose versus standard regimens. No differences were noted between low and normal GFR patients in NAC cycles (median, 3 for each), cystectomy rates (93% for each), time to cystectomy, and GFR change from baseline to after NAC. Pathologic complete response was higher among normal GFR patients (24% vs. 14%). Conclusion: Patients with low GFR had more NAC discontinuations and modifications, but most completed planned NAC cycles. For carefully selected patients with GFR < 60 mL/min, cisplatin‐based NAC remains a treatment option.

Prognostic Significance of a Negative Confirmatory Biopsy on Reclassification Among Men on Active Surveillance

OBJECTIVE To examine the association between absence of disease on confirmatory biopsy and risk of pathologic reclassification in men on active surveillance (AS). MATERIALS AND METHODS Men with grade groups 1 and 2 disease on AS between 2002 and 2015 were identified who received a confirmatory biopsy within 1 year of diagnosis and ≥3 biopsies overall. The primary outcomes were pathologic reclassification by grade (any increase in primary Gleason pattern or Gleason score) or volume (>33% of sampled cores involved or increase in the number of cores with >50% involvement). The effect of a negative confirmatory biopsy survival was evaluated using Kaplan-Meier analysis and a Cox proportional hazards modeling. RESULTS Out of 635 men, 224 met inclusion criteria (median follow-up: 55.8 months). A total of 111 men (49.6%) had a negative confirmatory biopsy. Decreased grade reclassification (69.7% vs 83.9%; P = .01) and volume reclassification (66.3% vs 87.4%; P = .004) was seen at 5 years for men with a negative confirmatory biopsy compared with those with a positive biopsy. On adjusted analysis, a negative confirmatory biopsy was associated with a decreased risk of grade reclassification (hazard ratio, 0.51; 95% confidence interval, 0.28-0.94; P = .03) and volume reclassification (hazard ratio, 0.32; 95% confidence interval, 0.17-0.61; P = .0006) at a median of 4.7 years. CONCLUSION Absence of cancer on the confirmatory biopsy is associated with a significant decrease in rate of grade and volume reclassification among men on AS. This information may be used to better counsel men on AS.

Management of the small renal mass

The increasing use of cross-sectional imaging has led to an increase in the diagnosis of incidental small renal masses (SRMs). About 20% of such masses are benign, while a significant proportion of malignant SRMs demonstrate slow growth kinetics and non-aggressive histologic features. Given these characteristics, lesions that were traditionally treated surgically are increasingly managed with less aggressive approaches. Further contributing to the evolving management paradigm is accumulating evidence supporting the safety of active surveillance and the efficacy of percutaneous renal mass biopsy in guiding management decisions. This review first discusses the epidemiology and diagnostic work-up of SRMs. The available management options are then examined, with emphasis placed on the clinical factors considered in selecting an appropriate approach. The existing evidence and long-term outcomes of each strategy are discussed. Finally, an overview of the current paradigm for the management of a patient with a SRM is provided. The goal is to provide physicians with the necessary understanding to appropriately manage this increasingly common condition.

Management of Challenging Urethro-ileal Anastomosis During Robotic Assisted Radical Cystectomy with Intracorporeal Neobladder Formation

BACKGROUND Robotic assisted radical cystectomy (RARC) is increasingly being adopted, but intracorporeal neobladder formation remains a challenging procedure limited to selected centers. Common challenges with intracorporeal neobladder formation relate to fashioning a tension-free urethro-ileal anastomosis. In this paper, we describe a series of maneuvers to overcome these challenges that we believe will be of great utility to surgeons performing intracorporeal neobladder. OBJECTIVE To describe maneuvers to overcome challenges during intracorporeal urethro-ileal anastomosis formation and to report postoperative outcomes for patients in whom these maneuvers were used. DESIGN, SETTING, AND PARTICIPANTS A retrospective review of medical records of patients who underwent RARC with intracorporeal neobladder performed by one surgeon (G.-P.H.) at our tertiary center from January 2012 to February 2015 in which at least one additional maneuver was required beyond preservation of urethral length, removal of the sigmoid colon from the pelvis, and careful ileal loop selection. The primary end point was 90-d complications. Follow-up ranged from 6 to 36 mo, and 16 patients had at least 1-yr follow-up. SURGICAL PROCEDURE RARC with intracorporeal neobladder formation. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSES Clinical and operative data collected from a prospectively maintained, institutional review board-approved database. Maneuvers used during intracorporeal urethro-ileal anastomosis were recorded. Descriptive statistics were used to evaluate postoperative outcomes. RESULTS AND LIMITATIONS Nineteen patients met the inclusion criteria. Mean operative time was 486 min (standard deviation: 112 min) with median hospitalization of 7 d (interquartile range: 7-9 d). Seven patients (36.8%) experienced a complication, with one (5.3%) major complication thought to be unrelated to surgery. No open conversions were required. There was no 90-d mortality. CONCLUSIONS Our stepwise approach can help overcome challenges of urethro-ileal anastomosis during intracorporeal neobladder formation. PATIENT SUMMARY When performing intracorporeal neobladder formation, challenges are often encountered in fashioning the urethro-ileal anastomosis. We describe a series of maneuvers that, when used in a stepwise manner, help overcome these challenges.