Mark Mann

A Phase I Trial of Intravesical Nanoparticle Albumin-Bound Paclitaxel in the Treatment of Bacillus Calmette-Guérin Refractory Nonmuscle Invasive Bladder Cancer

PURPOSE Up to 50% of patients treated with intravesical agents for high grade nonmuscle invasive bladder cancer will have disease recurrence. Response rates to current second line intravesical therapies are low and for these high risk patients novel agents are necessary. Our previously completed phase I trial showed docetaxel was a safe agent for intravesical use. Nanoparticle albumin-bound paclitaxel (Abraxane®, ABI-007) has been shown to have increased solubility and lower toxicity compared to docetaxel in systemic therapy. Thus, we assessed the dose limiting toxicity and maximum deliverable dose of intravesical nanoparticle albumin-bound paclitaxel. MATERIALS AND METHODS Inclusion criteria for this institutional review board approved phase I trial were recurrent high grade Ta, T1 and Tis transitional cell carcinoma of the bladder for which at least 1 prior standard intravesical regimen failed. Six weekly instillations of nanoparticle albumin-bound paclitaxel were administered with a modified Fibonacci dose escalation model used until the maximum deliverable dose was achieved. The primary end point was dose limiting toxicity and the secondary end point was response rate. RESULTS A total of 18 patients were enrolled in the study. One patient demonstrated measurable systemic absorption after 1 infusion. Grade 1 local toxicities were experienced by 10 (56%) patients with dysuria being the most common, and no grade 2, 3 or 4 drug related local toxicities were encountered. Of the 18 patients 5 (28%) had no evidence of disease at posttreatment evaluation. CONCLUSIONS Intravesical nanoparticle albumin-bound paclitaxel exhibited minimal toxicity and systemic absorption in the first human intravesical phase I trial to our knowledge. A larger phase II study has begun to formally evaluate the activity of this regimen.

Predictive significance of surgical margin status after prostatectomy for prostate cancer during PSA era.

OBJECTIVES The presence of positive surgical margins (PSMs) after prostatectomy for prostate cancer has long been an indicator of poor survival outcomes. However, with the downstaging of cancer occurring in the prostate-specific antigen testing era, we sought to determine whether the risk associated with PSMs retains the same effect on prognosis as before the prostate-specific antigen testing era. METHODS Of the 3460 patients in the Columbia University Urologic Oncology database, 2215 (64%) were identified who had undergone radical prostatectomy from 1991 to 2005 and had sufficient pathologic data to be analyzed and >or=1 year of follow-up. Three epochs were chosen: 1991-1995, 1996-2000, and 2001-2005. RESULTS The median age, preoperative prostate-specific antigen, and Gleason score was 61.6 years, 6 ng/mL, and 7, respectively, and >50% of patients had pathologic Stage T2 disease. On multivariate analysis, PSMs were a risk factor for biochemical failure for each epoch (P < .01). The Walds test indicated that the significance of PSMs had not changed over time (P = .8). The contribution of PSMs to the accuracy of predicting biochemical failure in a multivariate model was found only for the earliest epoch, because it improved the model by 0.15 (95% confidence interval 0.03-0.27). In the second epoch, it was 0.13 (95% confidence interval -0.01 to 0.27), and it was 0.13 for the third (95% confidence interval -0.06 to 0.32). CONCLUSIONS The results of this study suggest that the predictive contribution of PSMs to the accuracy of a multivariate model or nomogram used to predict the outcomes after prostatectomy has decreased during the past 15 years.

Efficacy and Safety of Blue Light Flexible Cystoscopy with Hexaminolevulinate in the Surveillance of Bladder Cancer: A Phase III, Comparative, Multicenter Study

Purpose: We compared blue light flexible cystoscopy with white light flexible cystoscopy for the detection of bladder cancer during surveillance. Materials and Methods: Patients at high risk for recurrence received hexaminolevulinate intravesically before white light flexible cystoscopy and randomization to blue light flexible cystoscopy. All suspicious lesions were documented. Patients with suspicious lesions were referred to the operating room for repeat white and blue light cystoscopy. All suspected lesions were biopsied or resected and specimens were examined by an independent pathology consensus panel. The primary study end point was the proportion of patients with histologically confirmed malignancy detected only with blue light flexible cystoscopy. Additional end points were the false‐positive rate, carcinoma in situ detection and additional tumors detected only with blue light cystoscopy. Results: Following surveillance 103 of the 304 patients were referred, including 63 with confirmed malignancy, of whom 26 had carcinoma in situ. In 13 of the 63 patients (20.6%, 95% CI 11.5–32.7) recurrence was seen only with blue light flexible cystoscopy (p <0.0001). Five of these cases were confirmed as carcinoma in situ. Operating room examination confirmed carcinoma in situ in 26 of 63 patients (41%), which was detected only with blue light cystoscopy in 9 of the 26 (34.6%, 95% CI 17.2–55.7, p <0.0001). Blue light cystoscopy identified additional malignant lesions in 29 of the 63 patients (46%). The false‐positive rate was 9.1% for white and blue light cystoscopy. None of the 12 adverse events during surveillance were serious. Conclusions: Office based blue light flexible cystoscopy significantly improves the detection of patients with recurrent bladder cancer and it is safe when used for surveillance. Blue light cystoscopy in the operating room significantly improves the detection of carcinoma in situ and detects lesions that are missed with white light cystoscopy.

Wolframin gene H611R polymorphism: no direct association with suicidal behavior but possible link to mood disorders.

Wolframin gene polymorphisms, including the H611R polymorphism, are reportedly associated with mood disorders and psychiatric hospitalization, but there is disagreement about the association of this specific variant with suicidality and impulsive traits. This study tested the association of the H611R polymorphism with mood disorders, suicidal behavior, and aggressive-impulsive traits. Two hundred and one subjects with mood disorders and 113 healthy volunteers were genotyped for the H611R polymorphism and underwent structured interviews for diagnosis and clinical ratings. All were Caucasians. The H611R polymorphism was associated with mood disorders but not suicidal behavior, aggressive/impulsive traits or suicidality in first-degree relatives. The HR heterozygote genotype was more frequent in mood disorder (chi(2)=7.505; df=2; p=.023). If this finding will be replicated, the H611R polymorphism may be a possible marker for mood disorders in a psychiatric population, and not just in relatives of Wolfram syndrome probands.

Role of Genetic Testing for Inherited Prostate Cancer Risk: Philadelphia Prostate Cancer Consensus Conference 2017

Purpose Guidelines are limited for genetic testing for prostate cancer (PCA). The goal of this conference was to develop an expert consensus-driven working framework for comprehensive genetic evaluation of inherited PCA in the multigene testing era addressing genetic counseling, testing, and genetically informed management. Methods An expert consensus conference was convened including key stakeholders to address genetic counseling and testing, PCA screening, and management informed by evidence review. Results Consensus was strong that patients should engage in shared decision making for genetic testing. There was strong consensus to test HOXB13 for suspected hereditary PCA, BRCA1/2 for suspected hereditary breast and ovarian cancer, and DNA mismatch repair genes for suspected Lynch syndrome. There was strong consensus to factor BRCA2 mutations into PCA screening discussions. BRCA2 achieved moderate consensus for factoring into early-stage management discussion, with stronger consensus in high-risk/advanced and metastatic setting. Agreement was moderate to test all men with metastatic castration-resistant PCA, regardless of family history, with stronger agreement to test BRCA1/2 and moderate agreement to test ATM to inform prognosis and targeted therapy. Conclusion To our knowledge, this is the first comprehensive, multidisciplinary consensus statement to address a genetic evaluation framework for inherited PCA in the multigene testing era. Future research should focus on developing a working definition of familial PCA for clinical genetic testing, expanding understanding of genetic contribution to aggressive PCA, exploring clinical use of genetic testing for PCA management, genetic testing of African American males, and addressing the value framework of genetic evaluation and testing men at risk for PCA-a clinically heterogeneous disease.

Utilization and Timing of Blood Transfusions Following Open and Robot Assisted Radical Prostatectomy.

INTRODUCTION AND OBJECTIVES Radical prostatectomy (RP) is associated with a high risk of intraoperative blood loss and subsequent blood transfusions. The shift in surgical technique from open radical prostatectomy (ORP) to robot-assisted radical prostatectomy (RARP) has resulted in lower operative blood loss, and reduced the need for transfusions. We analyzed the American College of Surgeons National Surgical Quality Improvement Project (NSQIP) database to compare real-world, contemporary trends in utilization and timing of blood transfusion following ORP and RARP. METHODS We identified men undergoing both RARP and ORP and then queried for patients who received a blood transfusion in the perioperative period. The outcomes of interest were need and timing of perioperative blood transfusion (PBT), which was categorized into early (post-operative day ≤ 1) or late (post-operative day ≥2). Logistic regression analysis was used to identify variables associated with the need and timing for perioperative blood transfusion. RESULTS A total of 16,144 men who underwent RP were identified from 2007-2012. The overall PBT rate was 3.1%. Highest rate of transfusions occurred on day of surgery for patients undergoing ORP, and first postoperative day for patients undergoing RARP. On multivariate analysis significant predictors of blood transfusion included history of bleeding disorder (OR:2.8,p=0.002), preoperative dyspnea (OR:1.7,p=0.03), starting hematocrit < 42% (OR:1.9,p<0.001), open approach (OR:0.09 p<0.001), year of surgery (OR:0.5,p<0.001), resident involvement (OR:1.6,p=0.003), and operative time (OR:4.4,p<0.001). The only predictor of receiving a blood transfusion on POD 2 or later was having the procedure performed through a robot-assisted approach (OR:3.7p<0.001). CONCLUSIONS In this study we found that the rate of perioperative transfusions is lower than previously published. A clear separation in timing of transfusion exists based on the utilized surgical approach. It is prudent that surgeons performing RARP be aware of the low, but present risk of a delayed blood transfusion.

Significant Change in Predicted Risk of Biochemical Recurrence After Radical Prostatectomy More Common in Black Than in White Men

OBJECTIVES To examine by race how frequently the data after radical prostatectomy translates into a substantial change in prognosis. Many nomograms exist to predict the survival outcomes using the pretreatment clinical parameters and post-treatment pathologic parameters. Race might be an important factor affecting their predictive ability. METHODS Kattan nomograms were used to calculate the pretreatment and post-radical prostatectomy 5-year progression-free probability for each patient. The difference between the nomogram scores was used to divide the patients into 3 groups. A decrease in probability of >or=15 percentage points was classified as a significant increase in the probability of recurrence, an increase of >or=15 points was classified as a significant decrease in the probability of recurrence, and an absolute change of <15 points was considered no significant change. RESULTS The data from 1709 (132 black and 1577 white) men were analyzed. Among the black men, 26.5% had an increase in the probability of recurrence, 57.6% had no change, and 15.9% had a decrease in the probability of recurrence. Among the white men, 13.8% had an increase in the probability of recurrence, 64.5% had no change, and 21.7% had a decrease in the probability of recurrence. Black men were twice as likely to have a significant increase in the probability of recurrence postoperatively compared with white men after adjusting for preoperative prostate-specific antigen level, clinical stage, and biopsy Gleason sum (odds ratio 2.0, 95% confidence interval 1.3-3.1, P = .002). CONCLUSIONS These data could assist clinicians when counseling black men regarding their treatment options according to their preoperative risk profile.

Chapter 37 – Posterior Approach to Robotic-Assisted Laparoscopic Radical Prostatectomy

Despite an inauspicious start, minimally invasive radical prostatectomy (MIRP) has become the standard of care over the past 15 years. The path to its popularity has been driven by socioeconomic and cost concerns as well as improved technology. The technique for MIRP has also evolved in approach and outcomes. The initial Montsouris technique for laparoscopic radical prostatectomy reported by Dr Guillonneau and Dr Vallancien demonstrated that MIRP is technically feasible and reproducible. Today, the Montsouris technique they developed remains the basis for the posterior approach to robotic-assisted laparoscopic radical prostatectomy. As technology and surgical skill improved, other approaches, including extraperitoneal dissection, anterior intraperitoneal dissection, and robotic-assisted MIRP became commonplace, with abandonment of the posterior approach in many centers. However, of late, there has been a resurgence in interest and application of the posterior approach to MIRP. At our center, the posterior Montsouris technique has become the preferred approach for MIRP. The essence of this approach is in performing the dissection of the vas deferens and seminal vesicles prior to the development of the space of Retzius. This allows for confidence in controlling the seminal vesicles and vas deferens after the posterior aspect of the bladder neck is incised and thereby removing the risk of blind damage to the rectum searching for those structures behind the posterior aspect of the bladder incision. To begin, one must first identify the peritoneal ridge nearest the recto-vesicle junction to make your incision, dissect out the vas deferens then the seminal vesicles behind them. The next step is to develop Denonvillier’s fascia posteriorly to the prostate until yellow perirectal fat is visible. At this point, attention returns anteriorly where the rest of dissection is performed allowing prostate removal and vesicourethral anastomosis.