Thenappan Chandrasekar

Mechanisms of resistance in castration-resistant prostate cancer (CRPC).

Despite advances in prostate cancer diagnosis and management, morbidity from prostate cancer remains high. Approximately 20% of men present with advanced or metastatic disease, while 29,000 men continue to die of prostate cancer each year. Androgen deprivation therapy (ADT) has been the standard of care for initial management of advanced or metastatic prostate cancer since Huggins and Hodges first introduced the concept of androgen-dependence in 1972, but progression to castration-resistant prostate cancer (CRPC) occurs within 2-3 years of initiation of ADT. CRPC, previously defined as hormone-refractory prostate cancer, is now understood to still be androgen dependent. Multiple mechanisms of resistance help contribute to the progression to castration resistant disease, and the androgen receptor (AR) remains an important driver in this progression. These mechanisms include AR amplification and hypersensitivity, AR mutations leading to promiscuity, mutations in coactivators/corepressors, androgen-independent AR activation, and intratumoral and alternative androgen production. More recently, identification of AR variants (ARVs) has been established as another mechanism of progression to CRPC. Docetaxel chemotherapy has historically been the first-line treatment for CRPC, but in recent years, newer agents have been introduced that target some of these mechanisms of resistance, thereby providing additional survival benefit. These include AR signaling inhibitors such as enzalutamide (Xtandi, ENZA, MDV-3100) and CYP17A1 inhibitors such as abiraterone acetate (Zytiga). Ultimately, these agents will also fail to suppress CRPC. While some of the mechanisms by which these agents fail are unique, many share similarities to the mechanisms contributing to CRPC progression. Understanding these mechanisms of resistance to ADT and currently approved CRPC treatments will help guide future research into targeted therapies.

Targeting molecular resistance in castration-resistant prostate cancer.

Multiple mechanisms of resistance contribute to the inevitable progression of hormone-sensitive prostate cancer to castration-resistant prostate cancer (CRPC). Currently approved therapies for CRPC include systemic chemotherapy (docetaxel and cabazitaxel) and agents targeting the resistance pathways leading to CRPC, including enzalutamide and abiraterone. While there is significant survival benefit, primary and secondary resistance to these therapies develops rapidly. Up to one-third of patients have primary resistance to enzalutamide and abiraterone; the remaining patients eventually progress on treatment. Understanding the mechanisms of resistance resulting in progression as well as identifying new targetable pathways remains the focus of current prostate cancer research. We review current knowledge of mechanisms of resistance to the currently approved treatments, development of adjunctive therapies, and identification of new pathways being targeted for therapeutic purposes.

Impact of Synchronous Metastasis Distribution on Cancer Specific Survival in Renal Cell Carcinoma after Radical Nephrectomy with Tumor Thrombectomy

PURPOSEnMetastatic renal cell carcinoma can be clinically diverse in terms of the pattern of metastatic disease and response to treatment. We studied the impact of metastasis and location on cancer specific survival.nnnMATERIALS AND METHODSnThe records of 2,017 patients with renal cell cancer and tumor thrombus who underwent radical nephrectomy and tumor thrombectomy from 1971 to 2012 at 22 centers in the United States and Europe were analyzed. Number and location of synchronous metastases were compared with respect to patient cancer specific survival. Multivariable Cox regression models were used to quantify the impact of covariates.nnnRESULTSnLymph node metastasis (155) or distant metastasis (725) was present in 880 (44%) patients. Of the patients with distant disease 385 (53%) had an isolated metastasis. The 5-year cancer specific survival was 51.3% (95% CI 48.6-53.9) for the entire group. On univariable analysis patients with isolated lymph node metastasis had a significantly worse cancer specific survival than those with a solitary distant metastasis. The location of distant metastasis did not have any significant effect on cancer specific survival. On multivariable analysis the presence of lymph node metastasis, isolated distant metastasis and multiple distant metastases were independently associated with cancer specific survival. Moreover higher tumor thrombus level, papillary histology and the use of postoperative systemic therapy were independently associated with worse cancer specific survival.nnnCONCLUSIONSnIn our multi-institutional series of patients with renal cell cancer who underwent radical nephrectomy and tumor thrombectomy, almost half of the patients had synchronous lymph node or distant organ metastasis. Survival was superior in patients with solitary distant metastasis compared to isolated lymph node disease.

Cardiopulmonary Bypass has No Significant Impact on Survival in Patients Undergoing Nephrectomy and Level III-IV Inferior Vena Cava Thrombectomy: Multi-Institutional Analysis

PURPOSEnThe impact of cardiopulmonary bypass in level III-IV tumor thrombectomy on surgical and oncologic outcomes is unknown. We determine the impact of cardiopulmonary bypass on overall and cancer specific survival, as well as surgical complication rates and immediate outcomes in patients undergoing nephrectomy and level III-IV tumor thrombectomy with or without cardiopulmonary bypass.nnnMATERIALS AND METHODSnWe retrospectively analyzed 362 patients with renal cell cancer and with level III or IV tumor thrombus from 1992 to 2012 at 22 U.S. and European centers. Cox proportional hazards models were used to compare overall and cancer specific survival between patients with and without cardiopulmonary bypass. Perioperative mortality and complication rates were assessed using logistic regression analyses.nnnRESULTSnMedian overall survival was 24.6 months in noncardiopulmonary bypass cases and 26.6 months in cardiopulmonary bypass cases. Overall survival and cancer specific survival did not differ significantly in both groups on univariate analysis or when adjusting for known risk factors. On multivariate analysis no significant differences were seen in hospital length of stay, Clavien 1-4 complication rate, intraoperative or 30-day mortality and cancer specific survival. Limitations include the retrospective nature of the study.nnnCONCLUSIONSnIn our multi-institutional analysis the use of cardiopulmonary bypass did not significantly impact cancer specific survival or overall survival in patients undergoing nephrectomy and level III or IV tumor thrombectomy. Neither approach was independently associated with increased mortality on multivariate analysis. Greater surgical complications were not independently associated with the use of cardiopulmonary bypass.

The effect of BMI on clinicopathologic and functional outcomes after open radical prostatectomy

OBJECTIVESnTo analyze the effect of body mass index (BMI) on pathologic and functional outcomes after open radical retropubic prostatectomy.nnnPATIENTS AND METHODSnWe retrospectively analyzed 2,471 patients who underwent RP. Clinicopathologic and patient characteristics were compared with respect to patients BMI (normal weight: BMI < 25 kg/m(2) [n = 795], overweight: BMI ≥ 25 kg/m(2) and < 30 kg/m(2) [n = 1305], and obese: BMI ≥ 30 kg/m(2) [n = 371]). Multivariable logistic and linear regression models were used to quantify the effect of BMI on pathologic and functional outcomes.nnnRESULTSnCompared with normal weight patients, overweight and obese patients demonstrated higher pathologic Gleason grade and higher pathologic T stage, without any difference in preoperative prostate-specific antigen levels. Overweight and obese men were less likely to have a negative surgical margin (odds ratio (OR) 0.74 [confidence interval (CI) 0.65-0.84, P<0.001] for overweight men and OR 0.66 [CI 0.49-0.89, P<0.01] for obese men) and had a lower rate of postoperative erectile function (OR 0.60 [CI 0.48-0.76, P<0.001] for overweight patients and OR 0.34 [CI 0.27-0.44, P<0.001] for obese patients). Moreover, duration of surgery and intraoperative blood loss increased significantly with an increase in BMI. When using BMI as a continuous variable, the same trends were demonstrated. However, a lower rate of continence was not evident for overweight or obese men.nnnCONCLUSIONSnIn contrast to many other studies, in this cohort of patients with prostate cancer, BMI was an independent risk factor for most analyzed pathologic and functional outcomes after radical prostatectomy, including negative surgical margin, potency, duration of surgery, and intraoperative blood loss.

Urinary Diversion during and after Pediatric Pyeloplasty: A Population Based Analysis of More than 2,000 Patients

PURPOSEnWe evaluated the use and efficacy of intraoperative urinary diversion with ureteral stent or nephrostomy tube during pyeloplasty in children.nnnMATERIALS AND METHODSnThe Faculty Practice Solutions Center® national billing database was queried to identify all pediatric pyeloplasties performed from 2009 to 2012. Patient variables, surgical approach, use of intraoperative stent/nephrostomy tube and return for postoperative stent/nephrostomy tube or second pyeloplasty were obtained.nnnRESULTSnA total of 2,435 children underwent open (1,792) or laparoscopic/robotic (643) pyeloplasty, with intraoperative urinary diversion rates of 45% and 83%, respectively. Comparing patients with and without an intraoperative stent/nephrostomy tube, 5.6% and 7.4%, respectively, returned to the hospital for urinary diversion. Multivariable analysis revealed no association with surgical approach, but higher surgeon volume (p <0.01) and use of an intraoperative stent/nephrostomy tube (p <0.01) were associated with decreased odds of requiring postoperative urinary diversion. Second pyeloplasty rate was 3.8% and was not associated with surgical approach or use of intraoperative stent/nephrostomy tube.nnnCONCLUSIONSnIntraoperative stent/nephrostomy tube use and increased surgeon volume were each independently associated with a significant but small decrease in risk of postoperative stent/nephrostomy tube placement. Use of an intraoperative stent/nephrostomy tube was not associated with rate of second (redo ipsilateral or contralateral metachronous) pyeloplasty.

Autophagy and urothelial carcinoma of the bladder: A review.

The incidence of urothelial carcinoma of the urinary bladder (bladder cancer) remains high. While other solid organ malignancies have seen significant improvement in morbidity and mortality, there has been little change in bladder cancer mortality in the past few decades. The mortality is mainly driven by muscle invasive bladder cancer, but the cancer burden remains high even in nonmuscle invasive bladder cancer due to high recurrence rates and risk of progression. While apoptosis deregulation has long been an established pathway for cancer progression, nonapoptotic pathways have gained prominence of late. Recent research in the role of autophagy in other malignancies, including its role in treatment resistance, has led to greater interest in the role of autophagy in bladder cancer. Herein, we summarize the literature regarding the role of autophagy in bladder cancer progression and treatment resistance. We address it by systematically reviewing treatment modalities for nonmuscle invasive and muscle invasive bladder cancer.

Internet-Based Patient Survey on Urolithiasis Treatment and Patient Satisfaction

PURPOSEnWe created an Internet-based survey of patients treated for urolithiasis to evaluate for trends in treatment, outcome, and patient satisfaction and to establish internet surveys as a feasible medium for future research of patient urolithiasis treatment experiences.nnnMATERIALS AND METHODSnWe used the website kidneystoners.org to disseminate the online survey, which queried respondents on treatment type, outcome, and satisfaction. Patient satisfaction was correlated with treatment type and outcome. Chi-square and analysis of variance tests were used to compare responses between treatment types.nnnRESULTSnFour hundred forty-three respondents completed the survey. The majority (46%) were treated ureteroscopically, followed by extracorporeal shock wave lithotripsy (SWL, 25%) and percutaneous nephrolithotomy (7%). Other treatments included spontaneous passage (13%), medical expulsive therapy (7%), and home remedies (2%). Sixty-four percent of respondents deemed their treatment successful, while 36% reported their treatment as either partially successful or unsuccessful. Unsuccessful treatment was more likely for SWL (17%) and home remedies (14%) (p=0.002). Most respondents (52%) reported being either satisfied or very satisfied with their treatment choice. Satisfaction did not vary significantly by treatment type, but was significantly associated with treatment success (mean satisfaction 3.8/5 for successful vs 1.9/5 for unsuccessful treatment; p<0.0001).nnnCONCLUSIONnUse of the Internet allows rapid gathering of patient information from a large geographic distribution. Our survey is consistent with previous studies in demonstrating an increased use of ureteroscopy to treat both renal and ureteral calculi. In general, patients are satisfied with treatment outcomes despite a large percentage of people reporting needing to have secondary procedures.

Perioperative Outcomes following Neoadjuvant Chemotherapy and Radical Cystectomy—Is There Room for Improvement?

Introduction: We identify the impact of neoadjuvant chemotherapy before open radical cystectomy on perioperative outcomes and identify actionable areas for improvement. Methods: The impact of neoadjuvant chemotherapy on perioperative outcomes after radical cystectomy for muscle invasive bladder cancer from 2003 to 2014 was assessed using an institutional database. Individual outcomes (venous thromboembolism, surgical site infection, cardiac event) and a composite score using the Clavien‐Dindo classification were identified. Univariable and multivariable logistic regression models were used to identify predictors of perioperative complication and 30‐day readmission rates. Results: A total of 241 patients were included in the study, of whom 175 underwent radical cystectomy alone (72.6%) and 66 were treated with neoadjuvant chemotherapy plus radical cystectomy (27.4%). The 30‐day readmission rate for the neoadjuvant chemotherapy cohort was 30.5% compared to 17.2% for radical cystectomy alone. Multivariable logistic regression analysis identified neoadjuvant chemotherapy as an independent predictor of 30‐day readmission (OR 3.47, p=0.01). Of the patients on neoadjuvant chemotherapy readmitted within 30 days 72.2% were readmitted with infections. All other outcomes were not significantly associated with neoadjuvant chemotherapy. Conclusions: While the administration of neoadjuvant chemotherapy did not significantly increase perioperative complications, patients receiving neoadjuvant chemotherapy had an increased rate of 30‐day readmission, with infection being the most common etiology. This increased readmission rate has not been previously identified in this patient population to our knowledge and is an important focus for quality improvement.

The Promise and Disappointment of Neoadjuvant Chemotherapy and Transurethral Resection for Muscle Invasive Bladder Cancer: Updated Results and Long-Term Followup

Introduction Radical cystectomy with neoadjuvant chemotherapy is the standard of care for patients with localized muscle invasive urothelial carcinoma of the bladder. One of the strongest predictors of survival in these patients is pathological response to initial treatment. Our objective was to determine whether we could stratify the need for radical cystectomy based on pathological response to neoadjuvant chemotherapy. Methods We present a cohort of patients with muscle invasive urothelial carcinoma of the bladder to whom surveillance and bladder preservation were offered if complete response was achieved following neoadjuvant chemotherapy. Descriptive statistics and survival analysis were performed to assess overall, cancer specific and metastasis‐free survival. Patients were stratified based on pathological response to neoadjuvant chemotherapy. Results A total of 60 patients were included in the cohort, of whom 32 (55%) had absence of residual disease on post‐neoadjuvant chemotherapy transurethral resection and 27 (45%) had persistent disease. Of patients undergoing surveillance 52% maintained the bladder without evidence of recurrence. By comparison, of those with recurrence only 20% preserved the bladder and were without evidence of disease. Conclusions Long‐term followup shows a subset of patients achieving good outcomes while preserving the bladder. However, we also observed an inability to reliably identify this subset of patients given current clinical and pathological markers. Until we are able to achieve that goal, the safest oncologic approach remains neoadjuvant chemotherapy followed by radical cystectomy.