Inhibition of Dihydrotestosterone Synthesis in Prostate Cancer by Combined Frontdoor and Backdoor Pathway Blockade

Androgen deprivation therapy (ADT) is palliative and prostate cancer (CaP) recurs as lethal castration-recurrent/resistant CaP (CRPC). One mechanism that provides CaP resistance to ADT is primary backdoor androgen metabolism, which uses up to four 3α-oxidoreductases to convert 5α-androstane-3α,17β-diol (DIOL) to dihydrotestosterone (DHT). The goal was to determine whether inhibition of 3α-oxidoreductase activity decreased conversion of DIOL to DHT. Protein sequence analysis showed that the four 3α-oxidoreductases have identical catalytic amino acid residues. Mass spectrometry data showed combined treatment using catalytically inactive 3α-oxidoreductase mutants and the 5α-reductase inhibitor, dutasteride, decreased DHT levels in CaP cells better than dutasteride alone. Combined blockade of frontdoor and backdoor pathways of DHT synthesis provides a therapeutic strategy to inhibit CRPC development and growth

A contemporary analysis of morbidity and outcomes in cytoreduction/hyperthermic intraperitoneal chemoperfusion

The risks and benefits of cytoreductive surgery combined with hyperthermic intraperitoneal chemotherapy ( CS / HIPEC ) continue to be debated by the oncology community. A retrospective analysis of contemporary data (2003–2011) was performed to provide objective information regarding surgical morbidity, mortality, and survival for patients undergoing CS / HIPEC at a comprehensive cancer center. While procedure‐associated morbidity was comparable to other major surgical oncology procedures, there was no operative or 30‐day mortality and 60‐day mortality was 2.7%. Increasing numbers of bowel resections were found to correlate to an increased incidence of deep surgical site infections (including abscess and enterocutaneous fistula) and need for reoperation which was in turn associated with a decreased overall survival ( OS ) and progression‐free survival ( PFS ). Five‐year OS rates varied by site of tumor origin and histology (disseminated peritoneal adenomucinosis [91.3%], Mesothelioma [80.8%], Appendiceal Adenocarcinoma [38.7%], and Colorectal Adenocarcinoma [38.2%]). With an acceptable morbidity and mortality rate, CS / HIPEC should be included as an effective treatment modality in the multidisciplinary care of select patients with peritoneal metastases. In the contemporary setting, cytoreductive surgery and hyperthermic intraperitoneal chemotherapy ( CS / HIPEC ) are associated with a low mortality and improved survival. When present, complications are associated with a decreased overall survival. This treatment modality should be considered within the context of multidisciplinary care for select peritoneal carcinomatosis patients.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/98274/1/cam480.pd

Prediction of Incontinence after Robot-Assisted Radical Prostatectomy: Development and Validation of a 24-Month Incontinence Nomogram.

Incontinence after robot-assisted radical prostatectomy (RARP) is feared by most patients with prostate cancer. Many risk factors for incontinence after RARP are known, but a paucity of data integrates them. Prospectively acquired data from 680 men who underwent RARP January 2008-December 2015 and met inclusion/exclusion criteria were queried retrospectively and then divided into model development (80%) and validation (20%) cohorts. The UCLA-PCI-Short Form-v2 Urinary Function questionnaire was used to categorize perfect continence (0 pads), social continence (1-2 pads), or incontinence (≥3 pads). The observed incontinence rates were 26% at 6 months, 7% at 12 months, and 3% at 24 months. Logistic regression was used for model development, with variables identified using a backward selection process. Variables found predictive included age, race, body mass index, and preoperative erectile function. Internal validation and calibration were performed using standard bootstrap methodology. Calibration plots and receiver operating curves were used to evaluate model performance. The initial model had 6-, 12-, and 24-month areas under the curves (AUCs) of 0.64, 0.66, and 0.80, respectively. The recalibrated model had 6-, 12-, and 24-month AUCs of 0.52, 0.52, and 0.76, respectively. The final model was superior to any single clinical variable for predicting the risk of incontinence after RARP

Prediction of Incontinence after Robot-Assisted Radical Prostatectomy: Development and Validation of a 24-Month Incontinence Nomogram

Incontinence after robot-assisted radical prostatectomy (RARP) is feared by most patients with prostate cancer. Many risk factors for incontinence after RARP are known, but a paucity of data integrates them. Prospectively acquired data from 680 men who underwent RARP January 2008–December 2015 and met inclusion/exclusion criteria were queried retrospectively and then divided into model development (80%) and validation (20%) cohorts. The UCLA-PCI-Short Form-v2 Urinary Function questionnaire was used to categorize perfect continence (0 pads), social continence (1–2 pads), or incontinence (≥3 pads). The observed incontinence rates were 26% at 6 months, 7% at 12 months, and 3% at 24 months. Logistic regression was used for model development, with variables identified using a backward selection process. Variables found predictive included age, race, body mass index, and preoperative erectile function. Internal validation and calibration were performed using standard bootstrap methodology. Calibration plots and receiver operating curves were used to evaluate model performance. The initial model had 6-, 12-, and 24-month areas under the curves (AUCs) of 0.64, 0.66, and 0.80, respectively. The recalibrated model had 6-, 12-, and 24-month AUCs of 0.52, 0.52, and 0.76, respectively. The final model was superior to any single clinical variable for predicting the risk of incontinence after RARP