Efficacy and safety of alvimopan use in benign urinary tract reconstruction.

PURPOSE: To analyze the use of alvimopan, a peripheral mu-opioid receptor antagonist, in expediting gastrointestinal recovery after benign abdominal urinary tract reconstruction. Alvimopan use has been well defined in the management of radical cystectomy and urinary diversion for oncologic indications. It has not been studied in benign abdominal genitourinary reconstruction. METHODS: Patients who underwent urinary reconstruction utilizing harvested bowel segments for benign conditions from 12/2014-7/2019 were retrospectively reviewed. From 5/2018-7/2019 our institution approved the use of perioperative alvimopan in the aforementioned patients (N = 11), who were paired 1:2 with patients from a cohort of alvimopan-eligible patients who did not receive the drug (N = 22). Patients were paired by (1) type of reconstruction and (2) presence of neurogenic bowel-bladder (NBB). RESULTS: Of the 70 patients who underwent urinary reconstruction during the study period, 46 patients (66%) were eligible to receive alvimopan. Length of stay was shorter for the alvimopan group compared to the non-alvimopan group (median 5 days [IQR 4-5 days] vs. 8 days [IQR 6-11 days]; P = 0.002). Time to first bowel movement was shorter for the alvimopan group (median 4 days [IQR 3-4 days] vs. 6 days [IQR 4-7], P = 0.001). No patient treated with alvimopan required a nasogastric (NG) tube for post-operative ileus compared to 7 (32%) patients in the non-treatment group (P = 0.035). Post-operative complications and 30-day readmissions were similar between the two groups. CONCLUSION: The use of perioperative alvimopan in benign abdominal urinary tract reconstruction expedited return of bowel function and decreased length of stay compared to a matched cohort of untreated patients.

p-21 Activated Kinase as a Molecular Target for Chemoprevention in Diabetes.

HYPOTHESIS: Anti-diabetic drugs modulate p-21 activated kinase (PAK) signaling. Introduction: Type 2 diabetes mellitus (T2DM) is a chronic inflammatory disease associated with increased cancer risk. PAK signaling is implicated in cellular homeostasis when regulated, and cancer when unrestrained. Recent reports provided a role for PAK signaling in glucose homeostasis, but the role of PAKs in the pathogenesis of T2DM is unknown. Here, we performed a mini-meta-analysis to explore if anti-diabetic drugs modify PAK signaling pathways, and provide insight regarding modulation of these pathways, to potentially reduce diabetes-associated cancer risk. Methods: PAK interacting partners in T2DM were identified using the online STRING database. Correlation studies were performed via systematic literature review to understand the effect of anti-diabetic drugs on PAK signaling. A mini-meta-analysis correlated multiple clinical studies and revealed the overall clinical response rate and percentage of adverse events in piogliazone (n = 53) and metformin (n = 91) treated patients with PAK-associated diseases. Results: A total of 30 PAK interacting partners were identified (10: reduced beta-cell mass; 10: beta-cell dysfunction; 10: obesity-insulin resistance), which were highly associated with Wnt, and G-protein signaling. The anti-diabetic drug metformin activated signaling pathways upstream; whereas pioglitazone inhibited pathways downstream of PAK. Overall, clinical response upon pioglitazone treatment was 53%. Seventy-nine percent of pioglitazone and 75% of metformin treated patients had adverse events. Pioglitazone reduced molecular-PAK biomarkers of proliferation (Ki67 and CyclinD1), and metformin had the opposite effect. Conclusions: PAK signaling in T2DM likely involves Wnt and G-protein signaling, which may be altered by the anti-diabetic drugs metformin and pioglitazone. Apart from the therapeutic limitations of adverse events, pioglitazone may be promising in chemoprevention. However long-term multi-centered studies, which initiate pioglitazone treatment early will be required to fully assess the full potential of these drugs.