Laparoscopic Cholecystectomy vs Endoscopic Retrograde Cholangiopancreatography With Sphincterotomy in Elderly Patients With Acute Gallstone Pancreatitis.

BACKGROUND: Gallstone pancreatitis (GSP) is common in elderly patients and carries worse outcomes. Laparoscopic cholecystectomy (LC) is recommended for prevention of recurrent GSP. In frail populations, an endoscopic retrograde cholangiopancreatography with sphincterotomy (ERCP-s) is an alternative. Management guidelines of GSP in the elderly are lacking. This study aimed to investigate and compare management strategies for GSP in the elderly. MATERIALS AND METHODS: A retrospective comparison of outcome of patients aged ≥65 years with first presentation of GSP treated either with (1) LC only, (2) ERCP-s, (3) ERCP-S followed by LC, or (4) no intervention. RESULTS: 216 patients were included. Median age was 76 years (interquartile range 70-83). Most (80%, n = 172) had mild pancreatitis, whilst 12% (n = 26) had severe disease. 24% (n = 55) were treated with ERCP-s; 40% (n = 87) underwent LC alone; 11% (n = 23) had ERCP-s followed by LC; and 25% (n = 55) received no intervention. Patients without intervention were older (P < .001) and frailer (P < .001). The LC-only group had lower post-procedure re-admission rates of 6% (n = 5) compared to 27% (n = 14) for ERCP-s, 33% (n = 7) for ERCP-S + LC, and 31% (n = 17) for the no intervention group (P = .0001). Biliary cause mortality was highest in the no intervention group (n = 11, 20%). CONCLUSION: Laparoscopic cholecystectomy represents the gold standard for elderly patients with GSP.

Phosphodiesterase type 5 inhibitors enhance chemotherapy in preclinical models of esophageal adenocarcinoma by targeting cancer-associated fibroblasts.

The chemotherapy resistance of esophageal adenocarcinomas (EACs) is underpinned by cancer cell extrinsic mechanisms of the tumor microenvironment (TME). We demonstrate that, by targeting the tumor-promoting functions of the predominant TME cell type, cancer-associated fibroblasts (CAFs) with phosphodiesterase type 5 inhibitors (PDE5i), we can enhance the efficacy of standard-of-care chemotherapy. In ex vivo conditions, PDE5i prevent the transdifferentiation of normal fibroblasts to CAF and abolish the tumor-promoting function of established EAC CAFs. Using shotgun proteomics and single-cell RNA-seq, we reveal PDE5i-specific regulation of pathways related to fibroblast activation and tumor promotion. Finally, we confirm the efficacy of PDE5i in combination with chemotherapy in close-to-patient and in vivo PDX-based model systems. These findings demonstrate that CAFs drive chemotherapy resistance in EACs and can be targeted by repurposing PDE5i, a safe and well-tolerated class of drug administered to millions of patients world-wide to treat erectile dysfunction.