Biliary Adverse Events During Neoadjuvant Therapy for Pancreatic Cancer.

OBJECTIVE: To describe a high-volume experience with biliary drainage before neoadjuvant therapy (NAT) for patients with operable pancreatic cancer (PC) and characterize the association between biliary adverse events (BAEs) and patient outcome. BACKGROUND: Patients with PC presenting with biliary obstruction require durable decompression before NAT. METHODS: Patients with operable PC and tumor-associated biliary obstruction were examined and grouped by the presence or absence of a BAE during NAT. The incidence, timing, and management of BAEs are described, and outcomes, including the completion of all treatment and overall survival (OS), were compared. RESULTS: Of 426 patients who received pretreatment biliary decompression, 92 (22%) experienced at least 1 BAE during NAT, and 56 (13%) required repeat intervention on their biliary stent. The median duration of NAT was 161 days for all patients and was not different in the group that experienced BAEs. The median time from initial stent placement to BAE was 64 days. An interruption in the delivery of NAT (median 7 days) occurred in 25 (6%) of 426 patients. Among 426 patients, 290 (68%) completed all NAT, including surgery: 60 (65%) of 92 patients with BAE and 230 (69%) of 334 patients without BAE ( P =0.51). Among 290 patients who completed NAT and surgery, the median OS was 39 months, 26 months for the 60 patients with BAE, and 43 months for the 230 patients without BAE ( P =0.02). CONCLUSIONS: During extended multimodal NAT for PC, 22% of patients experienced a BAE. Although BAEs were not associated with a significant interruption of treatment, patients who experienced a BAE had worse OS.

A single, peri-operative antibiotic can persistently alter the post-operative gut microbiome after Roux-en-Y gastric bypass.

INTRODUCTION: Roux-en-Y gastric bypass (RYGB) significantly alters the gut microbiome and may be a mechanism for post-operative cardiovascular disease improvement. We have previously found an association between the class of peri-operative, intravenous antibiotic administered at the time of RYGB and the resolution rate of hypertension suggesting the gut microbiome as a mechanism. In this study, we performed a prospective study of RYGB to determine if a single intravenous antibiotic could alter the gastrointestinal microbial composition. METHODS: Patients undergoing RYGB were randomized to a single, peri-operative antibiotic of intravenous cefazolin (n = 8) or clindamycin (n = 8). Stool samples were collected from four-time points: 2 weeks pre-op (- 2w), 2 days pre-op (- 2d), 2 weeks post-op (+ 2w) and 3 months post-op (+ 3m). Stool samples were processed for genomic DNA followed by Illumina 16S rRNA gene sequencing and shotgun metagenomic sequencing (MGS). RESULTS: A total of 60 stool samples (- 2w, n = 16; - 2d, n = 15; + 2w, n = 16; + 3m, n = 13) from 16 patients were analyzed. 87.5% of patients were female with an average age of 48.6 ± 12.2 years and pre-operative BMI of 50.9 ± 23.3 kg/m2. RYGB induced statistically significant differences in alpha and beta diversity. There were statistically significant differences in alpha diversity at + 2w and beta diversity at + 3m due to antibiotic treatment. MGS revealed significantly distinct gut microbiota with 11 discriminatory metagenomic assembled genomes driven by antibiotic treatment at 3 months post-op, including increased Bifidobacterium spp. with clindamycin. CONCLUSION: RYGB induces significant changes in the gut microbiome at 2 weeks that are maintained 3 months after surgery. However, the single peri-operative dose of antibiotic administered at the time of RYGB induces unique and persisting changes to the gut microbiome that are antibiotic-specific. Increased Bifidobacterium spp. with clindamycin administration may improve the metabolic efficacy of RYGB when considering gut-microbiome driven mechanisms for blood pressure resolution.

Sleeve Gastrectomy Improves High-Fat Diet-Associated Hepatic Steatosis Independent of the Glucagon-like-Petpide-1 Receptor in Rats.

BACKGROUND: The gastrointestinal hormone glucagon-like peptide-1 (GLP-1) is increased after sleeve gastrectomy (SG). Rat and clinical studies support, while mouse studies refute, a role for GLP-1R signaling after SG. Therefore, we developed a global GLP-1R knockout (KO) rat to test the hypothesis that a functional GLP-1R is critical to induce weight loss and metabolic disease improvement after SG. METHODOLOGY: A 4 bp deletion was created in exon 2 of the GLP-1R gene on a Lewis strain background to create a global GLP-1R KO rat. KO and Lewis rats were placed on a high-fat or low-fat diet and phenotyped followed by SG or Sham surgery and assessed for the effect of GLP-1R KO on surgical and metabolic efficacy. RESULTS: Loss of the GLP-1R created an obesity-prone rodent without changes in energy expenditure. Both male and female KO rats had significantly greater insulin concentrations after an oral glucose gavage, augmented by a high-fat diet, compared to Lewis rats despite similar glucose concentrations. GLP-1R KO caused hepatomegaly and increased triglyceride deposition compared to Lewis rats. We found no difference between SG GLP-1R KO and Lewis groups when considering efficacy on body weight, glucose tolerance, and a robustly preserved improvement in fatty liver disease. CONCLUSIONS: Loss of the GLP-1R in rats resulted in increased adiposity, insulin resistance, and severe steatosis. A functional GLP-1R is not critical to the metabolic efficacy of SG in Lewis rats, similar to mouse studies, but importantly including steatosis, supporting a GLP-1R-independent mechanism for the improvement in fatty liver disease after SG.