The rising incidence and persistent dismal 5-year overall survival of pancreatic ductal adenocarcinoma (PDAC) highlight the need for new effective systemic therapies. Immunotherapy has shown significant benefits in solid organ tumors, but has thus far been disappointing in the treatment of PDAC. There have been several promising preclinical studies, but translation into the clinic has proved to be challenging. This is likely a result of PDAC's complex immunosuppressive tumor microenvironment that acts to insulate the tumor against an effective cytotoxic immune response. Here, we summarize the mechanisms of immunosuppression within the PDAC tumor microenvironment and provide an up-to-date review of completed and ongoing clinical trials using various immunotherapy strategies.

Enhanced recovery after surgery (ERAS) components for liver resection lack standardization and compliance. We evaluated our ERAS protocol and describe the association of postoperative ERAS compliance with length of stay (LOS) and complications. We retrospectively reviewed patients undergoing liver resection at our institution from 2016 to 2020. Pre- and post-ERAS outcomes and compliance at 72 h were compared with LOS and complications. LOS beyond 72 h was defined as LOS72. 210 patients were included. Post-ERAS patients had significantly shorter LOS (5.1 vs. 7.3 days, p = 0.0014) with no difference in 30-day mortality, morbidity, or readmissions. ERAS components associated with shorter LOS72 were regular diet (HR 1.73), fluid discontinuation (HR 1.63), drain removal (HR 1.94), multimodal and oral analgesia (HR 1.51), and ambulation >100 ft (HR 2.23). LOS72 was 1-day for ≥9 ERAS component compliance, 4-days for 6-8 components, and 6-days for 100 ft by POD3 are associated with decreased LOS72. Achieving ≥6 components by POD3 predicts decreased LOS72 and complications.

Premature infants are often given glycerin suppositories or enemas to facilitate meconium evacuation and the transition to enteral feeds. We reviewed the best-available evidence for the use of glycerin suppositories and enemas in premature infants. We searched MEDLINE, Embase, and Cochrane Central for randomized controlled trials (RCTs) of premature infants treated with glycerin suppositories or enemas through January 2022. Studies were screened and data extracted independently and in duplicate. We included RCTs of premature infants <32 weeks gestation and/or birth weight <1500 g who were treated with glycerin suppositories or enemas. Meta-analysis was performed using random effects and reported as relative risk or mean difference. We identified 6 single-center, RCTs of 389 premature infants treated with glycerin suppositories (n = 207) or enemas (n = 182). Mortality rates ranged from 0% to 17%, and the meta-analysis revealed no differences between treatment groups (P = .86). Active treatment was associated with earlier meconium evacuation (mean, 1.5 days; 95% confidence interval, 3.0 to 0.01; P = .05) but not a faster time to enteral feeds (mean, 0.5 days; P = .48). We identified 1 ongoing trial with a target recruitment of 220 premature infants. The quality of evidence was very low to moderate because of inadequate statistical power and other methodologic issues. The use of glycerin suppositories and enemas in premature infants is associated with earlier meconium evacuation, but the clinical significance of this finding is uncertain. Treatment has no definitive effects on mortality, necrotizing enterocolitis, or enteral feeds.

Background: Cholangiocarcinoma (CCA) features highly desmoplastic stroma that promotes structural and functional resistance to therapy. Lysyl oxidases (LOX, LOXL1–4) catalyze collagen cross-linking, thereby increasing stromal rigidity and facilitating therapeutic resistance. Here, we evaluate the role of lysyl oxidases in stromal desmoplasia and the effects of pan-lysyl oxidase (pan-LOX) inhibition in CCA. Methods: Resected CCA and normal liver specimens were analyzed from archival tissues. Spontaneous and orthotopic murine models of intrahepatic CCA (iCCA) were used to assess the impact of the pan-LOX inhibitor PXS-5505 in treatment and correlative studies. The functional role of pan-LOX inhibition was interrogated through in vivo and ex vivo assays. Results: All 5 lysyl oxidases are upregulated in CCA and reduced lysyl oxidase expression is correlated with an improved prognosis in resected patients with CCA. Spontaneous and orthotopic murine models of intrahepatic cholangiocarcinoma upregulate all 5 lysyl oxidase isoforms. Pan-LOX inhibition reversed mechanical compression of tumor vasculature, resulting in improved chemotherapeutic penetrance and cytotoxic efficacy. The combination of chemotherapy with pan-LOX inhibition increased damage-associated molecular pattern release, which was associated with improved antitumor T-cell responses. Pan-LOX inhibition downregulated macrophage invasive signatures in vitro, rendering tumor-associated macrophages more susceptible to chemotherapy. Mice bearing orthotopic and spontaneously occurring intrahepatic cholangiocarcinoma tumors exhibited delayed tumor growth and improved survival following a combination of pan-LOX inhibition with chemotherapy. Conclusions: CCA upregulates all 5 lysyl oxidase isoforms, and pan-LOX inhibition reverses tumor-induced mechanical forces associated with chemotherapy resistance to improve chemotherapeutic efficacy and reprogram antitumor immune responses. Thus, combination therapy with pan-LOX inhibition represents an innovative therapeutic strategy in CCA. Export

BACKGROUND: Single-shot intrathecal morphine (ITM) is an effective strategy for postoperative analgesia, but there are limited data on its safety, efficacy, and relationship with functional recovery among patients undergoing pancreaticoduodenectomy. STUDY DESIGN: This was a retrospective review of patients undergoing pancreaticoduodenectomy from 2014 to 2020 as identified by the institutional NSQIP Hepato-pancreato-biliary database. Patients were categorized by having received no spinal analgesia, ITM, or ITM with transversus abdominus plane block (ITM+TAP). The primary outcomes were average daily pain scores from postoperative days (POD) 0 to 3, total morphine equivalents (MEQ) consumed over POD 0 to 3, and average daily inpatient MEQ from POD 4 to discharge. Secondary outcomes included the incidence of opioid related complications, length of stay, and functional recovery. RESULTS: A total of 233 patients with a median age of 67 years were included. Of these, 36.5% received no spinal analgesia, 49.3% received ITM, and 14.2% received ITM+TAP. Average pain scores in POD 0 to 3 were similar by mode of spinal analgesia (none [2.8], ITM [2.6], ITM+TAP [2.3]). Total MEQ consumed from POD 0 to 3 were lower for patients who received ITM (121 mg) and ITM+TAP (132 mg), compared with no spinal analgesia (232 mg) (p < 0.0001). Average daily MEQ consumption from POD 4 to discharge was lower for ITM (18 mg) and ITM+TAP (13.1 mg) cohorts compared with no spinal analgesia (32.9 mg) (p = 0.0016). Days to functional recovery and length of stay were significantly reduced for ITM and ITM+TAP compared with no spinal analgesia. These findings remained consistent through multivariate analysis, and there were no differences in opioid-related complications among cohorts. CONCLUSIONS: ITM was associated with reduced early postoperative and total inpatient opioid utilization, days to functional recovery, and length of stay among patients undergoing pancreaticoduodenectomy. ITM is a safe and effective form of perioperative analgesia that may benefit patients undergoing pancreaticoduodenectomy.