Purpose: Locally advanced pancreatic cancer (LAPC) accounts for 30% of pancreatic cancers. We assessed the efficacy and safety of a novel extended-release siRNA targeting KRASG12D/V mutations (siG12D-LODER) combined with chemotherapy in LAPC. Patients and Methods: This two-cohort, phase II multicenter, open-label study (NCT01676259) evaluated siG12D-LODER with chemotherapy in patients with LAPC, regardless of KRAS status. In cohort 1, patients were randomized to siG12D-LODER plus gemcitabine/nab-paclitaxel (arm 1) or gemcitabine/nab-paclitaxel alone (arm 2). In cohort 2, patients with LAPC or borderline resectable disease received siG12D-LODER plus standard chemotherapy (modified FOLFIRINOX or gemcitabine/nab-paclitaxel) in a single-arm, nonrandomized design. Primary endpoints were overall survival (OS) for cohort 1 and objective response rate (ORR) for cohort 2. Secondary endpoints included progression-free survival, duration of response, OS (cohort 2), and ORR (cohort 1). Results: Across two cohorts, 59 patients were enrolled. In cohort 1, the median OS in the modified intent-to-treat (mITT) population unselected for KRAS status was 22.7 months for siG12D-LODER + gemcitabine/nab-paclitaxel versus 21.9 months for chemotherapy alone (P > 0.05). Among patients with KRASG12D/V mutations, OS was 22.7 versus 13.5 months [HR, 0.59; 95% confidence interval (CI), 0.18–1.96; P = 0.39]. In cohort 2, ORR was 31.6% (95% CI, 0.13–0.57) in the mITT (unselected for KRAS); in the G12D/V subgroup, ORR was 57.1%, similar to 63.6% in cohort 1. Treatment-emergent adverse events were mainly procedure related, including grade 1/2 gastrointestinal events and higher infection rates in the intervention arm. Conclusions: siG12D-LODER plus chemotherapy is safe, tolerable, and warrants further investigation in KRASG12D/V-mutant LAPC.

Purpose: This study aimed to evaluate the efficacy, usability, and safety of the novel alginate-based sealants SEAL-G and SEAL-G MIST in reducing anastomotic leakage after colorectal resection.Methods: This prospective, multicenter study enrolled 160 patients undergoing elective colonic resection with primary anastomosis at 8 centers. SEAL-G was applied in open procedures (n=33), and SEAL-G MIST was used for minimally invasive procedures (n=127), with both sealants applied circumferentially to the anastomotic site. The primary endpoints included the rate of anastomotic coverage and the incidence of leakage within 30 days, classified according to the International Study Group of Rectal Cancer (ISGRC) criteria.Results: The overall anastomotic leak rate was 3.1% (5 of 160), with only 1 patient (0.6%) experiencing a grade C leak that required reoperation. Four patients (2.5%) developed grade A or B leaks, all of which were managed conservatively. Complete circumferential sealant coverage was achieved in 93.1% of cases. The overall leak rates were 6.1 percent and 2.4 percent, respectively. However, statistical analysis did not show a significant difference. Mean hospital stay was significantly shorter after laparoscopic surgery compared to open surgery (5.1±2.8 days vs. 8.4±5.5 days, P<0.001).Conclusion: Alginate-based sealants show promise in reducing the severity of anastomotic leaks and in supporting anastomotic healing, demonstrating high technical success and low complication rates.Trial registration: ClinicalTrials.gov iden­tifier: NCT04532515

Management of obesity potentially improves cardiometabolic risk factors in patients with metabolic syndrome (MetS). The Epitomee capsule is a non-pharmacological, biodegradable device treatment for weight reduction in patients with overweight and obesity. This secondary analysis of the Randomized Evaluation of Safety and Efficacy of the Epitomee capsule Trial (RESET) (a randomized, 24-week, multicenter, placebo-controlled, double-blind trial that enrolled 279 adults aged ≥18 years with a BMI of 27–40 kg/m2) evaluated changes in cardiometabolic parameters in participants treated with Epitomee or placebo combined with lifestyle counseling among (a) the entire RESET study population, and (b) participants meeting diagnostic criteria for prediabetes. Predefined and exploratory endpoints included changes in waist circumference, glycemic parameters, blood pressure, and lipid blood levels; this analysis also assessed percent weight loss in participants with MetS. Waist circumference, systolic and diastolic blood pressure and some measures of glycemia and lipids, improved with both Epitomee and placebo with no significant differences. Participants with prediabetes treated with Epitomee showed significantly greater reductions in HOMA-IR (p < 0.007) and insulin levels (p < 0.003) than the placebo group. Participants with MetS at baseline experienced significantly greater percent change in initial weight when treated with the Epitomee capsule (n = 27) compared to placebo (n = 31), −8.3% vs −5.2 %, respectively (p < 0.0004). Similar percentages of participants with MetS in both groups achieved ≥5 % weight reduction (59.3 % and 54.8 %, in Epitomee and placebo groups respectively). Significantly more participants with MetS treated with Epitomee achieved ≥10 % weight reduction compared with those treated with placebo (40.7 % vs. 6.5 %, respectively, p < 0.002). Treatment with either Epitomee and placebo combined with lifestyle improve cardiometabolic risk factors. Compared to placebo, Epitomee significantly reduced HOMA-IR and insulin levels in participants with prediabetes. Among participants with MetS, Epitomee significantly reduced body weight [ClinicalTrials.gov ID NCT04222322].

Background: Anastomotic leakage (AL) remains a major complication following colorectal surgery (3–19% incidence, 6–39% mortality). SEAL-G/SEAL-G MIST are alginate-based sealants for anastomotic reinforcement. While short-term safety and efficacy feasibility have been established in a previous study, this study reports long-term results. Methods: A multicenter, retrospective and comparative study at three centers (Israel, Italy). Retrospective Treatment group: 79 patients from the original study treated with SEAL-G/SEAL-G MIST during elective colon cancer resection (2021–2023). Retrospective Control group: 86 comparative patients with standard technique. Primary endpoint: Incidence of long-term complications (adhesions, stenosis, stricture, obstruction) at 1 year. Secondary endpoints: Complications at 1–4 years and 30-day AL rate. Non-inferiority assessed via Farrington–Manning method (margin 0.10). Results: Mean follow-up: 3.3 ± 0.63 years (treatment) vs. 3.4 ± 1.10 years (control). Groups were comparable for demographics and surgical characteristics. Long-term complications at 1 year: 1.27% (1/79) vs. 2.33% (2/86); 90% CI for difference: −0.067 to 0.046, p = 0.0048 (non-inferiority confirmed). No stenosis or stricture occurred in either group. No additional complications emerged at 1–4 years in the treatment group. Thirty-day AL rate: 1.27% (1/79) vs. 5.68% (5/88); all subclinical leaks (Grade B, n = 4) occurred in controls. Conclusions: Serosal reinforcement with alginate-based sealants does not introduce device-related long-term complications following colorectal anastomosis. The favorable short-term safety profile extends to 2–4 years. These findings support the safety of alginate-based sealants as anastomotic adjuncts, consistent with the paradigm of leak containment and severity reduction.

Long-term weight-loss maintenance remains challenging despite of the numerous available treatments. The previously published pivotal randomized RESET study demonstrated a mean weight reduction from baseline of 6.6 % with Epitomee and a mean weight reduction of 4.6 % with placebo (p < 0.001). In this study we investigated the efficacy and safety of the extended use of Epitomee, an FDA cleared, non-pharmacological treatment for weight management. In this open label extension study, a subset of participants in the RESET study who lost ≥3 % of initial body weight during a 24-week treatment with Epitomee capsule or placebo, as an adjunct to lifestyle counseling, were eligible for a 24-week open-label extension study (ELECT). Continuous treatment with Epitomee and lifestyle counseling for 48 weeks was associated with sustained reduction in body weight of 11.2 ± 8.4 % (p < 0.001) and sustained prior improvements in cardiometabolic risk factors and quality of life (QOL). Taking the Epitomee capsule for 24 weeks, after previous weight loss with the placebo treatment, was associated with an additional 1.5 ± 4.2 % weight loss, yielding a total 7.5 ± 5.5 % reduction at 48 weeks and additional improvements in QOL. Capsule adherence exceeded 94 %. Extended use of Epitomee had a favorable safety profile, with no serious adverse device-related events and no discontinuation due to adverse events. In this open-label study, extended use of Epitomee, combined with lifestyle counseling, was associated with maintenance of prior weight loss and favorable safety profile (NCT04994769).