Resistance to gemcitabine is mediated by the circ_0036627/miR-145/S100A16 axis in pancreatic cancer.

The development of gemcitabine (GEM) resistance severely limits the treatment efficacy in pancreatic cancer (PC) and increasing evidence highlights the vital roles of circular RNAs (circRNAs) in the tumorigenesis, progression and drug resistance of PC. However, the circRNAs underlying GEM resistance development of PC remains to be clarified. The current research aims to unveil the roles of circ_0036627 in dictating the aggressiveness and GEM sensitivity in PC. We reported the increased expression of circ_0036627 in PC tissues and PC cell lines. Elevated circ_0036627 expression level was correlated with advanced tumour grade and poor overall survival in PC patients. Functional assays and in vivo experiments demonstrated that circ_0036627 overexpression was required for the proliferation, migration invasion and GEM resistance in PC cells. circ_0036627 knockdown suppressed tumour development in vivo. The molecular analysis further showed that circ_0036627 increased S100A16 expression by sponging microRNA-145 (miR-145), a tumour-suppressive miRNA that could significantly attenuate PC cell proliferation, migration, invasion and GEM resistance. Furthermore, our findings suggested that S100A16 acted as an oncogenic factor to promote aggressiveness and GEM resistance in PC cells. In conclusion, the current findings provide new mechanistic insights into PC aggressiveness and GEM resistance, suggesting the critical role of circ_0036627/miR-145/S100A16 axis in PC progression and drug resistance development and offering novel therapeutic targets for PC therapy.

Effect of Laparoscopic and Open Pancreaticoduodenectomy for Pancreatic or Periampullary Tumors: Three-year Follow-up of a Randomized Clinical Trial.

OBJECTIVE: This study aimed to estimate whether the potential short-term advantages of laparoscopic pancreaticoduodenectomy (LPD) could allow patients to recover in a more timely manner and achieve better long-term survival than with open pancreaticoduodenectomy (OPD) in patients with pancreatic or periampullary tumors. BACKGROUND: LPD has been demonstrated to be feasible and may have several potential advantages over OPD in terms of shorter hospital stay and accelerated recovery than OPD. METHODS: This noninferiority, open-label, randomized clinical trial was conducted in 14 centers in China. The initial trial included 656 eligible patients with pancreatic or periampullary tumors enrolled from May 18, 2018, to December 19, 2019. The participants were randomized preoperatively in a 1:1 ratio to undergo either LPD (n=328) or OPD (n=328). The 3-year overall survival (OS), quality of life, which was assessed using the 3-level version of the European Quality of Life-5 Dimensions, depression, and other outcomes were evaluated. RESULTS: Data from 656 patients [328 men (69.9%); mean (SD) age: 56.2 (10.7) years] who underwent pancreaticoduodenectomy were analyzed. For malignancies, the 3-year OS rates were 59.1% and 54.3% in the LPD and OPD groups, respectively ( P =0.33, hazard ratio: 1.16, 95% CI: 0.86-1.56). The 3-year OS rates for others were 81.3% and 85.6% in the LPD and OPD groups, respectively ( P =0.40, hazard ratio: 0.70, 95% CI: 0.30-1.63). No significant differences were observed in quality of life, depression and other outcomes between the 2 groups. CONCLUSION: In patients with pancreatic or periampullary tumors, LPD performed by experienced surgeons resulted in a similar 3-year OS compared with OPD. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03138213.

METTL3 Deficiency Aggravates Hepatic Ischemia/Reperfusion Injury in Mice by Activating the MAPK Signaling Pathway.

Background: Inflammatory responses, apoptosis, and oxidative stress, are key factors that contribute to hepatic ischemia/reperfusion (I/R) injury, which may lead to the failure of liver surgeries, such as hepatectomy and liver transplantation. The N6-methyladenosine (m6A) modification has been implicated in multiple biological processes, and its specific role and mechanism in hepatic I/R injury require further investigation. Methods: Dot blotting analysis was used to profile m6A levels in liver tissues at different reperfusion time points in hepatic I/R mouse models. Hepatocyte-specific METTL3 knockdown (HKD) mice were used to determine the function of METTL3 during hepatic I/R. RNA sequencing and western blotting were performed to assess the potential signaling pathways involved with the deficiency of METTL3. Finally, AAV8-TBG-METTL3 was injected through the tail vein to further elucidate the role of METTL3 in hepatic I/R injury. Results: The m6A modification levels and the expression of METTL3 were upregulated in mouse livers during hepatic I/R injury. METTL3 deficiency led to an exacerbated inflammatory response and increased cell death during hepatic I/R, whereas overexpression of METTL3 reduced the extent of liver injury. Bioinformatic analysis revealed that the MAPK pathway was significantly enriched in the livers of METTL3-deficient mice. METTL3 protected the liver from I/R injury, possibly by inhibiting the phosphorylation of JNK and ERK, but not P38. Conclusions: METTL3 deficiency aggravates hepatic I/R injury in mice by activating the MAPK signaling pathway. METTL3 may be a potential therapeutic target in hepatic I/R injury.

The Long-Term Outcome of Laparoscopic Resection for Perihilar Cholangiocarcinoma Compared with the Open Approach: A Real-World Multicentric Analysis.

OBJECTIVE: The aim of this study was to compare the short- and long-term outcomes of laparoscopic surgery (LS) and open surgery (OP) for perihilar cholangiocarcinoma (PHC) using a large real-world dataset in China. METHODS: Data of patients with PHC who underwent LS and OP from January 2013 to October 2018, across 10 centers in China, were extracted from medical records. A comparative analysis was performed before and after propensity score matching (PSM) in the LS and OP groups and within the study subgroups. The Cox proportional hazards mixed-effects model was applied to estimate the risk factors for mortality, with center and year of operation as random effects. RESULTS: A total of 467 patients with PHC were included, of whom 161 underwent LS and 306 underwent OP. Postoperative morbidity, such as hemorrhage, biliary fistula, abdominal abscess, and hepatic insufficiency, was similar between the LS and OP groups. The median overall survival (OS) was longer in the LS group than in the OP group (NA vs. 22 months; hazard ratio [HR] 1.19, 95% confidence interval [CI] 1.02-1.39, p = 0.024). Among the matched datasets, OS was comparable between the LS and OP groups (NA vs. 35 months; HR 0.99, 95% CI 0.77-1.26, p = 0.915). The mixed-effect model identified that the surgical method was not associated with long-term outcomes and that LS and OP provided similar oncological outcomes. CONCLUSIONS: Considering the comparable long-term prognosis and short-term outcomes of LS and OP, LS could be a technically feasible surgical method for PHC patients with all Bismuth-Corlett types of PHC.

Laparoscopic versus open surgery for perihilar cholangiocarcinoma: a multicenter propensity score analysis of short- term outcomes.

BACKGROUND: Laparoscopic surgery (LS) has been increasingly applied in perihilar cholangiocarcinoma (pCCA). In this study, we intend to compare the short-term outcomes of LS versus open operation (OP) for pCCA in a multicentric practice in China. METHODS: This real-world analysis included 645 pCCA patients receiving LS and OP at 11 participating centers in China between January 2013 and January 2019. A comparative analysis was performed before and after propensity score matching (PSM) in LS and OP groups, and within Bismuth subgroups. Univariate and multivariate models were performed to identify significant prognostic factors of adverse surgical outcomes and postoperative length of stay (LOS). RESULTS: Among 645 pCCAs, 256 received LS and 389 received OP. Reduced hepaticojejunostomy (30.89% vs 51.40%, P = 0.006), biliary plasty requirement (19.51% vs 40.16%, P = 0.001), shorter LOS (mean 14.32 vs 17.95 d, P < 0.001), and lower severe complication (CD ≥ III) (12.11% vs. 22.88%, P = 0.006) were observed in the LS group compared with the OP group. Major postoperative complications such as hemorrhage, biliary fistula, abdominal abscess, and hepatic insufficiency were similar between LS and OP (P > 0.05 for all). After PSM, the short-term outcomes of two surgical methods were similar, except for shorter LOS in LS compared with OP (mean 15.19 vs 18.48 d, P = 0.0007). A series subgroup analysis demonstrated that LS was safe and had advantages in shorting LOS. CONCLUSION: Although the complex surgical procedures, LS generally seems to be safe and feasible for experienced surgeons. TRIAL REGISTRATION: NCT05402618 (date of first registration: 02/06/2022).

A comparative study of the "superior mesenteric artery first" approach versus the conventional approach in short-term and long-term outcomes in patients with pancreatic ductal adenocarcinoma undergoing laparoscopic pancreaticoduodenectomy.

BACKGROUND: The use of laparoscopic pancreaticoduodenectomy (LPD) in pancreatic head cancer remains controversial, and an appropriate surgical approach can help improve perioperative safety and oncological outcomes. This study aimed to assess the short-term outcomes and long-term survival of the superior mesenteric artery first (SMA-first) approach in patients with pancreatic ductal adenocarcinoma (PDAC) undergoing LPD. METHODS: The data of 91 consecutive PDAC patients who underwent LPD from June 2014 to June 2021 were retrospectively analyzed. Patients were divided into two groups, the modified SMA-first approach group, using a combined posterior and anterior approach, and the conventional approach group. Perioperative outcomes, pathologic results, and overall survival (OS) were compared between groups, and propensity score-matched (PSM) analysis was performed. RESULTS: The number of lymph nodes harvested was greater in the SMA-first approach group (19 vs. 15, P = 0.021), as did the results in the matched cohort (21 vs. 15, P = 0.046). No significant difference was observed in the R0 resection rate (93.3% vs. 82.6%, P = 0.197), but the involvement of the SMA margin was indeed lower in the SMA-first approach group (0 vs. 13%). There were no obvious variances between the two groups in terms of intraoperative bleeding, operative time, overall and major postoperative complication rates, and mortality in either the original cohort or matched cohort. The median OS was 21.8 months in the SMA-first group, whereas it was 19.8 months in the conventional group (P = 0.900). Survival also did not differ in the matched cohort (P = 0.558). TNM stage, resection margin, overall complications, and adjuvant therapy were independent risk factors affecting OS. CONCLUSION: The modified SMA-first approach is safe and feasible for PDAC patients undergoing LPD. It had a slight advantage in specimen quality, but OS was not significantly prolonged.

Retroperitonealization of the pancreatic stump in distal pancreatectomy: a novel technique to reduce postoperative pancreatic fistula.

PURPOSE: To evaluate the efficacy and safety of retroperitonealization of the pancreatic stump in distal pancreatectomy. METHODS: Clinical data from the Tongji Hospital pancreatic database were retrospectively reviewed in this study. The data of 68 patients who underwent retroperitonealized distal pancreatectomy from January, 2019, to April, 2021, were collected and analyzed. Sixty-four patients who underwent conventional distal pancreatectomy during the same period were matched. We compared and analyzed the operative outcomes and postoperative complications between the patients in the two groups before and after propensity score matching (PSM). RESULTS: Before PSM, the operative outcomes and postoperative complications were comparable between the two groups. After PSM, the retroperitonealized group had a lower incidence of postoperative pancreatic fistula (POPF) (10.53% vs 31.58%, P = 0.047) and shorter time until drainage removal (10.00, 8.00-13.00 days vs 13.00, 10.00-18.00 days, P = 0.005). In the univariate and multivariate regression analyses, non-retroperitonealization and intra-abdominal infection were found to be independent risk factors for postoperative pancreatic fistula (POPF). CONCLUSION: Retroperitonealization of the pancreatic stump can reduce the incidence of POPF after distal pancreatectomy.

The clinical implication of minimally invasive versus open pancreatoduodenectomy for non-pancreatic periampullary cancer: a systematic review and individual patient data meta-analysis.

BACKGROUND: Most studies on minimally invasive pancreatoduodenectomy (MIPD) combine patients with pancreatic and periampullary cancers even though there is substantial heterogeneity between these tumors. Therefore, this study aimed to evaluate the role of MIPD compared to open pancreatoduodenectomy (OPD) in patients with non-pancreatic periampullary cancer (NPPC). METHODS: A systematic review of Pubmed, Embase, and Cochrane databases was performed by two independent reviewers to identify studies comparing MIPD and OPD for NPPC (ampullary, distal cholangio, and duodenal adenocarcinoma) (01/2015-12/2021). Individual patient data were required from all identified studies. Primary outcomes were (90-day) mortality, and major morbidity (Clavien-Dindo 3a-5). Secondary outcomes were postoperative pancreatic fistula (POPF), delayed gastric emptying (DGE), postpancreatectomy hemorrhage (PPH), blood-loss, length of hospital stay (LOS), and overall survival (OS). RESULTS: Overall, 16 studies with 1949 patients were included, combining 928 patients with ampullary, 526 with distal cholangio, and 461 with duodenal cancer. In total, 902 (46.3%) patients underwent MIPD, and 1047 (53.7%) patients underwent OPD. The rates of 90-day mortality, major morbidity, POPF, DGE, PPH, blood-loss, and length of hospital stay did not differ between MIPD and OPD. Operation time was 67 min longer in the MIPD group (P = 0.009). A decrease in DFS for ampullary (HR 2.27, P = 0.019) and distal cholangio (HR 1.84, P = 0.025) cancer, as well as a decrease in OS for distal cholangio (HR 1.71, P = 0.045) and duodenal cancer (HR 4.59, P < 0.001) was found in the MIPD group. CONCLUSIONS: This individual patient data meta-analysis of MIPD versus OPD in patients with NPPC suggests that MIPD is not inferior in terms of short-term morbidity and mortality. Several major limitations in long-term data highlight a research gap that should be studied in prospective maintained international registries or randomized studies for ampullary, distal cholangio, and duodenum cancer separately. PROTOCOL REGISTRATION: PROSPERO (CRD42021277495) on the 25th of October 2021.

Comparison of laparoscopic versus open pancreaticoduodenectomy in patients with resectable pancreatic ductal adenocarcinoma: A propensity score-matching analysis of long-term survival.

BACKGROUND: Many studies have shown the short-term feasibility and effectiveness of laparoscopic pancreaticoduodenectomy (LPD) are comparable to open pancreaticoduodenectomy (OPD). However, the long-term oncological safety of LPD in patients with pancreatic ductal adenocarcinoma (PDAC) remains to be elucidated. METHODS: Patients who underwent LPD or OPD between July 2014 and July 2018 at our institution were identified, and those with resectable, pathologically diagnosed PDAC were analyzed. The primary outcome was overall survival (OS). Propensity score-matching (PSM) analysis was performed to balance the baseline characteristics between groups. Cox proportional hazards model was constructed to determine independent predictors of OS. RESULTS: The original cohort consisted of 64 LPD and 80 OPD cases, in which, the laparoscopic group had a significantly longer median OS (25 vs. 17 months; P = 0.034). A higher proportion of laparoscopic patients received adjuvant therapy (51.6 vs. 32.5%; P = 0.021). PSM analysis identified 47 patient pairs. No significant differences in OS (21 vs. 17 months; P = 0.220) or adjuvant therapy utilization (53.2 vs. 38.3%; P = 0.248) were observed between the matched groups. Multivariate Cox analyses showed that receiving adjuvant therapy (HR = 0.44; 95% CI, 0.28-0.68), histopathological differentiation (poor vs. moderate-to-well differentiation; HR = 1.93; 95% CI, 1.26-2.95), and sex (female vs. male, HR = 0.47, 95% CI, 0.30-0.75) were independent predictors of OS. CONCLUSIONS: LPD can be comparable to OPD in terms of long-term safety for patients with resectable pancreatic ductal adenocarcinoma when performed in a high-volume center.

OPA Interacting Protein 5 Antisense RNA 1 Expedites Cell Migration and Invasion Through FOXM1/ Wnt/ß-Catenin Pathway in Pancreatic Cancer.

BACKGROUND: Pancreatic cancer (PC) is a digestive tract malignancy with poor prognosis. Long noncoding RNA (lncRNA) OPA interacting protein 5 antisense RNA 1 (OIP5-AS1) was regarded to be correlated with human malignancy, working as tumor suppressor or promoter on the basis of tumor types. However, the function of OIP5-AS1 in PC remained unclear. AIMS: The study focused on the function and regulatory mechanism of OIP5-AS1 in PC. METHODS: OIP5-AS1 expression was assessed by the quantitative reverse transcription PCR (RT-qPCR) in tumor tissues and PC cell lines. 5-ethynyl-2'-deoxyuridine (EdU) incorporation and cell counting kit-8 (CCK-8) assays were applied to detect cell proliferation ability. Through wound healing and transwell assays, cell migration and invasion capacities were estimated. Flow cytometry analysis was performed to examine apoptosis capability of PC cells. RESULTS: OIP5-AS1 downregulating inhibited cell proliferation, migration, and invasion capacities, while promoting cell apoptosis rates. As a competing endogenous RNA (ceRNA), OIP5-AS1 competed with Forkhead Box M1 (FOXM1) for the binding sites on microRNA-320b (miR-320b). OIP5-AS1 was able to upregulate FOXM1 expression via silencing miR-320b. Furthermore, FOXM1 served as an activator of Wnt/ß-catenin pathway and mediated the effect of OIP5-AS1 on Wnt/ß-catenin pathway. CONCLUSION: OIP5-AS1 expedites the proliferative, migrated, and invasive capability of PC cells, while repressing cell apoptosis through regulating miRNA-320b/FOXM1 axis and FOXM1/Wnt/ß-catenin pathway in PC. OIP5-AS1 regulation on FOXM1/Wnt/ß-catenin pathway may offer novel efficient markers for PC treatments.