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.

ENO1 contributes to the gemcitabine resistance of pancreatic cancer through the YAP1 signaling pathway.

Pancreatic cancer (PC), a leading cause of cancer-related deaths, has a 5-year survival rate of approximately 10%. α-Enolase (ENO1) is a junction channel protein involved in tumor cell apoptosis and chemoresistance. However, the role of ENO1 in PC remains unclear. The expression and prognosis of ENO1 levels were determined in PC using public databases based on The Cancer Genome Atlas (TCGA) data sets. Cell viability, half maximal inhibitory concentration (IC50), autophagy, apoptosis, and autophagy markers were examined using cell counting kit-8 (CCK-8), transmission electron microscope, flow cytometry assays, and immunoblot, respectively. Using the Gene Expression Omnibus (GEO) and TCGA data sets, we found that ENO1 was significantly enriched in PC tumor tissues, and high expression levels of ENO1 were associated with an unfavorable prognosis. Whereas ENO1 silencing suppressed proliferation, autophagy, and induced cell apoptosis in PC cells, and inhibited tumor growth in vivo. Mechanistically, knockdown of ENO1 enhanced cellular cytotoxicity of gemcitabine (GEM), as well as reducing the expression of yes-associated protein 1 (YAP1), a major downstream effector of the Hippo pathway in vitro. YAP1 promoted autophagy and protected PC cells from GEM-induced apoptotic cell death. Furthermore, YAP1 overexpression attenuated the inhibition effects of ENO1 silencing. Our results suggest that ENO1 overexpression promotes cell growth and tumor progression by increasing the expression of YAP1 in PC. Further studies are required to understand the detailed mechanisms between ENO1 and YAP1 in PC.

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).

Clinical application of pancreatic-duct-jejunum end-to-side continuous suture anastomosis in total laparoscopic pancreaticoduodenectomy.

BACKGROUND: To present a new pancreaticojejunostomy technique for laparoscopic pancreaticoduodenectomy (LPD) and to evaluate its safety and reliability. METHODS: The data of 120 patients who underwent LPD at a single centre from October 2017 to October 2019 were retrospectively analysed. Of these patients, 71 received continuous suture pancreaticojejunostomy, and 49 received "8-character" suture pancreaticojejunostomy for LPD. We compared and analysed the operation time, anastomosis time, and incidence of postoperative complications between the patients in the two groups. RESULTS: All operations were successfully performed, with no transfer to open surgery. The operation time and anastomosis time in the continuous suture group were lower than those in the "8-character" suture group (305.8 ± 60.7 min vs. 354.3 ± 69.1 min; 28.6 ± 6.3 min vs. 39.4 ± 11.9 min P < 0.001), and the postoperative hospital stay was also shorter (12.9 ± 3.8 days vs. 15.4 ± 5.8 days P < 0.05) in the continuous suture group. There was no significant difference in the pancreatic duct diameter or intraoperative blood loss between the two groups. There was also no significant difference in the incidence of a pancreatic fistula between the continuous suture group and the "8-character" suture group. The data of patients in the continuous suture group with pancreatic duct diameters < 3 mm and ≥ 3 mm were statistically analysed. There was no significant difference in the operation time, pancreaticojejunostomy time, postoperative hospital stay, or incidence of pancreatic fistula in the different pancreatic duct diameter groups. CONCLUSIONS: Continuous suture of pancreaticojejunostomy in LPD is simple, safe, reliable, and rapid. This technique not only saves the anastomosis time but also suitable for pancreatic ducts < 3 mm.

Clinical application of a modified pancreatojejunostomy technique for laparoscopic pancreaticoduodenectomy.

BACKGROUND: The aim of this study was to present a modified pancreatojejunostomy technique for laparoscopic pancreaticoduodenectomy (LPD) and to evaluate its safety and reliability. METHODS: Clinical data from 67 patients who underwent LPD at a single center, from September 2016 to December 2017 were retrospectively collected and analysed. Of these patients, 31 cases were subjected to modified pancreatojejunostomy (modified group), and 36 cases received duct-to-mucosa pancreatojejunostomy (control group) for LPD. We compared and analysed the operative outcomes and postoperative complications between the patients in the two groups. RESULTS: All LPDs were successfully completed. The mean operation time for pancreatojejunostomy in the modified group was obviously lower than that of the control group (30.9 ± 6.6 min vs 45.3 ± 6.1 min, P < 0.01), and the total operative time was also shorter (321.8 ± 63.6 min vs 362.2 ± 59.6 min, P < 0.05) in the modified group. The overall incidence of postoperative complications was similar (29.0% vs 30.6% P = 0.724). Clinically relevant grade B/C POPF occurred in 2 patients (6.5%) in the modified group and 3 patients (8.3%) in the control group (P = 0.947); All cases were cured using conservative treatment. CONCLUSIONS: Our modified pancreatojejunostomy technique is safe, effective and easy to manipulate and learn following LPD.

Tribbles pseudokinase 3 promoted renal fibrosis by regulating the expression of DNA damage-inducible transcript 3 in diabetic nephropathy.

Diabetic nephropathy (DN) is a severe complication of prolonged diabetes, impacting millions worldwide with an increasing incidence. This study investigates the role of tribbles pseudokinase 3 (TRIB3), a protein implicated in the progression of DN, focusing on its mechanisms underlying glomerular damage. Through analysis of the Gene Expression Omnibus (GEO) database, we identified TRIB3 among differentially expressed genes in streptozotocin (STZ)-treated C57BL/6J mice. Both in vitro and in vivo experiments were conducted to examine the effects of TRIB3 inhibition on high glucose (HG)-induced damage in podocytes and DN mouse models. The results demonstrated that TRIB3 inhibition reduced inflammatory responses and extracellular matrix (ECM) production in MPC5 cells, mediated by the downregulation of DNA damage-inducible transcript 3 (DDIT3) - a critical regulator of proinflammatory cytokine secretion and ECM synthesis. Inhibiting TRIB3 decreased inflammatory factors and ECM deposition in diabetic mice in vivo, confirming its pivotal role in DN pathogenesis. These findings indicate that TRIB3 and its interaction with DDIT3 contribute significantly to DN by promoting inflammatory cascades and ECM accumulation, presenting potential therapeutic targets for managing the disease.

A Self-Sustaining Antioxidant Strategy for Effective Treatment of Myocardial Infarction.

Myocardial infarction (MI) is the leading cause of death worldwide and can lead to the loss of cardiac function and heart failure. Reactive oxygen species (ROS) play a key role in the pathological progression of MI. The levels and effects of ROS are significantly different in three unique pathological stages of MI, and most antioxidants cannot make corresponding adjustments to eliminate ROS, which leads to a great compromise to treat MI with antioxidants. Herein, an innovative self-sustaining antioxidant strategy is developed to treat MI with self-sustaining selenium-embedded nanoparticles (SSSe NPs). SSSe NPs possess unique self-sustaining antioxidant effects at different pathological stages of MI. This strategy of on-demand ROS elimination during different pathological stages demonstrated excellent MI treatment efficacy and effectively reversed heart failure to normal heart function. The therapeutic mechanism of SSSe NPs is intensively investigated through a series of experiments and mainly involved five critical aspects of myocardial repair: protecting mitochondria, reducing cardiomyocyte apoptosis and ferroptosis, reducing inflammation and fibrosis, and promoting angiogenesis. This strategy not only provides a promising treatment option for MI but also offers inspiration for other ischemic diseases.

Short-Term Outcomes Following Laparoscopic vs Open Pancreaticoduodenectomy in Patients With Pancreatic Ductal Adenocarcinoma: A Randomized Clinical Trial.

Importance: The safety and efficacy of laparoscopic pancreaticoduodenectomy for pancreatic ductal adenocarcinoma remain controversial. Objective: To compare laparoscopic and open pancreaticoduodenectomy performed by experienced surgeons in patients with pancreatic ductal adenocarcinoma. Design, Setting, and Participants: This was a noninferiority, open-label randomized clinical trial between September 20, 2019 and March 20, 2022, at 10 hospitals in China. A total of 412 adult patients were assessed for eligibility; 200 patients with histologically confirmed or clinically diagnosed pancreatic ductal adenocarcinoma who were eligible to undergo pancreaticoduodenectomy were enrolled. Study recruitment is complete, and follow-up is ongoing. This article reports prespecified early safety results from the trial. Interventions: Participants were randomized in a 1:1 ratio to undergo either laparoscopic or open pancreaticoduodenectomy, to be performed by experienced surgeons who had already performed at least 104 laparoscopic pancreaticoduodenectomy operations. Main Outcomes and Measures: The primary end point is 5-year overall survival, but the data for this end point are not yet mature; thus, secondary short-term outcomes, including operative findings, complications, mortality, and oncological results are reported here. The outcomes were analyzed according to a modified intention-to-treat and per-protocol principle. Results: Among 412 patients for eligibility, 200 patients were enrolled and randomly assigned 1:1 to have laparoscopic pancreaticoduodenectomy or open pancreaticoduodenectomy. The mean (SD) age was 61.3 (9.3) years, and 78 participants (39%) were female. Laparoscopic procedures had longer operative times (median [IQR], 330.0 [287.5-405.0] minutes vs 297.0 [245.0-340.0] minutes; P < .001). Patients in the laparoscopic group lost less blood than those in the open group (median [IQR], 145.0 [100.0-200.0] mL vs 200.0 [100.0-425.0] mL; P = .02). Ninety-day mortality occurred in 2 of 100 patients in the laparoscopic group and 0 of 100 patients in the open group. There was no difference in the rates of complications of the Clavien-Dindo grades III-IV (n = 17 [17.0%] vs n = 23 [23.0%]; P = .29), comprehensive complication index (median [IQR], 0.0 [0.0-22.6] vs 8.7 [0.0-26.2]; P = .79) or median (IQR) postoperative length of stay (14.0 [11.0-17.0] days vs 14.0 [12.0-18.5] days; P = .37) between the 2 groups. Conclusions and Relevance: Laparoscopic pancreaticoduodenectomy performed by experienced surgeons in high-volume specialized institutions resulted in similar short-term outcomes compared with open pancreaticoduodenectomy among patients with pancreatic ductal adenocarcinoma. Trial Registration: ClinicalTrials.gov Identifier: NCT03785743.

Laparoscopic versus open pancreatoduodenectomy for pancreatic or periampullary tumours: a multicentre, open-label, randomised controlled trial.

BACKGROUND: The benefit and safety of laparoscopic pancreatoduodenectomy (LPD) for the treatment of pancreatic or periampullary tumours remain controversial. Studies have shown that the learning curve plays an important role in LPD, yet there are no randomised studies on LPD after the surgeons have surmounted the learning curve. The aim of this trial was to compare the outcomes of open pancreatoduodenectomy (OPD) with those of LPD, when performed by experienced surgeons. METHODS: In this multicentre, open-label, randomised controlled trial done in 14 Chinese medical centres, we recruited patients aged 18-75 years with a benign, premalignant, or malignant indication for pancreatoduodenectomy. Eligible patients were randomly assigned (1:1) to undergo either LPD or OPD. Randomisation was centralised via a computer-generated system that used a block size of four. The patients and surgeons were unmasked to study group, whereas the data collectors, outcome assessors, and data analysts were masked. LPD and OPD were performed by experienced surgeons who had already done at least 104 LPD operations. The primary outcome was the postoperative length of stay. The criteria for discharge were based on functional recovery, and analyses were done on a modified intention-to-treat basis (ie, including patients who had a pancreatoduodenectomy regardless of whether the operation was the one they were assigned to). This trial is registered with Clinicaltrials.gov, number NCT03138213. FINDINGS: Between May 18, 2018, and Dec 19, 2019, we assessed 762 patients for eligibility, of whom 656 were randomly assigned to either the LPD group (n=328) or the OPD group (n=328). 31 patients in each group were excluded and 80 patients crossed over (33 from LPD to OPD, 47 from OPD to LPD). In the modified intention-to-treat analysis (297 patients in the LPD group and 297 patients in the OPD group), the postoperative length of stay was significantly shorter for patients in the LPD group than for patients in the OPD group (median 15·0 days [95% CI 14·0-16·0] vs 16·0 days [15·0-17·0]; p=0·02). 90-day mortality was similar in both groups (five [2%] of 297 patients in the LPD group vs six [2%] of 297 in the OPD group, risk ratio [RR] 0·83 [95% CI 0·26-2·70]; p=0·76). The incidence rate of serious postoperative morbidities (Clavien-Dindo grade of at least 3) was not significantly different in the two groups (85 [29%] of 297 patients in the LPD group vs 69 [23%] of 297 patients in OPD group, RR 1·23 [95% CI 0·94-1·62]; p=0·13). The comprehensive complication index score was not significantly different between the two groups (median score 8·7 [IQR 0·0-26·2] vs 0·0 [0·0-20·9]; p=0·06). INTERPRETATION: In highly experienced hands, LPD is a safe and feasible procedure. It was associated with a shorter length of stay and similar short-term morbidity and mortality rates to OPD. Nonetheless, the clinical benefit of LPD compared with OPD was marginal despite extensive procedural expertise. Future research should focus on identifying the populations that will benefit from LPD. FUNDING: National Natural Science Foundation of China and Tongji Hospital, Huazhong University of Science and Technology, China.

ADAMTS8 Inhibits Cell Proliferation and Invasion, and Induces Apoptosis in Breast Cancer.

INTRODUCTION: A disintegrin and metallopeptidase with thrombospondin motifs (ADAMTSs), whose expression is dysregulated in various cancers, is implicated in cancer development. Herein, we aimed to investigate the functional role of ADAMTS8 in breast cancer (BC) and explore the underlying mechanisms. METHODS: The protein expression of ADAMTS8 in BC cell lines and tumor tissues from BC patients was quantified by Western blot. ADAMTS8 overexpression was induced by transfection with pEZ-M90-ADAMTS8 plasmid using lipofectamine 2000. To generate ADAMTS8 stable knockdown cells, MDA-MB-231 cells were transfected with psi-H1-ADAMTS8siRNA plasmids. Cell counting kit-8 (CCK-8) assay, wound-healing assay, transwell assay and flow cytometry assay were employed to analyze the effects of ADAMTS8 on the proliferation, migration, invasion and apoptosis of BC cells. Chemosensitivity also was assessed using CCK-8 assay. The expressions of ß-catenin, MMP-7 and c-Myc were measured by Western blot. RESULTS: Our results showed that ADAMTS8 expression was significantly lower in BC tissues than that in adjacent non-tumor tissues. Overexpression of ADAMTS8 in MDA-MB-453 cells could inhibit the cell proliferation, migration and invasion and promote apoptosis. ADAMTS8 knockdown displayed the reverse effect in MDA-MB-231 cells. Consistently, in vivo data showed that ADAMTS8 overexpression led to a reduction in tumor growth. In addition, chemosensitivity testing in MDA-MB-453 cells transfected with pEZ-M90-ADAMTS8 plasmid indicated that cisplatin inhibited cell growth dramatically. Furthermore, attenuated ß-catenin, MMP-7 and c-Myc level was detected after ADAMTS8 overexpression. CONCLUSION: These results indicate that increased ADAMTS8 expression could modify the progression of BC by inhibiting cell proliferation and invasion while promoting the apoptosis of BC cells. Thus, ADAMTS8 represents a potential therapeutic target for BC therapy.