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.

Short­ and long­term outcomes after laparoscopic and open pancreatoduodenectomy for elderly patients: a propensity score­matched study.

BACKGROUND: The feasibility and safety of laparoscopic pancreatoduodenectomy (LPD) in elderly patients is still controversial. This study aimed to compare the clinical outcomes of LPD and open pancreatoduodenectomy (OPD) in elderly patients. METHODS: Clinical and follow-up data of elderly patients (≥ 65 years) who underwent LPD or OPD between 2015 and 2022 were retrospectively analyzed. A 1:1 propensity score-matching (PSM) analysis was performed to minimize differences between groups. Univariate and multivariate logistic regression analysis were used to select independent prognostic factors for 90-day mortality. RESULTS: Of the 410 elderly patients, 236 underwent LPD and 174 OPD. After PSM, the LPD group had a less estimated blood loss (EBL) (100 vs. 200 mL, P < 0.001), lower rates of intraoperative transfusion (10.4% vs. 19.0%, P = 0.029), more lymph node harvest (11.0 vs. 10.0, P = 0.014) and shorter postoperative length of stay (LOS) (13.0 vs. 16.0 days, P = 0.013). There were no significant differences in serious complications, reoperation, 90-day readmission and mortality rates (all P > 0.05). Multivariate logistic regression analysis showed that post-pancreatectomy hemorrhage (PPH) was an independent risk factor for 90-day mortality. Elderly patients with pancreatic ductal adenocarcinoma (PDAC) who underwent LPD or OPD had similar overall survival (OS) (22.5 vs.20.4 months, P = 0.672) after PSM. CONCLUSIONS: It is safe and feasible for elderly patients to undergo LPD with less EBL and a shorter postoperative LOS. There was no statistically significant difference in long-term survival outcomes between elderly PDAC patients who underwent LPD or OPD.

Outcomes of Robotic Versus Laparoscopic Pancreatoduodenectomy Following Learning Curves of Surgeons: A Multicenter Study on 2255 Patients.

OBJECTIVE: This study aimed to compare robotic pancreatoduodenectomy (RPD) with laparoscopic pancreatoduodenectomy (LPD) in operative and oncologic outcomes. BACKGROUND: Previous studies comparing RPD with LPD have only been carried out in small, single-center studies with variable quality. METHODS: Consecutive patients from nine centers in China who underwent RPD or LPD between 2015 and 2022 were included. A 1:1 propensity score matching (PSM) was used to minimize bias. RESULTS: Of the 2,255 patients, 1158 underwent RPD and 1097 underwent LPD. Following PSM, 1006 patients were enrolled in each group. The RPD group had significantly shorter operative time (270.0 vs. 305.0 minutes, P<0.001), lower intraoperative blood transfusion rate (5.9% vs. 12.0%, P<0.001), lower conversion rate (3.8% vs. 6.7%, P=0.004), and higher vascular reconstruction rate (7.9% vs. 5.6%, P=0.040) than the LPD group. There were no significant differences in estimated blood loss, postoperative length of stay, perioperative complications, and 90-day mortality. Patients who underwent vascular reconstruction had similar outcomes between the two groups, although they had significantly lower estimated blood loss (300.0 vs. 360.0 mL; P=0.021) in the RPD group. Subgroup analysis on pancreatic ductal adenocarcinoma (PDAC) found no significant differences between the two groups in median recurrence-free survival (14.3 vs. 15.3 mo, P=0.573) and overall survival (24.1 vs. 23.7 mo, P=0.710). CONCLUSIONS: In experienced hands, both RPD and LPD are safe and feasible procedures with similar surgical outcomes. RPD had the perioperative advantage over LPD especially in vascular reconstruction. For PDAC patients, RPD resulted in similar oncological and survival outcomes as LPD.

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.

Development and validation of web calculators to predict early recurrence and long-term survival in patients with duodenal papilla carcinoma after pancreaticoduodenectomy.

BACKGROUND: Duodenal papilla carcinoma (DPC) is prone to relapse even after radical pancreaticoduodenectomy (PD) (including robotic, laparoscopic and open approach). This study aimed to develop web calculators to predict early recurrence (ER) (within two years after surgery) and long-term survival in patients with DPC after PD. METHODS: Patients with DPC after radical PD were included. Univariate and multivariate logistic regression analyses were used to identify independent risk factors. Two web calculators were developed based on independent risk factors in the training cohort and then tested in the validation cohort. RESULTS: Of the 251 patients who met the inclusion criteria, 180 and 71 patients were enrolled in the training and validation cohorts, respectively. Multivariate logistic regression analysis revealed that tumor size [Odds Ratio (OR) 1.386; 95% confidence interval (CI) 1070-1.797; P = 0.014]; number of lymph node metastasis (OR 2.535; 95% CI 1.114-5.769; P = 0.027), perineural invasion (OR 3.078; 95% CI 1.147-8.257; P = 0.026), and tumor differentiation (OR 3.552; 95% CI 1.132-11.152; P = 0.030) were independent risk factors for ER. Nomogram based on the above four factors achieved good C-statistics of 0.759 and 0.729 in predicting ER in the training and the validation cohorts, respectively. Time-dependent ROC analysis (timeROC) and decision curve analysis (DCA) revealed that the nomogram provided superior diagnostic capacity and net benefit compared with single variable. CONCLUSIONS: This study developed and validated two web calculators that can predict ER and long-term survival in patients with DPC with high degree of stability and accuracy.

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).

Identification of a glycolysis-related gene signature for predicting prognosis in patients with hepatocellular carcinoma.

BACKGROUND: Hepatocellular carcinoma (HCC) is the most common primary liver cancer in the world. Although great advances in HCC diagnosis and treatment have been achieved, due to the complicated mechanisms in tumor development and progression, the prognosis of HCC is still dismal. Recent studies have revealed that the Warburg effect is related to the development, progression and treatment of various cancers; however, there have been a few explorations of the relationship between glycolysis and HCC prognosis. METHODS: mRNA expression profiling was downloaded from public databases. Gene set enrichment analysis (GSEA) was used to explore glycolysis-related genes (GRGs), and the LASSO method and Cox regression analysis were used to identify GRGs related to HCC prognosis and to construct predictive models associated with overall survival (OS) and disease-free survival (DFS). The relationship between the predictive model and the tumor mutation burden (TMB) and tumor immune microenvironment (TIME) was explored. Finally, real-time PCR was used to validate the expression levels of the GRGs in clinical samples and different cell lines. RESULTS: Five GRGs (ABCB6, ANKZF1, B3GAT3, KIF20A and STC2) were identified and used to construct gene signatures to predict HCC OS and DFS. Using the median value, HCC patients were divided into low- and high-risk groups. Patients in the high-risk group had worse OS/DFS than those in the low-risk group, were related to higher TMB and were associated with a higher rate of CD4+ memory T cells resting and CD4+ memory T cells activated. Finally, real-time PCR suggested that the five GRGs were all dysregulated in HCC samples compared to adjacent normal samples. CONCLUSIONS: We identified five GRGs associated with HCC prognosis and constructed two GRGs-related gene signatures to predict HCC OS and DFS. The findings in this study may contribute to the prediction of prognosis and promote HCC treatment.

Impact of Postoperative Complications on Long-Term Survival After Resection of Hepatocellular Carcinoma: A Systematic Review and Meta-Analysis.

BACKGROUND: Controversy exists over the relationship between postoperative complications (POCs) and long-term survival for hepatocellular carcinoma (HCC) after hepatectomy. This study aimed to evaluate the impact of POCs on overall survival (OS) and disease-free survival (DFS) for HCC after liver resection. PATIENTS AND METHODS: The PubMed, EMBASE, and Cochrane Library databases were used to search for eligible studies published through 18 April 2020, and studies comparing the long-term outcomes between HCC patients with and without POCs after hepatectomy were included. A random-effects model was used to calculate the pooled hazard ratio (HR) with a 95% confidence interval (CI). Subgroup analysis and meta-regression were performed to assess the potential influence of study-, patient-, and tumor-related factors on the relationship between POCs and oncologic outcomes and to adjust their effect. This study was registered at the International Prospective Register of Systematic Reviews (CRD42019136109). RESULTS: Thirty-seven studies, including 14,096 patients, were deemed eligible and included in this study. Compared with those without POCs, patients who developed POCs had a significant reduction in OS (HR 1.39, 95% CI 1.28-1.50, P < 0.001; prediction interval 1.04-1.85) and tended to have worse DFS (HR 1.25, 95% CI 1.16-1.35, P < 0.001; prediction interval 0.98-1.60). Contour-enhanced funnel plots suggested a risk of publication bias. Subgroup analysis and meta-regression showed that POCs remained a threat to OS and DFS regardless of the influence of clinicopathological factors. CONCLUSION: This study demonstrated that POCs had an adverse impact on OS and DFS in HCC patients after liver resection.

A Modified Suture Technique in Hepaticojejunostomy.

BACKGROUND Hepaticojejunostomy is a common biliary reconstruction procedure in hepatobiliary surgery. The suture technique plays a key role in the procedure. The conventional suture technique is complex and time-consuming. To facilitate the procedure, we performed it with a modified suture technique. In the present study, we evaluated the efficacy and safety of the technique in hepaticojejunostomy. MATERIAL AND METHODS We enrolled 120 adult patients who underwent hepaticojejunostomy. The patients were divided into a conventional group and a modified suture group according to the suture technique used. Clinical data were collected for analysis. RESULTS No significant differences were found between the 2 groups in terms of demographic data. No significant differences were found between the 2 groups in terms of serum bilirubin, albumin, AST, ALT, or hemoglobin (p>0.05). There were no significant differences between the 2 groups in terms of bile hemorrhage, fever, or cholangitis (p>0.05). The incidences of stenosis and cholelithiasis were similar in the 2 groups (p>0.05). The incidence of bile leakage was lower in the modified suture group than in the conventional group (p=0.04). The average bile duct diameter was 25±6 mm in the modified continuous suture group and 29±7mm in the conventional group, but the difference was not statistically significant (p=0.5). The duration of the anastomosis procedure was 15.4±4.4 min in the modified continuous suture group, which was shorter than in the conventional group (p<0.05). CONCLUSIONS The modified continuous suture technique is efficient and safe for use in hepaticojejunostomy. It can facilitate the procedure and reduce the incidence of bile leakage after hepaticojejunostomy.

Silencing of RAB42 down-regulated PD-L1 expression to inhibit the immune escape of hepatocellular carcinoma cells through inhibiting the E2F signaling pathway.

OBJECTIVE: To investigate the mechanistic role of RAB42 and corresponding regulatory path in hepatocellular carcinoma (HCC). METHODS: The expression of RAB42 in HCC tissue was checked by RT-qPCR and immunohistochemical staining assay. Cell proliferation was checked by colony formation and CCK-8 assay. Cell apoptosis and cycle distribution were analyzed with flow cytometry. The relevance of RAB42 and PD-L1 was analyzed from TCGA database. The binding of E2F1 to PD-L1 was detected by JASPAR database, luciferase and ChIP assay. The expression of PD-L1, cell apoptosis- and E2F pathway-related proteins were checked by western blotting. RESULTS: RAB42 was highly expressed in HCC tissue. RAB42 silencing could inhibit proliferation and induce G1 phase arrest and apoptosis of HCC cells. TCGA database disclosed that PD-L1 was highly associated with RAB42 expression. Silencing of RAB42 could retard PD-L1 expression in HCC cells. GSEA analysis showed RAB42 could activate E2F signaling pathway. Silencing of RAB42 could observably weaken the expression of E2F1, CDK1 and CDC20 in HCC cells. JASPAR database predicted the binding site between E2F1 and PD-L1, and E2F1 overexpression could promote PD-L1 expression. Overexpression of E2F1 could reverse the biological function of RAB42 silencing in HCC cells. CONCLUSION: Silencing of RAB42 could down-regulate PD-L1 expression to inhibit immune escape through inhibiting E2F signaling pathway in HCC cells. RAB42 may become a novel clinical diagnostic and therapy marker for HCC.

IronForge: An Open, Secure, Fair, Decentralized Federated Learning.

Federated learning (FL) offers an effective learning architecture to protect data privacy in a distributed manner. However, the inevitable network asynchrony, overdependence on a central coordinator, and lack of an open and fair incentive mechanism collectively hinder FL's further development. We propose IronForge, a new generation of FL framework, that features a directed acyclic graph (DAG)-based structure, where nodes represent uploaded models, and referencing relationships between models form the DAG that guides the aggregation process. This design eliminates the need for central coordinators to achieve fully decentralized operations. IronForge runs in a public and open network and launches a fair incentive mechanism by enabling state consistency in the DAG. Hence, the system fits in networks where training resources are unevenly distributed. In addition, dedicated defense strategies against prevalent FL attacks on incentive fairness and data privacy are presented to ensure the security of IronForge. Experimental results based on a newly developed test bed FLSim highlight the superiority of IronForge to the existing prevalent FL frameworks under various specifications in performance, fairness, and security. To the best of our knowledge, IronForge is the first secure and fully decentralized FL (DFL) framework that can be applied in open networks with realistic network and training settings.

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.

Incidence of postoperative pancreatic fistula after using a defined pancreaticojejunostomy technique for laparoscopic pancreaticoduodenectomy: A prospective multicenter study on 1033 patients.

OBJECTIVE: This prospective multicenter study aimed to study the incidence of postoperative pancreatice fistula using a defined technique of pancreaticojejunostomy (PJ) in laparoscopic pancreaticoduodenectomy (LPD). BACKGROUND: PJ is a technically challenging and time-consuming procedure in LPD. Up to now, only a few small sample size studies have been reported on various PJ techniques in LPD, none of which has widely been accepted by surgeons. METHODS: This prospective study enrolled consecutive patients who underwent LPD using a defined technique of PJ at four institutions in China between January 2017 and December 2020. RESULTS: Of 1045 patients, after excluding 12 patients (1.2%) due to conversion to open surgery, 1033 patients were analysed. The males comprised of 57.12% (590/1033), and females 42.88% (443/1033), with a mean age of 59.00 years. The mean ± s.d. operation time was (270.2 ± 101.8) min. The median time for PJ was 24min (IQR = 20.0-30.0). The overall incidence of postoperative pancreatic fistula was 12.6%, including 67 patients (6.5%) with Grade A biochemical leak, 50 patients (4.8%) with Grade B, and 13 patients (1.3%) with Grade C pancreatic fistulas. The overall incidence of major complications (Clavien-Dindo score ≥3) was 6.3% and the 30-day mortality was 2.8%. CONCLUSION: The pancreaticojejunostomy technique for LPD was safe, simple and reproduceable with favorable clinical outcomes. However, further validations using high-quality RCTs are still required to confirm the findings of this study.

Second Primary Malignancies in Patients With Hepatocellular Carcinoma: A Population-Based Analysis.

BACKGROUND: Second primary malignancy (SPM) is becoming a threat for the health of cancer survivors. However, data on the features and results of patients with hepatocellular carcinoma (HCC) with SPMs are scarce. This study aimed to explore the characteristics of HCC patients with SPMs and to screen HCC patients who are at a high risk of developing SPMs. METHOD: HCC patients diagnosed between 2000 and 2014 in the Surveillance, Epidemiology, and End Results (SEER) database were retrospectively analyzed. Eligible patients were divided into the only one primary malignancy and SPM groups. The Fine-Gray proportional subdistribution hazards model was used to explore the risk factors of developing SPMs, and a competing-risk model was established to predict the probability of developing SPMs for HCC patients after initial diagnosis. The calibration curves, concordance index (C-index), and decision curve analysis (DCA) were used to evaluate the performance of the nomogram. RESULTS: A total of 40,314 HCC patients were identified, 1,593 (3.95%) of whom developed SPMs 2 months after the initial diagnosis with a maximum follow-up time of approximately 18 years. The 3-, 5-, and 10-year cumulative incidence of SPMs were 2.35%, 3.12%, and 4.51%, respectively. Age at initial diagnosis, extent of disease, tumor size, and treatment were identified as the independent risk factors of developing SPMs and integrated into the competing-risk nomogram. The C-index of the nomogram was 0.677 (95% confidence interval 0.676-0.678), and the calibration curves showed an excellent agreement between the nomogram prediction and the actual observations. Furthermore, DCA indicated that the nomogram had good net benefits in clinical scenarios. CONCLUSIONS: HCC survivors remain at a high risk of developing SPMs. The development of SPMs was associated with the clinical features and treatment strategies. A competing-risk nomogram was constructed to help surgeons identify the patients who are at a high risk of developing SPMs and contribute to the further management of SPMs.

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.

Tenofovir Treatment Has Lower Risk of Hepatocellular Carcinoma than Entecavir Treatment in Patients with Chronic Hepatitis B: A Systematic Review and Meta-Analysis.

PURPOSE: Tenofovir (TDF) and entecavir (ETV) are both equally recommended as first-line treatments for patients with chronic hepatitis B (CHB). They have comparable efficacy in virologic response, but their effect on the development of hepatocellular carcinoma (HCC) in CHB is controversial. Therefore, we aimed to compare TDF and ETV evaluating the risk of HCC development in CHB patients. METHODS: A systematic literature search was conducted up to November 2019 in MEDLINE/PubMed, SCOPUS, and Web of Science databases without language and time restrictions. DerSimonian and Laird random-effects models were used to estimate combined hazard ratios (HRs) and 95% CIs. RESULTS: Seven studies containing 35,785 participants were included in this systematic review and meta-analysis. The pooled HR (95% CI) of HCC in the patients who used TDF versus patients who used ETV was 0.75 (0.56-0.96). There was no significant heterogeneity detected among the included studies results (I2 = 47.5%). There was no significant publication bias detected among the included studies (Begg's p = 0.88 and Egger's regression test p = 0.96). CONCLUSIONS: Evidence to date suggests that TDF treatment is associated with significantly fewer cases of HCC when compared to ETV.

Transcoronary concentration gradient of sCD40L and hsCRP in patients with coronary heart disease.

BACKGROUND: Recent studies indicated that local inflammation played a pivotal role in the pathogenesis of coronary heart disease. Soluble CD40 ligand (sCD40L) and hsC- reactive protein (hsCRP) are important inflammatory mediators. However, whether they can reflect local coronary inflammation is unclear. HYPOTHESIS: We hypothesized that transcoronary concentration gradient of sCD40L could reflect local inflammation in patients with coronary heart disease (CHD) more reliably. METHODS: Forty subjects were divided into unstable angina pectoris (UAP) group (n=20), stable angina pectoris (SAP) group (n=10), and controls (n=10). Blood samples were collected from the coronary sinus (CS), aortic root (AO), and femoral vein (FV). The coronary circulation was expressed as CS-AO difference, while system circulation was expressed as FV-AO difference. sCD40L and hs-CRP were measured. RESULTS: Complex lesions were more frequent in the UAP group than in the SAP group (85% vs. 40%, p < 0.05). CS-AO differences of sCD40L were much greater in the UAP group than in the SAP or control groups, and were greatly higher than FV-AO difference in UAP group (465.49 +/- 247.85 pg/mL vs. -14.94 +/- 83.41 pg/mL; 465.49 +/- 247.85 pg/mL vs. -7.66 +/- 78.54 pg/mL; 465.49 +/- 247.85 pg/mL vs. -7.99 +/- 141.34 pg/mL, all p < 0.001). CS-AO differences of sCD40L were higher in patients with complex lesions than with smooth lesions (657.86 +/- 384.76 pg/mL vs. 317.62 +/- 409.98 pg/mL, p < 0.01). There were no significant differences of CS-AO in hs-CRP among the three groups. CONCLUSIONS: In patients with CHD, the transcoronary concentration gradient of sCD40L is more sensitive than hsCRP, and sCD40L possibly a better marker of local inflammation and plaque instability.

Dynamic regulation of uncoupling protein 2 expression by microRNA-214 in hepatocellular carcinoma.

Gemcitabine (GEM), a commonly used chemotherapeutic agent in hepatocellular carcinoma (HCC) patients, uses oxidative stress induction as a common effector pathway. However, GEM alone or in combination with oxaliplatin hardly renders any survival benefits to HCC patients. We have recently shown that this is part due to the overexpression of the mitochondrial uncoupling protein 2 (UCP2) that in turn mediates resistance to GEM in HCC patients. However, not much is known about regulatory mechanisms underlying UCP2 overexpression in HCC. Differential protein expression in HCC cell lines did not show a concomitant change in UCP2 transcript level, indicating post-transcriptional or post-translational regulatory mechanism. In situ analysis revealed that UCP2 is a putative target of miR-214 miR-214 expression is significantly down-regulated in HCC patient samples as compared with normal adjacent tissues and in cell line, human hepatoblastoma cells (HuH6), with high UCP2 protein expression. We demonstrated using miR-214 mimic and antagomir that the miRNA targeted UCP2 expression by directly targeting the wild-type, but not a miR-214 seed mutant, 3' UTR of UCP2 Overexpression of miR-214 significantly attenuated cell proliferation. Finally, analysis in 20 HCC patients revealed an inverse correlation in expression of UCP2 and miR-214 (Pearson's correlation coefficient, r=-0.9792). Cumulatively, our data indicate that in the context of HCC, miR-214 acts as a putative tumour suppressor by targeting UCP2 and defines a novel mechanism of regulation of UCP2.