Evaluation of quality and quantity of randomized controlled trials in hepatobiliary surgery: A scoping/mapping review.

AIM: To evaluate the quantity and quality of randomized controlled trials (RCTs) in hepatobiliary surgery and for identifying gaps in current evidences. METHODS: A systematic search was conducted in MEDLINE (via PubMed), Web of Science, and Cochrane Controlled Register of Trials (CENTRAL) for RCTs of hepatobiliary surgery published from inception until the end of 2023. The quality of each study was assessed using the Cochrane risk-of-bias (RoB) tool. The associations between risk of bias and the region and publication date were also assessed. Evidence mapping was performed to identify research gaps in the field. RESULTS: The study included 1187 records. The number and proportion of published randomized controlled trials (RCTs) in hepatobiliary surgery increased over time, from 13 RCTs (.0005% of publications) in 1970-1979 to 201 RCTs (.003% of publications) in 2020-2023. There was a significant increase in the number of studies with a low risk of bias in RoB domains (p < .01). The proportion of RCTs with low risk of bias improved significantly after the introduction of CONSORT guidelines (p < .001). The evidence mapping revealed a significant research focus on major and minor hepatectomy and cholecystectomy. However, gaps were identified in liver cyst surgery and hepatobiliary vascular surgery. Additionally, there are gaps in the field of perioperative management and nutrition intervention. CONCLUSION: The quantity and quality of RCTs in hepatobiliary surgery have increased over time, but there is still room for improvement. We have identified gaps in current research that can be addressed in future studies.

Promising Results of Associating Liver Partition and Portal Vein Ligation for Staged Hepatectomy for Perihilar Cholangiocarcinoma in a Systematic Review and Single-Arm Meta-Analysis.

BACKGROUND: ALPPS popularity is increasing among surgeons worldwide and its indications are expanding to cure patients with primarily unresectable liver tumors. Few reports recommended limitations or even contraindications of ALPPS in perihilar cholangiocarcinoma (phCC). Here, we discuss the results of ALPPS in patients with phCC in a systematic review as well as a pooled data analysis. METHODS: MEDLINE and Web of Science databases were systematically searched for relevant literature up to December 2023. All studies reporting ALPPS in the management of phCC were included. A single-arm meta-analysis of proportions was carried out to estimate the overall rate of outcomes. RESULTS: After obtaining 207 articles from the primary search, data of 18 studies containing 112 phCC patients were included in our systematic review. Rates of major morbidity and mortality were calculated to be 43% and 22%, respectively. The meta-analysis revealed a PHLF rate of 23%. One-year disease-free survival was 65% and one-year overall survival was 69%. CONCLUSIONS: ALPPS provides a good chance of cure for patients with phCC in comparison to alternative treatment options, but at the expense of debatable morbidity and mortality. With refinement of the surgical technique and better perioperative patient management, the results of ALPPS in patients with phCC were improved.

Promising Outcomes of Modified ALPPS for Staged Hepatectomy in Cholangiocarcinoma.

Associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) is a two-stage procedure that can potentially cure patients with large cholangiocarcinoma. The current study evaluates the impact of modifications on the outcomes of ALPPS in patients with cholangiocarcinoma. In this single-center study, a series of 30 consecutive patients with cholangiocarcinoma (22 extrahepatic and 8 intrahepatic) who underwent ALPPS between 2011 and 2021 was evaluated. The ALPPS procedure in our center was modified in 2016 by minimizing the first stage of the surgical procedure through biliary externalization after the first stage, antibiotic administration during the interstage phase, and performing biliary reconstructions during the second stage. The rate of postoperative major morbidity and 90-day mortality, as well as the one- and three-year disease-free and overall survival rates were calculated and compared between patients operated before and after 2016. The ALPPS risk score before the second stage of the procedure was lower in patients who were operated on after 2016 (before 2016: median 6.4; after 2016: median 4.4; p = 0.010). Major morbidity decreased from 42.9% before 2016 to 31.3% after 2016, and the 90-day mortality rate decreased from 35.7% before 2016 to 12.5% after 2016. The three-year survival rate increased from 40.8% before 2016 to 73.4% after 2016. Our modified ALPPS procedure improved perioperative and postoperative outcomes in patients with extrahepatic and intrahepatic cholangiocarcinoma. Minimizing the first step of the ALPPS procedure was key to these improvements.

Risk factors and management of biliary leakage after Endocystectomy for hepatic cystic echinococcosis.

BACKGROUND: Endocystectomy is a conservative surgical approach to managing cystic echinococcosis. Bile leakage is the main complication of this technique. The aim of this study was to evaluate the factors associated with bile leakage and to assess the outcomes and cost efficiency of strategies used to treat bile leakage. METHODOLOGY/PRINCIPAL FINDINGS: Patients who underwent endocystectomy between 2005 and 2020 were included. The preoperative characteristics, intra- and postoperative outcomes, hospital costs, and cost efficiency (the Diagnosis-Related Group reimbursement minus the overall cost) were evaluated prospectively. A total of eighty patients with 142 cysts were included. Postoperative complications occurred in 17 patients (21%), including 11 patients with bile leakage (type A: 1, type B: 6 and type C: 4 patients, total 13%). Bile leakage was more frequent in patients with preoperative MRI signs of cysto-biliary fistulas or intraoperative visible cysto-biliary fistulas (p = 0.03 and p = 0.04, respectively) and in patients with cysts larger than 8 cm (p = 0.03). Patients with bile leakage who underwent reoperation (type C) had significantly shorter hospital stays (9 vs. 16 days, p<0.01) and better cost efficiency than those who received radiologic or endocscopic interventions (€2,072 vs. -€2,097 p = 0.01). No mortality was observed, and recurrence was seen in two patients. CONCLUSIONS/SIGNIFICANCE: Endocystectomy is a safe and efficient technique. Preoperative and intraoperative cysto-biliary fistulas and a cyst diameter larger than 8 cm are correlated to postoperative bile leakage. Early operative management of bile leakage reduces hospital stay and improves cost efficiency compared with radiologic or endoscopic treatments.

Association of perioperative use of statins, metformin, and aspirin with recurrence after curative liver resection in patients with hepatocellular carcinoma: A propensity score matching analysis.

BACKGROUND: Statins, metformin, and aspirin have been reported to reduce the incidence of hepatocellular carcinoma (HCC). However, the effect of their perioperative use on survival outcomes of HCC patients following curative liver resection still remains unclear. METHOD: Three hundred and fifty three patients with a first diagnosis of HCC who underwent curative liver resection were included. Propensity score matching analysis with a users: nonusers ratio of 1:2 were performed for each of the medications (statins, metformin, and aspirin). Overall survival (OS) and recurrence-free survival (RFS) were evaluated and multivariable Cox proportional hazard analysis was performed. RESULTS: Sixty two patients received statins, 48 patients used metformin, and 53 patients received aspirin for ≥90 days before surgery. None of the medications improved OS. RFS of statin users was significantly longer than that of nonusers (p = 0.021) in the matched cohort. Users of hydrophilic statins, but not lipophilic ones had a significantly longer RFS than nonusers. Multivariable analysis showed that statin use significantly improved RFS (hazard ratio [HR]: 0.41, 95% confidence interval [CI]: 0.17-0.97, p = 0.044). No difference was seen in RFS between metformin users and nonusers. Among patients with diabetes, RFS was nonsignificantly longer in metformin users than in non-metformin users (84.1% vs. 60.85%, p = 0.069) in the matched cohort. No difference in postoperative RFS was seen between aspirin users and nonusers. CONCLUSION: Preoperative use of statins in patients with HCC can increase RFS after curative liver resection, but metformin and aspirin were not associated with improved survival. Randomized controlled trials are needed to confirm the findings of the present study.

Assessing textbook outcomes following major liver surgery in association with obesity at a referral academic center.

INTRODUCTION: Outcomes of major surgeries in tertiary educational hospitals have been complicated by the referral of high-risk patients and the participation of trainees in surgical procedures. We analyzed outcomes of major hepatectomies in a tertiary academic setting emphasizing the role of training and obesity on textbook outcomes (TO). MATERIALS AND METHODS: 971 adult patients who underwent open major hepatectomy (Mesohepatectomy [n = 111], hemihepatectomy [n = 610], and extended hepatectomy [n = 250]) were evaluated. A TO was defined as: a negative resection margin, no grade B/C bile leak, no major complications, no in-hospital mortality, and no 30-day readmission. TOs were compared following operations performed by senior surgeons and those performed by junior surgeons under the supervision of senior surgeons and between patients with and without obesity. RESULTS: TO was achieved in 70.1% of patients overall (78.4% in mesohepatectomy, 73.1% in hemihepatectomy, and 59.2% in extended hepatectomy). The rate of TO was similar following operations performed by and supervised by a senior surgeon (69.3% vs 71.0%, p = 0.570). The rate of TO was significantly lower in patients with obesity (41.5% vs 74.6%, p < 0.001). Factors including increased age (odds ratio [OR] for 10-year increase = 0.83, 95% confidence interval [CI]: 0.73-0.96, p = 0.009), obesity (OR = 0.25, 95%CI: 0.16-0.37, p < 0.001), biliodigestive anastomosis (OR = 0.27, 95%CI: 0.19-0.40, p < 0.001), and portal vein resection (OR = 0.49, 95%CI: 0.28-0.87, p = 0.014) lower the rate of TO. CONCLUSION: Promising outcomes are possible after major hepatectomy in an academic setting. Obese patients and those undergoing more complex surgeries had a higher risk of poor postoperative outcomes.

Robot-assisted versus laparoscopic living donor nephrectomy: superior outcomes after completion of the learning curve.

The use of robots in donor nephrectomy has increased in recent years. However, whether robot-assisted methods have better outcomes than traditional laparoscopic methods and how surgical experience influences these outcomes remains unclear. This meta-analysis compares the outcomes of robot-assisted donor nephrectomy (RADN) with those of laparoscopic donor nephrectomy (LDN) and to investigate the effects of surgical experience on these outcomes. A systematic literature search was conducted in Medline (through PubMed) and Web of Science databases. Perioperative data were extracted for meta-analysis. To assess the impact of the learning curve, a subgroup analysis was performed to compare outcomes between inexperienced and experienced surgeons. Seventeen studies with 6970 donors were included. Blood loss was lower (mean difference [MD] = - 13.28, p < 0.01) and the warm ischemia time was shorter (MD = - 0.13, p < 0.05) in the LDN group than the RADN group. There were no significant differences in terms of conversion to open surgery, operation time, surgical complications, hospital stay, costs, and delayed graft function between the groups. Subgroup analysis revealed that operation time (MD = - 1.09, p < 0.01) and length of hospital stay (MD = - 1.54, p < 0.05) were shorter and the rate of conversion to open surgery (odds ratios [OR] = 0.14, p < 0.0001) and overall surgical complications (OR = 0.23, p < 0.05) were lower in experienced RADN surgeons than in experienced LDN surgeons. Surgical experience enhances the perioperative outcomes following RADN more than it does following LDN. This suggests that RADN could be the method of choice for living donor nephrectomy as soon as surgeons gain sufficient experience in robotic surgery.

Surgical management of primary liver cancers during the COVID-19 pandemic: overcoming the dilemma with standardization.

BACKGROUND: The present study evaluates the impact of the pandemic on outcomes after surgical treatment for primary liver cancer in a high-volume hepatopancreatobiliary surgery center. METHODS: Patients, who underwent liver resection for primary liver resection between January 2019 and February 2020, comprised pre-pandemic control group. The pandemic period was divided into two timeframes: early pandemic (March 2020-January 2021) and late pandemic (February 2021-December 2021). Liver resections during 2022 were considered as the post-pandemic period. Peri-, and postoperative patient data were gathered from a prospectively maintained database. RESULTS: Two-hundred-eighty-one patients underwent liver resection for primary liver cancer. The number of procedures decreased by 37.1% during early phase of pandemic, but then increased by 66.7% during late phase, which was comparable to post-pandemic phase. Postoperative outcomes were similar between four phases. The duration of hospital stay was longer during the late phase, but not significantly different compared to other groups. CONCLUSION: Despite an initial reduction in number of surgeries, COVID-19 pandemic had no negative effect on outcomes of surgical treatment for primary liver cancer. The structured standard operating protocol in a high-volume and highly specialized surgical center can withstand negative effects, a pandemic may have on treatment of patients.

Correction: Oweira et al. Kynurenine Is the Main Metabolite of Tryptophan Degradation by Tryptophan 2,3-Dioxygenase in HepaRG Tumor Cells. J. Clin. Med. 2022, 11, 4794.

There was an error in the original publication [...].

Comparison of the modified piggyback with standard piggyback and conventional orthotopic liver transplantation techniques: a network meta-analysis.

BACKGROUND: In conventional orthotopic liver transplantation (OLT), the recipient's retrohepatic inferior vena cava (IVC) is completely clamped and replaced with the donor IVC. The piggyback technique has been used to preserve venous return, either via an end-to-side or standard piggyback (SPB), or via a side-to-side or modified piggyback (MPB) anastomosis, using a venous cuff from the recipient hepatic veins with partially clamping and preserves the recipient's inferior vena cava. However, whether these piggyback techniques improve the efficacy of OLT is unclear. To address the low quality of the available evidence, we performed a meta-analysis to compare the efficacy of conventional, MPB, and SPB techniques. METHODS: Literature was searched in Medline and Web of Science databases for relevant articles published until 2021 without any time restriction. A Bayesian network meta-analysis was performed to compare the intra- and postoperative outcomes of conventional OLT, MPB, and SPB techniques. RESULTS: Forty studies were included, comprising 10,238 patients. MPB and SPB had significantly shorter operation times and fewer transfusions of red blood cell and fresh frozen plasma than conventional techniques. However, there were no differences between MPB and SPB in operation time and blood product transfusion. There were also no differences in primary non-function, retransplantation, portal vein thrombosis, acute kidney injury, renal dysfunction, venous outflow complications, length of hospital and intensive care unit stay, 90-day mortality rate, and graft survival between the three techniques. CONCLUSION: MBP and SBP techniques reduce the operation time and need for blood transfusion compared with conventional OLT, but postoperative outcomes are similar. This indicates that all techniques can be implemented based on the experience and policy of the transplant center.

Distal Pancreatectomy With En Bloc Celiac Axis Resection (DP-CAR) for Locally Advanced Pancreatic Cancer: A Safe and Effective Procedure.

OBJECTIVE: To determine perioperative and oncologic outcomes after distal pancreatectomy with en bloc resection of the celiac axis (DP-CAR). BACKGROUND: DP-CAR can be used in a selective group of patients to resect locally advanced pancreatic cancer involving the celiac axis or common hepatic artery without arterial reconstruction by preserving retrograde blood flow via the gastroduodenal artery to the liver and stomach. METHODS: We analyzed all consecutive patients who had undergone DP-CAR between May 2003 and April 2022 at a tertiary hospital specialized in pancreatic surgery and present one of the largest single-center studies. RESULTS: A total of 71 patients underwent DP-CAR. Additional venous resection (VR) of the mesenterico-portal axis was performed in 31 patients (44%) and multivisceral resection (MVR) in 42 patients (59%). Margin-free (R0) resection was achieved in 40 patients (56%). The overall 90-day mortality rate was 8.4% for the entire patient cohort. After a cumulated experience of 16 cases, the 90-day mortality dropped to 3.6% in the following 55 patients. Extended procedures with (+) additional MVR with or without (+/-) VR resulted in higher major morbidity (Clavien-Dindo ≥IIIB; standard DP-CAR: 19%; DP-CAR + MVR +/- VR: 36%) and higher 90-day mortality (standard DP-CAR: 0%; DP-CAR + MVR +/- VR: 11%). Median overall survival after DP-CAR was 28 months. CONCLUSIONS: DP-CAR is a safe and effective procedure but requires experience. Frequently, surgical resection has to be extended with MVR and VR to accomplish tumor resection, which results in promising oncologic outcomes. However, extended resections were associated with increased morbidity and mortality.

Declined Organs for Liver Transplantation: A Right Decision or a Missed Opportunity for Patients with Hepatocellular Carcinoma?

BACKGROUND: Liver transplantation is the only promising treatment for end-stage liver disease and patients with hepatocellular carcinoma. However, too many organs are rejected for transplantation. METHODS: We analyzed the factors involved in organ allocation in our transplant center and reviewed all livers that were declined for transplantation. Reasons for declining organs for transplantation were categorized as major extended donor criteria (maEDC), size mismatch and vascular problems, medical reasons and risk of disease transmission, and other reasons. The fate of the declined organs was analyzed. RESULTS: 1086 declined organs were offered 1200 times. A total of 31% of the livers were declined because of maEDC, 35.5% because of size mismatch and vascular problems, 15.8% because of medical reasons and risk of disease transmission, and 20.7% because of other reasons. A total of 40% of the declined organs were allocated and transplanted. A total of 50% of the organs were completely discarded, and significantly more of these grafts had maEDC than grafts that were eventually allocated (37.5% vs. 17.7%, p < 0.001). CONCLUSION: Most organs were declined because of poor organ quality. Donor-recipient matching at time of allocation and organ preservation must be improved by allocating maEDC grafts using individualized algorithms that avoid high-risk donor-recipient combinations and unnecessary organ declination.

Bariatric surgery in patients with obesity and end-stage renal disease.

BACKGROUND: Bariatric surgery has been suggested as a treatment for obesity and end-stage renal disease (ESRD). Although the number of bariatric surgeries in patients with ESRD is increasing, its safety and effectiveness in these patients are still controversial and the surgical method of choice in these patients is under debate. OBJECTIVES: To compare the outcomes of bariatric surgery between patients with and without ESRD and to assess different methods of bariatric surgery in patients with ESRD. SETTING: Meta-analysis. METHODS: A comprehensive search was conducted in Web of Science and Medline (via Pubmed) until May 2022. Tow meta-analyses were performed: A) to compare bariatric surgery outcomes among patients with and without ESRD, and B) to compare outcomes of Roux-en-Y gastric bypass (RYGB) and sleeve gastrectomy (SG) in patients with ESRD. Using a random-effect model, odds ratios (ORs) and mean differences (MDs) with 95% confidence intervals (CIs) were computed for surgical and weight loss outcomes. RESULTS: Of 5895 articles, 6 studies were included in meta-analysis A and 8 studies in meta-analysis B. The risk of bias was moderate to serious among studies. Major postoperative complications (OR = 2.82; 95% CI = 1.66-4.77; P = .0001), reoperation (OR = 2.66; 95% CI = 1.99-3.56; P < .00001), readmission (OR = 2.37; 95% CI = 1.55-3.64; P < .0001), and in-hospital/90-d mortality (OR = 4.03; 95% CI = 1.80-9.03; P = .0007) were higher in patients with ESRD. Patients with ESRD also had a longer hospital stay (MD = 1.23; 95% CI = .32-2.14; P = .008). Bleeding, leakage, and total weight loss were comparable among groups. SG showed a 10% lower rate of overall complications and significantly shorter hospital stay than RYGB did. The quality of evidence was very low for the outcomes CONCLUSIONS: Bariatric surgery in patients with ESRD seems to have higher rates of major complications and perioperative mortality than in patients without ESRD, but a comparable rate of overall complications. SG has fewer postoperative complications and could be the method of choice in these patients. These findings should be interpreted cautiously in light of the moderate to high risk of bias in most included studies.

Outcomes of Robot-Assisted Surgery in Rectal Cancer Compared with Open and Laparoscopic Surgery.

With increasing trends for the adoption of robotic surgery, many centers are considering changing their practices from open or laparoscopic to robot-assisted surgery for rectal cancer. We compared the outcomes of robot-assisted rectal resection with those of open and laparoscopic surgery. We searched Medline, Web of Science, and CENTRAL databases until October 2022. All randomized controlled trials (RCTs) and prospective studies comparing robotic surgery with open or laparoscopic rectal resection were included. Fifteen RCTs and 11 prospective studies involving 6922 patients were included. The meta-analysis revealed that robotic surgery has lower blood loss, less surgical site infection, shorter hospital stays, and higher negative resection margins than open resection. Robotic surgery also has lower conversion rates, lower blood loss, lower rates of reoperation, and higher negative circumferential margins than laparoscopic surgery. Robotic surgery had longer operation times and higher costs than open and laparoscopic surgery. There were no differences in other complications, mortality, and survival between robotic surgery and the open or laparoscopic approach. However, heterogeneity between studies was moderate to high in some analyses. The robotic approach can be the method of choice for centers planning to change from open to minimally invasive rectal surgery. The higher costs of robotic surgery should be considered as a substitute for laparoscopic surgery (PROSPERO: CRD42022381468).

Kynurenine Is the Main Metabolite of Tryptophan Degradation by Tryptophan 2,3-Dioxygenase in HepG2 Tumor Cells.

There are two main enzymes that convert tryptophan (Trp) to kynurenine (Kyn): tryptophan-2,3-dioxygenase (TDO) and indoleamine 2,3-dioxygenase (IDO). Kyn accumulation can promote immunosuppression in certain cancers. In this study, we investigated Trp degradation to Kyn by IDO and TDO in primary human hepatocytes (PHH) and tumoral HepG2 cells. To quantify Trp-degradation and Kyn-accumulation, using reversed-phase high-pressure liquid chromatography, the levels of Trp and Kyn were determined in the culture media of PHH and HepG2 cells. The role of IDO in Trp metabolism was investigated by activating IDO with IFN-γ and inhibiting IDO with 1-methyl-tryptophan (1-DL-MT). The role of TDO was investigated using one of two TDO inhibitors: 680C91 or LM10. Real-time PCR was used to measure TDO and IDO expression. Trp was degraded in both PHH and HepG2 cells, but degradation was higher in PHH cells. However, Kyn accumulation was higher in the supernatants of HepG2 cells. Stimulating IDO with IFN-γ did not significantly affect Trp degradation and Kyn accumulation, even though it strongly upregulated IDO expression. Inhibiting IDO with 1-DL-MT also had no effect on Trp degradation. In contrast, inhibiting TDO with 680C91 or LM10 significantly reduced Trp degradation. The expression of TDO but not of IDO correlated positively with Kyn accumulation in the HepG2 cell culture media. Furthermore, TDO degraded L-Trp but not D-Trp in HepG2 cells. Kyn is the main metabolite of Trp degradation by TDO in HepG2 cells. The accumulation of Kyn in HepG2 cells could be a key mechanism for tumor immune resistance. Two TDO inhibitors, 680C91 and LM10, could be useful in immunotherapy for liver cancers.

Long-Term Outcomes of Mesohepatectomy for Centrally Located Liver Tumors: Two-Decade Single-Center Experience.

BACKGROUND: Mesohepatectomy is a viable treatment option for patients diagnosed with centrally located liver tumors (CLLTs). There are several reports from Eastern centers, but few data are available on this topic from Western centers. STUDY DESIGN: Data of 128 consecutive patients who underwent mesohepatectomy between September 2000 and September 2020 in our center were analyzed from a prospectively collected database. Patient demographic data, liver tumor characteristics, and intraoperative data were collected. In addition, posthepatectomy bile leakage (PHBL), posthepatectomy hemorrhage (PHH), posthepatectomy liver failure (PHLF), and 90-day mortality after mesohepatectomy were assessed. Long-term outcomes were also reported, and factors that may influence disease-free survival were evaluated. RESULTS: Of 128 patients, 113 patients (88.3%) had malignant hepatic tumors (primary and metastatic tumors in 41 [32%] and 72 [56.3%] patients, respectively), and 15 patients suffered from benign lesions (11.7%). Among the relevant surgical complications (grade B or C), PHBL was the most common complication after mesohepatectomy and occurred in 11.7% of patients, followed by PHLF in 3.1% of patients and PHH in 2.3% of patients. Only four patients (3.1%) died within 90 days after mesohepatectomy. The 5-year overall survival and overall recurrence (for malignant lesion) rates were 76.5% and 45.1%, respectively. CONCLUSION: Mesohepatectomy is a safe and feasible surgical treatment with low morbidity and mortality for patients with CLLT. Long-term outcomes can be improved by increased surgical expertise.