Entecavir versus tenofovir on the recurrence of hepatitis B-related HCC after liver transplantation: A multicenter observational study.

Considerable controversy exists regarding the superiority of tenofovir disoproxil fumarate (TDF) over entecavir (ETV) for reducing the risk of HCC. This study aimed to compare outcomes of ETV versus TDF after liver transplantation (LT) in patients with HBV-related HCC. We performed a multicenter observational study using data from the Korean Organ Transplantation Registry. A total of 845 patients who underwent LT for HBV-related HCC were divided into 2 groups according to oral nucleos(t)ide analogue used for HBV prophylaxis post-LT: ETV group (n = 393) and TDF group (n = 452). HCC recurrence and overall death were compared in naïve and propensity score (PS)-weighted populations, and the likelihood of these outcomes according to the use of ETV or TDF were analyzed with various Cox models. At 1, 3, and 5 years, the ETV and TDF groups had similar HCC recurrence-free survival (90.7%, 85.6%, and 84.1% vs. 90.9%, 84.6%, and 84.2%, respectively, p = 0.98) and overall survival (98.4%, 94.7%, and 93.5% vs. 99.3%, 95.8%, and 94.9%, respectively, p = 0.48). The propensity score-weighted population showed similar results. In Cox models involving covariates adjustment, propensity score-weighting, competing risk regression, and time-dependent covariates adjustment, both groups showed a similar risk of HCC recurrence and overall death. In subgroup analyses stratified according to HCC burden (Milan criteria, Up-to-7 criteria, French alpha-fetoprotein risk score), pretransplantation locoregional therapy, and salvage LT, neither ETV nor TDF was superior. In conclusion, ETV and TDF showed mutual noninferiority for HCC outcomes when used for HBV prophylaxis after LT.

Consensus subtypes of hepatocellular carcinoma associated with clinical outcomes and genomic phenotypes.

BACKGROUND AND AIMS: Although many studies revealed transcriptomic subtypes of HCC, concordance of the subtypes are not fully examined. We aim to examine a consensus of transcriptomic subtypes and correlate them with clinical outcomes. APPROACH AND RESULTS: By integrating 16 previously established genomic signatures for HCC subtypes, we identified five clinically and molecularly distinct consensus subtypes. STM (STeM) is characterized by high stem cell features, vascular invasion, and poor prognosis. CIN (Chromosomal INstability) has moderate stem cell features, but high genomic instability and low immune activity. IMH (IMmune High) is characterized by high immune activity. BCM (Beta-Catenin with high Male predominance) is characterized by prominent ß-catenin activation, low miRNA expression, hypomethylation, and high sensitivity to sorafenib. DLP (Differentiated and Low Proliferation) is differentiated with high hepatocyte nuclear factor 4A activity. We also developed and validated a robust predictor of consensus subtype with 100 genes and demonstrated that five subtypes were well conserved in patient-derived xenograft models and cell lines. By analyzing serum proteomic data from the same patients, we further identified potential serum biomarkers that can stratify patients into subtypes. CONCLUSIONS: Five HCC subtypes are correlated with genomic phenotypes and clinical outcomes and highly conserved in preclinical models, providing a framework for selecting the most appropriate models for preclinical studies.

Survival outcome of surgical resection compared to non-resection for Bismuth type IV perihilar cholangiocarcinoma.

BACKGROUND/OBJECTIVES: Bismuth type IV perihilar cholangiocarcinoma has been considered an unresectable disease. The aim of the study was to assess whether the surgical resection of type IV perihilar cholangiocarcinoma was associated with better survival rates. METHODS: The data of 117 patients diagnosed with type IV perihilar cholangiocarcinoma at Keimyung University Dongsan Hospital from 2005 to 2020 were retrospectively reviewed. The Bismuth type was assigned based on the patient's radiological imaging findings. The primary outcomes were the surgical results and median overall survival. RESULTS: The demographic characteristics of the 117 patients with type IV perihilar cholangiocarcinoma were comparable between the surgical resection and non-resection groups. Thirty-two (27.4%) patients underwent surgical resections. A left hepatectomy was performed in 16 patients, right hepatectomy in 13 patients, and a central bi-sectionectomy in three patients. The remaining 85 patients received non-surgical treatments. Thirteen (10.9%) received palliative chemotherapy, and 72 (60.5%) patients received conservative treatment including biliary drainage. The patients in the resection group showed significantly longer median overall survival than the patients in the non-resection group (32.4 vs 16.0 months; P = 0.002), even though the positive resection margin rate was high (62.5%). Surgical complications occurred in 15 (46.9%) patients. Complications of Clavien-Dindo classification grade III or higher occurred in 13 (40.6%) patients and grade V in two patients (6.3%). CONCLUSION: Surgical resection for Bismuth type IV perihilar cholangiocarcinoma is technically demanding. The survival of the resection group was significantly better than that of the non-resection group. The resection of selected patients achieved a curative goal with acceptable postoperative morbidity, although the microscopically positive resection margin rate was high.

Liver Resection Versus Local Ablation Therapies for Hepatocellular Carcinoma Within the Milan Criteria: A Systematic Review and Meta-analysis.

OBJECTIVE: To compare the oncologic outcomes of liver resection (LR) and local ablation therapies for HCC. SUMMARY OF BACKGROUND DATA: Although several studies have compared LR and local ablation therapies, the optimal treatment of choice for HCC within the Milan criteria remains controversial. METHODS: We systemically searched the MEDLINE, Embase, and Cochrane Library databases for randomized control trials (RCTs) and matched nonrandomized trials (NRTs) that compared LR and local ablation therapies for HCC within the Milan criteria. The primary outcome was overall survival (OS). Secondary outcomes were recurrence free survival (RFS) and recurrence pattern. RESULTS: A total of 7 RCTs and 18 matched NRTs, involving 2865 patients in the LR group and 2764 patients in the local ablation therapy group [RFA, MWA, RFA plus trans-arterial chemoembolization (TACE)], were included. Although there was no significant difference in OS between LR and RFA, LR showed a significantly better 5-year RFS than RFA in the analysis of RCTs (hazards ratio: 0.75; 95% confidence interval: 0.62-0.92; P = 0.006). The RFA group showed a significantly higher local recurrence than the LR group in both analyses of RCTs and NRTs. Additionally, the LR group showed better OS and RFS than the MWA or RFA plus TACE groups. CONCLUSION: Our meta-analysis showed that LR was superior to RFA in terms of RFS and incidence of local recurrence. Moreover, LR showed better oncologic outcomes than MWA or RFA plus TACE.

Perihilar Cholangiocarcinoma - Novel Benchmark Values for Surgical and Oncological Outcomes From 24 Expert Centers.

OBJECTIVE: The aim of this study was to define robust benchmark values for the surgical treatment of perihilar cholangiocarcinomas (PHC) to enable unbiased comparisons. BACKGROUND: Despite ongoing efforts, postoperative mortality and morbidity remains high after complex liver surgery for PHC. Benchmark data of best achievable results in surgical PHC treatment are however still lacking. METHODS: This study analyzed consecutive patients undergoing major liver surgery for PHC in 24 high-volume centers in 3 continents over the recent 5-year period (2014-2018) with a minimum follow-up of 1 year in each patient. Benchmark patients were those operated at high-volume centers (≥50 cases during the study period) without the need for vascular reconstruction due to tumor invasion, or the presence of significant co-morbidities such as severe obesity (body mass index ≥35), diabetes, or cardiovascular diseases. Benchmark cutoff values were derived from the 75th or 25th percentile of the median values of all benchmark centers. RESULTS: Seven hundred eight (39%) of a total of 1829 consecutive patients qualified as benchmark cases. Benchmark cut-offs included: R0 resection ≥57%, postoperative liver failure (International Study Group of Liver Surgery): ≤35%; in-hospital and 3-month mortality rates ≤8% and ≤13%, respectively; 3-month grade 3 complications and the CCI: ≤70% and ≤30.5, respectively; bile leak-rate: ≤47% and 5-year overall survival of ≥39.7%. Centers operating mostly on complex cases disclosed better outcome including lower post-operative liver failure rates (4% vs 13%; P = 0.002). Centers from Asia disclosed better outcomes. CONCLUSION: Surgery for PHC remains associated with high morbidity and mortality with now the availability of benchmark values covering 21 outcome parameters, which may serve as key references for comparison in any future analyses of individuals, group of patients or centers.

Choices of Therapeutic Strategies for Colorectal Liver Metastases Among Expert Liver Surgeons: A Throw of the Dice?

OBJECTIVE: To test the degree of agreement in selecting therapeutic options for patients suffering from colorectal liver metastasis (CRLM) among surgical experts around the globe. SUMMARY/BACKGROUND: Only few areas in medicine have seen so many novel therapeutic options over the past decades as for liver tumors. Significant variations may therefore exist regarding the choices of treatment, even among experts, which may confuse both the medical community and patients. METHODS: Ten cases of CRLM with different levels of complexity were presented to 43 expert liver surgeons from 23 countries and 4 continents. Experts were defined as experienced surgeons with academic contributions to the field of liver tumors. Experts provided information on their medical education and current practice in liver surgery and transplantation. Using an online platform, they chose their strategy in treating each case from defined multiple choices with added comments. Inter-rater agreement among experts and cases was calculated using free-marginal multirater kappa methodology. A similar, but adjusted survey was presented to 60 general surgeons from Asia, Europe, and North America to test their attitude in treating or referring complex patients to expert centers. RESULTS: Thirty-eight (88%) experts completed the evaluation. Most of them are in leading positions (92%) with a median clinical experience of 25 years. Agreement on therapeutic strategies among them was none to minimal in more than half of the cases with kappa varying from 0.00 to 0.39. Many general surgeons may not refer the complex cases to expert centers, including in Europe, where they also engage in complex liver surgeries. CONCLUSIONS: Considerable inconsistencies of decision-making exist among expert surgeons when choosing a therapeutic strategy for CRLM. This might confuse both patients and referring physicians and indicate that an international high-level consensus statements and widely accepted guidelines are needed.

Hepatitis B Prophylaxis after Liver Transplantation in Korea: Analysis of the KOTRY Database.

BACKGROUND: Prophylaxis for hepatitis B virus (HBV) recurrence is essential after liver transplantation (LT) in HBV-associated recipients. We conducted real-world analysis of HBV prophylaxis after LT in the Korean population. METHODS: Korean Organ Transplantation Registry (KOTRY) database and additionally collected data (n = 326) were analyzed with special reference to types of HBV prophylaxis. RESULTS: The study cohort comprised 267 cases of living-donor LT and 59 cases of deceased-donor LT. Hepatocellular carcinoma (HCC) was diagnosed in 232 (71.2%) of these subjects. Antiviral agents were used in 255 patients (78.2%) prior to LT. HBV DNA was undetectable in 69 cases (21.2%) and detectable over wide concentrations in the other 257 patients (78.8%) prior to LT. Polymerase chain reaction analysis of the store blood samples detected HBV DNA in all patients, with 159 patients (48.9%) showing concentrations > 100 IU/mL. Post-transplant HBV regimens during the first year included combination therapy in 196 (60.1%), hepatitis B immunoglobulin (HBIG) monotherapy in 121 (37.1%), and antiviral monotherapy in 9 (2.8%). In the second post-transplant year, these regimens had changed to combination therapy in 187 (57.4%), HBIG monotherapy in 112 (34.4%), and antiviral monotherapy in 27 (8.3%). Trough antibody to hepatitis B surface antigen titers > 500 IU/mL and >1,000 IU/mL were observed in 61.7% and 25.2%, respectively. The mean simulative half-life of HBIG was 21.6 ± 4.3 days with a median 17.7 days. Up to 2-year follow-up period, HCC recurrence and HBV recurrence developed in 18 (5.5%) and 6 (1.8%), respectively. HCC recurrence developed in 3 of 6 patients with HBV recurrence. CONCLUSION: Combination therapy is the mainstay of HBV prophylaxis protocols in a majority of Korean LT centers, but HBIG was often administered excessively. Individualized optimization of HBIG treatments using SHL is necessary to adjust the HBIG infusion interval.

Clinicopathologic analysis of intraductal papillary neoplasm of bile duct: Korean multicenter cohort study.

BACKGROUND: IPNB is very rare disease and most previous studies on IPNB were case series with a small number due to low incidence. The aim of this study is to validate previously known clinicopathologic features of intraductal papillary neoplasm of bile duct (IPNB) based on the first largest multicenter cohort. METHODS: Among 587 patients previously diagnosed with IPNB and similar diseases from each center in Korea, 387 were included in this study after central pathologic review. We also reviewed all preoperative image data. RESULTS: Of 387 patients, 176 (45.5%) had invasive carcinoma and 21 (6.0%) lymph node metastasis. The 5-year overall survival was 80.9% for all patients, 88.8% for IPNB with mucosal dysplasia, and 70.5% for IPNB with invasive carcinoma. According to the "Jang & Kim's modified anatomical classification," 265 (68.5%) were intrahepatic, 103 (26.6%) extrahepatic, and 16 (4.1%) diffuse type. Multivariate analysis revealed that tumor invasiveness was a unique predictor for survival analysis. (p = 0.047 [hazard ratio = 2.116, 95% confidence interval 1.010-4.433]). CONCLUSIONS: This is the first Korean multicenter study on IPNB through central pathologic and radiologic review process. Although IPNB showed good long-term prognosis, relatively aggressive features were also found in invasive carcinoma and extrahepatic/diffuse type.

Donor safety in living donor liver transplantation: The Korean organ transplantation registry study.

Major concerns about donor safety cause controversy and limit the use of living donor liver transplantation to overcome organ shortages. The Korean Organ Transplantation Registry established a nationwide organ transplantation registration system in 2014. We reviewed the prospectively collected data of all 832 living liver donors who underwent procedures between April 2014 and December 2015. We allocated the donors to a left lobe group (n = 59) and a right lobe group (n = 773) and analyzed the relations between graft types and remaining liver volumes and complications (graded using the Clavien 5-tier grading system). The median follow-up was 19 months (range, 10-31 months). During the study period, 553 men and 279 women donated livers, and there were no deaths after living liver donation. The overall, biliary, and major complication (grade ≥ III) rates were 9.3%, 1.7%, and 1.9%, respectively. The graft types and remaining liver volume were associated with significantly different overall, biliary, and major complication rates. Of the 16 patients with major complications, 9 (56.3%) involved biliary complications (2 biliary strictures [12.5%] and 7 bile leakages [43.8%]). Among the 832 donors, the mean aspartate transaminase, alanine aminotransferase, and total bilirubin levels were 23.9 ± 8.1 IU/L, 20.9 ± 11.3 IU/L, and 0.8 ± 0.4 mg/dL, respectively, 6 months after liver donation. In conclusion, biliary complications were the most common types of major morbidity in living liver donors. Donor hepatectomy can be performed successfully with minimal and easily controlled complications. Our study shows that prospective, nationwide cohort data provide an important means of investigating the safety in living liver donation. Liver Transplantation 23 999-1006 2017 AASLD.

Retinoic acid-related orphan receptor alpha reprograms glucose metabolism in glutamine-deficient hepatoma cells.

UNLABELLED: The metabolism of glutamine and glucose is recognized as a promising therapeutic target for the treatment of cancer; however, targeted molecules that mediate glutamine and glucose metabolism in cancer cells have not been addressed. Here, we show that restricting the supply of glutamine in hepatoma cells, including HepG2 and Hep3B cells, markedly increased the expression of retinoic acid-related orphan receptor alpha (RORα). Up-regulation of RORα in glutamine-deficient hepatoma cells resulted from an increase in the level of cellular reactive oxygen species and in the nicotinamide adenine dinucleotide phosphate/nicotinamide adenine dinucleotide phosphate reduced (NADP+ /NADPH) ratio, which was consistent with a reduction in the glutathione/glutathione disulfide (GSH/GSSG) ratio. Adenovirus (Ad)-mediated overexpression of RORα (Ad-RORα) or treatment with the RORα activator, SR1078, reduced aerobic glycolysis and down-regulated biosynthetic pathways in hepatoma cells. Ad-RORα and SR1078 reduced the expression of pyruvate dehydrogenase kinase 2 (PDK2) and inhibited the phosphorylation of pyruvate dehydrogenase and subsequently shifted pyruvate to complete oxidation. The RORα-mediated decrease in PDK2 levels was caused by up-regulation of p21, rather than p53. Furthermore, RORα inhibited hepatoma growth both in vitro and in a xenograft model in vivo. We also found that suppression of PDK2 inhibited hepatoma growth in a xenograft model. These findings mimic the altered glucose utilization and hepatoma growth caused by glutamine deprivation. Finally, tumor tissue from 187 hepatocellular carcinoma patients expressed lower levels of RORα than adjacent nontumor tissue, supporting a potential beneficial effect of RORα activation in the treatment of liver cancer. CONCLUSION: RORα mediates reprogramming of glucose metabolism in hepatoma cells in response to glutamine deficiency. The relationships established here between glutamine metabolism, RORα expression and signaling, and aerobic glycolysis have implications for therapeutic targeting of liver cancer metabolism.

Confinement to the intrapancreatic bile duct is independently associated with a better prognosis in extrahepatic cholangiocarcinoma.

BACKGROUND: Actual differences of long term outcome of extrahepatic cholangiocarcinoma according to the location of the tumor have not yet been studied. The aim of this study was to evaluate the prognosis and optimal surgical procedure for middle (BD) cancer. METHODS: Among 109 patients with carcinoma of the extrahepatic BD underwent surgical resection, curative resection of extrahepatic BD cancer was performed in 90 patients. They were classified into three groups according to the location of tumors: DISTAL (n = 32), tumor was confined to the intrapancreatic bile duct; MID (n = 20), tumor was located between below the confluence of the hepatic duct bifurcation and suprapancreatic portion of the BD; and DIFFUSE (n = 38), tumor was located diffusely. RESULTS: Tumor involving the middle BD (MID or DIFFUSE) had a higher rate of perineural invasion as compared to the DISTAL group. The overall and disease-free survival rate for the MID or DIFFUSE group was significantly worse than that of DISTAL. In the MID/DIFFUSE group, there was no significant difference of survival according to the type of the operation (pancreaticoduodenectomy or segmental BD resection). The multivariate analysis showed that tumor involving middle BD (MID or DIFFUSE group) and node metastasis were independently poor prognostic factors for the disease free and overall survival. CONCLUSION: Extrahepatic cholangiocarcinoma involving the extrapancreatic BD has a worse prognosis than those confined to the intrapancreatic BD. In patients with tumors confined to the middle BD, BD resection can be considered as an alternative surgical procedure to pancreaticoduodenectomy, if an R0 resection can be accomplished.

Impact of Preoperative ERCP on Laparoscopic Cholecystectomy: A Case-Controlled Study with Propensity Score Matching.

BACKGROUND: Although inflammation induced by endoscopic retrograde cholangiopancreatography (ERCP) may affect laparoscopic cholecystectomy (LC), making the procedure more difficult, clinical impact of ERCP on LC is unclear. The aim of this study was to evaluate the effects of ERCP on LC and to determine appropriate time of LC after ERCP. METHODS: Six hundred twenty-one patients who underwent LC for gallstone disease were enrolled. These patients were divided into two groups; patients with preoperative ERCP prior to LC (ERCP group) and patients who underwent LC without ERCP (non-ERCP group). Among these patients, patients who had shown acute cholecystitis or cholangitis were excluded. To control for different demographic factors in the two groups, propensity score case matching was used at a 1:1 ratio. Finally, 142 patients were matched with 71 patients of the ERCP group and 71 patients of the non-ERCP group. Intraoperative inflammation degree, technical difficulty, and postoperative outcome were analyzed. RESULTS: In the ERCP group, the degree of inflammation was severe and operations were more difficult than those of the non-ERCP group. The operation time was longer, and rates of open conversion were higher in the ERCP group. On multivariate analysis, preoperative ERCP was significant factor for difficult operations. The difficulty of operation was not different according to the operation timing after ERCP. CONCLUSION: Preoperative ERCP is a significant factor in difficult LC. Therefore, experienced surgeons should perform LC after preoperative ERCP. Since operation difficulty was similar according to the timing of cholecystectomy after ERCP, there is no reason to delay LC after ERCP.

AROS Is a Significant Biomarker for Tumor Aggressiveness in Non-cirrhotic Hepatocellular Carcinoma.

Despite a low risk of liver failure and preserved liver function, non-cirrhotic hepatocellular carcinoma (HCC) has a poor prognosis. In the current study, we evaluated an active regulator of SIRT1 (AROS) as a prognostic biomarker in non-cirrhotic HCC. mRNA levels of AROS were measured in tumor and non-tumor tissues obtained from 283 non-cirrhotic HCC patients. AROS expression was exclusively up-regulated in recurrent tissues from the non-cirrhotic HCC patients (P = 0.015) and also in tumor tissues irrespective of tumor stage (P < 0.001) or BCLC stage (P < 0.001). High mRNA levels of AROS were statistically significantly associated with tumor stage (P < 0.001), BCLC stage (P = 0.007), alpha fetoprotein (AFP) level (P = 0.013), microvascular invasion (P = 0.001), tumor size (P = 0.036), and portal vein invasion (P = 0.005). Kaplan-Meir curve analysis demonstrated that HCC patients with higher AROS levels had shorter disease-free survival (DFS) in both the short-term (P < 0.001) and long-term (P = 0.005) compared to those with low AROS. Cox regression analysis demonstrated that AROS is a significant predictor for DFS along with large tumor size, tumor multiplicity, vascular invasion, and poor tumor differentiation, which are the known prognostic factors. In conclusion, AROS is a significant biomarker for tumor aggressiveness in non-cirrhotic hepatocellular carcinoma.

Genomic predictors for recurrence patterns of hepatocellular carcinoma: model derivation and validation.

BACKGROUND: Typically observed at 2 y after surgical resection, late recurrence is a major challenge in the management of hepatocellular carcinoma (HCC). We aimed to develop a genomic predictor that can identify patients at high risk for late recurrence and assess its clinical implications. METHODS AND FINDINGS: Systematic analysis of gene expression data from human liver undergoing hepatic injury and regeneration revealed a 233-gene signature that was significantly associated with late recurrence of HCC. Using this signature, we developed a prognostic predictor that can identify patients at high risk of late recurrence, and tested and validated the robustness of the predictor in patients (n = 396) who underwent surgery between 1990 and 2011 at four centers (210 recurrences during a median of 3.7 y of follow-up). In multivariate analysis, this signature was the strongest risk factor for late recurrence (hazard ratio, 2.2; 95% confidence interval, 1.3-3.7; p = 0.002). In contrast, our previously developed tumor-derived 65-gene risk score was significantly associated with early recurrence (p = 0.005) but not with late recurrence (p = 0.7). In multivariate analysis, the 65-gene risk score was the strongest risk factor for very early recurrence (<1 y after surgical resection) (hazard ratio, 1.7; 95% confidence interval, 1.1-2.6; p = 0.01). The potential significance of STAT3 activation in late recurrence was predicted by gene network analysis and validated later. We also developed and validated 4- and 20-gene predictors from the full 233-gene predictor. The main limitation of the study is that most of the patients in our study were hepatitis B virus-positive. Further investigations are needed to test our prediction models in patients with different etiologies of HCC, such as hepatitis C virus. CONCLUSIONS: Two independently developed predictors reflected well the differences between early and late recurrence of HCC at the molecular level and provided new biomarkers for risk stratification. Please see later in the article for the Editors' Summary.

A prospective randomized controlled study comparing outcomes of standard resection and extended resection, including dissection of the nerve plexus and various lymph nodes, in patients with pancreatic head cancer.

OBJECTIVE: To prospectively evaluate the survival benefit of dissection of the nerve plexus and lymphadenectomy in patients with pancreatic head cancer. BACKGROUND: Despite randomized controlled trials on the extent of surgery in pancreatic cancer, attempts have been made to perform more extended resections. METHODS: A total of 244 patients were enrolled; of these, 200 were randomized to undergo standard resection or extended resection, with the latter including the dissection of additional lymph nodes and the right half of the nerve plexus around the superior mesenteric artery and celiac axis. We evaluated 167 patients from 7 centers who fulfilled all of the required criteria. RESULT: Operation time was longer and estimated blood loss was higher in the extended resection group than in the standard resection group, but the R0 resection rate was comparable. The mean number of lymph nodes retrieved per patient was higher in the extended resection group than in the standard resection group (33.7 vs 17.3; P < 0.001). The morbidity rate was slightly higher in the extended resection group than in the standard resection group. Two patients in the extended resection group died in hospital. Median survival after R0 resection was similar in the extended resection and standard resection groups (18.0 vs 19.0 months; P = 0.239) regardless of lymph node metastasis. Adjuvant chemoradiation had a positive impact on overall survival. CONCLUSIONS: This study suggests that extended lymphadenectomy with dissection of the nerve plexus does not provide a significant survival benefit compared with standard resection in pancreatic head cancer. Standard resection can be performed safely and efficiently, without negatively affecting oncologic efficacy or long-term survival, when compared with extended pancreaticoduodenal resection. (NCT00679913)?

A Machine Learning-Based Clustering Using Radiomics of F-18 Fluorodeoxyglucose Positron Emission Tomography/Computed Tomography for the Prediction of Prognosis in Patients with Intrahepatic Cholangiocarcinoma.

BACKGROUND: Intrahepatic cholangiocarcinoma (IHCC) is highly aggressive primary hepatic malignancy with an increasing incidence. OBJECTIVE: This study aimed to develop machine learning-based radiomic clustering using F-18 fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) for predicting recurrence-free survival (RFS) and overall survival (OS) in IHCC. METHODS: We retrospectively reviewed pretreatment F-18 FDG PET/CT scans of 60 IHCC patients who underwent surgery without neoadjuvant treatment between January 2008 and July 2020. Radiomic features such as first order, shape, and gray level were extracted from the scans of 52 patients and analyzed using unsupervised hierarchical clustering. RESULTS: Of the 60 patients, 36 experienced recurrence and 31 died during follow-up. Eight patients with a negative FDG uptake were classified as Group 0. The unsupervised hierarchical clustering analysis divided the total cohort into three clusters (Group 1: n = 27; Group 2: n = 23; Group 3: n = 2). The Kaplan-Meier curves showed significant differences in RFS and OS among the clusters (p < 0.0001). Multivariate analyses showed that the PET radiomics grouping was an independent prognostic factor for RFS (hazard ratio (HR) = 3.03, p = 0.001) and OS (HR = 2.39, p = 0.030). Oxidative phosphorylation was significantly activated in Group 1, and the KRAS, P53, and WNT ß-catenin pathways were enriched in Group 2. CONCLUSIONS: This study demonstrated that machine learning-based PET radiomics clustering can preoperatively predict prognosis and provide valuable information complementing the genomic profiling of IHCC.

Surgical outcome and risk scoring to predict survival after hepatic resection for hepatocellular carcinoma with portal vein tumor thrombosis.

Backgrounds/Aims: The hepatocellular carcinoma (HCC) with portal vein tumor thrombosis (PVTT) is classified as the advanced stage (BCLC stage C) with extremely poor prognosis, and in current guidelines is recommended for systemic therapy. This study aimed to evaluate the surgical outcomes and long-term prognosis after hepatic resection (HR) for patients who have HCC combined with PVTT. Methods: We retrospectively analyzed 332 patients who underwent HR for HCC with PVTT at ten tertiary referral hospitals in South Korea. Results: The median overall and recurrence-free survival after HR were 32.4 and 8.6 months, while the 1-, 3-, and 5-year overall survival rates were 75%, 48%, and 39%, respectively. In multivariate analysis, tumor number, tumor size, AFP, PIVKA-II, neutrophil-to-lymphocyte ratio, and albumin-bilirubin (ALBI) grade were significant prognostic factors. The risk scoring was developed using these seven factors-tumor, inflammation and hepatic function (TIF), to predict patient prognosis. The prognosis of the patients was well stratified according to the scores (log-rank test, p < 0.001). Conclusions: HR for patients who have HCC combined with PVTT provided favorable survival outcomes. The risk scoring was useful in predicting prognosis, and determining the appropriate treatment strategy for those patients who have HCC with PVTT.

Benefit of systematic segmentectomy of the hepatocellular carcinoma: revisiting the dye injection method for various portal vein branches.

BACKGROUND: Systematic segmentectomy is useful in treating small hepatocellular carcinoma in the cirrhotic liver. However, accomplishment of an exact systematic segmentectomy still remains a challenging procedure because of the variable anatomy of portal branches. We evaluated the usefulness of the dye injection method for systematic segmentectomy, which focuses on the various patterns of portal vein (PV) branches feeding the tumor. METHODS: From January 2001 to May 2011, systematic segmentectomy by the dye injection method was performed in 70 patients. We evaluated the efficiency of systematic segmentectomy by ultrasonogram-guided dye injection into the portal branches that feed the tumor-bearing segments. The type of tumor-feeding PV branch, perioperative outcome, and survival rates were analyzed retrospectively. RESULTS: There were variations in the PV branches that fed the masses in 70 patients in whom the dye injection method for anatomical segmentectomy was tried. Forty masses (54.8%) were fed by a single main PV branch (type 1), 17 masses (23.3%) by a couple of PV branches (type 2), and 11 masses (15.1%) were supplied partially by single PV branch (type 3). In 5 patients (7.1%), masses were supplied by several small distributed PVs (type 4). For types 1 and 2, the tumor-bearing segments were resected anatomically with the help of staining; type 3 was partially stained and as the opposite side was not discrete, it was demarcated through counterstaining; and in type 4, dye injection could not be performed. Anatomical systematic segmentectomy was obtained in types 1 to 3; however, nonanatomical resection was inevitable for type 4. The 3- and 5-year overall survival rates were 80.5% and 67.2%, respectively, and the 3- and 5-year disease-free survival rates were 61.5% and 42.5%, respectively. The anatomical segmentectomy group showed better overall and disease-free survival than the nonanatomical group, even though it is not significant statistically. CONCLUSION: Systematic segmentectomy by the dye injection method overcomes the variation in PV tributaries in the segments and can be done according to the natural branching pattern of PVs.

Effect of anatomical liver resection for hepatocellular carcinoma: a systematic review and meta-analysis.

BACKGROUND: Despite retrospective studies comparing anatomical liver resection (AR) and non-anatomical liver resection (NAR), the efficacy and benefits of AR for hepatocellular carcinoma remain unclear. MATERIALS AND METHODS: The authors systemically reviewed MEDLINE, Embase, and Cochrane Library for propensity score matched cohort studies that compared AR and NAR for hepatocellular carcinoma. Primary outcomes were overall survival (OS) and recurrence-free survival (RFS). Secondary outcomes were recurrence patterns and perioperative outcomes. RESULTS: Overall, 22 propensity score matched studies (AR, n =2,496; NAR, n =2590) were included. AR including systemic segmentectomy was superior to NAR regarding the 3-year and 5-year OS. AR showed significantly better 1-year, 3-year, and 5-year RFS than NAR, with low local and multiple intrahepatic recurrence rates. In the subgroup analyses of tumour diameter less than or equal to 5 cm and tumours with microscopic spread, the RFS in the AR group was significantly better than that in the NAR group. Patients with cirrhotic liver in the AR group showed comparable 3-year and 5-year RFS with the NAR group. Postoperative overall complications were comparable between AR and NAR. CONCLUSIONS: This meta-analysis demonstrated that AR showed better OS and RFS with a low local and multiple intra-hepatic recurrence rate than NAR, especially in patients with tumour diameter less than or equal to 5 cm and non-cirrhotic liver.

Diagnostic Role of Bile Pigment Components in Biliary Tract Cancer.

Bile pigment, bilirubin, and biliverdin concentrations may change as a results of biliary tract cancer (BTC) altering the mechanisms of radical oxidation and heme breakdown. We explored whether changes in bile pigment components could help distinguish BTC from benign biliary illness by evaluating alterations in patients with BTC. We collected bile fluid from 15 patients with a common bile duct stone (CBD group) and 63 individuals with BTC (BTC group). We examined the bile fluid's bilirubin, biliverdin reductase (BVR), heme oxygenase (HO-1), and bacterial taxonomic abundance. Serum bilirubin levels had no impact on the amounts of bile HO-1, BVR, or bilirubin. In comparison to the control group, the BTC group had considerably higher amounts of HO-1, BVR, and bilirubin in the bile. The areas under the curve for the receiver operating characteristic curve analyses of the BVR and HO-1 were 0.832 (p<0.001) and 0.891 (p<0.001), respectively. Firmicutes was the most prevalent phylum in both CBD and BTC, according to a taxonomic abundance analysis, however the Firmicutes/Bacteroidetes ratio was substantially greater in the BTC group than in the CBD group. The findings of this study showed that, regardless of the existence of obstructive jaundice, biliary carcinogenesis impacts heme degradation and bile pigmentation, and that the bile pigment components HO-1, BVR, and bilirubin in bile fluid have a diagnostic significance in BTC. In tissue biopsies for the diagnosis of BTC, particularly for distinguishing BTC from benign biliary strictures, bile pigment components can be used as additional biomarkers.