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The carcinogenic mechanism of extrahepatic cholangiocarcinoma (ECC) is unclear, due at least in part to the lack of an appropriate mouse model. Because human studies have reported frequent genetic alterations in the Ras- and TGFβ/SMAD-signaling pathways in ECC, mice with tamoxifen-inducible, duct-cell–specific Kras activation and a TGFβ receptor type 2 (TGFβR2) deletion were first generated by crossing LSL-KrasG12D, Tgfbr2flox/flox , and K19CreERT mice (KT-K19CreERT ). However, KT-K19CreERT mice showed only mild hyperplasia of biliary epithelial cells (BECs) in the extrahepatic bile duct (EHBD) and died within 7 wk, probably a result of lung adenocarcinomas. Next, to analyze the additional effect of E-cadherin loss, KT-K19CreERT mice were crossed with CDH1flox/flox mice (KTCK19CreERT ). Surprisingly, KTC-K19CreERT mice exhibited a markedly thickened EHBD wall accompanied by a swollen gallbladder within 4 wk after tamoxifen administration. Histologically, invasive periductal infiltrating-type ECC with lymphatic metastasis was observed. Time-course analysis of EHBD revealed that recombined BECs lining the bile duct lumen detached due to E-cadherin loss, whereas recombined cells could survive in the peribiliary glands (PBGs), which are considered a BEC stem-cell niche. Detached dying BECs released high levels of IL-33, as determined by microarray analysis using biliary organoids, and stimulated inflammation and a regenerative response by PBGs, leading eventually to ECC development. Cell lineage tracing suggested PBGs as the cellular origin of ECC. IL-33 cooperated with Kras and TGFβR2 mutations in the development of ECC, and anti–IL-33 treatment suppressed ECC development significantly. Thus, this mouse model provided insight into the carcinogenic mechanisms, cellular origin, and potential therapeutic targets of ECC.

Most patients with hepatocellular carcinoma (HCC) have underlying liver disease, therefore, precise preoperative evaluation of the patient's liver function is essential for surgical decision making. We developed a grading system incorporating only two variables, namely, the serum albumin level and the indocyanine green retention rate at 15 minutes (ICG R15), to assess the preoperative liver function, based on the overall survival of 1868 patients with HCC who underwent liver resection. We then tested the model in a European cohort (n = 70) and analyzed the predictive power for the postoperative short-term outcome. The Albumin-Indocyanine Green Evaluation (ALICE) grading system was developed in a randomly assigned training cohort: linear predictor = 0.663 × log10ICG R15 (%)-0.0718 × albumin (g/L) (cut-off value: -2.20 and -1.39). This new grading system showed a predictive power for the overall survival similar to the Child-Pugh grading system in the validation cohort. Determination of the ALICE grade in Child-Pugh A patients allowed further stratification of the postoperative prognosis. This result was reproducible in the European cohort. Determination of the ALICE grade allowed better prediction of the risk of postoperative liver failure and mortality (ascites: grade 1, 2.1%; grade 2, 6.5%; grade 3, 16.0%; mortality: grade 1, 0%; grade 2, 1.3%; grade 3, 5.3%) than the previously reported model based on the presence/absence of portal hypertension. This new grading system is a simple method for prediction of the postoperative long-term and short-term outcomes.

Background Indocyanine green (ICG) fluorescent imaging has been used effectively to identify hepatocellular carcinoma (HCC) in intraoperative setting. However, whether extrahepatic metastatic lesions from HCC can also be detected by this imaging is unknown. Methods This study was conducted on 17 patients with suspected extrahepatic HCC metastases in the lung ( n  = 3), adrenal gland ( n  = 1), lymph node ( n  = 7), peritoneum ( n  = 5) and both lymph node and peritoneum ( n  = 1). ICG was administered intravenously at a dose of 0.5 mg/kg prior to operation for liver function evaluation. Intraoperative ICG fluorescent imaging was performed with a near-infrared light camera system. The surgical specimens were also examined in all cases for the presence of ICG fluorescence. Results Of 28 lesions for which ICG fluorescence was examined intraoperatively, 24 lesions exhibited fluorescence and were proved to be HCC metastases pathologically. Five of them were newly identified by ICG fluorescent imaging. The other four lesions included two HCC metastases and two benign tumors. Of 33 suspicious metastatic lesions extirpated, 26 lesions emitting fluorescence from the specimen were all metastatic HCC. The other 7 lesions consisted of 6 benign tumors and one HCC metastasis. Accordingly, the positive predictive value of in vivo and ex vivo ICG fluorescent imaging were both 100 %, while the negative predictive value of those methods were 50 and 86 %, respectively. Conclusions Extrahepatic metastases from HCC exhibited ICG fluorescence when illuminated by near-infrared light, indicating their capability to transport ICG. This imaging can be a useful tool for intraoperative detection of metastasis in HCC patients.

Despite the increasing prevalence of Nonalcoholic steatohepatitis (NASH) worldwide, there is no effective treatment available for this disease. “Ballooned hepatocyte” is a characteristic finding in NASH and is correlated with disease prognosis, but their mechanisms of action are poorly understood; furthermore, neither animal nor in vitro models of NASH have been able to adequately represent ballooned hepatocytes. Herein, we engineered cell sheets to develop a new in vitro model of ballooned hepatocytes. Primary human hepatocytes (PHH) and Hepatic stellate cells (HSC) were co-cultured to produce cell sheets, which were cultured in glucose and lipid containing medium, following which histological and functional analyses were performed. Histological findings showed hepatocyte ballooning, accumulation of fat droplets, abnormal cytokeratin arrangement, and the presence of Mallory–Denk bodies and abnormal organelles. These findings are similar to those of ballooned hepatocytes in human NASH. Functional analysis showed elevated levels of TGFβ-1, SHH, and p62, but not TNF-α, IL-8. Exposure of PHH/HSC sheets to a glucolipotoxicity environment induces ballooned hepatocyte without inflammation. Moreover, fibrosis is an important mechanism underlying ballooned hepatocytes and could be the basis for the development of a new in vitro NASH model with ballooned hepatocytes.

This paper presents the first version of clinical practice guidelines for intrahepatic cholangiocarcinoma (ICC) established by the Liver Cancer Study Group of Japan. These guidelines consist of 1 treatment algorithm, 5 background statements, 16 clinical questions, and 1 clinical topic, including etiology, staging, pathology, diagnosis, and treatments. Globally, a high incidence of ICC has been reported in East and Southeast Asian countries, and the incidence has been gradually increasing in Japan and also in Western countries. Reported risk factors for ICC include cirrhosis, hepatitis B/C, alcohol consumption, diabetes, obesity, smoking, nonalcoholic steatohepatitis, and liver fluke infestation, as well as biliary diseases, such as primary sclerosing cholangitis, hepatolithiasis, congenital cholangiectasis, and Caroli disease. Chemical risk factors include thorium-232, 1,2-dichloropropane, and dichloromethane. CA19-9 and CEA are recommended as tumor markers for early detection and diagnostic of ICC. Abdominal ultrasonography, CT, and MRI are effective imaging modalities for diagnosing ICC. If bile duct invasion is suspected, imaging modalities for examining the bile ducts may be useful. In unresectable cases, tumor biopsy should be considered when deemed necessary for the differential diagnosis and drug therapy selection. The mainstay of treatment for patients with Child-Pugh class A or B liver function is surgical resection and drug therapy. If the patient has no regional lymph node metastasis (LNM) and has a single tumor, resection is the treatment of choice. If both regional LNM and multiple tumors are present, drug therapy is the first treatment of choice. If the patient has either regional LNM or multiple tumors, resection or drug therapy is selected, depending on the extent of metastasis or the number of tumors. If distant metastasis is present, drug therapy is the treatment of choice. Percutaneous ablation therapy may be considered for patients who are ineligible for surgical resection or drug therapy due to decreased hepatic functional reserve or comorbidities. For unresectable ICC without extrahepatic metastasis, stereotactic radiotherapy (tumor size ≤5 cm) or particle radiotherapy (no size restriction) may be considered. ICC is generally not indicated for liver transplantation, and palliative care is recommended for patients with Child-Pugh class C liver function.

Background Postoperative pancreatic fistula (POPF) remains a leading cause of morbidity after pancreaticoduodenectomy (PD). In the present study we sought to establish a preoperative scoring system with which to predict this complication. Patients and methods The clinical records of 387 consecutive patients who underwent PD for periampullary tumor between 2004 and 2009 were reviewed retrospectively. Patients were divided into two groups; 279 consecutive patients constituted the study group and the next 108 patients constituted the validation group. Univariate and multivariate logistic regression analyses were performed using preoperative and surgical factors potentially influencing grade B or C POPF in the study group, and a score to predict POPF was constructed. This score was confirmed in the validation group. Results In the study group, grade A POPF was recognized in 45 patients (16%), grade B in 98 (35%), and grade C in 5 (2%). A preoperative predictive scoring system for POPF (0-7 points) was constructed using the following 5 factors; main pancreatic duct index <0.25 (2 points), away from portal vein on computed tomography (2 points), disease other than pancreatic cancer (1 point), male (1 point), and intra-abdominal thickness >65 mm (1 point). The nomogram showed an area under the curve (AUC) of 0.808. This scoring system was highly predictive for grade B or C POPF in the validation group (AUC = 0.834). Conclusions The present scoring system satisfactorily predicted the occurrence of POPF and thus will be useful for the perioperative risk management of patients undergoing PD in a high-volume center hospital.

ObjectiveThe Endoscopic Surgical Skill Qualification System (ESSQS) was developed by the Japan Society for Endoscopic Surgery as a means of subjectively assessing the proficiency of laparoscopic surgeons. We conducted a study to evaluate how involvement of an ESSQS skill-qualified (SQ) surgeon influences short-term outcomes of laparoscopic cholecystectomy performed for acute cholecystitis.Summary of background dataPrevious reports suggest that assessment of the video-rating system is a potential tool to discriminate laparoscopic surgeons’ proficiency and top-rated surgeons face less surgical mortality and morbidity in bariatric surgery.MethodsData from the National Clinical Database regarding laparoscopic cholecystectomy performed for acute cholecystitis between January 2016 and December 2018 were analyzed. Outcomes were compared between patients grouped according to involvement vs. non-involvement of an SQ surgeon. Outcomes were also compared between patients grouped according to whether their operation was performed by biliary tract-, stomach-, or colon-qualified surgeon.ResultsOf the 309,998 laparoscopic cholecystectomies during the study period, 65,295 were suitable for inclusion in the study and 13,670 (20.9%) were performed by an SQ surgeon. Patients’ clinical characteristics did not differ between groups. Thirty-day mortality was significantly lower in the SQ group (0.1%) 16/13,670 than in the non-SQ group (0.2%) 140/51,625 (P = 0.001). Thirty-day mortality was [0.1% (9/7173)] in the biliary tract-qualified group, [0.2% (5/3527)] in the stomach-qualified group, and [0.1% (2/3240)] in the colon-qualified group.ConclusionSurgeons with ESSQS certification outperform the non-skilled surgeons in terms of surgical mortality in 30 and 90 days. Further verification of the value of the ESSQS is warranted and similar systems may be needed in countries across the world to ensure patient safety and control the quality of surgical treatments.

Pancreatic ductal adenocarcinoma (PDAC) remains a lethal malignancy with poor prognosis. We investigated intratumoral deoxyribonucleic acid methylation heterogeneity by analyzing 44 tumor samples and 5 normal samples from 6 cases of PDAC by using high-resolution methylation arrays. Two distinct methylation profiles were identified: T1, which is similar to normal pancreatic tissue and is associated with well-differentiated histology, and T2, which is significantly different from normal tissue and is linked to poorly differentiated morphology and squamous features. Validation using The Cancer Genome Atlas (TCGA) confirmed these profiles and revealed the association of T2 with shorter disease-free survival ( p  = 0.04). Differentially methylated region analysis identified the substantial hypomethylation of transcription regulation genes in T2 profiles (false discovery rate [FDR] q < 0.001). Gene set enrichment analysis with TCGA gene expression data demonstrated the upregulation of DNA repair and MYC target genes in T2 samples (FDR q < 0.001). Phylogenetic analysis with our multi-sampling dataset suggested an evolutionary trajectory from T1 to T2 profiles coinciding with aggressive phenotypes and increased genomic instability. Cases exhibited varying degrees of intratumoral heterogeneity from distinctly separated clusters to minimal differences. This comprehensive characterization of the epigenetic landscape of PDAC provides insights into tumor evolution and heterogeneity with potential implications for patient stratification and the development of epigenetic-based diagnostic and therapeutic strategies.

Background Although laparoscopic hepatectomy has increasingly been used to treat cancers in the liver, the accuracy of intraoperative diagnosis may be inferior to that of open surgery because the ability to visualize and palpate the liver surface during laparoscopy is relatively limited. Fluorescence imaging has the potential to provide a simple compensatory diagnostic tool for identification of cancers in the liver during laparoscopic hepatectomy. Methods In 17 patients who were to undergo laparoscopic hepatectomy, 0.5 mg/kg body weight of indocyanine green (ICG) was administered intravenously within the 2 weeks prior to surgery. Intraoperatively, a laparoscopic fluorescence imaging system obtained fluorescence images of its surfaces during mobilization of the liver. Results In all, 16 hepatocellular carcinomas (HCCs) and 16 liver metastases (LMs) were resected. Of these, laparoscopic ICG fluorescence imaging identified 12 HCCs (75 %) and 11 LMs (69 %) on the liver surfaces distributed over Couinaud’s segments 1–8, including the 17 tumors that had not been identified by visual inspections of normal color images. The 23 tumors that were identified by fluorescence imaging were located closer to the liver surfaces than another nine tumors that were not identified by fluorescence imaging (median [range] depth 1 [0–5] vs. 11 [8–30] mm; p  < 0.001). Conclusions Like palpation during open hepatectomy, laparoscopic ICG fluorescence imaging enables real-time identification of subcapsular liver cancers, thus facilitating estimation of the required extent of hepatic mobilization and determination of the location of an appropriate hepatic transection line.

Patent ductus venosus is a congenital portosystemic shunt that may cause progressive portal hypertension, hepatic encephalopathy, and focal nodular hyperplasia of the liver. Embolization of the Arantius' duct is the first choice of treatment in infants and children. However, it carries the risk of coil migration into the systemic circulation in adult patients with larger Arantius ducts. Additionally, the primary closure of the Arantius' duct may result in acute portal hypertension. Herein, we present a two‐stage treatment for adult patent large ductus venosus (Arantius' duct). A 23‐year‐old female patient with hypoalbuminemia showed a patent large Arantius' duct (diameter = 45 mm), intrahepatic portal venous hypoplasia, and multiple hepatic nodules with dynamic computed tomography (CT). Preoperative angiography showed the absence of the intrahepatic portal vein, and tentative occlusion of the Arantius' duct increased the portal pressure from 9 to 15 mmHg with visualization of only a few portal branches. Therefore, we conducted a two‐stage treatment for the Arantius' duct. In the first stage, we used an open approach to perform angioplasty of the Arantius' duct to reduce the size from 45 to 8 mm in diameter, which gradually increased the intrahepatic portal blood flow in the follow‐up CT scan. The second‐stage embolization of the Arantius' duct was performed using an interventional procedure via the internal jugular vein 4 months after the first stage. The patient's recovery was uneventful, and post‐treatment CT showed increased intrahepatic portal flow. Serum albumin value increased from 2.7 to 3.7 g/dL 2 weeks post‐treatment. This is the first report of a two‐stage treatment for an adult large PDV involving the first stage surgical angioplasty of the large Arantius' duct and second stage embolization of the formed small Arantius' duct. The two‐stage approach could avoid embolic material migration into the systemic circulation or acute portal hypertension associated with the closure of the large PDV. Hepatic function increased 5 months post‐treatment.