Abstract Background and Aims Intrahepatic cholangiocarcinoma (iCCA) is a tumor type with a high lethality due to late diagnosis and profound resistance to conventional chemotherapy. To date the molecular mechanisms underlying multidrug resistance remain poorly defined. Here, we integrate single-cell transcriptomics, clinicopathological analysis, and functional genomics to elucidate the molecular basis of cisplatin resistance in iCCA. Approach and Results Single-cell RNA sequencing of iCCA and adjacent liver tissues revealed pronounced expression of Y-box–binding protein 1 (YB-1) in aneuploid malignant cholangiocarcinoma cells, with YB-1 expression progressively increasing during malignant evolution and strongly associated with chemoresistance. Clinically, elevated YB-1 expression-particularly its nuclear localization-robustly predicts poor overall survival and chemotherapy failure in patients with iCCA. Mechanistically, we demonstrate that cisplatin induces phosphorylation-dependent nuclear translocation of YB-1, enabling direct transcriptional activation of the drug efflux transporter ABCB1. Importantly, this process requires ABCB1 promoter demethylation, which is driven by cisplatin-induced, m⁶A-dependent destabilization of DNMT1 and DNMT3B mRNAs. This destabilization occurs through disruption of the YB-1-IGF2BP1/3-DNMT mRNA stabilizing complex and subsequent recruitment of DNMT transcripts to YTHDF2-mediated processing bodies for degradation. Conclusions Our findings uncover a previously unrecognized YB-1-m⁶A-DNMT regulatory axis that drives chemotherapeutic resistance in iCCA, highlighting YB-1 as both a prognostic biomarker and a promising therapeutic target.

BACKGROUND Hepatocellular carcinoma (HCC) is one of the leading causes of death due to its complexity, heterogeneity, rapid metastasis and easy recurrence after surgical resection. We demonstrated that combination therapy with transcatheter arterial chemoembolization (TACE), hepatic arterial infusion chemotherapy (HAIC), Epclusa, Lenvatinib and Sintilimab is useful for patients with advanced HCC. CASE SUMMARY A 69-year-old man who was infected with hepatitis C virus (HCV) 30 years previously was admitted to the hospital with abdominal pain. Enhanced computed tomography (CT) revealed a low-density mass in the right lobe of the liver, with a volume of 12.9 cm × 9.4 cm × 15 cm, and the mass exhibited a “fast-in/fast-out” pattern, with extensive filling defect areas in the right branch of the portal vein and an alpha-fetoprotein level as high as 657 ng/mL. Therefore, he was judged to have advanced HCC. During treatment, the patient received three months of Epclusa, three TACE treatments, two HAIC treatments, three courses of sintilimab, and twenty-one months of lenvatinib. In the third month of treatment, the patient developed severe side effects and had to stop immunotherapy, and the Lenvatinib dose had to be halved. Postoperative pathological diagnosis indicated a complete response. The patient recovered well after the operation, and no tumor recurrence was found. CONCLUSION Multidisciplinary conversion therapy for advanced enormous HCC caused by HCV infection has a significant effect. Individualized drug adjustments should be made during any treatment according to the patient's tolerance to treatment.

Perihilar cholangiocarcinoma, a formidable adversary in the field of hepatobiliary surgery, presents multifaceted challenges. This paper reviews its historical context, classification criteria, and regional variations in definition. It emphasizes the critical role of preoperative assessment, including hepatic hilum anatomy, biliary infiltration characteristics, and residual liver volume evaluation. The impact of the Bismuth-Corlette classification on surgical approach selection is elucidated, providing insights into tailored surgical options for each subtype based on the authors’ center experience in the last ten years. The article also touches upon laparoscopic and robotic surgery potential, underscoring the need for further research in this domain. Finally, it explores the potential role of liver transplantation as a treatment option for select patients ineligible for conventional surgery.

Background: Insufficient remnant liver volume (RLV) after the resection of hepatic malignancy could lead to liver failure and mortality. Portal vein ligation (PVL) prior to hepatectomy is subsequently introduced to increase the remnant liver volume and improve the outcome of hepatic malignancy. IL -22 has previously been reported to promote liver regeneration, while facilitating tumor development in the liver via Steap4 upregulation. Here we performed PVL in mouse models to study the role of IL -22 in liver regeneration post-PVL Methods: Liver weight and volume was measured via magnetic resonance imaging (MRI). Immunohistochemistry for Ki67 and hepatocyte growth factor (HGF) was performed. IL -22 was analyzed by flow cytometry and quantitative polymerase chain reaction (qPCR) was used for acquisition of Il-33, Steap4, Fga, Fgb and Cebpd . To analyze signaling pathways, mice with deletion of STAT3 and a neutralizing antibody for IL -22 were used. Results: The remnant liver weight and volume increased over time after PVL. Additionally, we found that liver regenerative molecules, including Ki67 and HGF, were significantly increased in remnant liver at day 3 post-PVL, as well as IL -22. Administration of IL -22 neutralizing antibody could reduce Ki67 expression after PVL. The upregulation of IL -22 after PVL was mainly derived from innate cells. IL -22 blockade resulted in lower levels of IL -33 and Steap4 in the remnant liver, which was also the case in mice with deletion of STAT3, the main downstream signaling molecule of IL -22, in hepatocytes. Conclusion: IL -22 promotes liver regeneration after PVL. Thus, a combination of IL -22 supplementation and Steap4 blockade could potentially be applied as a novel therapeutic approach to boost liver regeneration without facilitating tumor progression after PVL.

BACKGROUND A comprehensive understanding of the extrahepatic bile duct anatomy is vital to guide surgical procedures and perform endoscopic retrograde cholangiography. Anatomical irregularities within the extrahepatic bile duct may increase susceptibility to bile duct stones. AIM To investigate the anatomical risk factors associated with extrahepatic bile ducts in patients diagnosed with choledocholithiasis, with a specific focus on preventing stone recurrence after surgical intervention and endoscopic lithotomy. METHODS We retrospectively analyzed the medical records of 124 patients without choledocholithiasis and 108 with confirmed choledocholithiasis who underwent magnetic resonance cholangiopancreatography examinations at our center between January 2022 and October 2022. Logistic regression analyses were conducted to identify the anatomical risk factors influencing the incidence of common bile duct stones. RESULTS Multivariate logistic regression analysis revealed that several factors independently contributed to choledocholithiasis risk. Significant independent risk factors for choledocholithiasis were diameter of the common hepatic [adjusted odds ratio (aOR) = 1.43, 95% confidence interval (CI): 1.07-1.92, adjusted P value = 0.016] and common bile (aOR = 1.68, 95%CI: 1.27-2.23, adjusted P value < 0.001) ducts, length of the common hepatic duct (aOR = 0.92, 95%CI: 0.84-0.99, adjusted P value = 0.034), and angle of the common bile duct (aOR = 0.92, 95%CI: 0.89-0.95, adjusted P value < 0.001). CONCLUSION The anatomical features of the extrahepatic bile duct were directly associated with choledocholithiasis risk. Key risk factors include an enlarged diameter of the common hepatic and bile ducts, a shorter length of the common hepatic duct, and a reduced angle of the common bile duct.

Background and Aims: Alterations in liver histology influence the liver’s capacity to regenerate, but the relevance of each of the different changes in rapid liver growth induction is unknown. This study aimed to analyze the influence of the degree of histological alterations during the first and second stages on the ability of the liver to regenerate. Methods: This cohort study included data obtained from the International ALPPS Registry between November 2011 and October 2020. Only patients with colorectal liver metastases were included in the study. We developed a histological risk score based on histological changes (stages 1 and 2) and a tumor pathology score based on the histological factors associated with poor tumor prognosis. Results: In total, 395 patients were included. The time to reach stage 2 was shorter in patients with a low histological risk stage 1 (13 vs 17 days, P ˂0.01), low histological risk stage 2 (13 vs 15 days, P <0.01), and low pathological tumor risk (13 vs 15 days, P <0.01). Regarding interval stage, there was a higher inverse correlation in high histological risk stage 1 group compared to low histological risk 1 group in relation with future liver remnant body weight ( r =−0.1 and r =−0.08, respectively), and future liver remnant ( r =−0.15 and r =−0.06, respectively). Conclusions: ALPPS is associated with increased histological alterations in the liver parenchyma. It seems that the more histological alterations present and the higher the number of poor prognostic factors in the tumor histology, the longer the time to reach the second stage.

PDF file 69K, Distribution of cases and controls included in the analysis, by study center and ethnic group

Background:The outcomes of liver surgery worldwide remain unknown. The true population-based outcomes are likely different to those vastly reported that reflect the activity of highly specialized academic centers. The aim of this study was to measure the true worldwide practice of liver surgery and associated outcomes by recruiting from centers across the globe. The geographic distribution of liver surgery activity and complexity was also evaluated to further understand variations in outcomes.Methods:LiverGroup.org was an international, prospective, multicenter, cross-sectional study following the Global Surgery Collaborative Snapshot Research approach with a 3-month prospective, consecutive patient enrollment within January-December 2019. Each patient was followed up for 90 days postoperatively. All patients undergoing liver surgery at their respective centers were eligible for study inclusion. Basic demographics, patient and operation characteristics were collected. Morbidity was recorded according to the Clavien-Dindo Classification of Surgical Complications. Country-based and hospital-based data were collected, including the Human Development Index (HDI). (NCT03768141).Results:A total of 2159 patients were included from six continents. Surgery was performed for cancer in 1785 (83%) patients. Of all patients, 912 (42%) experienced a postoperative complication of any severity, while the major complication rate was 16% (341/2159). The overall 90-day mortality rate after liver surgery was 3.8% (82/2,159). The overall failure to rescue rate was 11% (82/ 722) ranging from 5 to 35% among the higher and lower HDI groups, respectively.Conclusions:This is the first to our knowledge global surgery study specifically designed and conducted for specialized liver surgery. The authors identified failure to rescue as a significant potentially modifiable factor for mortality after liver surgery, mostly related to lower Human Development Index countries. Members of the LiverGroup.org network could now work together to develop quality improvement collaboratives.

PDF file 199K, RINT1 c.1334-5delA, c.1334-1_1335delGTT minigene assay

PDF file 65K, Primers used in assessment of RINT1 transcripts

ANZ Journal of SurgeryVolume 93, Issue 11 p. 2766-2767 IMAGES FOR SURGEONS Successful management of giant delayed liver metastasis of gastric gastrointestinal stromal tumours with inferior vena cava syndrome I-Chin Lee MD, I-Chin Lee MD orcid.org/0000-0002-1027-2654 Department of surgery, Jiahui International Hospital, Jiahui Health, Shanghai, China Contribution: ​Investigation, Writing - original draftSearch for more papers by this authorJun Li MD, FEBS, Jun Li MD, FEBS [email protected] orcid.org/0000-0003-1553-8105 Department of surgery, Jiahui International Hospital, Jiahui Health, Shanghai, China Contribution: Supervision, Writing - review & editingSearch for more papers by this author I-Chin Lee MD, I-Chin Lee MD orcid.org/0000-0002-1027-2654 Department of surgery, Jiahui International Hospital, Jiahui Health, Shanghai, China Contribution: ​Investigation, Writing - original draftSearch for more papers by this authorJun Li MD, FEBS, Jun Li MD, FEBS [email protected] orcid.org/0000-0003-1553-8105 Department of surgery, Jiahui International Hospital, Jiahui Health, Shanghai, China Contribution: Supervision, Writing - review & editingSearch for more papers by this author First published: 31 July 2023 https://doi.org/10.1111/ans.18641Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onEmailFacebookTwitterLinkedInRedditWechat No abstract is available for this article. References 1Choi H, Charnsangavej C, Faria SC et al. Correlation of computed tomography and positron emission tomography in patients with metastatic gastrointestinal stromal tumor treated at a single institution with imatinib mesylate: proposal of new computed tomography response criteria. J. Clin. Oncol 2007; 25: 1753–1759. 10.1200/JCO.2006.07.3049 PubMedWeb of Science®Google Scholar 2von Mehren M, Kane JM, Riedel RF et al. NCCN guidelines® insights: gastrointestinal stromal tumors, version 2.2022. JNCCN 2022; 20: 1204–1214. Google Scholar 3Cananzi FC, Belgaumkar A, Lorenzi B, Mudan S. Liver surgery in the multidisciplinary management of gastrointestinal stromal tumor. ANZ J. Surg. 2014; 84: 937–942. 10.1111/ans.12199 PubMedWeb of Science®Google Scholar 4Lin TS, Chen CL, Concejero AM et al. Technical details of microsurgical biliary reconstruction in living donor liver transplantation. Transplantation 2014; 97: S34–S36. 10.1097/01.tp.0000446273.13310.77 PubMedWeb of Science®Google Scholar Volume93, Issue11November 2023Pages 2766-2767 ReferencesRelatedInformation

Hepatocellular carcinoma (HCC) has high recurrence rates exceeding 50% despite curative resection. The serum biomarker alpha-fetoprotein (AFP) is a well-known prognostic marker for HCC. EpCAM-positive circulating tumor cells (CTC) have a high predictive value for early HCC recurrence after curatively intended resection, most likely indicating micro-metastases at the time of resection. However, sensitivity remains low. The objective of this study was to evaluate a composite test comprising both CTC and AFP to identify patients at high risk for early HCC recurrence. We prospectively enrolled 58 patients undergoing curative intended resection for HCC at a tertiary referral center. Blood specimens were obtained prior to resection and analyzed for EpCAM-positive CTC and serum AFP levels. A positive result was defined as either detection of CTC or AFP levels ≥ 400 ng/ml. Eight patients tested positive for CTC, seven for AFP, and two for both markers. A positive composite test was significantly associated with shorter early recurrence-free survival (5 vs. 16 months, p = 0.005), time to recurrence (5 vs. 16 months, p = 0.011), and overall survival (37 vs. not reached, p = 0.034). Combining CTC and AFP identified patients with poor outcome after surgical resection, for whom adjuvant or neoadjuvant therapies may be particularly desirable.

PDF file 73K, Primers for RINT1 HRM

ANZ Journal of SurgeryVolume 93, Issue 7-8 p. 2012-2013 IMAGES FOR SURGEONS Unintended retention of a rare foreign object from the laparoscope I-Chin Lee MD, I-Chin Lee MD orcid.org/0000-0002-1027-2654 Department of Surgery, Jiahui International Hospital, Jiahui Health, Shanghai, China Contribution: ​Investigation, Writing - original draft, Writing - review & editingSearch for more papers by this authorJun Li MD, FEBS, Jun Li MD, FEBS orcid.org/0000-0003-1553-8105 Department of Surgery, Jiahui International Hospital, Jiahui Health, Shanghai, China Contribution: Project administration, Supervision, Writing - review & editingSearch for more papers by this author I-Chin Lee MD, I-Chin Lee MD orcid.org/0000-0002-1027-2654 Department of Surgery, Jiahui International Hospital, Jiahui Health, Shanghai, China Contribution: ​Investigation, Writing - original draft, Writing - review & editingSearch for more papers by this authorJun Li MD, FEBS, Jun Li MD, FEBS orcid.org/0000-0003-1553-8105 Department of Surgery, Jiahui International Hospital, Jiahui Health, Shanghai, China Contribution: Project administration, Supervision, Writing - review & editingSearch for more papers by this author First published: 26 April 2023 https://doi.org/10.1111/ans.18473Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onEmailFacebookTwitterLinkedInRedditWechat No abstract is available for this article. References 1 The Joint Commission. Preventing unintended retained foreign objects [Updated, October 17, 2013; cited 25 December 2022.] Available from URL: https://www.jointcommission.org/resources/sentinel-event/sentinel-event-alert-newsletters/sentinel-event-alert-issue-51-preventing-unintended-retained-foreign-objects/ Google Scholar 2Pisal N, Sindos M, Henson G. Risk factors for retained instruments and sponges after surgery. N. Engl. J. Med. 2003; 348: 1724–5. 10.1056/NEJM200304243481720 PubMedWeb of Science®Google Scholar 3Medina LG, Martin O, Cacciamani GE, Ahmadi N, Castro JC, Sotelo R. Needle lost in minimally invasive surgery: management proposal and literature review. J. Robot Surg. 2018; 12: 391–5. 10.1007/s11701-018-0802-9 PubMedWeb of Science®Google Scholar 4Weprin S, Crocerossa F, Meyer D et al. Risk factors and preventive strategies for unintentionally retained surgical sharps: a systematic review. Patient Saf. Surg. 2021; 15: 24. 10.1186/s13037-021-00297-3 PubMedWeb of Science®Google Scholar 5Steelman VM, Shaw C, Shine L, Hardy-Fairbanks AJ. Unintentionally retained foreign objects: a descriptive study of 308 sentinel events and contributing factors. Jt. Comm. J. Qual. Patient Saf. 2019; 45: 249–58. 10.1016/j.jcjq.2018.09.001 PubMedWeb of Science®Google Scholar 6Hariharan D, Lobo DN. Retained surgical sponges, needles and instruments. Ann. R. Coll. Surg. Engl. 2013; 95: 87–92. 10.1308/003588413X13511609957218 CASPubMedWeb of Science®Google Scholar 7 AORN recommended practices committee. Recommended practices for sponge, sharps, and instrument counts. AORN J. 2006; 83: 418 421–6, 429–33. 10.1016/S0001-2092(06)60172-5 PubMedGoogle Scholar 8Cima RR, Kollengode A, Garnatz J, Storsveen A, Weisbrod C, Deschamps C. Incidence and characteristics of potential and actual retained foreign object events in surgical patients. J. Am. Coll. Surg. 2008; 207: 80–7. 10.1016/j.jamcollsurg.2007.12.047 PubMedWeb of Science®Google Scholar Volume93, Issue7-8July/August 2023Pages 2012-2013 ReferencesRelatedInformation

Hepatocellular carcinoma (HCC) ranks among the five most common cancer entities worldwide and leads to hundred-thousands of deaths every year. Despite some groundbreaking therapeutical revelations during the last years, the overall prognosis remains poor. Although the immune system fights malignant transformations with a robust anti-tumor response, certain immune mediators have also been shown to promote cancer development. For example, interleukin (IL)-22 has been associated with HCC progression and worsened prognosis in multiple studies. However, the underlying mechanisms of the pathological role of IL-22-signaling as well as the role of its natural antagonist IL-22 binding protein (IL-22BP) in HCC remain elusive. Here, we corroborate the pathogenic role of IL-22 in HCC by taking advantage of two mouse models. Moreover, we observed a protective role of IL-22BP during liver carcinogenesis. While IL-22 was mainly produced by CD4+ T cells in HCC, IL-22BP was abundantly expressed by neutrophils during liver carcinogenesis. Hepatocytes could be identified as a major target of this pathological IL-22-signaling. Moreover, abrogation of IL-22 signaling in hepatocytes in IL22ra1flox/flox × AlbCre+ mice reduced STEAP4 expression-a known oncogene-in HCC in vivo. Likewise, STEAP4 expression correlated with IL22 levels in human HCC samples, but not in healthy liver specimens. In conclusion, these data encourage the development of therapeutical approaches that target the IL-22–IL-22BP axis in HCC.

Background:The role of the computed tomography (CT)-derived skeletal muscle index (SMI) as a parameter of muscle quantity on the outcome after major liver resection remains contradictory and that of the muscle radiodensity attenuation (MRA) as a parameter of muscle quality has not been sufficiently evaluated. This observational study aimed to investigate the influence of metric SMI and MRA values and cut-off-based CT sarcopenia detection on liver-surgery specific complications measured by the new FABIB (liver failure, ascites, biliary leakage, infection, bleeding) score and survival after hemihepatectomy.Methods:A total of 183 patients with major hepatectomy were retrospectively included. The SMI and MRA were determined from the abdominal muscle area of preoperative CT scans. Patients were classified as sarcopenic by the SMI and MRA cut-off values of Prado et al., Martin et al., and van der Werf et al. Postoperative complications were documented according to the Clavien-Dindo classification and FABIB score. The relation of the continuous, non-categoric SMI and MRA values and of the cut-off-based sarcopenia detection to the postoperative complications and survival was analyzed by multivariable linear, logistic, and Cox proportional hazards regression.Results:A higher MRA was associated with less severe postoperative complications in the Clavien-Dindo [-0.59 (95% CI: -0.95 to -0.23), P=0.002] and the FABIB score [-0.65 (95% CI: -1.19 to -0.12), P=0.017]. An increase of the SMI did not result in less severe complications in the Clavien-Dindo [0.14 (95% CI: -0.27 to 0.55), P=0.503] or FABIB score [0.17 (95% CI: -0.42 to 0.76), P=0.572]. For patients classified as sarcopenic by the cut-off-based systems no relevant relation to postoperative complications was found. Overall survival was better for a higher MRA [hazard ratio (HR): 0.75 (95% CI: 0.58-0.97), P=0.029], as long-term survival was for a higher SMI [HR: 0.68 (95% CI: 0.47-0.96), P=0.031]. Only below van der Werf's MRA cut-off the probability of overall and long-term survival was reduced [HR: 2.32 (95% CI: 1.18-4.54), P=0.015; 2.68 (95% CI: 1.25-5.74), P=0.011].Conclusions:The MRA has a stronger influence on complications in the Clavien-Dindo classification and the liver-surgery specific FABIB score than the SMI. Continuous, non-categoric MRA and SMI values are superior to cut-off-based systems in predicting the outcome after major hepatic surgery.