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Torin2 overcomes sorafenib resistance via suppressing mTORC2-AKT-BAD pathway in hepatocellular carcinoma cells

hepatobiliary & pancreatic Diseases International 2020年第6期19卷 547-554页

作者： Yi-Ting Hu Zhe-Yue Shu Jing-Hua Jiang Qin-Fen Xie Shu-Sen Zheng Department of hepatobiliary and pancreatic Surgery Shulan(Hangzhou)HospitalZhejiang Shuren UniversityShulan International Medical CollegeHangzhou 310022China Division of hepatobiliary pancreatic Surgery First Affiliated HospitalZhejiang University School of MedicineHangzhou 310003China Department of hepatobiliary and pancreatic Surgery Jinhua Municipal Central HospitalJinhua 321000China

Background:Sorafenib is an oral multi-kinase inhibitor that was approved by the US Food and Drug Administration for the treatment of patients with advanced hepatocellular carcinoma(HCC).However,resistance to sorafenib is an urgent problem to be resolved to improve the therapeutic efficacy of *** the activation of AKT/mTOR played a pivotal role in sorafenib resistance,we evaluated the effect of a dual mTOR complex 1/2 inhibitor Torin2 on overcoming the sorafenib resistance in HCC ***:The sorafenib-resistant Huh7 and Hep3B cell lines were established from their parental cell *** synergistic effect of sorafenib and Torin2 on these cells was measured by cell viability assay and quantified using the Chou-Talalay *** induced by the combination of sorafenib and Torin2 and the alteration in the specific signaling pathways of interest were detected by Western ***:Sorafenib treatment inversely inhibited AKT in parental but activated AKT in sorafenib-resistant Huh7 and Hep3B HCC cells,which underscores the significance of AKT ***2 and sorafenib synergistically suppressed the viability of sorafenib-resistant cells via apoptosis ***2 successfully suppressed the sorafenib-activated mTORC2-AKT axis,leading to the dephosphorylation of Ser136 in BAD protein,and increased the expression of total BAD,which contributed to the apoptosis in sorafenibresistant HCC ***:In this study,Torin2 and sorafenib showed synergistic cytostatic capacity in sorafenibresistant HCC cells,via the suppression of mTORC2-AKT-BAD *** results suggest a novel strategy of drug combination for overcoming sorafenib resistance in HCC.

关键词： Torin2 Sorafenib resistance Hepatocellular carcinoma mTORC2-AKT-BAD pathway

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Factors associated with failure of enhanced recovery after surgery program in patients undergoing pancreaticoduodenectomy

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hepatobiliary & pancreatic Diseases International 2020年第1期19卷 51-57页

作者： Xiao-Yu Zhang Xiao-Zhen Zhang Fang-Yan Lu Qi Zhang Wei Chen Tao Ma Xue-Li Bai Ting-Bo Liang Department of hepatobiliary and pancreatic Surgery the First Affiliated HospitalZhejiang University School of MedicineHangzhou 310003China Department of hepatobiliary and pancreatic Surgery the Second Affliated HospitalZhejiang University School of MedicineHangzhou 310009China Key Laboratory of pancreatic Disease of Zhejiang Province Hangzhou 310003China

Background: The enhanced recovery after surgery (ERAS) protocol is an evidence-based perioperative care program aimed at reducing surgical stress response and accelerating recovery. However, a small propor- tion of patients fail to bene t from the ERAS program following pancreaticoduodenectomy. This study aimed to identify the risk factors associated with failure of ERAS program in pancreaticoduodenectomy. Methods: Between May 2014 and December 2017, 176 patients were managed with ERAS program fol-lowing pancreaticoduodenectomy. ERAS failure was indicated by prolonged hospital stay, unplanned read- mission or unplanned reoperation. Demographics, postoperative recovery and compliance were compared of those ERAS failure groups to the ERAS success group. Results: ERAS failure occurred in 59 patients, 33 of whom had prolonged hospital stay, 18 were readmitted to hospital within 30 days after discharge, and 8 accepted reoperation. Preoperative American Society of Anesthesiologists (ASA) score of ≥III (OR = 2.736;95% CI: 1.276 6.939;P=0.028) and albumin (ALB) level of 70 years) were on a high risk of unplanned reoperation (62.5% vs. 23.1%, P=0.026). Patients with prolonged hospital stay and unplanned reoperation had delayed intake and increased intolerance of oral foods. Prolonged stay patients got off bed later than ERAS success patients did (65h vs. 46h, P =0.012). Unplanned reoperation patients tended to experience severer pain than ERAS success patients did (3 score vs. 2 score, P =0.035). Conclusions: Patients with high ASA score, low ALB level or age >70 years were at high risk of ERAS failure in pancreaticoduodenectomy. These preoperative demographic and clinical characteristics are important determinants to obtain successful postoperative recovery in ERAS program.

关键词： Enhanced recovery after surgery ERAS pancreaticoduodenectomy Failure of ERAS Risk factors

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pancreaticojejunostomy, hepaticojejunostomy and double Roux-en-Y digestive tract reconstruction for benign pancreatic diseases

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World Journal of Gastroenterology 2014年第36期20卷 13200-13204页

作者： Chang-Ku Jia Xue-Fei Lu Qing-Zhuang Yang Jie Weng You-Ke Chen Yu Fu Department of hepatobiliary pancreatic Surgery the Affiliated Hospital of Hainan Medical College

Surgery such as digestive tract reconstruction is usually required for pancreatic trauma and severe pancreatitis as well as malignant pancreatic lesions. The most common digestive tract reconstruction techniques (e.g., Child’s type reconstruction) for neoplastic diseases of the pancreatic head often encompass pancreaticojejunostomy, choledochojejunostomy and then gastrojejunostomy with pancreaticoduodenectomy, whereas these techniques may not be applicable in benign pancreatic diseases due to an integrated stomach and duodenum in these patients. In benign pancreatic diseases, the aforementioned reconstruction will not only increase the distance between the pancreaticojejunostomy and choledochojejunostomy, but also the risks of traction, twisting and angularity of the jejunal loop. In addition, postoperative complications such as mixed fistula are refractory and life-threatening after common reconstruction procedures. We here introduce a novel pancreaticojejunostomy, hepaticojejunostomy and double Roux-en-Y digestive tract reconstruction in two cases of benign pancreatic disease, thus decreasing not only the distance between the pancreaticojejunostomy and choledochojejunostomy, but also the possibility of postoperative complications compared to common reconstruction methods. Postoperatively, the recovery of these patients was uneventful and complications such as bile leakage, pancreatic leakage and digestive tract obstruction were not observed during the follow-up period.

关键词： Pancreatitis pancreatic trauma Digestive tract reconstruction

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Mirizzi syndrome:Problems and strategies

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hepatobiliary & pancreatic Diseases International 2024年第3期23卷 234-240页

作者： Jun Wu Shuang-Yong Cai Xu-Liang Chen Zhi-Tao Chen Shao-Hua Shi Department of hepatobiliary and pancreatic Surgery People’s Hospital of Jiulongpo DistrictChongqing 400050China Department of hepatobiliary and pancreatic Surgery Shulan(Hangzhou)Hospital Affiliated to Zhejiang Shuren University Shulan International Medical CollegeHangzhou 310003China

Mirizzi syndrome is a serious complication of gallstone *** is caused by the impacted stones in the gallbladder neck or cystic *** of the features of Mirizzi syndrome is severe inflammation or dense fibrosis at the Calot’s *** our clinical practice,bile duct,branches of right hepatic artery and right portal vein clinging to gallbladder infundibulum are often observed due to gallbladder infundibulum adhered to right hepatic *** intraoperative damage of branches of right hepatic artery occurs more easily than that of bile duct,all of which are hidden pitfalls for *** resonance cholangiopancreatography(MRCP)and endoscopic retrograde cholangiopancreatography(ERCP)are the preferable tools for the diagnosis of Mirizzi *** cholecystectomy in Mirizzi syndrome is easy to damage branches of right hepatic artery and bile duct due to gallbladder infundibulum adhered to right hepatic *** cholecystectomy is an easy,safe and definitive approach to Mirizzi *** combined with the application of ERCP,a laparoscopic management of Mirizzi syndrome by well-trained surgeons is feasible and *** objective of this review was to highlight its existing problems:(1)low preoperative diagnostic rate,(2)easy to damage bile duct and branches of right hepatic artery,and(3)high concomitant gallbladder ***,the review aimed to discuss the possible therapeutic strategies:(1)to enhance its preoperative recognition by imaging findings,and(2)to avoid potential pitfalls during surgery.

关键词： Mirizzi syndrome Bile duct injury Artery injury surgical treatment Subtotal cholecystectomy

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Development and multicenter validation of a nomogram for preoperative prediction of lymph node positivity in pancreatic cancer(NeoPangram)

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hepatobiliary & pancreatic Diseases International 2021年第2期20卷 163-172页

作者： Jie Hua Xue-Min Chen Yun-Jie Chen Bao-Chun Lu Jin Xu Wei Wang Si Shi Xian-Jun Yu Department of pancreatic Surgery Fudan University Shanghai Cancer CenterShanghai 200032China Department of Oncology Shanghai Medical College of Fudan UniversityShanghai 200032China Shanghai pancreatic Cancer Institute Shanghai 200032China Department of hepatobiliary and pancreatic Surgery The First People’s Hospital of ChangzhouChangzhou 213004China Department of Minimally Invasive hepatobiliary and pancreatic Surgery Ningbo No.2 HospitalNingbo 315010China Department of hepatobiliary and pancreatic Surgery Shaoxing People’s HospitalShaoxing 312000China

Background:Neoadjuvant therapy is associated with nodal downstaging and improved oncological outcomes in patients with lymph node(LN)-positive pancreatic *** study aimed to develop and validate a nomogram to preoperatively predict LN-positive ***:A total of 558 patients with resected pancreatic cancer were randomly and equally divided into development and internal validation *** logistic regression analysis was used to construct the *** performance was evaluated by discrimination,calibration,and clinical *** independent multicenter cohort consisting of 250 patients was used for external ***:A four-marker signature was built consisting of carbohydrate antigen 19–9(CA19–9),CA125,CA50,and CA242.A nomogram was constructed to predict LN metastasis using three predictors identified by multivariate analysis:risk score of the four-marker signature,computed tomography-reported LN status,and clinical tumor *** prediction model exhibited good discrimination ability,with C-indexes of 0.806,0.742 and 0.763 for the development,internal validation,and external validation cohorts,*** model also showed good calibration and clinical usefulness.A cut-off value(0.72)for the probability of LN metastasis was determined to separate low-risk and high-risk ***-Meier survival analysis revealed a good agreement of the survival curves between the nomogram-predicted status and the true LN ***:This nomogram enables the identification of pancreatic cancer patients at high risk for LN positivity who may have more advanced disease and thus could potentially benefit from neoadjuvant therapy.

关键词： Lymph node metastasis pancreatic ductal adenocarcinoma Nomogram Neoadjuvant therapy

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Development and Validation of an RNA Binding Proteinassociated Prognostic Model for Hepatocellular Carcinoma

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Journal of Clinical and Translational Hepatology 2021年第5期9卷 635-646页

作者： Hao Zhang Peng Xia Weijie Ma Yufeng Yuan Department of hepatobiliary and pancreatic Surgery Zhongnan Hospital of Wuhan UniversityWuhanHubeiChina

Background and Aims:The survival rate of patients with hepatocellular carcinoma is *** abnormal expression of RNA-binding proteins(RBPs)is closely related to the occurrence and development of malignant *** primary aim of this study was to identify RBPs related to the prognosis of liver cancer and to construct a prognostic model of liver ***:We downloaded the hepatocellular carcinoma gene sequencing data from The Cancer Genome Atlas(***/)database,constructed a protein-protein interaction network,and used Cytoscape to realize the *** among 325 abnormally expressed genes for RBPs,9(XPO5,enhancer of zeste 2 polycomb repressive complex 2 subunit[EZH2],CSTF2,BRCA1,RRP12,MRPL54,EIF2AK4,PPARGC1A,and SEPSECS)were selected for construction of the prognostic ***,we further verified the results through the Gene Expression Omnibus(***/geo/)database and in vitro ***:A prognostic model was constructed,which determined that the survival time of patients in the high-risk group was significantly shorter than that of the low-risk group(p<0.01).Univariate and multivariate Cox regression analysis suggested that the risk score was an independent prognostic factor(p<0.01).We also constructed a nomogram based on the risk score,survival time,and survival *** the same time,we verified the high expression and cancer-promoting effects of EZH2 in ***:Survival,receiver operating characteristic curve and independent prognostic analyses demonstrated that we constructed a good prognostic model,which might be useful for estimating the survival of patients with hepatocellular carcinoma.

关键词： Hepatocellular carcinoma RNA binding protein Prognostic model Nomogram

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Utility of routine blood tests after elective laparoscopic cholecystectomy for symptomatic gallstones

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World Journal of Gastrointestinal Surgery 2017年第6期9卷 149-152页

作者： Offir Ben-Ishay Marina Zeltser Yoram Kluger surgical Oncology Pancreatic and Hepatobiliary Surgery ServiceDepartment of General SurgeryDivision of SurgeryRambam Health Care CampusHaifa 35254Israel

AIM To evaluate the value of blood testing after elective laparoscopic cholecystectomy and its association with procedure related *** Charts of all patients undergoing elective laparoscopic cholecystectomy from January 2013 through December2014 were reviewed retrospectively for demographics,indication for surgery,operative course and *** our institution the decision to perform postoperative blood analysis is left for the discretion of the surgeon,therefore we had the possibility to compare the results of those who had blood analyses results to those who did *** was performed to identify variables associated with the decision to perform postoperative blood *** a univariate and multivariate analyses was performed comparing the two *** subgroup analysis was performed to identify factors associated with procedure related *** Five hundred and thirty-two elective laparoscopic cholecystectomies for symptomatic gallstones were performed during the study ***-four percent of the patients(n=340)had blood tests taken post *** that had laboratory tests taken were older(P=0.006,OR=1.01),had longer surgery(P<0.001,OR=3.22)had more drains placed(P<0.001,OR=3.2)and stayed longer in the hospital(P<0.001,OR=1.2).A subgroup analysis of the patients who experienced complications revealed longer stay in the hospital(P<0.001),higher body mass index(BMI)(P=0.04,OR=1.08),increased rates of drain placement(P=0.006,OR=3.1)and higher conversion rates(P=0.01,OR=14.6).Postoperative blood tests withdrawals were not associated with complications(P=0.44).On Multivariate analysis BMI and drain placement were independently associated with *** The current study indicate that routine postoperative blood tests after elective laparoscopic cholecystectomy for symptomatic gallstones does not predict complications and may have an added benefit in diagnosis and management of cases w

关键词： Cholecystectomy Blood tests Laparoscopy Complications Post-operative Gallstones symptomatic

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Liver transplantation benefits selected patients with hilar cholangiocarcinoma and colorectal liver metastases

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hepatobiliary & pancreatic Diseases International 2018年第5期17卷 385-386页

作者： Ji-Qiao Zhu Qiang He Xian-Liang Li Department of hepatobiliary and pancreatic Surgery Beijing Chaoyang Hospital Capital Medical University

Hilarcholangiocarcinoma(HCCA)isanaggressivemalignancy with a dismal prognosis. The 5-year survival rate has been reported to range from 39%to 50%if an R0 resection is obtained [1]. Approximately 25%patients with early stage HCCA of all cases can be treated with radical surgical resection [2], while most patients do not have a chance to receive a surgical procedure due to the advanced stage at the time of diagnosis. The poor prognosis is gen-

关键词： Liver transplantation benefits selected patients with hilar cholangiocarcinoma and colorectal liver metastases

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Identification of Expression Pattern and Clinical Significance of the Small Cajal Body-specific RNA SCARNA16 in Hepatocellular Carcinoma

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Journal of Clinical and Translational Hepatology 2022年第1期10卷 104-111页

作者： Sitong Zhang Yuan Ding Zhongquan Sun Yao Ge Yanjie Li Xin Han Qianhui Xu Liuzhi Zhou Yining Chen Hao Xu Yang Bai Chang Xu Hao Ding Sheng Yan Weilin Wang Department of hepatobiliary and pancreatic Surgery The Second Affiliated HospitalZhejiang University School of Medi-cineKey Laboratory of Precision Diagnosis and Treatment for Hepatobiliary and Pancreatic Tumor of Zhejiang ProvinceRe-search Center of Diagnosis and Treatment Technology for Hepatocellular Carcinoma of Zhejiang ProvinceClinical Medicine Innovation Center of Precision Diagnosis and Treatment for Hepatobiliary and Pancreatic Disease of Zhejiang UniversityClinical Research Center of Hepatobiliary and Pancreatic Diseases of Zhejiang ProvinceZhejiang University Cancer CenterHangzhouZhejiangChina Key Laboratory of Precision Diagnosis and Treatment for hepatobiliary and pancreatic Tumor of Zhejiang Province Research Center of Diagnosis and Treatment Technology for Hepatocellular Carcinoma of Zhejiang ProvinceClinical Medicine Innovation Center of Precision Diagnosis and Treatment for Hepatobiliary and Pancreatic Disease of Zhejiang UniversityClinical Research Center of Hepatobiliary and Pancreatic Diseases of Zhejiang ProvinceZhejiang University Cancer CenterHangzhouZhejiangChina

Background and Aims:For high morbidity and mortality,hepatocellular carcinoma(HCC)becomes a major health issue ***,numerous non-coding RNAs(ncRNAs)are known to regulate the occurrence and patho-genesis of *** ncRNAs have also been developed as tumor biomarkers and therapeutic ***,the potential function of the small Cajal body-specific RNA(scaRNA)SCARNA16,a newly identified ncRNA,remains to be explored in ***:In both HCC cell lines and specimens from 120 enrolled patients,the expression val-ues of SCARNA16 were *** divided patients into SCARNA16 high and low expression subgroups,and then analyzed the difference of various clinical characteristics and prognosis data between ***:Compared to paired controls,SCARNA16 was significantly down-regulated in HCC cell lines and clinical specimens(p<0.01).Besides,HCC patients with lower SCARNA16 expression commonly presented with larger and more tumor lesions,more ves-sel carcinoma emboli,more capsular invasion and higher TNM stages(p<0.05).Moreover,SCARNA16 expression was negatively correlated with postoperative prognosis of HCC patients in 5-year follow-up,including tumor-free survival(TFS)(median time of low *** subgroups:14 vs.48 months,p=0.006)and overall survival(OS)(median time of low *** subgroups:39 vs.52 months,p=0.001).Besides,SCARNA16 acted as an independent prognostic bio-marker in TFS(hazard ratio[HR]:0.578,95%CI:0.345-0.969,p=0.038)and OS(HR:0.366,95%CI:0.178-0.752,p=0.006).Conclusions:Low expression patterns of SCAR-NA16 remarkably associated with severe clinical status and poor survival of patients,suggesting that SCARNA16 pos-sesses potency as a novel biomarker for HCC.

关键词： Hepatocellular carcinoma Non-coding RNA SCARNA16 Clinical assessment Biomarker

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Radiofrequency ablation-assisted liver resection a step toward bloodless liver resection

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hepatobiliary & pancreatic Diseases International 2015年第1期14卷 69-74页

作者： Athanasios Petrou Kyriakos Neofytou Constantinos Mihas Jessamy Bagenal Michael Kontos John Griniatsos Evangelos Felekouras Nicosia surgical Department Division of Hepatobiliary Pancreatic Surgery Nicosia General Hospital First Department of Surgery University of Athens Medical School LAIKO Teaching Hospital Bristol Heart Institute Severn School of Surgery

BACKGROUND： Liver resection is currently the most efficient curative approach for a wide variety of liver tumors. The application of modern techniques and new surgical devices has improved operative outcomes. Radiofrequency ablation is used more often for liver parenchymal transection. This study aimed to assess the efficacy and safety of radiofrequency ablation-assisted liver ***： A retrospective study of 145 consecutive patients who underwent radiofrequency ablation-assisted liver resection was performed. Intraoperative blood loss, need for transfusion or intraoperative Pringle maneuver, the duration of liver parenchymal transection, perioperative complications, and postoperative morbidity and mortality were all ***： Fifty minor and ninety-five major liver resections were performed. The mean intraoperative blood loss was 251 m L, with a transfusion rate of 11.7%. The Pringle maneuver was necessary in 12 patients（8.3%）. The mean duration for parenchymal transection was 51.75 minutes. There were 47 patients（32.4%） with postoperative complications. There is no mortality within 30 days after surgery. CONCLUSIONS： Radiofrequency ablation-assisted liver resection permits both major and minor liver resections with minimal blood loss and without occlusion of hepatic inflow. Furthermore it decreases the need for blood transfusion and reduces morbidity and mortality.

关键词： bleeding complications hepatectomy radiofrequency ablation Pringle maneuver

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