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Multiomics analysis reveals metabolic subtypes and identifies diacylglycerol kinase α (DGKA) as a potential therapeutic target for intrahepatic cholangiocarcinoma

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Cancer Communications 2024年第2期44卷 226-250页

作者： Weiren Liu Huqiang Wang Qianfu Zhao Chenyang Tao Weifeng Qu Yushan Hou Run Huang Zimei Sun Guiqi Zhu Xifei Jiang Yuan Fang Jun Gao Xiaoling Wu Zhixiang Yang Rongyu Ping Jiafeng Chen Rui Yang Tianhao Chu Jian Zhou Jia Fan Zheng Tang Dong Yang Yinghong Shi Department of Liver Surgery and Transplantation Liver Cancer InstituteZhongshan HospitalFudan UniversityKey Laboratory of Carcinogenesis and Cancer Invasion of Ministry of EducationShanghaiP.R.China Research Unit of Liver cancer Recurrence and Metastasis Chinese Academy of Medical SciencesBeijingP.R.China State Key Laboratory of Medical Proteomics Beijing Proteome Research CenterNational Center for Protein Sciences(Beijing)Beijing Institute of LifeomicsBeijingP.R.China

Background:intrahepatic cholangiocarcinoma(iCCA)is a highly heteroge-neous and lethal hepatobiliary tumor with few therapeutic *** metabolic reprogramming of tumor cells plays an essential role in the develop-ment of tumors,while the metabolic molecular classification of iCCA is largely ***,we performed an integrated multiomics analysis and metabolic classification to depict differences in metabolic characteristics of iCCA patients,hoping to provide a novel perspective to understand and treat ***:We performed integrated multiomics analysis in 116 iCCA samples,including whole-exome sequencing,bulk RNA-sequencing and proteome *** on the non-negative matrix factorization method and the protein abundance of metabolic genes in human genome-scale metabolic models,the metabolic subtype of iCCA was *** and prognostic gene analy-ses were used to compare overall survival(OS)differences between metabolic *** proliferation analysis,5-ethynyl-2’-deoxyuridine(EdU)assay,colony formation assay,RNA-sequencing and Western blotting were performed to investigate the molecular mechanisms of diacylglycerol kinaseα(DGKA)in iCCA ***:Three metabolic subtypes(S1-S3)with subtype-specific biomarkers of iCCA were *** metabolic subtypes presented with distinct prog-noses,metabolic features,immune microenvironments,and genetic *** S2 subtype with the worst survival showed the activation of some special metabolic processes,immune-suppressed microenvironment and Kirsten ratsar-coma viral oncogene homolog(KRAS)/AT-rich interactive domain 1A(ARID1A)*** the S2 subtype-specific upregulated proteins,DGKA was further identified as a potential drug target for iCCA,which promoted cell proliferation by enhancing phosphatidic acid(PA)metabolism and activating mitogen-activated protein kinase(MAPK)***:Viamultiomics analyses,we identified three metabolic subtypes of iCCA,revealing

关键词： diacylglycerol kinaseα intrahepatic cholangiocarcinoma MAPK signaling metabolic classifi-cation multiomics analysis phosphatidic acid metabolism

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Establishing prognostic models for intrahepatic cholangiocarcinoma based on immune cells

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World Journal of Gastrointestinal Oncology 2024年第10期16卷 4092-4103页

作者： Zhuo-Ran Wang Cun-Zhen Zhang Zhan Ding Yi-Zhuo Li Jian-Hua Yin Nan Li Department of Hepatic Surgery I(Ward I)Shanghai Eastern Hepatobiliary Surgery Hospital Navy Medical UniversityShanghai 200433China Key Laboratory of Biological Defense Ministry of EducationNavy Medical UniversityShanghai 200433China Shanghai Key Laboratory of Medical Bioprotection Navy Medical UniversityShanghai 200433China Department of Epidemiology Faculty of Navy MedicineNavy Medical UniversityShanghai 200433China Department of Oncology 905 Hospital of People’s Liberation Army NavyShanghai 200050China Department of Hepatobiliary Surgery The Second Affiliated HospitalWenzhou Medical UniversityWenzhou 325000Zhejiang ProvinceChina

BACKGROUND intrahepatic cholangiocarcinoma(ICC)is a malignant liver tumor that is challenging to treat and manage and current prognostic models for the disease are inefficient or ***-associated immune cells are critical for tumor development and *** main goal of this study was to establish models based on tumor-associated immune cells for predicting the overall survival of patients undergoing surgery for *** To establish 1-year and 3-year prognostic models for ICC after surgical *** Immunohistochemical staining was performed for CD4,CD8,CD20,pan-cytokeratin(CK),and CD68 in tumors and paired adjacent tissues from 141 patients with ICC who underwent curative *** of variables was based on regression diagnostic procedures and goodness-of-fit tests(PH assumption).Clinical parameters and pathological diagnoses,combined with the distribution of immune cells in tumors and paired adjacent tissues,were utilized to establish 1-and 3-year prognostic *** This is an important application of immune cells in the tumor ***4,CD8,CD20,and CK were included in the establishment of our prognostic model by stepwise selection,whereas CD68 was not significantly associated with the prognosis of *** integrating clinical data associated with ICC,distinct prognostic models were derived for 1-and 3-year survival outcomes using variable *** 1-year prediction model yielded a C-index of 0.7695%confidence interval(95%CI):0.65-0.87 and the 3-year prediction model produced a C-index of 0.69(95%CI:0.65-0.73).Internal validation yielded a C-index of 0.761(95%CI:0.669-0.853)for the 1-year model and 0.693(95%CI:0.642-0.744)for the 3-year *** We developed Cox regression models for 1-year and 3-year survival predictions of patients with ICC who underwent resection,which has positive implications for establishing a more comprehensive prognostic model for ICC based on tumor immune microenvironment an

关键词： intrahepatic cholangiocarcinoma Tumor immune cells Biomarkers Prognosis Prediction models

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Conversion surgery after gemcitabine and cisplatin plus durvalumab for advanced intrahepatic cholangiocarcinoma:A case report

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World Journal of Clinical Cases 2024年第34期12卷 6721-6727页

作者： Yu Igata Masashi Kudo Motohiro Kojima Shota Kami Keishiro Aoki Tomoyuki Satake Tatsushi Kobayashi Motokazu Sugimoto Shin Kobayashi Masaru Konishi Naoto Gotohda Department of Hepatobiliary and Pancreatic Surgery National Cancer Center Hospital EastKashiwa 277-8577Japan Exploratory Oncology Research and Clinical Trial Center National Cancer CenterKashiwa 277-8577Japan Department of Hepatobiliary and Pancreatic Oncology National Cancer Center Hospital EastKashiwa 277-8577Japan Department of Diagnostic Radiology National Cancer Center Hospital EastChiba 277-8577Japan

BACKGROUND The combination of immune checkpoint inhibitors and chemotherapy has shown promising results for the treatment of advanced biliary tract cancer(BTC).Based on the results of the TOPAZ-1 trial,a gemcitabine and cisplatin plus durvalumab(GCD)regimen was recently approved as first-line therapy for patients with advanced ***,post-GCD conversion surgery has not been previously ***,we describe a case of advanced intrahepatic cholangiocarcinoma(ICC)successfully treated with radical surgery after *** SUMMARY A 65-year-old female diagnosed with advanced ICC with periductal infiltration into the hepatic hilum underwent eight cycles of GCD,followed by durvalumab maintenance treatment,with mild adverse *** response was ***,a conversion surgery with extended left hepatectomy and bile duct resection was *** resection margins were negative,and the pathological diagnosis was compatible with small duct type *** patient remained disease-free for 8 months without adjuvant *** We describe the case of a patient who received successful conversion surgery after GCD treatment for advanced ICC.

关键词： Conversion surgery intrahepatic cholangiocarcinoma Small duct type Immunotherapy Case report

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intrahepatic cholangiocarcinoma: Introducing the preoperative prediction score based on preoperative imaging

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Hepatobiliary & Pancreatic Diseases International 2021年第3期20卷 262-270页

作者： Fabian Bartsch Felix Hahn Lukas Müller Janine Baumgart Maria Hoppe-Lotichius Roman Kloeckner Hauke Lang Department of General Visceral and Transplant SurgeryUniversity Medical Center of the Johannes Gutenberg-University MainzLangenbeckst155131 MainzGermany Department of Diagnostic and Interventional Radiology University Medical Center of the Johannes Gutenberg-University MainzLangenbeckst155131 MainzGermany

Background: intrahepatic cholangiocarcinoma(ICC) still has a poor long-term outcome, even after complete resection. We investigated different parameters gathered in preoperative imaging and analyzed their influence on resectability, recurrence, and survival. Methods: All patients who underwent exploration due to ICC between January 2008 and June 2018 were analyzed retrospectively. Kaplan-Meier model, log-rank test and Cox regression were used. Results: Out of 184 patients, 135(73.4%) underwent curative intended resection. Median overall survival(OS) was 22.2 months with a consecutive 1-, 3-and 5-year OS of 73%, 29%, and 17%. Median recurrencefree survival(RFS) was 9.3 months with a consecutive 1-, 3-and 5-year RFS of 36%, 15%, and 11%. Site of tumor, parenchymal localization, tumor configuration/dissemination, and estimated tumor volume had significant influence on resectability. Univariate analyses showed that site of tumor, tumor configuration/dissemination, number of nodules, and estimated tumor volume had predictive values for OS and RFS. Together with tumor size the preoperative prediction(POP) score was created showing significance for OS and RFS(all P<0.001). In multivariate analysis, POP score(HR=1.779;95% CI: 1.26 8-2.4 95;P=0.001), T stage(HR=1.255;95% CI: 1.040-1.514;P=0.018) and N stage(HR=1.334;95% CI: 1.081-1.645;P=0.007) were the independent predictors for OS. For RFS, POP score(HR=1.733;95% CI: 1.30 0-2.311;P<0.0 01) and M stage(HR=3.036;95% CI: 1.376-6.697;P=0.006) were the independent predictors. Conclusions: The POP score showed to have a highly significant influence on OS and RFS. The score is easy to assess through preoperative imaging. For patients in the high risk group at least staging laparoscopy or preoperative chemotherapy should be evaluated, because they showed equal outcome compared to the irresectable group.

关键词： intrahepatic cholangiocarcinoma cholangiocarcinoma Liver surgery Preoperative imaging Survival

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intrahepatic cholangiocarcinoma and Thermal Ablation:Long-term Results of An Italian Retrospective Multicenter Study

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Journal of Clinical and Translational Hepatology 2019年第4期7卷 287-292页

作者： Antonio Giorgio Pietro Gatti Luca Montesarchio Bruno Santoro Andrea Dell’Olio Nicola Crucinio Carmine Coppola Ferdinando Scarano Fabio De Biase Emanuela Cirac Stefano Semeraro Valentina Giorgio Liver Unit and Interventional Ultrasound Unit Athena Clinical InstitutePiedimonte Matese(CE)Italy Internal Medicine Unit Brindisi General HospitalBrindisiItaly General Surgery Unit Polla General HospitalPolla(SA)Italy Department of Radiology Bisceglie Hospital-ASL BATBisceglieItaly Gastroenterology Unit Foggia General HospitalFoggiaItaly Department of Internal Medicine Hepatology Interventional UnitGragnano HospitalGragnano(NA)Italy Internal Medicine Unit Ostuni HospitalOstuni(BR)Italy Fondazione Policlinico A.Gemelli IRCCS Department of Woman and Child Health and Public HealthLargo A GemelliRomaItaly

Background and Aims: Despite resection being considered the treatment of choice for intrahepatic cholangiocarcinoma(ICC),percutaneous thermal ablation can be an alter-native treatment for patients unfit for *** aim was to compare long-term results of percutaneous sonographi-cally-guided radiofrequency ablation(RFA)with high-powered microwave ablation(MWSA)in treatment of ***: Results of 71 ICC patients with 98 nodules treated with RFA(36 patients)or MWSA(35 patients)between January 2008 and June 2018 in 5 Interventional Ultrasound centers of Southern Italy were retrospectively ***-mulative overall survival curves were calculated with the Ka-plan-Meyer method and differences with the log-rank *** possible factors affecting survival were ***: Overall survival of the entire series was 88%,65%,45%and 34%at 12,36,60 and 80 months,*** treated with MWSA survived longer than pa-tients treated with RFA(p 4 cm,no significant difference was ***-free sur-vival and progression-free survival were better in the MWSA group compared to the RFA group(p < 0.005).Diameter of nodules and MWSA were independent factors predicting a better *** major complications were ***: MWSA is superior to RFA in treating ICC unfit for surgery,achieving better long-term survival in small(≤3 cm)ICC nodules as well as nodules up to 4 cm of neo-plastic tumors and should replace RFA.

关键词： intrahepatic cholangiocarcinoma Thermal ablation Microwaves Radiofrequency Percutaneous treatment

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intrahepatic cholangiocarcinoma and Hepatocellular Carcinoma:Real-life Data on Liver Disease,Treatment and Prognosis

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Journal of Clinical and Translational Hepatology 2023年第5期11卷 1106-1117页

作者： Xavier Adhoute Olivia Pietri Guillaume Pénaranda Thomas Wolf Patrick Beaurain Olivier Monnet Arthur Laquière Justine Bonomini Frédéric Neumann Olivier Levrel Jean-Pascal Buono Xavier Hanna Paul Castellani HervéPerrier Marc Bourliere Rodolphe Anty Department of Gastroenterology and Hepatology Hôpital Saint-JosephMarseilleFrance Department of Biostatistics AlphaBio-Biogroup LaboratoryMarseilleFrance Department of Radiology Hôpital Saint-JosephMarseilleFrance Department of Clinical Research Hôpital Saint-JosephMarseilleFrance Medipath EguillesFrance Department of Hepatobiliary Surgery Hôpital Saint-JosephMarseilleFrance Department of Gastroenterology and Hepatology Hôpital Universitaire de l’ArchetNiceFrance

Background and Aims:Hepatocellular carcinoma(HCC)and intrahepatic cholangiocarcinoma(iCCA)have common features and *** real-life study investigated their characteristics,treatment modalities,and ***:This retrospective comparative study was performed in 1,075 patients seen at one tertiary center between January 2008 and December *** survival(OS)was estimated by the Kaplan-Meier *** of iCCAs after histological and radiological review,and molecular profiling was ***:HCCs patients were more likely to have early-stage disease than iCCA *** patients were more likely to be female,especially those patients without cirrhosis(43%vs.17%).Cirrhosis was prominent among HCC patients(89%vs.34%),but no difference in underlying liver disease among cirrhotic patients was *** of HCC patients was 18.4(95%CI:6.4,48.3)months,that of iCCA patients was 7.0(95%CI:3.4,20.1)*** of Barcelona Clinic Liver Cancer C HCC patients was 7.8(95%CI:4.3,14.2)months,that of advanced/metastatic iCCA patients was 8.5(95%CI:5.7,12.3)*** patients treated with sorafenib,OS was longer in HCC patients who received subsequent tyrosine kinase inhibitor *** significant OS difference was found between iCCA patients with and without cirrhosis or according to histological subtype.A targetable molecular alteration was detected in 50%of the iCCA ***:In this French series,cirrhosis was common in iCCA,which showed etiological factors comparable to those of HCC,implying a distinct oncogenic *** entities had a dismal prognosis at advanced ***,systemic therapies sequencing in HCC and molecular profiling in iCCA offer new insights.

关键词： intrahepatic cholangiocarcinoma Hepatocellular carcinoma Cirrhosis NASH Oncogenic alterations

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intrahepatic cholangiocarcinoma is more complex than we thought:A case report

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World Journal of Clinical Cases 2021年第6期9卷 1469-1474页

作者： Jian-Ting Zeng Jie-Feng Zhang Yu Wang Zhou Qing Zhen-Hua Luo Yan-Lin Zhang Yi Zhang Xian-ZhangLuo Key Laboratory for Biorheological Science and Technology of Ministry of Education Chongqing UniversityChongqing University Cancer HospitalChongqing 400030China Chongqing Key Laboratory of Translational Research for Cancer Metastasis and Individualized Treatment Chongqing University Cancer HospitalChongqing 400030China

BACKGROUND Brain metastasis from intrahepatic cholangiocarcinoma is *** the best of our knowledge,only a few cases have been *** biological behavior was complex,and treatment requires further *** SUMMARY A 62-year-old woman complained of left limb *** computed tomography showed a 5.0 cm×5.6 cm lesion in the left lobe of the *** markers were *** analysis indicated absence of hepatitis *** magnetic resonance imaging revealed a 1.0 cm×1.3 cm mass in the right frontal *** cholangiocarcinoma with brain metastasis was diagnosed by our liver cancer multidisciplinary *** sufficient preparation,the patient underwent partial frontal lobotomy and left *** results confirmed that both the lesions were *** cycles of gemcitabine combined with S1 were *** a 39 mo postoperative follow-up,no sign of local recurrence or distant metastasis was *** This case expands our knowledge concerning the complex and heterogeneous nature of tumor metastasis.

关键词： intrahepatic cholangiocarcinoma Brain metastasis Multidisciplinary team Synchronous brain metastasis Case report

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intrahepatic cholangiocarcinoma in patients with primary sclerosing cholangitis and ulcerative colitis: Two case reports

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World Journal of Gastrointestinal Surgery 2023年第6期15卷 1224-1231页

作者： Takahiro Miyazu Natsuki Ishida Yusuke Asai Satoshi Tamura Shinya Tani Mihoko Yamade Moriya Iwaizumi Yasushi Hamaya Satoshi Osawa Satoshi Baba Ken Sugimoto First Department of Medicine Hamamatsu University School of MedicineHamamatsu 431-3192Japan Department of Endoscopic and Photodynamic Medicine Hamamatsu University School of MedicineHamamatsu 431-3192Japan Department of Laboratory Medicine Hamamatsu University School of MedicineHamamatsu 431-3192Japan Department of Diagnostic Pathology Hamamatsu University School of MedicineHamamatsu 431-3192Japan

BACKGROUND Primary sclerosing cholangitis(PSC)is an extraintestinal manifestation of ulcerative colitis(UC).PSC is a well-known risk factor for intrahepatic cholangiocarcinoma(ICC),and ICC is known to have a poor *** SUMMARY We present two cases of ICC in patients with PSC associated with *** the first case,a tumor was found by magnetic resonance imaging(MRI)in the liver of a patient with PSC and UC who presented to our hospital with right-sided rib *** second patient was asymptomatic,but we unexpectedly detected two liver tumors in an MRI performed to evaluate bile duct stenosis associated with *** was strongly suspected by computed tomography and MRI in both cases,and surgery was performed,but unfortunately,the first patient died of ICC recurrence 16 mo postoperatively,and the second patient died of liver failure 14 mo *** Careful follow-up of patients with UC and PSC with imaging and blood tests is necessary for early detection of ICC.

关键词： Ulcerative colitis Primary sclerosing cholangitis intrahepatic cholangiocarcinoma Hepatic lobectomy Inflammatory bowel disease Case report

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Distinct Immune Signatures in Peripheral Blood Predict Chemosensitivity in intrahepatic cholangiocarcinoma Patients

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Engineering 2021年第10期7卷 1381-1392页

作者： Tong Wu Ying-Cheng Yang Bo Zheng Xue-Bing Shi Wei Li Wen-Cong Ma Shan Wang Zhi-Xuan Li Yan-Jing Zhu Jian-Min Wu Kai-Ting Wang Yan Zhao Rui Wu Cheng-Jun Sui Si-Yun Shen Xuan Wu Lei Chen Zhen-Gang Yuan Hong-Yang Wang International Cooperation Laboratory on Signal Transduction&Key Laboratory of Signaling Regulation and Targeting Therapy of Liver Cancer Ministry of Education&Shanghai Key Laboratory of Hepatobiliary Tumor BiologyEastern Hepatobiliary Surgery HospitalSecond Military Medical UniversityShanghai 200438China National Center for Liver Cancer Shanghai 201805China Department of Hepatobiliary Surgery Eastern Hepatobiliary Surgery HospitalSecond Military Medical UniversityShanghai 200438China Fudan University Shanghai Cancer Center Shanghai 200032China Institute of Metabolism and Integrative Biology Fudan UniversityShanghai 200433China Department of Laboratory Medicine The Tenth People’s Hospital of ShanghaiTongji UniversityShanghai 200072China Key Laboratory of Signaling Regulation and Targeting Therapy of Liver Cancer Ministry of EducationShanghai 200438China Department of Oncology Eastern Hepatobiliary Surgery HospitalSecond Military Medical UniversityShanghai 200438China

intrahepatic cholangiocarcinoma(ICC)is the second most common liver *** remains the main therapeutic strategy for advanced ICC patients,but chemosensitivity varies ***,we applied cytometry by time-of-flight(CyTOF)to establish the immune profile of peripheral blood mononuclear cells(PBMCs)on the single-cell level at indicated time points before,during,and after *** immunofluorescence staining was applied to examine the spatial distribution of certain immune *** microarrays(TMAs)were used for prognostic evaluation.A total of 20 ICC patients treated with gemcitabine(GEM)were enrolled in our study,including eight cases with good response(R)and 12 cases with non-response(NR).Tremendous changes in PBMC composition,including an increased level of CD4/CD8 double-positive T cells(DPT),were observed after *** with higher level of CD4^(+)CD45RO^(+)CXCR3^(+)T cells before treatment had a favorable response to *** study identified a positive correlation between the percentage of T cell subpopulations and clinical response after chemotherapy,which suggests that it is practical to predict the potential response before treatment by evaluating the proportions of the cell population in PBMCs.

关键词： intrahepatic cholangiocarcinoma Gemcitabine Chemosensitivity Peripheral blood mononuclear cells

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Effect of contrast-enhanced ultrasound on differential diagnosis of intrahepatic cholangiocarcinoma and arterial phase enhanced hepatic inflammatory lesions

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Chinese Journal of Cancer Research 2017年第3期29卷 272-280页

作者： Shanshan Yin Qiuli Cui Kun Yan Wei Yang Wei Wu Liping Bao Minhua Chen Key Laboratory of Carcinogenesis and Translational Research(Ministry of Education/Beijing) Department of UltrasoundPeking University Cancer Hospital&InstituteBeijing 100142China

Objective: To investigate differential diagnosis between intrahepatic cholangiocarcinoma (ICC) and arterial phase enhanced hepatic inflammatory lesions in patients without liver cirrhosis using contrast-enhanced ultrasound (CEUS). Methods: ICC and hepatic inflammatory lesions cases with CEUS and pathological diagnosis between Sep 2013 and Oct 2016 were investigated retrospectively. Imaging features of conventional ultrasound and CEUS were analyzed. The parameters of time intensity curve (TIC), including the arrival time, peak intensity (PI) in the lesions, the starting time for washout, and the intensity difference at 3 min (Delta I-3) after contrast agent infection between the lesion and the liver parenchyma, were compared between ICC and hepatic inflammatory lesions. Results: Twenty-five ICC and fifteen inflammatory patients were included in this study. Seventeen ICC (68.0%) and two inflammatory cases (13.3%) showed bile duct dilatation on conventional ultrasound. Using CEUS, three ICC cases (12.0%) were misdiagnosed as inflammatory lesions and three inflammatory lesions (20.0%) as ICC; two ICC (8.0%) and one inflammatory case (6.7%) could not be made definite diagnosis. Washout started at 34.5 +/- 3.5 s and 61.5 +/- 12.9 s for ICC and inflammatory lesions respectively (P < 0.001). The intensity difference between lesion and liver parenchyma at 3 min after contrast agent injection was 10.8 +/- 3.1 dB in ICC and 4.2 +/- 2.3 dB in inflammatory group (P < 0.001). The sensitivity and specificity differentiating ICC and inflammatory lesions were 76% and 87% if the cut-off value of the intensity difference was 7.7 dB. Conclusions: Combined with TIC analysis, and particularly with the characteristic of the early-starting and obvious washout in ICC, CEUS can be useful in differential diagnosis between hepatic inflammatory lesions and ICC.

关键词： intrahepatic cholangiocarcinoma inflammatory lesions ultrasound contrast enhanced ultrasound

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