1,913 results on '"Intrahepatic cholangiocarcinoma"'
Search Results
2. Disseminated Carcinomatosis of Bone Marrow as the Initial Presentation of Intrahepatic Cholangiocarcinoma without Jaundice: An Autopsy Case Report
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Yukio Gibo, Kenta Mitsui, Hiroko Itagaki, Seiichi Daikuhara, Taiki Okumura, Toshiharu Tatai, and Hideharu Miyabayashi
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Adult ,Male ,medicine.medical_specialty ,Carcinosis ,Jaundice ,Autopsy ,digestive system ,Gastroenterology ,Cholangiocarcinoma ,Bone Marrow ,Stomach Neoplasms ,Intensive care ,Internal medicine ,Antineoplastic Combined Chemotherapy Protocols ,Internal Medicine ,Humans ,Medicine ,Peritoneal Neoplasms ,Intrahepatic Cholangiocarcinoma ,Disseminated intravascular coagulation ,business.industry ,General Medicine ,Disseminated Intravascular Coagulation ,medicine.disease ,digestive system diseases ,Tumor lysis syndrome ,Bile Ducts, Intrahepatic ,medicine.anatomical_structure ,Bile Duct Neoplasms ,Bone marrow ,medicine.symptom ,Bone Marrow Neoplasms ,business - Abstract
Disseminated carcinomatosis of the bone marrow (DCBM) is often accompanied by disseminated intravascular coagulation (DIC) and has a poor prognosis. DCBM develops most frequently in gastric cancer and is rarely associated with intrahepatic cholangiocarcinoma. A 41-year-old man was incidentally found to have DIC on his regular visit for ulcerative colitis and was diagnosed with DCBM with intrahepatic cholangiocarcinoma. He received intensive care, including chemotherapy, but died suddenly from hyperkalemia, possibly due to tumor lysis syndrome (TLS). The autopsy showed the periductal infiltrating type of intrahepatic cholangiocarcinoma and tumor necrosis, possibly due to chemotherapy, indicating the effectiveness of chemotherapy for DCBM with intrahepatic cholangiocarcinoma.
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- 2022
3. Liver Transplantation for Intrahepatic Cholangiocarcinoma: Ready for Prime Time?
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Tommy Ivanics, Gonzalo Sapisochin, and Julie K. Heimbach
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Oncology ,medicine.medical_specialty ,Cirrhosis ,medicine.medical_treatment ,Antineoplastic Agents ,Disease ,Liver transplantation ,Radiosurgery ,Malignancy ,Cholangiocarcinoma ,Internal medicine ,Proton Therapy ,medicine ,Hepatectomy ,Humans ,Chemoembolization, Therapeutic ,Immune Checkpoint Inhibitors ,Contraindication ,Neoadjuvant therapy ,Intrahepatic Cholangiocarcinoma ,Clinical Trials as Topic ,Radiofrequency Ablation ,Hepatology ,business.industry ,medicine.disease ,Neoadjuvant Therapy ,Liver Transplantation ,Bile Ducts, Intrahepatic ,Bile Duct Neoplasms ,Hepatocellular carcinoma ,Lymph Node Excision ,business - Abstract
Cholangiocarcinoma (CCA) represents the second most common primary liver malignancy after hepatocellular carcinoma and has risen in incidence globally in the past decades. Intrahepatic cholangiocarcinoma (iCCA) comprises 20% of all CCAs, with the rest being extrahepatic (including perihilar [pCCA] and distal CCA). Though long representing an absolute contraindication for liver transplantation (LT), recent analyses of outcomes of LT for iCCA have suggested that iCCA may be a potentially feasible option for highly selected patients. This has been motivated both by successes seen in outcomes of LT for other malignancies such as HCC and perihilar CCA and by several retrospective reviews demonstrating favorable results with LT for a selected group of iCCA patients with small lesions. LT for iCCA is primarily relevant within two clinical scenarios. The first includes patients with very early disease (single tumor ≤2 cm) with cirrhosis and are not candidates for liver resection (LR). The second scenario is patients with locally advanced iCCA, but where the extent of LR would be too extensive to be feasible. Preliminary single-center reports have described LT in a selected group of patients with locally advanced tumors which have responded to neoadjuvant therapy and have a period of disease stability. Currently, there are three prospective trials underway that will help clarify the role of LT in iCCA. This review seeks to explore the available studies involving LT for iCCA, the challenges of ongoing trials, and opportunities for the future.
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- 2022
4. Globo H Is a Promising Theranostic Marker for Intrahepatic Cholangiocarcinoma
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Chiao-En Wu, Li-Chun Lai, Fei-Yun Lo, Jung-Tung Hung, Alice L. Yu, Chien-Wei Lee, John Yu, Chau-Ting Yeh, Yenlin Huang, Tsai-Hsien Hung, Chun-Nan Yeh, Yi-Hsiu Chung, and John K Tung
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Male ,RC799-869 ,law.invention ,Cholangiocarcinoma ,Rats, Sprague-Dawley ,chemistry.chemical_compound ,In vivo ,law ,Risk Factors ,medicine ,Animals ,Humans ,Antigens, Tumor-Associated, Carbohydrate ,Polymerase chain reaction ,Intrahepatic Cholangiocarcinoma ,Tumor microenvironment ,Hepatology ,biology ,business.industry ,Cancer ,Antibodies, Monoclonal ,Original Articles ,Diseases of the digestive system. Gastroenterology ,medicine.disease ,Prognosis ,Disease Models, Animal ,chemistry ,Bile Duct Neoplasms ,biology.protein ,Cancer research ,Immunohistochemistry ,Original Article ,Antibody ,Thioacetamide ,business - Abstract
Recent studies support the development of cancer therapeutics to target Globo H-ceramide, the most prevalent tumor-associated carbohydrate antigen in epithelial cancers. Herein, we evaluated the expression of Globo H and its prognostic significance in intrahepatic cholangiocarcinoma (ICC) and conducted preclinical studies to assess the antitumor activity of Globo H-specific antibody in thioacetamide (TAA)-induced ICC in rats. Globo H-ceramide in tumor specimens was detected by immunohistochemistry (IHC) and mass spectrometry. Antitumor efficacy of anti-Globo H mAbVK9 was evaluated in TAA-induced ICC in rat. Natural killer (NK) cells and their related genes were analyzed by IHC and quantitative real-time polymerase chain reaction. Data mining revealed that B3GALT5 and FUT2, the key enzymes for Globo H biosynthesis, were significantly up-regulated in human ICC. In addition, Globo H expression was detected in 41% (63 of 155) of ICC tumor specimens by IHC staining, and validated by mass spectrometric analysis of two IHC-positive tumors. Patients with Globo H positive tumors had significantly shorter relapse-free survival (RFS) and overall survival (P = 0.0003 and P = 0.002, respectively). Multivariable Cox regression analysis identified Globo H expression as an independent unfavorable predictor for RFS (hazard ratio: 1.66, 95% confidence interval: 1.08-2.36, P = 0.02) in ICC. Furthermore, gradual emergence of Globo H in liver tissues over 6 months in TAA-treated rats recapitulated the multistage progression of ICC in vivo. Importantly, administration of anti-Globo H mAbVK9 in rats bearing TAA-induced ICC significantly suppressed tumor growth with increased NK cells in the tumor microenvironment. Conclusion: Globo H is a theranostic marker in ICC.
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- 2022
5. Pattern of progression of intrahepatic cholangiocarcinoma: Implications for second‐line clinical trials
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Francesco Caputo, Piera Federico, Ingrid Garajová, Matteo Renzulli, Bruno Daniele, Massimo Iavarone, Alessandro Granito, Fabio Gelsomino, Stefania De Lorenzo, Matilde Coriano, Francesco Tovoli, Fabio Piscaglia, Massimiliano Salati, Tovoli F., Garajova I., Gelsomino F., Iavarone M., Federico P., Salati M., Coriano M., Caputo F., De Lorenzo S., Granito A., Renzulli M., Daniele B., and Piscaglia F.
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medicine.medical_specialty ,Gastroenterology ,liver cancer ,FOLFOX ,biliary tract cancer ,Internal medicine ,medicine ,Humans ,Intrahepatic Cholangiocarcinoma ,Retrospective Studies ,Hepatology ,Performance status ,business.industry ,Liver Neoplasms ,Hazard ratio ,medicine.disease ,Gemcitabine ,Discontinuation ,Bile Ducts, Intrahepatic ,Bile Duct Neoplasms ,Hepatocellular carcinoma ,outcome ,prognosis ,cholangiocarcinoma ,Liver cancer ,business ,medicine.drug - Abstract
Background: Intrahepatic cholangiocarcinoma (iCCA) is the second most frequent liver cancer. The overall survival of iCCA and other biliary tract cancers (BTC) remains poor. Recently, the ABC-06 trial reported the superiority of FOLFOX vs clinical observation as a second-line treatment. Still, the survival benefit was less than expected. We hypothesized that the pattern of progression of iCCA can drive post-progression survival (PPS), similar to hepatocellular carcinoma. Methods: Multicentre retrospective evaluation of consecutive iCCA patients who progressed after frontline systemic treatment with gemcitabine as monotherapy or in combination with platinum. Radiological assessment of progression was evaluated according to RECIST 1.1. The progression pattern was divided according to the presence/absence of new extrahepatic lesions (NEH). Results: We included 206 patients from 5 centres. The median OS was 14.1months and its independent predictors (hazard ratio [HR], 95% confidence interval [CI]) were previous surgery 0.699 [0.509-0.961], performance status >2.445 [1.788-3.344], permanent first-line discontinuation 16.072 [5.102-50.633], registration of ascites 2.226 [1.448-3.420] or bilirubin >3mg/dl 3.004 [1.935-4.664] during the follow-up, and disease progression 2.523 [1.261-5.050]. The appearance of NEH independently predicted OS 2.18 [1.55-3.06] in patients with radiological progression. Amongst 138 patients eligible for second-line treatment, PPS was 16.8 and 5.9months in cases without and with NEH, respectively (P=.001). Progression owing to NEH lesions was an independent predictor of PPS 1.873 [1.333-2.662], together with performance status, time to progression to the frontline treatment, bilirubin >3mg/dl and ascites. Conclusions: PPS of iCCA is influenced by progression pattern, with important implications for second-line trial design and analysis.
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- 2021
6. Single-cell atlas of tumor cell evolution in response to therapy in hepatocellular carcinoma and intrahepatic cholangiocarcinoma
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Yongmei Zhao, Michael C. Kelly, Jeremy L. Davis, Bradford J. Wood, Marshonna Forgues, Lichun Ma, Limin Wang, Dana A. Dominguez, David E. Kleiner, Maria O. Hernandez, Julián Candia, Jonathan M. Hernandez, Bao Tran, Tim F. Greten, Subreen A. Khatib, Ching Wen Chang, Xin Wei Wang, and Sophia Heinrich
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0301 basic medicine ,Carcinoma, Hepatocellular ,Biopsy ,medicine.medical_treatment ,Cell ,medicine.disease_cause ,Cholangiocarcinoma ,Transcriptome ,03 medical and health sciences ,0302 clinical medicine ,medicine ,Humans ,Intrahepatic Cholangiocarcinoma ,Tumor microenvironment ,Hepatology ,business.industry ,Liver Neoplasms ,Immunotherapy ,Neoplastic Cells, Circulating ,medicine.disease ,Editorial ,030104 developmental biology ,medicine.anatomical_structure ,Hepatocellular carcinoma ,Cancer research ,030211 gastroenterology & hepatology ,Carcinogenesis ,business ,Liver cancer - Abstract
Background & Aims Intratumor molecular heterogeneity is a key feature of tumorigenesis and is linked to treatment failure and patient prognosis. Herein, we aimed to determine what drives tumor cell evolution by performing single-cell transcriptomic analysis. Methods We analyzed 46 hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (iCCA) biopsies from 37 patients enrolled in interventional studies at the NIH Clinical Center, with 16 biopsies collected before and after treatment from 7 patients. We developed a novel machine learning-based consensus clustering approach to track cellular states of 57,000 malignant and non-malignant cells including tumor cell transcriptome-based functional clonality analysis. We determined tumor cell relationships using RNA velocity and reverse graph embedding. We also studied longitudinal samples from 4 patients to determine tumor cellular state and its evolution. We validated our findings in bulk transcriptomic data from 488 patients with HCC and 277 patients with iCCA. Results Using transcriptomic clusters as a surrogate for functional clonality, we observed an increase in tumor cell state heterogeneity which was tightly linked to patient prognosis. Furthermore, increased functional clonality was accompanied by a polarized immune cell landscape which included an increase in pre-exhausted T cells. We found that SPP1 expression was tightly associated with tumor cell evolution and microenvironmental reprogramming. Finally, we developed a user-friendly online interface as a knowledge base for a single-cell atlas of liver cancer. Conclusions Our study offers insight into the collective behavior of tumor cell communities in liver cancer as well as potential drivers of tumor evolution in response to therapy. Lay summary Intratumor molecular heterogeneity is a key feature of tumorigenesis that is linked to treatment failure and patient prognosis. In this study, we present a single-cell atlas of liver tumors from patients treated with immunotherapy and describe intratumoral cell states and their hierarchical relationship. We suggest osteopontin, encoded by the gene SPP1, as a candidate regulator of tumor evolution in response to treatment.
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- 2021
7. Patch venoplasty for resecting tumor invading the retrohepatic inferior vena cava using total and selective hepatic vascular exclusion
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Shin Hwang, Deok-Bog Moon, Dong-Hwan Jung, Sung-Gyu Lee, and Sung-Min Kim
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medicine.medical_specialty ,Hepatic ischemia ,business.industry ,medicine.medical_treatment ,Case Report ,medicine.disease ,Pancreaticoduodenectomy ,Inferior vena cava ,Total hepatic vascular exclusion ,Surgery ,Cavernous hemangioma ,Hemangioma ,Stenosis ,Dissection ,medicine.anatomical_structure ,medicine.vein ,cardiovascular system ,medicine ,Duodenum ,General Materials Science ,Vein ,business ,Intrahepatic Cholangiocarcinoma ,Intrahepatic cholangiocarcinoma - Abstract
Large hepatic tumors can invade the retrohepatic inferior vena cava (IVC). Resecting the involved IVC wall is necessary to achieve complete tumor resection. We present detailed surgical procedures of IVC resection and patch venoplasty under the standard and modified total hepatic vascular exclusion (THVE) techniques applied to two patients who underwent aggressive surgery for hepatic tumors. The first case was a 55-year-old male with advanced intrahepatic cholangiocarcinoma. The extent of resection was extended right hepatectomy with caudate lobe resection, right adrenalectomy, and portal vein segmental resection-anastomosis. The invasion site at the IVC was excised and repaired with an expanded polytetrafluoroethylene patch under modified THVE. This patient recovered uneventfully. At postoperative 10 months, second primary cancer occurred in the duodenum. The patient underwent pancreaticoduodenectomy but passed away at post-surgery 6 weeks due to pneumonia-associated sepsis. The second case was a 35-year-old female with giant cavernous hemangioma. As separating the right liver from the IVC was infeasible through conventional dissection techniques, standard THVE was performed. The short hepatic vein was too large to repair directly without risk of IVC stenosis. Thus, a cryopreserve iliac vein allograft patch was applied to repair the defect. The patient recovered uneventfully from the operation. The patient is currently doing well for 6 years. However, progressive hemangiomatosis occurred. In conclusion, standard and modified THVE techniques are proposed as useful techniques to achieve complete tumor resection in patients with large liver tumors invading the retrohepatic IVC.
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- 2021
8. Combined arterial and delayed enhancement patterns of MRI assist in prognostic prediction for intrahepatic mass-forming cholangiocarcinoma (IMCC)
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Kaipu Jin, Chun Yang, Mengsu Zeng, and Rou-fan Sheng
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medicine.medical_specialty ,Necrosis ,Radiological and Ultrasound Technology ,medicine.diagnostic_test ,business.industry ,Urology ,Gastroenterology ,Prognostic prediction ,Magnetic resonance imaging ,Delayed enhancement ,medicine.disease ,Peripheral ,Metastasis ,Internal medicine ,medicine ,Radiology, Nuclear Medicine and imaging ,Lymph ,medicine.symptom ,business ,Intrahepatic Cholangiocarcinoma - Abstract
OBJECTIVES This study valued MR delayed enhancement pattern in predicting postoperative prognosis of intrahepatic mass-forming cholangiocarcinoma (IMCC). METHODS From 2011 to 2015, 231 patients of IMCC underwent DCE-MRI preoperatively. Enhancement patterns and MRI characteristics were evaluated. Recurrence and mortality data were compared among IMCCs with different enhancement patterns. Prognostic factor analysis was performed using preoperative and postoperative clinical-pathologic factors, as well as imaging findings. RESULTS Fifty-six (24.2%), 142 (61.5%) and 33 (14.3%) tumors showed hypo, peripheral rim and diffuse hyper enhancement in AP. Fifty-six (24.2%), 81 (35.1%) and 94 (40.7%) tumors showed hypo, heterogeneous and uniform enhancement in DP. Patients with arterial diffuse hyper enhancement or delayed uniform enhancement IMCCs had lower preoperative CA19-9 levels, smaller tumor sizes and minor operations than the rest patients (p
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- 2021
9. Genetic, Clinicopathological, and Radiological Features of Intrahepatic Cholangiocarcinoma with Ductal Plate Malformation Pattern
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Gi Hong Choi, Young Nyun Park, Haeryoung Kim, Hyungjin Rhee, Taek Chung, Jeong Eun Yoo, and Hyo Sup Shim
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BAP1 ,Pathology ,medicine.medical_specialty ,IDH1 ,Hepatology ,business.industry ,Liver Neoplasms ,Gastroenterology ,STK11 ,medicine.disease ,medicine.disease_cause ,Cholangiocarcinoma ,Ductal Plate Malformation ,Bile Ducts, Intrahepatic ,Bile Duct Neoplasms ,CDKN2A ,Hepatocellular carcinoma ,medicine ,Humans ,KRAS ,business ,Intrahepatic Cholangiocarcinoma ,Retrospective Studies - Abstract
Background/aims Intrahepatic cholangiocarcinoma (iCCA) with a ductal plate malformation (DPM) pattern is a recently recognized rare variant. The genomic profile of iCCA with DPM pattern needs to be elucidated. Methods Cases of iCCA with DPM pattern were retrospectively reviewed based on the medical records, pathology slides, and magnetic resonance imaging (MRI) reports collected between 2010 to 2019 at a single center. Massive parallel sequencing was performed for >500 cancer-related genes. Results From a total of 175 iCCAs, five (2.9%) cases of iCCA with DPM pattern were identified. All cases were of the small duct type, and background liver revealed chronic B viral or alcoholic hepatitis. Three iCCAs with DPM pattern harbored MRI features favoring the diagnosis of hepatocellular carcinoma, whereas nonspecific imaging features were observed in two cases. All patients were alive without recurrence during an average follow-up period of 57 months. Sequencing data revealed 64 mutated genes in the five cases, among which FGFR and PTPRT were most frequently mutated (three cases each) including an FGFR-TNC fusion in one case. Mutations in ARID1A and CDKN2A were found in two cases, and mutations in TP53, BAP1, ATM, NF1, and STK11 were observed in one case each. No IDH1, KRAS, or PBRM1 mutations were found. Conclusions iCCAs with DPM pattern have different clinico-radio-pathologic and genetic characteristics compared to conventional iCCAs. Moreover, FGFR and ARID1A variants were identified. Altogether, these findings further suggest that iCCA with DPM pattern represents a specific subtype of small duct type iCCA.
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- 2021
10. Challenges and Opportunities for Treating Intrahepatic Cholangiocarcinoma
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Timothy M. Pawlik, Daniel J Cloonan, Diamantis I. Tsilimigras, and Nikolaos Serifis
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medicine.medical_specialty ,Hepatology ,business.industry ,medicine.medical_treatment ,General surgery ,Cancer ,Review ,Disease ,Liver transplantation ,liver ,outcomes ,medicine.disease ,Occult ,Systemic therapy ,Clinical trial ,intrahepatic cholangiocarcinoma ,medicine ,Lymphadenectomy ,resection ,business ,Intrahepatic Cholangiocarcinoma - Abstract
Intrahepatic cholangiocarcinoma (ICC) is one of the rarest and most aggressive types of cancer. The symptoms of ICC patients can be vague, leading to late diagnosis and dismal prognosis. In this review, we investigated the treatment options for ICC, as well as ways to overcome challenges in identifying and treating this disease. Imaging remains the gold standard to diagnose ICC. Patients are staged based on the tumor, nodes and metastases (TNM) staging system. Patients eligible for surgical resection should undergo surgery with curative intent with the goal of microscopically disease-free margins (R0 resection) along with lymphadenectomy. Minimal invasive surgery (MIS) and liver transplantation have recently been offered as possible ways to improve disease outcomes. ICC recurrence is relatively common and, thus, most patients will need to be treated with systemic therapy. Several clinical trials have recently investigated the use of neoadjuvant (NT) and adjuvant therapies for ICC. NT may offer an opportunity to downsize larger tumors and provide patients, initially ineligible for surgery, with an opportunity for resection. NT may also treat occult micro-metastatic disease, as well as define tumor biology prior to surgical resection, thereby decreasing the risk for early postoperative recurrence. Adjuvant systemic therapy may improve outcomes of patients with ICC following surgery. Ongoing clinical trials are investigating new targeted therapies that hold the hope of improving long-term outcomes of patients with ICC.
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- 2021
11. Expression of Tspan8 in Patients with Intrahepatic Cholangiocarcinoma and Its Relationship with Clinicopathological Features and Prognosis
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Zhiping Pan, Minzhi Chen, Ping Xie, Yan Shen, Zhenhua Tan, Peng Li, Hai Qian, and Ren-Rui Wan
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Oncology ,medicine.medical_specialty ,Multivariate analysis ,business.industry ,TSPAN8 ,Logistic regression ,medicine.disease ,Metastasis ,Other systems of medicine ,Complementary and alternative medicine ,Internal medicine ,Medicine ,Stage (cooking) ,business ,Pathological ,RZ201-999 ,Intrahepatic Cholangiocarcinoma ,Survival analysis ,Research Article - Abstract
The incidence and mortality of intrahepatic cholangiocarcinoma (ICC) are increasing worldwide. High invasion and metastasis are one of the main causes of death in patients. The selection of reasonable and effective molecular markers to evaluate the prognosis of patients with ICC has important clinical guiding significance. In this study, the expression of Tspan protein in ICC and normal tissues was compared, the correlation between Tspan expression and pathological features of patients was analyzed by the logistic regression model using multivariate analysis, and the relationship between Tspan8 expression and prognosis of ICC patients was analyzed by the Kaplan–Meier survival curve. The results showed that Tspan8 is highly positive in ICC tissues, TNM stage, degree of tumor differentiation, lymph node metastasis, and Tspan8 protein expression were independently correlated, and the overexpression of Tspan was associated with the prognosis of ICC invasion and metastasis. This provides a new idea for clinical treatment.
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- 2021
12. Isolated liver metastasis detected 11 years after the curative resection of rectal cancer: A case report
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Yoshikuni Yonenaga and Satoshi Yokoyama
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Curative resection ,Isolated liver ,medicine.medical_specialty ,Colorectal cancer ,business.industry ,Late recurrence ,General Medicine ,medicine.disease ,Gastroenterology ,Metastasis ,Internal medicine ,Case report ,Late Recurrence ,medicine ,business ,Liver metastasis ,Intrahepatic Cholangiocarcinoma ,Intrahepatic cholangiocarcinoma - Abstract
BACKGROUND The duration of surveillance after curative resection of colorectal cancer (CRC) is generally 5 years. The overall incidence of recurrence more than 5 years after surgery for CRC in Japan has been reported to be 0.6%. Moreover, it is rare for CRC to have metachronous liver metastasis more than 10 years after surgery. Here, we present a case of liver metastasis detected 11 years after the curative resection of rectal cancer. CASE SUMMARY A 72-year-old man was referred to our hospital after a liver tumor was detected by abdominal ultrasonography at another hospital. He had undergone surgery for rectal cancer 11 years previously. Contrast-enhanced computed tomography (CT) showed a tumor with a diameter of approximately 8 cm in the posterior segment, which was weakly and gradually enhanced. 18F-fluorodeoxyglucose-positron emission tomography/CT showed an abnormally high uptake on the tumorous lesion, which showed that the tumor appeared to spread convexly along the intrahepatic bile ducts. Intrahepatic cholangiocarcinoma was therefore diagnosed, and he had an extended right posterior sectionectomy and regional lymph node dissection. Histopathological examination showed that the tumor was a moderately differentiated adenocarcinoma and showed the same pathological characteristics as the rectal cancer. Immunohistological examination showed that the cancer cells of both the liver tumor and rectal cancer were positive for cytokeratin (CK) 20 and weakly positive for CK 7. These findings were consistent with the liver metastasis from the rectal cancer. CONCLUSION It is possible that a liver tumor is metastatic in a patient with a previous history of CRC, even if it was more than 10 years earlier.
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- 2021
13. Impact of aging on primary liver cancer: epidemiology, pathogenesis and therapeutics
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Rui E. Castro, Rocio I.R. Macias, Jose J.G. Marin, Javier González-Gallego, Maria J. Monte, André L. Simão, Jesús M. González-Santiago, Maria A. Serrano, José L. Mauriz, and Isabel Martín-Arribas
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Male ,Genome instability ,Senescence ,Aging ,Carcinoma, Hepatocellular ,senescence ,Review ,Bioinformatics ,Genomic Instability ,Cholangiocarcinoma ,Risk Factors ,Humans ,Medicine ,Epigenetics ,Contraindication ,Telomere Shortening ,Intrahepatic Cholangiocarcinoma ,Aged ,Aged, 80 and over ,business.industry ,Liver Neoplasms ,Age Factors ,fragility ,Cell Biology ,Middle Aged ,medicine.disease ,Proteostasis ,hepatocarcinoma ,Hepatocellular carcinoma ,Female ,Stem cell ,business - Abstract
Aging involves progressive physiological and metabolic reprogramming to adapt to gradual deterioration of organs and functions. This includes mechanisms of defense against pre-malignant transformations. Thus, certain tumors are more prone to appear in elderly patients. This is the case of the two most frequent types of primary liver cancer, i.e., hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (iCCA). Accordingly, aging hallmarks, such as genomic instability, telomere attrition, epigenetic alterations, altered proteostasis, mitochondrial dysfunction, cellular senescence, exhaustion of stem cell niches, impaired intracellular communication, and deregulated nutrient sensing can play an important role in liver carcinogenesis in the elders. In addition, increased liver fragility determines a worse response to risk factors, which more frequently affect the aged population. This, together with the difficulty to carry out an early detection of HCC and iCCA, accounts for the late diagnosis of these tumors, which usually occurs in patients with approximately 60 and 70 years, respectively. Furthermore, there has been a considerable controversy on what treatment should be used in the management of HCC and iCCA in elderly patients. The consensus reached by numerous studies that have investigated the feasibility and safety of different curative and palliative therapeutic approaches in elders with liver tumors is that advanced age itself is not a contraindication for specific treatments, although the frequent presence of comorbidities in these individuals should be taken into consideration for their management.
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- 2021
14. Inhibin-positive hepatic carcinoma: proposal for a solid-tubulocystic variant of intrahepatic cholangiocarcinoma
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Sameer Al Diffalha, Nancy M. Joseph, Michael G. Drage, Amitabh Srivastava, Joseph Rank, Dhanpat Jain, Sanjay Kakar, Tara A. Saunders, Michael Feely, Rondell P. Graham, Kwun Wah Wen, Ali Zarrinpar, and Paul B. Shyn
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Adult ,Pathology ,medicine.medical_specialty ,In situ hybridization ,Pathology and Forensic Medicine ,Metastasis ,Cholangiocarcinoma ,Biomarkers, Tumor ,Humans ,Medicine ,Inhibins ,Liver neoplasm ,Intrahepatic Cholangiocarcinoma ,biology ,business.industry ,Liver Neoplasms ,Thyroid ,Chromogranin A ,medicine.disease ,medicine.anatomical_structure ,Bile Duct Neoplasms ,Hepatocellular carcinoma ,biology.protein ,Synaptophysin ,Female ,business - Abstract
Summary Inhibin-positive hepatic carcinoma is a rare primary liver neoplasm that resembles sex cord–stromal tumor and thyroid follicular tumors. The term “cholangioblastic variant of intrahepatic cholangiocarcinoma” has been proposed. This study describes the clinicopathologic, immunophenotypic, and molecular features of a small series (n = 6) of this rare tumor. Albumin in situ hybridization (ISH) and capture-based next-generation sequencing (NGS) were also performed. All tumors occurred in young women (mean age 32.5 years, range 19–44 years) as a solitary large mass (mean 15.8 cm, range 6.9–23.5 cm). All tumors showed a highly distinctive morphology with sheets and large nests of tumor cells alternating with tubular and cystic areas imparting a sex cord–like or thyroid follicle–like morphology. Cytologic atypia was mild, and mitotic activity was low. All cases were positive for inhibin, as well as pancytokeratin, CK7, CK19, and albumin ISH. Synaptophysin and chromogranin showed focal or patchy staining, whereas INSM1 was negative. Markers for hepatocellular differentiation, thyroid origin, and sex cord–stromal tumor were negative. There were no recurrent genomic changes based on capture-based NGS of ∼500 cancer genes. Recurrence and/or metastasis was seen in three (50%) cases (follow-up time range for all cases: 5 months to 2 years). In conclusion, this series describes the distinctive morphology, immunophenotypic features, and diffuse albumin staining in six cases of a rare inhibin-positive primary liver carcinoma that runs an aggressive course similar to intrahepatic cholangiocarcinoma. Genomic changes typical of cholangiocarcinoma or hepatocellular carcinoma were not identified, and there were no recurrent genetic abnormalities. We propose the term “solid-tubulocystic variant of intrahepatic cholangiocarcinoma” to reflect the spectrum of morphologic patterns observed in this tumor.
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- 2021
15. The prognostic role of tumor-associated unilateral portal vein occlusion in perihilar cholangiocarcinoma
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Ulf P. Neumann, Tom Luedde, Tom Florian Ulmer, Jan Bednarsch, Georg Wiltberger, Zoltan Czigany, Philipp Bruners, Sven Arke Lang, Marcel den Dulk, Lara R. Heij, MUMC+: MA Heelkunde (9), RS: NUTRIM - R2 - Liver and digestive health, and Surgery
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medicine.medical_specialty ,LIVER ,Portal vein ,HILAR CHOLANGIOCARCINOMA ,030230 surgery ,Cholangiocarcinoma ,03 medical and health sciences ,POSITRON-EMISSION-TOMOGRAPHY ,0302 clinical medicine ,Occlusion ,MANAGEMENT ,INTRAHEPATIC CHOLANGIOCARCINOMA ,Humans ,Medicine ,Perihilar Cholangiocarcinoma ,Intrahepatic Cholangiocarcinoma ,VASCULAR RESECTION ,Retrospective Studies ,Hepatology ,Portal Vein ,business.industry ,Proportional hazards model ,Gastroenterology ,Cancer ,Perioperative ,Prognosis ,medicine.disease ,CANCER ,Log-rank test ,CURATIVE-INTENT RESECTION ,TISSUE FACTOR ,Bile Duct Neoplasms ,SURGICAL-TREATMENT ,030220 oncology & carcinogenesis ,Radiology ,business ,Klatskin Tumor - Abstract
Background While a certain degree of tumor infiltration of the portal vein is common in patients with perihilar cholangiocarcinoma (pCCA) scheduled for surgery, complete tumor-associated portal vein occlusion (PVO) is less frequently observed. Here, we analyzed the impact of PVO on perioperative and oncological outcomes in pCCA patients. Methods Between 2010 and 2019, 127 patients with pCCA underwent surgery in curative intent at our department of which 17.3% (22/127) presented with PVO. Extensive group comparisons were conducted and the association of cancer-specific (CSS) and disease-free survival (DFS) with PVO and other clinico-pathological characteristics were assessed using Cox regression models. Results Patients without PVO showed a median CSS of 65 months (3-year-CSS = 64%, 5-year-CSS = 53%) compared to 31 months (3-year-CSS = 43%, 5-year-CSS = 17%) in patients with PVO (p = 0.025 log rank). Patients with PVO did also display significant perioperative mortality (22.7%, 5/22) compared to patients without PVO (14.3%, 15/105, p = 0.323). Further, PVO (CSS: HR = 5.25, p = 0.001; DFS: HR = 5.53, p = 0.001) was identified as independent predictors of oncological outcome. Conclusions PVO has been identified as an important prognostic marker playing a role in inferior oncological outcome in patients with pCCA. As PVO is also associated with notable perioperative mortality, surgical therapy should be considered carefully in pCCA patients.
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- 2021
16. Distinct Immune Signatures in Peripheral Blood Predict Chemosensitivity in Intrahepatic Cholangiocarcinoma Patients
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Chengjun Sui, Lei Chen, Wencong Ma, Xue-Bing Shi, Zhen-Gang Yuan, Jianmin Wu, Hongyang Wang, Rui Wu, Wei Li, Siyun Shen, Bo Zheng, Tong Wu, Xuan Wu, Shan Wang, Yingcheng Yang, Kaiting Wang, Yanjing Zhu, Zhixuan Li, and Yan Zhao
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Oncology ,medicine.medical_specialty ,Environmental Engineering ,General Computer Science ,Materials Science (miscellaneous) ,General Chemical Engineering ,T cell ,Population ,Energy Engineering and Power Technology ,Peripheral blood mononuclear cell ,Immune system ,Internal medicine ,medicine ,education ,Chemosensitivity ,Intrahepatic cholangiocarcinoma ,education.field_of_study ,Tissue microarray ,business.industry ,General Engineering ,Engineering (General). Civil engineering (General) ,medicine.disease ,Gemcitabine ,medicine.anatomical_structure ,Peripheral blood mononuclear cells ,TA1-2040 ,Liver cancer ,business ,CD8 ,medicine.drug - Abstract
Intrahepatic cholangiocarcinoma (ICC) is the second most common liver cancer. Chemotherapy remains the main therapeutic strategy for advanced ICC patients, but chemosensitivity varies individually. Here, 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 chemotherapy. Multiplex immunofluorescence staining was applied to examine the spatial distribution of certain immune clusters. Tissue 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 chemotherapy. Patients with higher level of CD4+CD45RO+CXCR3+ T cells before treatment had a favorable response to chemotherapy. Our 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.
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- 2021
17. Liver Transplantation for Intrahepatic Cholangiocarcinoma: A Meta-analysis and Meta-regression of Survival Rates
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Dimitrios Giannis, Ioannis A. Ziogas, Sophoclis P. Alexopoulos, Lea Matsuoka, Martin I. Montenovo, Konstantinos P. Economopoulos, and Muhammad Hashim Hayat
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Adult ,Male ,medicine.medical_specialty ,Time Factors ,Cirrhosis ,medicine.medical_treatment ,Liver transplantation ,Cochrane Library ,Risk Assessment ,Gastroenterology ,Cholangiocarcinoma ,Risk Factors ,Internal medicine ,medicine ,Humans ,Progression-free survival ,Contraindication ,Intrahepatic Cholangiocarcinoma ,Neoadjuvant therapy ,Aged ,Transplantation ,business.industry ,Middle Aged ,medicine.disease ,Progression-Free Survival ,Liver Transplantation ,Bile Duct Neoplasms ,Meta-analysis ,Disease Progression ,Female ,Neoplasm Recurrence, Local ,business - Abstract
Background Intrahepatic cholangiocarcinoma (iCCA) is a contraindication to liver transplantation in most centers worldwide. Therefore, only a few such cases have been performed in each individual center, and the need for a systematic review and meta-analysis to cumulatively pool these results is apparent. Methods A systematic literature review was conducted using the MEDLINE and Cochrane Library databases according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses statement (end-of-search date: May 29, 2020). Meta-analyses of proportions were conducted to pool the overall survival (OS), recurrence-free survival (RFS), and overall recurrence rates using the random-effects model. Meta-regression was used to examine cirrhosis and incidental diagnosis as confounders on OS and RFS. Results Eighteen studies comprising 355 patients and a registry study of 385 patients were included. The pooled 1-, 3-, and 5-y OS rates were 75% (95% CI, 64%-84%), 56% (95% CI, 46%-67%), and 42% (95% CI, 29%-55%), respectively. The pooled 1-, 3-, and 5-y RFS rates were 70% (95% CI, 63%-75%), 49% (95% CI, 41%-57%), and 38% (95% CI, 27%-50%), respectively. Cirrhosis was positively associated with RFS, while incidental diagnosis was not. Neither cirrhosis nor incidental diagnosis was associated with OS. The pooled overall recurrence rate was 43% (95% CI, 33%-53%) over a mean follow-up of 40.6 ± 37.7 mo. Patients with very early (single ≤2 cm) iCCA exhibited superior pooled 5-y RFS (67%; 95% CI, 47%-86%) versus advanced iCCA (34%; 95% CI, 23%-46%). Conclusions Cirrhotics with very early iCCA or carefully selected patients with advanced iCCA after neoadjuvant therapy may benefit from liver transplantation under research protocols.
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- 2021
18. Effect of stereotactic body radiotherapy on regional metabolic liver function investigated in patients by dynamic [18F]FDGal PET/CT
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Michael Sørensen, Marianne Ingerslev Holt, Morten Høyer, Mette Marie Fode, and Jørgen B. B. Petersen
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Colorectal cancer ,medicine.medical_treatment ,R895-920 ,Galactokinase ,Medical physics. Medical radiology. Nuclear medicine ,medicine ,Radiology, Nuclear Medicine and imaging ,Intrahepatic Cholangiocarcinoma ,RC254-282 ,PET-CT ,medicine.diagnostic_test ,business.industry ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,medicine.disease ,Radiation therapy ,Oncology ,Positron emission tomography ,Liver function ,Functional imaging ,Liver cancer ,Nuclear medicine ,business ,Stereotactic body radiotherapy ,Metabolic liver function - Abstract
Purpose Stereotactic body radiotherapy (SBRT) is increasingly used for treatment of liver tumors but the effect on metabolic liver function in surrounding tissue is largely unknown. Using 2-deoxy-2-[18F]fluoro-d-galactose ([18F]FDGal) positron emission tomography (PET)/computed tomography (CT), we aimed to determine a dose–response relationship between radiation dose and metabolic liver function as well as recovery. Procedures. One male subject with intrahepatic cholangiocarcinoma and five subjects (1 female, 4 male) with liver metastases from colorectal cancer (mCRC) underwent [18F]FDGal PET/CT before SBRT and after 1 and 3 months. The dose response was calculated using the data after 1 month and the relative recovery was evaluated after 3 months. All patients had normal liver function at time of inclusion. Results A linear dose–response relationship for the individual liver voxel dose was seen until approximately 30 Gy. By fitting a polynomial curve to data, a mean TD50 of 18 Gy was determined with a 95% CI from 12 to 26 Gy. After 3 months, a substantial recovery was observed except in tissue receiving more than 25 Gy. Conclusions [18F]FDGal PET/CT makes it possible to determine a dose–response relationship between radiation dose and metabolic liver function, here with a TD50 of 18 Gy (95% CI 12–26 Gy). Moreover, the method makes it possible to estimate metabolic recovery in liver tissue.
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- 2021
19. Intrahepatic Cholangiocarcinoma Coexisting With Multiple Bile Duct Adenoma Treated as Liver Metastasis from a Pancreatic Neuroendocrine Tumor
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Shinichi Akahoshi, Kazuki Matsumura, Hideaki Yuki, Koji Ohnishi, Fujio Matsumura, Eri Oda, Kensuke Yamamura, Yoshihiro Hara, Hideaki Miyamoto, Toru Beppu, Koichi Kinoshita, Yoshihiro Komohara, and Toshihiko Motohara
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Adenoma ,Cancer Research ,Pathology ,medicine.medical_specialty ,Liver tumor ,Pancreatic neuroendocrine tumor ,Metastasis ,Cholangiocarcinoma ,Diagnosis, Differential ,medicine ,Humans ,Doubling time ,Bile Duct Adenoma ,Intrahepatic Cholangiocarcinoma ,Aged ,business.industry ,Liver Neoplasms ,General Medicine ,Prognosis ,medicine.disease ,Pancreatic Neoplasms ,Neuroendocrine Tumors ,Bile Duct Neoplasms ,Oncology ,Female ,business - Abstract
Background Bile duct adenomas (BDA) may be precursor lesions of small duct-type, including mass-forming type intrahepatic cholangiocarcinoma (ICC). Case report A 68-year-old woman was transferred to our facility for the treatment of a liver tumor, possibly metastasized from a pancreatic neuroendocrine tumor. Finally, two liver tumors were resected and histopathologically diagnosed as "BDA" and "ICC with a BDA-like component". In the BDA-like component, the MUC6 positive rate was notably lower and the Ki-67 positive rate was higher than the other BDAs and ICC component, respectively. The doubling time of the tumor volume in BDA was very long but was shortened (1,510 and 719 days). Distinct enlargement of the tumor and appearance of enhancement through diagnostic imaging was useful in diagnosing the transformation from a BDA to an ICC. Conclusion An "adenoma-carcinoma sequence" may exist in the transformation process from a BDA to an ICC.
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- 2021
20. Indeterminate liver lesions on gadoxetic acid-enhanced magnetic resonance imaging of the liver: Case-based radiologic-pathologic review
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Ankur Arora, Jurate Noreikaite, Vijay Chidambaram, Ashok Katti, and Dekan Albasha
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Pathology ,medicine.medical_specialty ,Gadoxetic acid ,Hepatology ,medicine.diagnostic_test ,Hepatocellular carcinoma ,business.industry ,Focal nodular hyperplasia ,Indeterminate liver lesions ,Minireviews ,Magnetic resonance imaging ,Hepatocellular adenoma ,medicine.disease ,Pleomorphic Liposarcoma ,Hepatobiliary phase ,medicine ,business ,Contrast-enhanced Magnetic Resonance Imaging ,Intrahepatic Cholangiocarcinoma ,medicine.drug - Abstract
Different histopathological manifestations of focal liver lesions show varying common and uncommon imaging findings and some pathologies may show similar appearance despite of different histopathology. It is necessary to characterise focal liver lesions accurately as not only benign and malignant lesions are managed differently, but also certain benign lesions have differing management. These lesions are increasingly being detected due to rapid growth of use of cross-sectional imaging as well as improvement in image quality and new imaging techniques. Contrast enhanced magnetic resonance imaging (MRI) is considered the gold standard technique in characterising focal liver lesions. Addition of gadoxetic acid has been shown to significantly increase diagnostic accuracy in the detection and characterization of liver abnormalities. Classic imaging characteristics of common liver lesions, including their behaviour on gadoxetic acid enhanced MRI, have been described in literature over recent years. It is important to be familiar with the typical aspects of these lesions as well as know the uncommon and overlapping imaging features to reach an accurate diagnosis. In this article, we will review the well-described characteristic imaging findings of common and rare focal liver lesions and present several challenging cases encountered in the clinical setting, namely hepatocellular adenoma, focal nodular hyperplasia, hepatic angiomyolipoma, hepatocellular carcinoma, intrahepatic cholangiocarcinoma, neuroendocrine tumours as well as a pleomorphic liposarcoma of the liver.
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- 2021
21. Comparison of Clinical Features and Outcomes Between Intrahepatic Cholangiocarcinoma and Hepatocellular Carcinoma in the United States
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Michael Luu, Ju Dong Yang, Gregory J. Gores, Yi Te Lee, Tushar Patel, Nicholas N. Nissen, Lewis R. Roberts, Amit G. Singal, Jasmine J. Wang, and Mazen Noureddin
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Male ,Oncology ,medicine.medical_specialty ,Carcinoma, Hepatocellular ,Kaplan-Meier Estimate ,Logistic regression ,Cholangiocarcinoma ,Internal medicine ,Epidemiology ,medicine ,Humans ,Lymph node ,Intrahepatic Cholangiocarcinoma ,Aged ,Neoplasm Staging ,Hepatology ,Proportional hazards model ,business.industry ,Liver Neoplasms ,Hazard ratio ,Middle Aged ,Prognosis ,medicine.disease ,United States ,digestive system diseases ,Tumor Burden ,Bile Ducts, Intrahepatic ,medicine.anatomical_structure ,Bile Duct Neoplasms ,Liver ,Hepatocellular carcinoma ,Female ,Liver cancer ,business ,SEER Program - Abstract
BACKGROUND AND AIMS Intrahepatic cholangiocarcinoma (iCCA) and hepatocellular carcinoma (HCC) are the most common primary liver cancers (PLCs). Differences in their clinical features and outcomes are open for investigation in a large-scale study. We aim to investigate the differences in clinical features and outcomes between iCCA and HCC. APPROACH AND RESULTS The Surveillance, Epidemiology, and End Results Program 18 Database (2000-2017) was used to extract demographic and clinical features of HCC and iCCA patients. Logistic regression analysis was performed to identify factors associated with iCCA diagnosis versus HCC. Cox regression analysis was used to assess factors affecting overall survival (OS). There were 13,611 iCCA and 96,151 HCC patients. Half of iCCA (50.7%) and three quarters of HCC (76.3%) patients were male. Diagnosis in recent year, age (
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- 2021
22. Differences of intraoperative outcomes and postoperative complications between intrahepatic cholangiocarcinoma and colorectal liver metastasis in different surgical methods
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Xinyu Bi, Jianguo Zhou, Jianjun Zhao, Jianqiang Cai, Jinghua Chen, Jianxiong Wu, Yiling Zheng, Liming Wang, Zhen Huang, Zhiyu Li, Yefan Zhang, Qichen Chen, and Hong Zhao
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Intrahepatic cholangiocarcinoma (IHCC) ,Cancer Research ,medicine.medical_specialty ,business.industry ,medicine.disease ,Surgical methods ,Metastasis ,hepatectomy ,Oncology ,Medicine ,Original Article ,postoperative complication ,Radiology, Nuclear Medicine and imaging ,Radiology ,business ,colorectal liver metastasis (CRLM) ,Intrahepatic Cholangiocarcinoma - Abstract
Background Hepatectomy is the only potentially curable treatment for intrahepatic cholangiocarcinoma (IHCC) and colorectal liver metastasis (CRLM). This study aimed to explore the difference in intraoperative outcomes and postoperative complications between IHCC and CRLM in different surgical methods including major hepatectomy and minor hepatectomy. Methods We included 319 patients with IHCC or CRLM who underwent hepatectomy at our hospital. According to major hepatectomy and minor hepatectomy, eligible patients were divided into two groups. In each group, the clinicopathological characteristics of IHCC and CRLM patients were compared, then propensity score matching (PSM) was performed based on the results. Intraoperative outcomes and postoperative complications were compared between IHCC and CRLM before and after PSM. Intraoperative variables, including intraoperative blood transfusion, duration of operation, and intraoperative blood loss, were used to evaluate the intraoperative conditions of patients. The postoperative complications were measured according to the Clavien-Dindo classification. Grade III to V complications were defined as major complications. Results The major hepatectomy group included 118 patients with IHCC and 93 patients with CRLM. IHCC patients presented a longer operation time and a higher postoperative complication rate than CRLM patients. The infection-related complication rate of the CRLM patients was significantly higher than the IHCC patients. In multivariate analysis, major hepatectomy for IHCC was independently associated with the presence of postoperative complications. The minor hepatectomy group included 146 IHCC patients and 62 CRLM patients. Compared with CRLM patients, IHCC patients presented a longer operation time. There was no significant difference in the intra-operative blood loss, postoperative complication rate, the major complications rate, and the minor complications rate between the IHCC patients and CRLM patients. Conclusions This study revealed major hepatectomy for IHCC led to significantly higher morbidity of postoperative complications than CRLM patients. For minor hepatectomy, there was no difference in postoperative complications between IHCC and CRLM. More attention should be paid to improving the preoperative planning and surgical management of hepatic malignancies especially in the setting of IHCC.
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- 2021
23. Maffucci Syndrome with Intrahepatic Cholangiocarcinoma: A Case Report
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Kiyotaka Hosoda, Tsuyoshi Notake, Koji Kubota, Mai Iwaya, Hikaru Hayashi, Yuji Soejima, Koya Yasukawa, Kenji Sano, Shinsuke Sugenoya, Yayoi Satoh, Akira Shimizu, and Ryoichiro Kobayashi
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medicine.medical_specialty ,Chemotherapy ,IDH1 ,biology ,business.industry ,medicine.medical_treatment ,Cancer ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,Case Report ,maffucci syndrome ,medicine.disease ,IDH2 ,Carcinoembryonic antigen ,Oncology ,Maffucci syndrome ,isocitrate dehydrogenase 1 ,medicine ,biology.protein ,Hepatic tumor ,Radiology ,business ,cholangiocarcinoma ,Intrahepatic Cholangiocarcinoma ,RC254-282 - Abstract
Maffucci syndrome is characterized by multiple hemangiomas and enchondromas. Somatic mutations in IDH1 and IDH2 are associated with the development of Maffucci syndrome, and these patients develop various malignant nonskeletal tumors in addition to malignant skeletal tumors. We report a case of Maffucci syndrome with IDH1 mutation complicated by intrahepatic cholangiocarcinoma. The patient was a 35-year-old woman who was diagnosed with Maffucci syndrome in childhood. She was referred to our department because of a large hepatic tumor. Serum carcinoembryonic antigen was 27.1 ng/mL upon laboratory examination. CT scanning showed a large low-density tumor (90 × 70 mm) in the right lobe of the liver, and MRI revealed a multilobulated and fibrous tumor, which was observed as high signal intensity on T2- and diffusion-weighted images and low signal intensity on T1-weighted images. Positron emission tomography-CT revealed peritoneal dissemination and cancer spread to the muscles of the back. Finally, she was diagnosed with intrahepatic cholangiocarcinoma with dissemination and metastases. We performed a tumor biopsy to determine a treatment plan for chemotherapy. Sanger sequencing of a tumor biopsy identified a mutation in IDH1 at c.394C>T (R132C), but the patient died of rapid cancer progression before the chemotherapy could be initiated. Although rare, malignant tumors can develop in patients with Maffucci syndrome; therefore, it is necessary to monitor these tumors through careful and periodic observation.
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- 2021
24. Proposed modification of the eighth edition of the AJCC staging system for intrahepatic cholangiocarcinoma
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Xu Feng Zhang, Timothy M. Pawlik, Guillaume Martel, Feng Xue, Sorin Alexandrescu, Bas Groot Koerkamp, Luca Aldrighetti, Shishir K. Maithel, Hugo Marques, Yi Lv, Feng Shen, Jin He, Oliver Soubrane, Carlo Pulitano, Endo Itaru, George A. Poultsides, Todd W. Bauer, Zhang, X. -F., Xue, F., He, J., Alexandrescu, S., Marques, H. P., Aldrighetti, L., Maithel, S. K., Pulitano, C., Bauer, T. W., Shen, F., Poultsides, G. A., Soubrane, O., Martel, G., Koerkamp, B. G., Itaru, E., Lv, Y., Pawlik, T. M., and Surgery
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medicine.medical_specialty ,Lymph node metastasis ,Stage ii ,TNM staging system ,Cholangiocarcinoma ,Cholangiocarcinoma* / surgery ,SDG 3 - Good Health and Well-being ,Cholangiocarcinoma* / pathology ,medicine ,Humans ,Stage (cooking) ,Bile Ducts, Intrahepatic / pathology ,Intrahepatic Cholangiocarcinoma ,Intrahepatic cholangiocarcinoma ,AJCC staging system ,Neoplasm Staging ,Hepatology ,business.industry ,Gastroenterology ,External validation ,Cancer ,Bile Duct Neoplasms* / pathology ,medicine.disease ,HCC CIR ,Prognosis ,Bile Duct Neoplasms* / surgery ,Bile Ducts, Intrahepatic ,Bile Duct Neoplasms ,Radiology ,business - Abstract
Background: To improve the prognostic accuracy of the 8th edition of the American Joint Committee on Cancer (AJCC) staging system for intrahepatic cholangiocarcinoma (ICC) with establishment and validation of a modified TNM (mTNM) staging system. Methods: Data on patients who underwent curative-intent resection for ICC was collected from 15 high-volume centers worldwide (n = 643). An external validation dataset was obtained from the SEER registry (n = 797). The mTNM staging system was proposed by redefining T categories, and incorporating the recently proposed N status as N0 (no lymph node metastasis [LNM]), N1 (1-2 LNM) and N2 (≥3 LNM). Results: The 8th AJCC TNM staging system failed to stratify overall survival (OS) of stage II versus IIIA, stage IIIB versus IV, as well as overall stage III versus IV among all patients from the two databases, as well as stage I versus II, and stage III versus III among patients who had ≥6 LNs examined. There was a monotonic decrement in survival based on the proposed mTNM staging classification among patients derived from both the multi-institutional (Median OS, stage I 69.8 vs. II 37.1 vs. III 18.9 vs. IV 16.4 months, all p < 0.05), and SEER (Median OS, stage I 87.0 vs. II 29.3 vs. III 17.7 vs. IV 14.2 months, all p < 0.05) datasets, which was also verified among patients who had ≥6 lymph node harvested from both databases. Conclusion: The modified TNM staging system for ICC using the new T and N definitions provided an improved means to stratify patients relative to long-term OS versus the 8th AJCC staging. info:eu-repo/semantics/publishedVersion
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- 2021
25. Oncological outcomes of surgery for recurrent biliary tract cancer: who are the best candidates?
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Kazuyasu Takizawa, Chie Kitami, Tatsuya Nomura, Naoyuki Yokoyama, Yoshifumi Shimada, Masahiro Minagawa, Takashi Aono, Jun Sakata, Yuki Hirose, Takashi Kobayashi, Masayuki Nagahashi, Kohei Miura, Toshifumi Wakai, and Hiroshi Ichikawa
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medicine.medical_specialty ,medicine.medical_treatment ,MEDLINE ,Disease ,030230 surgery ,Cholangiocarcinoma ,03 medical and health sciences ,0302 clinical medicine ,medicine ,Humans ,In patient ,Perihilar Cholangiocarcinoma ,Gallbladder cancer ,Intrahepatic Cholangiocarcinoma ,Retrospective Studies ,Chemotherapy ,Biliary tract cancer ,Hepatology ,business.industry ,Gastroenterology ,Prognosis ,medicine.disease ,Surgery ,Bile Ducts, Intrahepatic ,Biliary Tract Neoplasms ,Bile Duct Neoplasms ,030220 oncology & carcinogenesis ,Neoplasm Recurrence, Local ,business - Abstract
This study aimed to investigate the impact of surgery on outcomes in patients with recurrent biliary tract cancer (BTC) and elucidate factors affecting survival after surgery for this disease.A single-center study was undertaken in 178 patients with recurrent BTC, of whom 24 underwent surgery for recurrence, 85 received chemotherapy, and 69 received best supportive care. Then, we carried out a multicenter study in 52 patients undergoing surgery for recurrent BTC (gallbladder cancer, 39%; distal cholangiocarcinoma, 27%; perihilar cholangiocarcinoma, 21%; intrahepatic cholangiocarcinoma, 13%).In the single-center study, 3-year survival after recurrence was 53% in patients who underwent surgery, 4% in those who received chemotherapy, and 0% in those who received best supportive care (p 0.001). Surgery was an independently prognostic factor (p 0.001). In the multicenter series, the respective 3-year and 5-year survival after surgery for recurrence was 50% and 29% in the 52 patients. Initial site of recurrence was the only independent prognostic factor (p = 0.019). Five-year survival after surgery for recurrence in patients with single distant, multifocal distant, and locoregional recurrence was 51%, 0%, and 0%, respectively (p = 0.002). Sites of single distant recurrence included the liver (n = 13, 54%), distant lymph nodes (all from gallbladder cancer, n = 7, 29%), lung (n = 2, 9%), peritoneum (n = 1, 4%), and abdominal wall (n = 1, 4%).Surgery may be an effective option for patients with less aggressive tumor biology characterized by single distant recurrence in recurrent BTC.
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- 2021
26. Liver transplantation in malignant disease
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Ulf P. Neumann, Sven Arke Lang, Tony Bruns, Andreas Kroh, Pavel Strnad, Daniel Heise, Jan Bednarsch, Zoltan Czigany, Florian Ulmer, I. Amygdalos, and Katharina Joechle
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Oncology ,medicine.medical_specialty ,Hepatocellular carcinoma ,medicine.medical_treatment ,Review ,Cholangiocellular carcinoma ,Liver transplantation ,Milan criteria ,Undifferentiated embryonal sarcoma of the liver ,Internal medicine ,medicine ,Stage (cooking) ,Neoadjuvant therapy ,Intrahepatic Cholangiocarcinoma ,business.industry ,Cancer ,medicine.disease ,digestive system diseases ,Transplantation ,Neuroendocrine cancer liver metastases ,Colorectal cancer liver metastases ,Hepatic epithelioid hemangioendothelioma ,business - Abstract
Liver transplantation for malignant disease has gained increasing attention as part of transplant oncology. Following the implementation of the Milan criteria, hepatocellular carcinoma (HCC) was the first generally accepted indication for transplantation in patients with cancer. Subsequently, more liberal criteria for HCC have been developed, and research on this topic is still ongoing. The evident success of liver transplantation for HCC has led to the attempt to extend its indication to other malignancies. Regarding perihilar cholangiocarcinoma, more and more evidence supports the use of liver transplantation, especially after neoadjuvant therapy. In addition, some data also show a benefit for selected patients with very early stage intrahepatic cholangiocarcinoma. Hepatic epithelioid hemangioendothelioma is a very rare but nonetheless established indication for liver transplantation in primary liver cancer. In contrast, patients with hepatic angiosarcoma are currently not considered to be optimal candidates. In secondary liver tumors, neuroendocrine cancer liver metastases are an accepted but comparability rare indication for liver transplantation. Recently, some evidence has been published supporting the use of liver transplantation even for colorectal liver metastases. This review summarizes the current evidence for liver transplantation for primary and secondary liver cancer.
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- 2021
27. Clinical Staging of Mass‐Forming Intrahepatic Cholangiocarcinoma: Computed Tomography Versus Magnetic Resonance Imaging
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Eun-Suk Cho, Suk Keu Yeom, Ji Hoon Park, Mi-Suk Park, Sumi Park, Hyejung Shin, Seung Soo Lee, Sang Hyun Choi, Hyungjin Rhee, and Yeun-Yoon Kim
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Male ,Single tumor ,Computed tomography ,RC799-869 ,Partial hepatectomy ,Sensitivity and Specificity ,Cholangiocarcinoma ,Medicine ,Humans ,Stage (cooking) ,Multiple tumors ,Intrahepatic Cholangiocarcinoma ,Aged ,Neoplasm Staging ,Retrospective Studies ,Hepatology ,medicine.diagnostic_test ,business.industry ,Cancer ,Reproducibility of Results ,Magnetic resonance imaging ,Original Articles ,Diseases of the digestive system. Gastroenterology ,Middle Aged ,medicine.disease ,Magnetic Resonance Imaging ,Bile Ducts, Intrahepatic ,Bile Duct Neoplasms ,Original Article ,Female ,business ,Nuclear medicine ,Tomography, X-Ray Computed - Abstract
We compared the performance of computed tomography (CT) and magnetic resonance imaging (MRI) for preoperative clinical staging of mass‐forming intrahepatic cholangiocarcinoma (iCCA), using the eighth American Joint Committee on Cancer (AJCC) system. This retrospective, multicenter, cohort study consecutively identified patients who underwent partial hepatectomy for mass‐forming iCCA and had preoperative CT and MRI performed from January 2009 to December 2015. CT and MRI characteristics were used to determine clinical stage based on the eighth AJCC system. Performances of CT and MRI for clinical T and N staging were compared using generalized estimating equations. In 334 patients (median age, 63 years; 221 men), MRI sensitivities were significantly higher than CT sensitivities for detecting T1b or higher stages (91.0% vs. 80.5%, respectively, P 5 cm (i.e., T1b for single tumor) and extrahepatic organ invasion (i.e., T4). Sensitivities of CT and MRI were not different for N stage (65.0% vs. 64.0%, respectively, P = 0.808), but the specificity of CT was significantly higher than that of MRI (80.7% vs. 72.9%, respectively, P = 0.001) when using a composite reference standard. Conclusion: MRI showed superior sensitivity to CT for diagnosing T2 and T3 stages, particularly multiple tumors. CT and MRI had comparable sensitivity for N staging, but CT provided higher specificity than MRI.
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- 2021
28. Molecular Characterization of Biliary Tract Cancer Predicts Chemotherapy and Programmed Death 1/Programmed Death‐Ligand 1 Blockade Responses
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Hoguen Kim, Jihoon G. Yoon, Mi Jang, Young Nyun Park, Chang Moo Kang, Min Goo Lee, Beodeul Kang, Hyun Cheol Chung, Choong-kun Lee, Min Hwan Kim, Woo Jung Lee, Hye Jin Choi, and Ho Kyoung Hwang
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Adult ,Male ,Ampulla of Vater ,medicine.medical_treatment ,Common Bile Duct Neoplasms ,Programmed Cell Death 1 Receptor ,Antineoplastic Agents ,medicine.disease_cause ,B7-H1 Antigen ,Bile duct cancer ,Cholangiocarcinoma ,Proto-Oncogene Proteins p21(ras) ,Lymphocytes, Tumor-Infiltrating ,Bile Ducts, Extrahepatic ,Tumor Microenvironment ,medicine ,Humans ,Immune Checkpoint Inhibitors ,Intrahepatic Cholangiocarcinoma ,Aged ,Smad4 Protein ,Aged, 80 and over ,Tumor microenvironment ,Chemotherapy ,Massive parallel sequencing ,Hepatology ,Tumor-infiltrating lymphocytes ,business.industry ,Tumor Suppressor Proteins ,Carcinoma ,Immunotherapy ,Middle Aged ,medicine.disease ,Isocitrate Dehydrogenase ,Bile Ducts, Intrahepatic ,Biliary Tract Neoplasms ,Treatment Outcome ,Bile Duct Neoplasms ,Cancer research ,Female ,Gallbladder Neoplasms ,KRAS ,business ,Ubiquitin Thiolesterase - Abstract
BACKGROUND AND AIMS Biliary tract cancer (BTC) exhibits diverse molecular characteristics. However, reliable biomarkers that predict therapeutic responses are yet to be discovered. We aimed to identify the molecular features of treatment responses to chemotherapy and immunotherapy in BTCs. APPROACH AND RESULTS We enrolled 121 advanced BTC patients (68 cholangiocarcinomas [33 intrahepatic, 35 extrahepatic], 41 gallbladder cancers, and 12 Ampulla of Vater cancers) whose specimens were analyzed by clinical sequencing platforms. All patients received first-line palliative chemotherapy; 48 patients underwent programmed death 1 (PD-1)/programmed death-ligand 1 (PD-L1) blockade therapy after failed chemotherapy. Molecular and histopathological characterization was performed using targeted sequencing and immunohistochemical staining to investigate treatment response-associated biomarkers. Genomic analysis revealed a broad spectrum of mutational profiles according to anatomical location. Favorable responses to chemotherapy were observed in the small-duct type compared with the large-duct type intrahepatic cholangiocarcinoma, with frequent mutations in BRCA1-associated protein-1/isocitrate dehydrogenase 1/2 and KRAS proto-oncogene, GTPase/SMAD family member 4 genes, respectively. The molecular features were further analyzed in BTCs, and transforming growth factor beta and DNA damage response pathway-altered tumors exhibited poor and favorable chemotherapy responses, respectively. In PD-1/PD-L1 blockade-treated patients, KRAS alteration and chromosomal instability tumors were associated with resistance to immunotherapy. The majority of patients (95.0%) with these resistance factors show no clinical benefit to PD-1/PD-L1 blockade and low tumor mutational burdens. Low tumor-infiltrating lymphocyte (TIL) density in tumors with these resistance factors indicated immune-suppressive tumor microenvironments, whereas high intratumoral TIL density was associated with a favorable immunotherapy response. CONCLUSIONS This study proposes predictive molecular features of chemotherapy and immunotherapy responses in advanced BTCs using clinical sequencing platforms. Our result provides an intuitive framework to guide the treatment of advanced BTCs benefiting from therapeutic agents based on the tumors' molecular features.
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- 2021
29. Perioperative and oncologic outcomes of right anterior sectionectomy for liver disease: A single‐center experience with 415 patients
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Ki Byung Song, Dae Wook Hwang, Woohyung Lee, Jae Hoon Lee, Young-Joo Lee, Jaewoo Kwon, Yejong Park, and Song Cheol Kim
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medicine.medical_specialty ,Carcinoma, Hepatocellular ,Colorectal cancer ,Bile leakage ,Single Center ,Metastasis ,Liver disease ,Overall survival ,Hepatectomy ,Humans ,Medicine ,General Materials Science ,Intrahepatic Cholangiocarcinoma ,Retrospective Studies ,business.industry ,Medical record ,Liver Neoplasms ,General Medicine ,Perioperative ,medicine.disease ,Surgery ,Hepatocellular carcinoma ,Laparoscopy ,business ,Right anterior - Abstract
Introduction Right anterior sectionectomy (RAS) is technically difficult and performed infrequently, so there were a few reports of small numbers about this surgery. We described large number of clinicopathologic and oncologic outcomes associated with RAS. Methods We retrospectively reviewed the medical records of 415 patients treated with RAS for hepatic tumors located at segment 5 and/or 8 between January 2008 and December 2017. Results All patients underwent RAS with the alternative Glissonean pedicle clamp and Kelly clamp-crushing methods for transection. The mean operative time was 165 minutes and the mean transection time was 28 minutes. Major morbidities (≥ grade III) occurred in 28 cases (6.7%). Bile leakage occurred in 63 patients (15.1%), but no patients required reoperation. Grade A/B/C post-hepatectomy liver failure occurred in 39/7/0 (9.4%/1.7%/0.0%) patients, respectively. There were no in-hospital mortality caused by postoperative complications. The mean hospital stay was 13.3 days. The most common diagnosis was hepatocellular carcinoma (HCC; n = 361, 87.0%), followed by intrahepatic cholangiocarcinoma (n = 15, 3.6%), mixed HCC and cholangiocarcinoma (n = 17, 4.1%), colorectal cancer liver metastasis (n = 12, 2.9%). The mean tumor size was 3.8 cm. Among HCC patients, the 5- and 10- year overall survival (OS) rate was 78.3%, 64.4%, and 5- and 10- year disease-free survival (DFS) rate was 57.2%, 37.7%, respectively. Operative time, tumor size, and vessel invasion were factors significantly associated with OS and DFS for HCC patients. Conclusions RAS was associated with acceptable procedure-related morbidity and mortality as well as appropriate oncologic outcomes for HCC patients.
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- 2021
30. Update on the association of hepatitis B with intrahepatic cholangiocarcinoma: Is there new evidence?
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Emmanouil Sinakos, Christos Emmanouilides, Panteleimon Panas, Lazaros Sideras, and Nikolaos Fragkou
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Oncology ,medicine.medical_specialty ,Hepatocellular carcinoma ,Context (language use) ,Review ,medicine.disease_cause ,Chronic liver disease ,Cholangiocarcinoma ,Internal medicine ,Chemotherapy ,Humans ,Medicine ,Intrahepatic Cholangiocarcinoma ,Intrahepatic ,Hepatitis B virus ,business.industry ,Liver Neoplasms ,Gastroenterology ,Cancer ,General Medicine ,Odds ratio ,Hepatitis B ,Resection ,medicine.disease ,digestive system diseases ,Bile Ducts, Intrahepatic ,Bile Duct Neoplasms ,business - Abstract
Intrahepatic cholangiocarcinoma (iCCA) is a subgroup of cholangiocarcinoma that accounts for about 10%-20% of the total cases. Infection with hepatitis B virus (HBV) is one of the most important predisposing factors leading to the formation of iCCA. It has been recently estimated based on abundant epidemiological data that the association between HBV infection and iCCA is strong with an odds ratio of about 4.5. The HBV-associated mechanisms that lead to iCCA are under intense investigation. The diagnosis of iCCA in the context of chronic liver disease is challenging and often requires histological confirmation to distinguish from hepatocellular carcinoma. It is currently unclear whether antiviral treatment for HBV can decrease the incidence of iCCA. In terms of management, surgical resection remains the mainstay of treatment. There is a need for effective treatment modalities beyond resection in both first- and second-line treatment. In this review, we summarize the epidemiological evidence that links the two entities, discuss the pathogenesis of HBV-associated iCCA, and present the available data on the diagnosis and management of this cancer.
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- 2021
31. Chemotherapy with gemcitabine for unresectable intrahepatic cholangiocarcinoma in a patient undergoing maintenance hemodialysis
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Nobuhiro Katsukura, Hiromichi Tsunashima, Yuta Namura, Kanji Okamoto, Ayako Watanabe, Go Saito, Shinpei Doi, Kentaro Kikuchi, Kotaro Matsumoto, Katsuyuki Matsui, Takako Adachi, Tomohiro Kikuyama, and Takayuki Tsujikawa
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Male ,medicine.medical_specialty ,Liver tumor ,medicine.medical_treatment ,Urology ,Deoxycytidine ,Cholangiocarcinoma ,Renal Dialysis ,Antineoplastic Combined Chemotherapy Protocols ,medicine ,Humans ,Dialysis ,Intrahepatic Cholangiocarcinoma ,Chemotherapy ,medicine.diagnostic_test ,business.industry ,Gastroenterology ,General Medicine ,Middle Aged ,medicine.disease ,Gemcitabine ,Bile Duct Neoplasms ,Abdominal ultrasonography ,Hemodialysis ,business ,Progressive disease ,medicine.drug - Abstract
A 56-year-old man with chronic renal failure due to diabetic nephropathy had received maintenance dialysis (every 4 h, three times/week). A hypoechoic tumor measuring 67 × 50 mm in the right lobe of the liver was discovered following routine abdominal ultrasonography. Dynamic computed tomography showed a low-density liver tumor, enlarged hilar lymph node, and a small nodule on the dorsal side of the lower lobe of the left lung. Histopathological examination of the liver tumor revealed intrahepatic cholangiocarcinoma. We developed a chemotherapy treatment plan with gemcitabine, which can be performed concurrently with hemodialysis. Gemcitabine (1000 mg/m2, three times/cycle) was administered on Friday afternoon, and hemodialysis was performed on Tuesday, Thursday, and Saturday. Anemia and hypotension occurred after gemcitabine administration. Therefore, the dose of darbepoetin alpha was increased, and packed red blood cells were transfused. The patient was treated with gemcitabine for approximately 5 and a half months until computed tomography findings showed progressive disease; the survival time after treatment start was 8 months. Chemotherapy using gemcitabine has not been established in dialysis patients and has little evidence. We report a case of unresectable intrahepatic cholangiocarcinoma that developed during maintenance dialysis and was treated using gemcitabine chemotherapy.
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- 2021
32. DNA methylation biomarkers for diagnosis of primary liver cancer and distinguishing hepatocellular carcinoma from intrahepatic cholangiocarcinoma
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Zhisong Liu, Fei Miao, Rui Shi, Hao Wu, Fucun Xie, Long Yang, Wen Tong, Lianjiang Wang, Qiang Zhao, Yi Bai, Liuyang Zhu, and Yaming Zhang
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Aging ,Protein Folding ,diagnostic biomarker ,Carcinoma, Hepatocellular ,primary liver cancer ,Biology ,Sensitivity and Specificity ,Cholangiocarcinoma ,Cohort Studies ,Diagnosis, Differential ,intrahepatic cholangiocarcinoma ,Predictive Value of Tests ,medicine ,Biomarkers, Tumor ,Humans ,Gene ,Intrahepatic Cholangiocarcinoma ,Liver Neoplasms ,Reproducibility of Results ,Cell Biology ,Methylation ,hepatocellular carcinoma ,DNA Methylation ,medicine.disease ,Prognosis ,Glutathione ,digestive system diseases ,Oxidative Stress ,CpG site ,Tumor progression ,Hepatocellular carcinoma ,DNA methylation ,Cancer research ,Hepatocytes ,methylation ,Primary liver cancer ,Algorithms ,Research Paper - Abstract
Hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC) are the two most common pathology subtypes of primary liver cancer (PLC). Identifying DNA methylation biomarkers for diagnosis of PLC and further distinguishing HCC from ICC plays a vital role in subsequent treatment options selection. To obtain potential diagnostic DNA methylation sites for PLC, differentially methylated CpG (DMC) sites were first screened by comparing the methylation data between normal liver samples and PLC samples (ICC samples and HCC samples). A random forest algorithm was then used to select specific DMC sites with top Gini value. To avoid overfitting, another cohort was taken as an external validation for evaluating the area under curves (AUCs) of different DMC sites combination. A similar model construction strategy was applied to distinguish HCC from ICC. In addition, we identified DNA Methylation-Driven Genes in HCC and ICC via MethylMix method and performed pathway analysis by utilizing MetaCore. Finally, we not only performed methylator phenotype based on independent prognostic sites but also analyzed the correlations between methylator phenotype and clinical factors in HCC and ICC, respectively. To diagnose PLC, we developed a model based on three PLC-specific methylation sites (cg24035245, cg21072795, and cg00261162), whose sensitivity and specificity achieved 98.8%,94.8% in training set and 97.3%,81% in validation set. Then, to further divide the PLC samples into HCC and ICC, we established another mode through three methylation sites (cg17769836, cg17591574, and cg07823562), HCC accuracy and ICC accuracy achieved 95.8%, 89.8% in the training set and 96.8%,85.4% in the validation set. In HCC, the enrichment pathways were mainly related to protein folding, oxidative stress, and glutathione metabolism. While in ICC, immune response, embryonic hepatocyte maturation were the top pathways. Both in HCC and ICC, methylator phenotype correlated well with overall survival time and clinical factors involved in tumor progression. In summary, our study provides the biomarkers based on methylation sites not only for the diagnosis of PLC but also for distinguishing HCC from ICC.
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- 2021
33. Relationship between PD-L1 expression, CD8+ T-cell infiltration and prognosis in intrahepatic cholangiocarcinoma patients
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Yudong Qiu, Jun Chen, Xiaopeng Yan, Shao-Hua Li, Rong Ping Guo, Xu Fu, and Min Deng
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0301 basic medicine ,Cancer Research ,medicine.medical_specialty ,medicine.medical_treatment ,Gastroenterology ,Cholangiocarcinoma ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,Genetics ,medicine ,Cytotoxic T cell ,Programmed death-ligand 1 ,Intrahepatic Cholangiocarcinoma ,RC254-282 ,Intrahepatic ,QH573-671 ,business.industry ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,Immunotherapy ,medicine.disease ,Prognosis ,030104 developmental biology ,Oncology ,030220 oncology & carcinogenesis ,Cancer cell ,Immunohistochemistry ,Pd l1 expression ,Primary Research ,business ,CD8+ T cell ,Cytology ,Infiltration (medical) ,CD8 - Abstract
Background Programmed death- ligand 1 (PD-L1) seems to be associated with the immune escape of tumors, and immunotherapy may be a favorable treatment for PD-L1-positive patients. We evaluated intrahepatic cholangiocarcinoma (ICC) specimens for their expression of PD-L1, infiltration of CD8+ T cells, and the relationship between these factors and patient survival. Methods In total, 69 resections of ICC were stained by immunohistochemistry for PD-L1, programmed death factor-1 (PD-1), and CD8+ T cells. CD8+ T-cell densities were analyzed both within tumors and at the tumor-stromal interface. Patient survival was predicted based on the PD-L1 status and CD8+ T-cell density. Results The expression rate of PD-L1 was 12% in cancer cells and 51% in interstitial cells. The expression rate of PD-1 was 30%, and the number of CD8+ T-cells increased with the increase of PD-L1 expression (p Conclusions The expression of PD-L1 in the tumor is related to poor OS, and the number of tumor or interstitial CD8+ T-cells is related to poor OS and DFS. For patients who lose their chance of surgery, PD-L1 immunosuppressive therapy may be the focus of future research as a potential treatment.
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- 2021
34. Comparative Genomic Analysis of Intrahepatic Cholangiocarcinoma: Biopsy Type, Ancestry, and Testing Patterns
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Jason K. Sicklick, Hanna Tukachinsky, Kimberly McGregor, Shumei Kato, Mason A. Israel, Halla Nimeiri, Geoffrey R. Oxnard, Jeffrey S. Ross, Karthikeyan Murugesan, Ethan Sokol, Razelle Kurzrock, Ole Gjoerup, and Natalie Danziger
- Subjects
0301 basic medicine ,Oncology ,Cancer Research ,medicine.medical_specialty ,IDH1 ,Biopsy ,Cholangiocarcinoma ,03 medical and health sciences ,0302 clinical medicine ,Text mining ,Internal medicine ,medicine ,Humans ,Liquid biopsy ,Intrahepatic Cholangiocarcinoma ,medicine.diagnostic_test ,business.industry ,Genomics ,medicine.disease ,Primary tumor ,Clinical trial ,Bile Ducts, Intrahepatic ,030104 developmental biology ,Bile Duct Neoplasms ,030220 oncology & carcinogenesis ,Biomarker (medicine) ,Hepatobiliary ,business - Abstract
BackgroundAt diagnosis, the majority of patients with intrahepatic cholangiocarcinoma (IHCC) present with advanced disease and a poor prognosis. Comprehensive genomic profiling (CGP) early in the disease course may increase access to targeted therapies and clinical trials; however, unresolved issues remain surrounding the optimal biopsy type to submit for CGP.Patients and MethodsMutational frequencies between primary tumor biopsies (Pbx), metastatic biopsies (Mbx), and liquid biopsies (Lbx) in 1,632 patients with IHCC were compared.ResultsPotentially actionable alterations were found in 52%, 34%, and 35% of patients in the Pbx, Mbx, and Lbx cohorts, respectively. In Pbx, Mbx, and Lbx, FGFR2 rearrangements were found in 9%, 6%, and 4%, and IDH1 mutations were identified in 16%, 5%, and 9% patients, respectively. Moreover, alterations in FGFR2 and IDH1 were significantly associated with distinct ancestries, including 2.1-fold enrichment for FGFR2 rearrangements in patients with African ancestry and 1.5-fold enrichment for IDH1 mutations in patients with admixed American (Hispanic) ancestry. Finally, the publication of biomarker-driven clinical trials in IHCC correlated with changing CGP testing patterns. Significant correlations between patient characteristics and IHCC trial disclosures were observed, including a significant decrease from time between biopsy and CGP testing, and more frequent testing of primary versus metastatic samples.ConclusionOverall, because of the high likelihood of identifying actionable genomic alterations, CGP should be considered for the majority of patients with inoperable IHCC, and Lbx and Mbx can be considered as part of the diagnostic suite.Implications for PracticeComprehensive genomic profiling (CGP) should be considered for all patients with intrahepatic cholangiocarcinoma (IHCC) or suspected IHCC, as actionable alterations were commonly found in multiple genes and a wide variety of FGFR2 fusion partners were identified. The disclosure of IHCC trial data correlated with increased use of CGP, an encouraging trend that moves new therapeutic options forward for rare cancers with a rare biomarker. Although tissue from the primary lesion may identify actionable alterations at higher rates, CGP of a liquid biopsy or metastatic site can be considered, particularly if the primary tissue block is exhausted.
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- 2021
35. Extent of Lymph Node Dissection for Accurate Staging in Intrahepatic Cholangiocarcinoma
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Kyung Sik Kim, Dai Hoon Han, Gi Hong Choi, Sung Hyun Kim, and Jin Sub Choi
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medicine.medical_specialty ,Metastasis ,Cholangiocarcinoma ,medicine.artery ,medicine ,Humans ,Radical surgery ,Lymph node ,Intrahepatic Cholangiocarcinoma ,Survival analysis ,Neoplasm Staging ,Retrospective Studies ,Common hepatic artery ,business.industry ,Gastroenterology ,Hepatoduodenal ligament ,Prognosis ,medicine.disease ,Dissection ,Bile Ducts, Intrahepatic ,medicine.anatomical_structure ,Bile Duct Neoplasms ,Lymph Node Excision ,Surgery ,Lymph Nodes ,Radiology ,business - Abstract
Although lymph node metastasis is a known factor predictive of a poor prognosis after radical surgery for intrahepatic cholangiocarcinoma (ICC), few studies have investigated lymph node dissection (LND) areas for accurate staging. The aim of this study was to identify the optimal LND level for ICC considering lymphatic flow. Clinical characteristics and pathologic nodal status (presence of metastasis) for 163 patients were reviewed according to tumor location. In the node-positive (N1) group, the distribution of metastatic nodes was described. The coverage of metastatic nodes according to dissection level was assessed, and the minimum dissection level for accurate ICC staging was estimated accordingly. For validation, the node-negative (N0) group was divided into two subgroups according to the estimated dissection level, and survival outcomes were compared. In the N1 group, expanding dissection to stations no. 12 and 8 covered 82.0% (n = 50) of metastatic cases regardless of tumor location. In survival analysis of N0 group, patients who underwent LND covering stations no. 8+12 showed better disease-free survival (DFS) and overall survival (OS), although the differences were not statistically significant (DFS: covering no. 12+8 vs. not covering no. 12+8, 109.0 months [24.2–193.8] vs. 33.0 months [10.3–55.7], p = 0.078; OS: covering no. 12+8 vs. not covering no. 12+8, 180.0 months [21.6–338.4] vs. 73.0 months [42.8–103.2], p = 0.080). LND including at least stations no. 12 (hepatoduodenal ligament) and 8 (common hepatic artery), regardless of tumor location, is recommended for accurate staging in ICC patients.
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- 2021
36. Prediction of mismatch repair deficient biliary tract cancer: Role of morphological features and host immune response detected by routine hematoxylin‐eosin staining
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Yohei Kawasaki, Takashi Mishima, Takayuki Ishige, Masayuki Ohtsuka, Kazuyuki Matsushita, Nozomu Sakai, Ryuichiro Suda, Yuki Shiko, Katsunori Furukawa, and Eri Nakadai
- Subjects
Pathology ,medicine.medical_specialty ,H&E stain ,DNA Mismatch Repair ,03 medical and health sciences ,0302 clinical medicine ,Humans ,Medicine ,Stromal tumor ,Hematoxylin ,Intrahepatic Cholangiocarcinoma ,Staining and Labeling ,Hepatology ,business.industry ,Tumor-infiltrating lymphocytes ,Signet ring cell ,Immunity ,Microsatellite instability ,medicine.disease ,Biliary Tract Neoplasms ,030220 oncology & carcinogenesis ,Eosine Yellowish-(YS) ,Microsatellite Instability ,030211 gastroenterology & hepatology ,Surgery ,DNA mismatch repair ,business ,Immunostaining - Abstract
BACKGROUND/PURPOSE The objective of this study was to determine the frequency and predictors of biliary tract cancer (BTC) with deficient DNA mismatch repair (dMMR) in Japan. METHODS Immunostaining and microsatellite instability analysis were performed for mismatch repair-related proteins in tissue specimens from 662 patients who underwent surgery for BTC between 2001 and 2017 to identify dMMR-BTC. We compared dMMR-BTC and proficient MMR (pMMR)-BTC based on patient demographics, pathological features, and host immune responses characterized by the percentage of stromal tumor infiltrating lymphocytes (sTIL percentage) and tertiary lymphoid structures (TLS). RESULTS The incidence of dMMR-BTC was 2.3%. Significant predictors of dMMR-BTC were its primary lesion being intrahepatic cholangiocarcinoma (odds ratio [OR] 6.34, P = .004), presence of signet ring cell component (OR 35.62, P
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- 2021
37. Combination of albumin-globulin score and skeletal muscle index predicts long-term outcomes of intrahepatic cholangiocarcinoma patients after curative resection
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Tian Lan, Lin Xu, Bole Cai, Hui Li, Hailing Liu, Gen-shu Wang, Hong Wu, Junlong Dai, Kefei Yuan, and Jinju Wang
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Male ,0301 basic medicine ,Curative resection ,China ,Sarcopenia ,medicine.medical_specialty ,030209 endocrinology & metabolism ,Critical Care and Intensive Care Medicine ,Gastroenterology ,Cholangiocarcinoma ,03 medical and health sciences ,0302 clinical medicine ,Albumins ,Internal medicine ,Multidetector Computed Tomography ,medicine ,Long term outcomes ,Humans ,In patient ,Muscle, Skeletal ,Intrahepatic Cholangiocarcinoma ,Retrospective Studies ,030109 nutrition & dietetics ,Nutrition and Dietetics ,business.industry ,Skeletal muscle ,Globulins ,Middle Aged ,Prognosis ,medicine.disease ,Survival Analysis ,Albumin/Globulin ,Nutrition Assessment ,medicine.anatomical_structure ,Bile Duct Neoplasms ,Cohort ,Female ,business - Abstract
Summary Background & aims Sarcopenia is characterized by loss of skeletal muscle mass and associated with poor postoperative outcomes. This study aimed to investigate the prognostic value of preoperative albumin-globulin score (AGS), skeletal muscle index (SMI) as well as their combination in patients with intrahepatic cholangiocarcinoma (ICC) treated with surgical resection. Methods A total of 613 newly diagnosed ICC patients from two centers were retrospectively analyzed (460 in discovery cohort and 153 in validation cohort). The plain computed tomography images were used to measure SMI. The effect of AGS, SMI and CAS grade on clinicopathological characteristics and long-term outcomes of patients with ICC were analyzed. Results The SMI was significantly greater in males than in females. Patients with decreased AGS, increased SMI were associated with improved overall survival (OS) and recurrence-free survival (RFS). Stratefied by CAS grade, 68 (14.8%) patients in grade 1 were associated with increased body mass index (BMI) and best postoperative prognosis, whereas 194 (42.1%) patients in grade 3 were linked to worst OS and RFS. The CAS grade showed a promising accuracy in predicting OS and RFS of ICC patients (area under curves [AUCs] were 0.732 and 0.768). Multiple tumors, MVI and elevated CAS grades were identified as independent risk factors for OS and RFS of ICC patients. These results were confirmed by validation cohort. Conclusion The present study provided compelling evidence that a novel index based on combination of preoperative AGS and SMI was closely related to postoperative long-term outcomes for surgically treated ICC patients. Preoperative evaluation of CAS grade may be useful for risk classification and clinical therapeutic decision-making for ICC patients.
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- 2021
38. Expanding indications for liver transplantation in the era of liver transplant oncology
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Flavio Paterno, James V. Guarrera, Nyan L. Latt, Nikolaos Pyrsopoulos, Guergana Panayotova, and Keri E Lunsford
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Oncology ,medicine.medical_specialty ,Hepatocellular carcinoma ,medicine.medical_treatment ,030230 surgery ,Liver transplantation ,Malignancy ,03 medical and health sciences ,0302 clinical medicine ,Colorectal metastases ,Surgical oncology ,Transplant oncology ,Internal medicine ,medicine ,Neoadjuvant therapy ,Intrahepatic Cholangiocarcinoma ,Intrahepatic cholangiocarcinoma ,business.industry ,Cancer ,Minireviews ,medicine.disease ,Mixed hepatocholangiocarcinoma ,Transplantation ,030211 gastroenterology & hepatology ,business - Abstract
Despite numerous advances and emerging data, liver transplantation in the setting of gastrointestinal malignancies remains controversial outside of certain accepted indications. In an era of persistent organ shortage and increasing organ demand, allocation of liver grafts must be considered carefully. While hepatocellular carcinoma and hilar cholangiocarcinoma have become accepted indications for transplantation, tumor size and standardized multi-disciplinary treatment protocols are necessary to ensure optimal patient outcomes. As more studies seeking to expand the oncologic indications for liver transplantation are emerging, it is becoming increasingly clear that tumor biology and response to therapy are key factors for optimal oncologic outcomes. In addition, time from diagnosis to transplantation appears to correlate with survival, as stable disease over time portends better outcomes post-operatively. Identifying aggressive disease pre-transplant remains difficult with current imaging and tissue sampling techniques. While tumor size and stage are important prognostic predictors for most malignancies, patient and tumor selection protocols are necessary. As the fields of medical and surgical oncology continue to evolve, it is clear that a protocolized interdisciplinary treatment approach is necessary for combatting any cancer effectively. Disease stability over time and response to neoadjuvant therapy may be the best predictors for successful patient outcomes and can be easily incorporated in our treatment paradigms. Current data evaluating liver transplantation for expanded oncologic indications such as: expanded criteria hepatocellular carcinoma, intrahepatic cholangiocarcinoma, mixed tumors, and liver limited metastatic colorectal carcinomas, incorporate multi-modal therapies and evaluation of tumor treatment response. While further investigation is necessary, initial results suggest there is an expanded role for transplant surgery in malignancy in a new era of liver transplant oncology.
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- 2021
39. Success rate of microsatellite instability examination and complete response with pembrolizumab in biliary tract cancer
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Kazuyoshi Ohkawa, Takuo Yamai, Nobuyasu Fukutake, Yugo Kai, Hiroyuki Uehara, Ryoji Takada, Shingo Maeda, Hiroshi Wada, Kazuma Daiku, Yutaro Abe, Shigenori Nagata, Kenji Ikezawa, and Tasuku Nakabori
- Subjects
Endoscopic ultrasound ,congenital, hereditary, and neonatal diseases and abnormalities ,medicine.medical_specialty ,RC799-869 ,Pembrolizumab ,03 medical and health sciences ,0302 clinical medicine ,Biopsy ,medicine ,neoplasms ,Intrahepatic Cholangiocarcinoma ,endoscopic ultrasound‐guided fine‐needle aspiration ,Hepatology ,medicine.diagnostic_test ,Bile duct ,business.industry ,Gallbladder ,Gastroenterology ,nutritional and metabolic diseases ,Microsatellite instability ,Cancer ,Original Articles ,Diseases of the digestive system. Gastroenterology ,biliary tract neoplasms ,medicine.disease ,digestive system diseases ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,Original Article ,microsatellite instability ,030211 gastroenterology & hepatology ,pembrolizumab ,Radiology ,cholangiocarcinoma ,business - Abstract
Background and Aim The success rate of microsatellite instability (MSI) examination in biliary tract cancer (BTC) and the treatment outcomes of pembrolizumab in patients with MSI‐high (MSI‐H) BTC have not been fully investigated. We examined the success rate of MSI examination and the rate of MSI‐H status in patients with BTC as well as the treatment outcomes of patients with MSI‐H status who underwent pembrolizumab treatment. Methods We retrospectively reviewed 60 consecutive patients with unresectable or postoperative recurrent BTC who underwent MSI examination in a Japanese cancer referral center between January 2019 and September 2020. Results The study included 24 intrahepatic cholangiocarcinomas, 12 hilar cholangiocarcinomas, 4 distal cholangiocarcinomas, 16 gallbladder carcinomas, and 4 ampullary carcinomas. The methods of cancer tissue sampling were percutaneous liver tumor biopsy in 26 cases, surgery in 15 cases, endoscopic ultrasound fine‐needle aspiration in 12 cases, transpapillary bile duct biopsy in 5 cases, and others in 2 cases. The success rate of MSI examination was 98.3% (59 of 60). MSI examination failed in only one case using a surgical specimen due to time‐dependent degradation of DNA. The frequency of MSI‐H BTC was 3.3% (2 of 60 cases). One patient with MSI‐H intrahepatic cholangiocarcinoma achieved a complete response with pembrolizumab treatment. Conclusions MSI examinations in BTC were successful in almost all cases, regardless of tissue sampling methods. We experienced a case in which pembrolizumab resulted in a complete response to MSI‐H BTC. Since pembrolizumab for MSI‐H BTC could prolong survival time, MSI examination should be performed proactively to increase treatment options., We retrospectively reviewed 60 consecutive patients with advanced biliary tract cancer (BTC) who underwent microsatellite instability (MSI) examination. MSI examinations were successful in almost all cases (59 of 60 cases), regardless of tissue sampling methods including endoscopic ultrasound fine‐needle aspiration and liver tumor biopsy. The frequency of MSI‐high (MSI‐H) was 3.3%, and we experienced a case in which pembrolizumab resulted in a complete response to MSI‐H BTC.
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- 2021
40. Significance of Carbohydrate Antigen 19-9 as a biomarker in Hepatocellular Carcinoma and Cholangiocarcinoma
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Waleed El Agawy, Walid A. Abdel Halim, Mohamed El-Tantawy Ibrahim, Medhat A. Khalil, and Badawy A. Abdulaziz
- Subjects
business.industry ,Biochemistry (medical) ,Clinical Biochemistry ,Medicine (miscellaneous) ,medicine.disease ,digestive system diseases ,03 medical and health sciences ,0302 clinical medicine ,030220 oncology & carcinogenesis ,Hepatocellular carcinoma ,medicine ,Cancer research ,Biomarker (medicine) ,030211 gastroenterology & hepatology ,business ,Alpha-fetoprotein ,Carbohydrate antigen ,Intrahepatic Cholangiocarcinoma - Abstract
Background & Aims: Combined hepatocellular - cholangiocarcinomas (cHCC-CCs) are rare malignancies representing less than 1% of all primary liver cancers. Correct preoperative diagnosis is desirable because the frequency of lymph node metastasis in ICC and cHCC-CC, making lymph node dissection a necessity if curative resection to be attempted. This study aimed to investigate the significance of elevated CA19-9 in suspecting a diagnosis of Intrahepatic Cholangiocarcinoma (ICC) “non-invasively” in patients with typical radiological features of HCC. Methods This cross-sectional study was conducted on 54 patients with typical radiological criteria of HCC and elevated CA19-9 level. And were classified into two groups I included 22 patients (40.74%) who were diagnosed as HCC, group II included 30 patients (55.56%) were diagnosed as ICC, and there were 2 patients (3.7%) were diagnosed as cHCC-CC. Tumor markers (AFP and CA19-9), dynamic study (Triphasic CT or Dynamic MRI) were done for all patients. Target liver biopsy was done for histopathology and immuno-histochemistry using specific monoclonal antibodies against Glypican-3, Hep-par1, CK-7, CK-19 and CK-20 were done. Results: There was a statistically significant difference between HCC and ICC as regard CA19-9 and Alpha-fetoprotein (AFP). CA19-9 and AFP cut-offs were ˃ 58.9 U/mL and ˂ 25.8 ng/mL, respectively favoring the diagnosis of ICC, with very high sensitivity and specificity. CA19-9 level was 176.3 and 156.7 U/mL while AFP level was 460 and 170 ng/mL in cHCC-CC cases, respectively. Conclusion: CA19-9 could be a diagnostic marker of ICC in cases of typical radiological criteria of HCC with elevated CA19-9.
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- 2021
41. A new pathological classification of intrahepatic cholangiocarcinoma according to protein expression of SSTR2 and Bcl2
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Koichi Tsuneyama, Katsuki Miyazaki, Shoko Yamashita, Kazunori Tokuda, Yuji Morine, Yu Saito, Mitsuo Shimada, Takeshi Oya, Tetsuya Ikemoto, Chie Takasu, Shohei Okikawa, Shinichiro Yamada, and Satoru Imura
- Subjects
medicine.medical_specialty ,Bcl2 ,RD1-811 ,Gastroenterology ,SSTR2 ,Cholangiocarcinoma ,Clinicopathological characteristics ,Surgical oncology ,Internal medicine ,hemic and lymphatic diseases ,medicine ,Humans ,Somatostatin receptor 2 ,Receptors, Somatostatin ,Stage (cooking) ,Pathological ,Intrahepatic Cholangiocarcinoma ,RC254-282 ,business.industry ,Research ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,medicine.disease ,Prognosis ,Immunohistochemistry ,Lymphoma ,Leukemia ,Bile Ducts, Intrahepatic ,Bile Duct Neoplasms ,Proto-Oncogene Proteins c-bcl-2 ,Oncology ,Surgery ,business - Abstract
Background No universal classification method for intrahepatic cholangiocarcinoma (IHCC) has been reported based on the embryological origin of biliary epithelial cells. The aim of this study was to classify IHCC according to protein expression levels of somatostatin receptor 2 (SSTR2) and b-cell leukemia/lymphoma 2 (Bcl2) and to elucidate the clinicopathological features of each group. Methods Fifty-two IHCC patients who underwent hepatic resection were enrolled in this study. Protein expression levels of SSTR2 and Bcl2 were examined using immunohistochemistry. Clinicopathological factors were compared between the three groups and prognostic factors were investigated. Results The patients were divided into three groups: SSTR2 positive and Bcl2 negative (p-Group H, n = 21), SSTR2 negative and Bcl2 positive (p-Group P, n = 14), and the indeterminate group (p-Group U, n = 17) for cases where SSTR2 and Bcl2 were both positive or both negative. All p-Group P cases displayed curability A or B. The 5-year survival rates of p-Group H and U patients were worse than those in p-Group P. p-Group H had higher T-factor, clinical stage, and incidence of periductal infiltration than p-Group P. Conclusions This method could be used to classify IHCC into peripheral and perihilar type by embryological expression patterns of SSTR2 and Bcl2.
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- 2021
42. Rare DNA Mismatch Repair-Related Protein Loss in Patients with Intrahepatic Cholangiocarcinoma and Combined Hepatocellular-Cholangiocarcinoma and Their Response to Immunotherapy
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Qiyue Huang, Jing Yu, Xi Zhang, Sirui Tan, Xianze Xiong, and Hongfeng Gou
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0301 basic medicine ,Oncology ,medicine.medical_specialty ,medicine.medical_treatment ,MLH1 ,Metastasis ,immune checkpoint inhibitors ,03 medical and health sciences ,0302 clinical medicine ,intrahepatic cholangiocarcinoma ,Internal medicine ,PMS2 ,Medicine ,Intrahepatic Cholangiocarcinoma ,Original Research ,combined hepatocellular-cholangiocarcinoma ,business.industry ,Immunotherapy ,medicine.disease ,digestive system diseases ,MSH6 ,030104 developmental biology ,Cancer Management and Research ,MSH2 ,030220 oncology & carcinogenesis ,DNA mismatch repair ,mismatch-repair deficiency ,prognosis ,business - Abstract
Jing Yu,1,* Xi Zhang,1,2,* Qiyue Huang,1 Sirui Tan,1 Xianze Xiong,3 Hongfeng Gou1 1Department of Abdominal Cancer, West China Medical School, Cancer Center, West China Hospital, Sichuan University, Chengdu, People’s Republic of China; 2Department of Radiotherapy, The Affiliated Hospital of Hebei University, Baoding, 07100, People’s Republic of China; 3Department of Bile Duct Surgery, West China Hospital, Sichuan University, Chengdu, People’s Republic of China*These authors contributed equally to this workCorrespondence: Hongfeng GouDepartment of Abdominal Cancer, West China Medical School, Cancer Center, West China Hospital, Sichuan University, No. 37, Guo Xue Xiang, Chengdu, 610041, Sichuan Province, People’s Republic of ChinaTel +86-28-85422589Fax +86-28-85423609Email gouhongfeng1977@wchscu.cnXianze XiongDepartment of Bile Duct Surgery, West China Hospital, Sichuan University, No. 37, Guo Xue Xiang, Chengdu, 610041, Sichuan Province, People’s Republic of ChinaEmail xianzexiong123@163.comPurpose: The patients with advanced mismatch repair deficiency (dMMR) cancers can benefit from programmed cell death 1 (PD-1) pathway blockade, regardless of the tumor type. Little is known about the prevalence of dMMR in intrahepatic cholangiocarcinoma (ICC) and combined hepatocellular-cholangiocarcinoma (cHCC-CC). This study aimed to assess the mismatch repair (MMR)-related protein expression in patients with ICC and cHCC-CC.Patients and Methods: Formalin-fixed, paraffin-embedded tumor specimens were obtained from patients undergoing surgery at the West china Hospital between 2009 and 2017. The immunoreactions for MLH1, MSH2, MSH6, and PMS2 were investigated to determine the MMR status.Results: A total of 97 patients were evaluated, including 73 ICC patients and 24 cHCC-CC patients. The prevalence of dMMR was only found in two cases of 97 patients (2.06%). Both patients are ICC. In 24 cHCC-CC patients, no dMMR was observed. They did not receive an adjuvant chemotherapy after surgery. At the end of the follow-up, one patient was in a tumor-free state, and the other patient had local recurrence and metastasis. After receiving sintilimumab (an immune checkpoint inhibitor [ICI] for PD- 1), the patient had a partial response.Conclusion: DMMR was detected in few patients with ICC and cHCC-CC. Thus, it is not recommended to routinely evaluate the MMR status of patients with ICC or cHCC-CC after surgery, but that of patients with advanced ICC or cHCC-CC should be assessed.Keywords: mismatch-repair deficiency, intrahepatic cholangiocarcinoma, combined hepatocellular-cholangiocarcinoma, immune checkpoint inhibitors, prognosis
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- 2021
43. Dynamic 18F-FDG PET imaging of liver lesions: evaluation of a two-tissue compartment model with dual blood input function
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Bowei Liu, Jingnan Wang, Hui Zhang, Fang Li, Li Huo, Yunwen Shao, Haitao Zhao, Xiang Li, Xuezhu Wang, Haiyan Ding, Marcus Hacker, and Barbara Katharina Geist
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Tissue compartment ,Dual input function ,Kinetic model ,Chemistry ,FDG ,Hepatocellular carcinoma ,Input function ,FDG-Positron Emission Tomography ,medicine.disease ,030218 nuclear medicine & medical imaging ,18f fdg pet ,03 medical and health sciences ,0302 clinical medicine ,medicine.anatomical_structure ,Nuclear magnetic resonance ,030220 oncology & carcinogenesis ,medicine ,Medical technology ,Radiology, Nuclear Medicine and imaging ,Tomography ,R855-855.5 ,Artery ,Intrahepatic cholangiocarcinoma - Abstract
Background Dynamic PET with kinetic modeling was reported to be potentially helpful in the assessment of hepatic malignancy. In this study, a kinetic modeling analysis was performed on hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC) from dynamic FDG positron emission tomography/computer tomography (PET/CT) scans. Methods A reversible two-tissue compartment model with dual blood input function, which takes into consideration the blood supply from both hepatic artery and portal vein, was used for accurate kinetic modeling of liver dynamic 18F-FDG PET imaging. The blood input functions were directly measured as the mean values over the VOIs on descending aorta and portal vein respectively. And the contribution of hepatic artery to the blood input function was optimization-derived in the process of model fitting. The kinetic model was evaluated using dynamic PET data acquired on 24 patients with identified hepatobiliary malignancy. 38 HCC or ICC identified lesions and 24 healthy liver regions were analyzed. Results Results showed significant differences in kinetic parameters $${K}_{1}-{k}_{4}$$ K 1 - k 4 , blood supplying fraction $${f}_{A}$$ f A , and metabolic rate constant $${K}_{i}$$ K i between malignant lesions and healthy liver tissue. And significant differences were also observed in $${K}_{1}$$ K 1 , $${k}_{3}$$ k 3 , $${f}_{A}$$ f A and $${K}_{i}$$ K i between HCC and ICC lesions. Further investigations of the effect of SUV measurements on the derived kinetic parameters were conducted. And results showed comparable effectiveness of the kinetic modeling using either SUVmean or SUVmax measurements. Conclusions Dynamic 18F-FDG PET imaging with optimization-derived hepatic artery blood supply fraction dual-blood input function kinetic modeling can effectively distinguish malignant lesions from healthy liver tissue, as well as HCC and ICC lesions.
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- 2021
44. The strength of cytomorphology and efficacy of immuno‐cytochemistry in distinguishing hepatocellular carcinoma from its mimics on fine‐needle aspiration cytology
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Neelaiah Siddaraju, Pampa Ch Toi, Mangesh Chikhale, and Ramesh Ananthakrishnan
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Adult ,Liver Cirrhosis ,Male ,Pathology ,medicine.medical_specialty ,Carcinoma, Hepatocellular ,Histology ,Adenoma ,Cytodiagnosis ,Biopsy, Fine-Needle ,030209 endocrinology & metabolism ,Adenocarcinoma ,Pathology and Forensic Medicine ,Metastasis ,Cholangiocarcinoma ,Diagnosis, Differential ,03 medical and health sciences ,0302 clinical medicine ,Cytology ,Biomarkers, Tumor ,medicine ,Humans ,Intrahepatic Cholangiocarcinoma ,Aged ,Aged, 80 and over ,medicine.diagnostic_test ,business.industry ,Liver Neoplasms ,General Medicine ,Middle Aged ,HCCS ,medicine.disease ,Immunohistochemistry ,digestive system diseases ,Cross-Sectional Studies ,Fine-needle aspiration ,030220 oncology & carcinogenesis ,Hepatocellular carcinoma ,Female ,business - Abstract
BACKGROUND Cytomorphologic distinction of hepatocellular carcinoma (HCC) from its mimics on fine-needle aspiration cytology (FNAC) is often problematic. The present study evaluates the strength of cytomorphology and the utility of an immuno-panel of arginase-1, glypican-3, HepPar-1, thyroid transcription factor (TTF-1) and CK-19 in resolving this diagnostic issue. METHODS FNAC features of 71 nodular hepatic lesions were studied with an immunocyto/ histochemical (ICC/IHC) panel of arginase-1, glypican-3, HepPar-1, TTF-1 taking 10% positivity as "cut-off." Cytomorpholologic diagnoses were compared with diagnoses made on combined cytomorphologic and ICC/IHC approach. RESULTS Of 71 cases, 32, 10 and 29 had histopathologic, cell block and clinico-radiologic correlation respectively with 55 metastatic adenocarcinomas (MAC), 13 HCCs and one case each of hepatic adenoma (HA), cirrhotic nodule (CN) and intrahepatic cholangiocarcinoma (CC). Cytoplasmic positivity of HepPar-1 and glypican-3 were noted in 11/13 and 8/13 HCCs respectively; while only 3/13 and 1/13 HCCs revealed cytoplasmic positivity for arginase-1 and TTF-1 respectively. Benign hepatic lesions were negative for glypican-3 and TTF-1, but expressed both arginase-1and HepPar-1. Twenty-one of 55 MACs and the lone case of CC were positive for CK-19; however, all MACs and CC cases were negative for HepPar-1, arginase-1, glypican-3 and TTF-1. The immune-panel had sensitivity, specificity and diagnostic accuracy of 100%, 88.9% and 90.6%, respectively, for differentiating HCC from its morphologic mimics. CONCLUSION Though a meticulous cytologic evaluation in conjunction with clinicoradiologic profile helps in distinguishing HCC from its benign and malignant mimics; an immunopanel of arginase-1, glypican-3, HepPar-1, TTF-1 and CK-19 drastically improves the diagnostic accuracy.
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- 2021
45. Lymphoepithelioma-like Intrahepatic Cholangiocarcinoma Is a Distinct Entity With Frequent pTERT/TP53 Mutations and Comprises 2 Subgroups Based on Epstein-Barr Virus Infection
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Jau-Yu Liau, Yung-Ming Jeng, Chia-Hsiang Lee, and Jia-Huei Tsai
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Adult ,Male ,Epstein-Barr Virus Infections ,Herpesvirus 4, Human ,IDH1 ,DNA Mutational Analysis ,Biology ,Pathology and Forensic Medicine ,Cholangiocarcinoma ,Pathogenesis ,hemic and lymphatic diseases ,Biomarkers, Tumor ,medicine ,Humans ,Telomerase ,Intrahepatic Cholangiocarcinoma ,Aged ,Lymphoepithelioma ,BAP1 ,medicine.diagnostic_test ,High-Throughput Nucleotide Sequencing ,Middle Aged ,medicine.disease ,Immunohistochemistry ,Molecular biology ,Bile Duct Neoplasms ,Mutation ,RNA, Viral ,Female ,Surgery ,Anatomy ,Tumor Suppressor p53-Binding Protein 1 ,Viral hepatitis ,Fluorescence in situ hybridization - Abstract
The molecular characteristics of lymphoepithelioma-like intrahepatic cholangiocarcinoma (LELCC) remain elusive. We examined 27 LELCC cases through next-generation sequencing using a panel of genes commonly mutated in primary liver cancers. Alterations in BAP1, ARID1A, ARID2, and PBRM1 were detected through immunohistochemistry. Fluorescence in situ hybridization was performed to analyze FGFR2 fusions and CCND1 amplification. LELCC is histologically classified as predominantly undifferentiated or glandular. Epstein-Barr virus-encoded small RNA (EBER) expression was found in 16 LELCCs. Approximately 50% of LELCCs expressed programmed death-ligand 1 strongly. Notably, recurrent pTERT and TP53 mutations were detected in 9 (38%) and 8 (33%) tumors, respectively. Only 2 LELCCs exhibited loss of expression for PBRM1. Alterations in genes typically involved in intrahepatic cholangiocarcinoma, including IDH1, IDH2, ARID1A, ARID2, and BAP1, and FGFR2 fusions, were not identified. The 2-step clustering analysis showed 2 distinct subgroups in LELCC, which were separated by EBER expression. A meta-analysis of all reported cases (n=85) has shown that EBER+ LELCC is strongly associated with the female sex, younger age, and exhibited predominantly glandular differentiation (P=0.001, 0.012, and
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- 2021
46. Prognostic impact of tumor microvessels in intrahepatic cholangiocarcinoma: association with tumor-infiltrating lymphocytes
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Tomoharu Yoshizumi, Kenichi Kohashi, Noboru Harada, Shinji Itoh, Kyohei Yugawa, Takeo Toshima, Yoshinao Oda, Norifumi Iseda, Takahiro Tomiyama, and Masaki Mori
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Adult ,Male ,0301 basic medicine ,Pathology ,medicine.medical_specialty ,CD34 ,Pathology and Forensic Medicine ,Metastasis ,Cholangiocarcinoma ,03 medical and health sciences ,Lymphocytes, Tumor-Infiltrating ,0302 clinical medicine ,Biomarkers, Tumor ,Tumor Microenvironment ,Humans ,Medicine ,Lymph node ,Intrahepatic Cholangiocarcinoma ,Aged ,Retrospective Studies ,Aged, 80 and over ,Tumor microenvironment ,Cluster of differentiation ,business.industry ,Tumor-infiltrating lymphocytes ,Middle Aged ,Prognosis ,medicine.disease ,Immunohistochemistry ,digestive system diseases ,030104 developmental biology ,medicine.anatomical_structure ,Bile Duct Neoplasms ,030220 oncology & carcinogenesis ,Microvessels ,cardiovascular system ,Female ,business ,Microvascular Density - Abstract
Tumor microvessel density (MVD) is a prognostic factor for patients with intrahepatic cholangiocarcinoma (ICC). Tumor-infiltrating lymphocytes (TILs) are also key components of the tumor microenvironment that play important roles in ICC progression. This study aimed to clarify the relationships between the MVD and immune status and prognosis in patients with ICC. Immunohistochemical staining for cluster of differentiation 34 (CD34), cluster of differentiation 8 (CD8), forkhead box protein P3 (Foxp3), and programmed death-ligand 1 (PD-L1) was performed. The relationships between the MVD and clinicopathological characteristics and outcomes were analyzed. Additionally, the correlations between the MVD, CD8+ and Foxp3+ TIL counts, and PD-L1 expression were evaluated. One hundred ICC patients were classified into high (n = 50) and low (n = 50) MVD groups. The serum platelet and carbohydrate antigen 19-9 levels were higher in the low MVD group than in the high MVD group (P = 0.017 and P = 0.008, respectively). The low MVD group showed a significantly larger tumor size (P = 0.016), more frequent microvascular invasion (P = 0.001), and a higher rate of intrahepatic (P = 0.023) and lymph node (P < 0.001) metastasis than the high MVD group. Moreover, the MVD showed a high positive correlation with CD8+ TILs (r = 0.754, P < 0.001) and a negative correlation with Foxp3+ TILs (r = -0.302, P = 0.003). In contrast, no significant correlation was observed between the MVD and PD-L1 expression in cancer cells (P = 0.817). Patients with low MVDs had a significantly worse prognosis than those with high MVDs. Furthermore, multivariable analyses revealed that a low MVD influenced recurrence-free survival. A decreased intratumoral MVD might predict ICC patient outcomes. Tumor microvessels might be associated with ICC progression, possibly by altering TIL recruitment.
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- 2021
47. Tumor Burden Dictates Prognosis Among Patients Undergoing Resection of Intrahepatic Cholangiocarcinoma
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Dimitrios Moris, J. Madison Hyer, Kazunari Sasaki, Timothy M. Pawlik, Alfredo Guglielmi, Todd W. Bauer, Anghela Z. Paredes, Diamantis I. Tsilimigras, Itaru Endo, Olivier Soubrane, Shishir K. Maithel, George A. Poultsides, Carlo Pulitano, Kota Sahara, Federico Aucejo, Hugo Marques, Luca Aldrighetti, Sorin Alexandrescu, Bas Groot Koerkamp, Guillaume Martel, Matthew J. Weiss, Xu-Feng Zhang, Feng Shen, Tsilimigras, Diamantis I, Hyer, J Madison, Paredes, Anghela Z, Moris, Dimitrio, Sahara, Kota, Guglielmi, Alfredo, Aldrighetti, Luca, Weiss, Matthew, Bauer, Todd W, Alexandrescu, Sorin, Poultsides, George A, Maithel, Shishir K, Marques, Hugo P, Martel, Guillaume, Pulitano, Carlo, Shen, Feng, Soubrane, Olivier, Koerkamp, Bas Groot, Endo, Itaru, Sasaki, Kazunari, Aucejo, Federico, Zhang, Xu-Feng, Pawlik, Timothy M, and Surgery
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medicine.medical_specialty ,Adjuvant chemotherapy ,medicine.medical_treatment ,030230 surgery ,Gastroenterology ,Resection ,Cholangiocarcinoma ,03 medical and health sciences ,0302 clinical medicine ,Chemothearpy ,Surgical oncology ,Internal medicine ,Medicine ,Hepatectomy ,Humans ,Chemotherapy ,Intrahepatic Cholangiocarcinoma ,Survival analysis ,Adjuvant ,Tumor ,business.industry ,medicine.disease ,Prognosis ,HCC CHBPT ,Tumor Burden ,Oncology ,Bile Duct Neoplasms ,Chemotherapy, Adjuvant ,030220 oncology & carcinogenesis ,Hepatocellular carcinoma ,Cohort ,Surgery ,business - Abstract
Introduction: While tumor burden (TB) has been associated with outcomes among patients with hepatocellular carcinoma, the role of overall TB in intrahepatic cholangiocarcinoma (ICC) remains poorly defined. Methods: Patients undergoing curative-intent resection of ICC between 2000 and 2017 were identified from a multi-institutional database. The impact of TB on overall (OS) and disease-free survival (DFS) was evaluated in the multi-institutional database and validated externally. Results: Among 1101 patients who underwent curative-intent resection of ICC, 624 (56.7%) had low TB, 346 (31.4%) medium TB, and 131 (11.9%) high TB. OS incrementally worsened with higher TB (5-year OS; low TB: 48.3% vs medium TB: 29.8% vs high TB: 17.3%, p < 0.001). Similarly, patients with low TB had better DFS compared with medium and high TB patients (5-year DFS: 38.3% vs 18.7% vs 6.9%, p < 0.001). On multivariable analysis, TB was independently associated with OS (medium TB: HR = 1.40, 95% CI 1.14-1.71; high TB: HR = 1.89, 95% CI 1.46-2.45) and DFS (medium TB, HR = 1.61, 95% CI 1.33-1.96; high TB: HR = 2.03, 95% CI 1.56-2.64). Survival analysis revealed an excellent prognostic discrimination using the TB among the external validation cohort (3-year OS; low TB: 44.8%, medium TB: 29.3%; high TB: 23.3%, p = 0.03; 3-year DFS: low TB: 32.7%, medium TB: 10.7%; high TB: 0%, p < 0.001). While neoadjuvant chemotherapy was not associated with survival across the TB groups, receipt of adjuvant chemotherapy was associated with increased survival among patients with high TB (5-year OS: 24.4% vs 13.4%, p = 0.02). Conclusion: Overall TB dictated prognosis among patients with resectable ICC. TB may be used as a tool to help guide post-resection treatment strategies. info:eu-repo/semantics/publishedVersion
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- 2021
48. Fibroblast growth factor receptor 2 (FGFR2) fusions in Japanese patients with intrahepatic cholangiocarcinoma
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Masanori Tsujie, Tomohisa Iwai, Shoji Kubo, Takashi Ura, Etsuro Hatano, Daisuke Sakai, Yutaka Takeda, Masaki Kaibori, Tomoe Kobayashi, Akio Katanuma, Yu Katayose, Koji Fukase, Naoki Sakurai, Yukiko Ito, Fumiya Sato, Atsuyuki Maeda, Masanori Asada, and Chigusa Morizane
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Adult ,Male ,Cancer Research ,Poor prognosis ,Oncogene Proteins, Fusion ,medicine.medical_treatment ,In situ hybridization ,Cholangiocarcinoma ,Gene Frequency ,Japan ,intrahepatic cholangiocarcinoma ,medicine ,Humans ,AcademicSubjects/MED00300 ,Radiology, Nuclear Medicine and imaging ,Genetic Predisposition to Disease ,Receptor, Fibroblast Growth Factor, Type 2 ,Intrahepatic Cholangiocarcinoma ,Genetic Association Studies ,In Situ Hybridization, Fluorescence ,Aged ,Aged, 80 and over ,Chemotherapy ,business.industry ,Fibroblast growth factor receptor 2 ,General Medicine ,Middle Aged ,medicine.disease ,Chemotherapy regimen ,Bile Ducts, Intrahepatic ,Oncology ,Bile Duct Neoplasms ,Fibroblast growth factor receptor ,break-apart fluorescent in situ hybridization ,Cancer research ,Adenocarcinoma ,Female ,Original Article ,FGFR2 fusions ,Neoplasm Recurrence, Local ,Erratum ,business - Abstract
Objective Fibroblast growth factor receptor gene alterations have emerged as promising drug targets for intrahepatic cholangiocarcinoma, a rare cancer that has a poor prognosis. This study evaluated the frequency of fibroblast growth factor receptor 2 fusions in clinical specimens from Japanese patients with iCCA. Methods This study enrolled 116 patients who had histologically or cytologically confirmed adenocarcinoma and been diagnosed as relapsing after resection or with unresectable intrahepatic cholangiocarcinoma. We evaluated the frequency of fibroblast growth factor receptor 2 fusions-positive cells in their specimens using break-apart fluorescent in situ hybridization ‘for 114 patients who met the study protocol’. Results Of a total of 114 cases, six (5.3%) were identified as fibroblast growth factor receptor 2 fusions-positive with a high frequency (87% or more) of fibroblast growth factor receptor 2 fusions-positive tumour cells whereas the remainder, with the exception of three cases with indeterminate results, were identified as fibroblast growth factor receptor 2 fusions-negative. The patients’ baseline characteristics as well as their objective response rates, disease control rates, times to progression, and times to treatment failure with previous or ongoing first-line chemotherapy did not have any obvious relationship to the proportion of fibroblast growth factor receptor 2 fusions-positive case. Conclusions Further detailed elucidation of fibroblast growth factor receptor 2 fusion status is expected to contribute to the development of promising therapeutic options for patients suffering from recurrent or unresectable intrahepatic cholangiocarcinoma., A multicenter study on the frequency of fibroblast growth factor receptor 2 fusions-positive tumour specimens in Japanese patients with recurrent or unresectable intrahepatic cholangiocarcinoma.
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- 2021
49. Differentiation of hepatocellular carcinoma from intrahepatic cholangiocarcinoma and combined hepatocellular-cholangiocarcinoma in high-risk patients matched to MR field strength: diagnostic performance of LI-RADS version 2018
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Yan Luo, Xianlun Zou, Daoyu Hu, John N. Morelli, Xuemei Hu, and Yaqi Shen
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medicine.medical_specialty ,High risk patients ,Radiological and Ultrasound Technology ,medicine.diagnostic_test ,Tumor size ,business.industry ,Urology ,Gastroenterology ,Magnetic resonance imaging ,Hepatology ,Malignancy ,medicine.disease ,digestive system diseases ,030218 nuclear medicine & medical imaging ,03 medical and health sciences ,0302 clinical medicine ,030220 oncology & carcinogenesis ,Internal medicine ,Hepatocellular carcinoma ,medicine ,Radiology, Nuclear Medicine and imaging ,business ,neoplasms ,Intrahepatic Cholangiocarcinoma - Abstract
To eliminate the effects of field strength in determining the diagnostic performance of the LI-RADS version 2018 (LI-RADS v2018) in differentiating hepatocellular carcinoma (HCC) from non-HCC primary liver malignancy in high-risk patients. Patients who were pathologically confirmed intrahepatic cholangiocarcinoma (iCCA) or combined hepatocellular-cholangiocarcinoma (cHCC-CCA) were retrospectively reviewed. Patients with HCC were matched to the iCCA or cHCC-CCA patients on age, tumor size, MR scanner, and number of tumors. Two readers independently evaluated the lesions according to LI-RADS v2018. Diagnostic performance of LI-RADS v2018 in differentiating HCC from non-HCC primary liver malignancy were analyzed. A total of 198 patients with 204 lesions (102 HCCs, 78 iCCAs, and 24 cHCC-CCAs) were enrolled. The sensitivity and specificity of LR-5 or LR-TIV (definitely due to HCC) in diagnosing HCC were 68.63% and 85.29%, respectively. LR-M or LR-TIV (may be due to non-HCC malignancy) had a sensitivity of 72.55% and a specificity of 86.27% in diagnosing non-HCC malignancy. The sensitivity of LR-M or LR-TIV (may be due to non-HCC malignancy) for iCCA and cHCC-CCA was 82.05% and 41.67%, respectively. Nearly half (11/24, 45.83%) of cHCC-CCAs were categorized as LR-5. Three tesla MR showed higher sensitivity than 1.5 T in diagnosing HCC (80.00% vs 57.69%, P = 0.015). When the effect of field strength was eliminated, LI-RADS v2018 demonstrated high specificity but suboptimal sensitivity in distinguishing HCC from non-HCC primary liver carcinomas. Most iCCAs were categorized as LR-M or LR-TIV (may be due to non-HCC malignancy). However, nearly half of cHCC-CCAs were assigned as LR-5.
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- 2021
50. Mutational spectrum and precision oncology for biliary tract carcinoma
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Yi Bai, Jianzhen Lin, Xiaoyue Wang, Xinting Sang, Xin Lu, Xu Yang, Henghui Zhang, Lei Zhang, Xueshuai Wan, Yang Shi, Guangyu Li, Haitao Zhao, Dongxu Wang, Jie Pan, Jinzhu Mao, Li Huo, Junyu Long, Yilei Mao, Yinghao Cao, Fucun Xie, Mei Guan, Ke Hu, Anqiang Wang, Yang Song, Kai Wang, Lin Zhao, and Xiaobo Yang
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0301 basic medicine ,Oncology ,Male ,ARID1A ,medicine.medical_treatment ,Medicine (miscellaneous) ,medicine.disease_cause ,Targeted therapy ,Cholangiocarcinoma ,0302 clinical medicine ,INDEL Mutation ,CDKN2A ,Medicine ,Molecular Targeted Therapy ,Pharmacology, Toxicology and Pharmaceutics (miscellaneous) ,Intrahepatic Cholangiocarcinoma ,education.field_of_study ,Genomics ,Middle Aged ,targeted therapy ,DNA-Binding Proteins ,030220 oncology & carcinogenesis ,molecular screening ,Female ,Gallbladder Neoplasms ,KRAS ,Research Paper ,medicine.medical_specialty ,DNA Copy Number Variations ,precision medicine ,Population ,Polymorphism, Single Nucleotide ,Proto-Oncogene Proteins p21(ras) ,03 medical and health sciences ,Germline mutation ,Internal medicine ,biliary tract cancer ,Exome Sequencing ,Humans ,Gallbladder cancer ,education ,Cyclin-Dependent Kinase Inhibitor p16 ,Aged ,Neoplasm Staging ,business.industry ,Carcinoma ,genomic alterations ,medicine.disease ,030104 developmental biology ,Bile Ducts, Intrahepatic ,Bile Duct Neoplasms ,Receptors, LDL ,Mutation ,Tumor Suppressor Protein p53 ,business ,Transcription Factors - Abstract
Background: The genomic spectrum of biliary tract carcinoma (BTC) has been characterized and is associated with distinct anatomic and etiologic subtypes, yet limited studies have linked genomic alterations with personalized therapies in BTC patients. Methods: This study analyzed 803 patients with BTC:164 with gallbladder cancer, 475 with intrahepatic cholangiocarcinoma (ICC) and 164 with extrahepatic cholangiocarcinoma. We determined genomic alterations, mutational signatures related to etiology and histopathology and prognostic biomarkers. Personalized targeted therapies for patients harboring potentially actionable targets (PATs) were investigated. Results: The median tumor mutation burden (TMB) was 1.23 Mut/Mb, with 4.1% of patients having hypermutated BTCs. Unlike the results obtained from the Western population, the most frequently altered cancer-related genes in our cohort included TP53 (53%), KRAS (26%), ARID1A (18%), LRP1B (14%) and CDKN2A (14%). Germline mutations occurred mostly in DNA damage repair genes. Notably, 35.8% of the ICCs harbored aristolochic acid related signatures and an elevated TMB. TP53 and KRAS mutations and amplified 7q31.2 were demonstrated to negatively affect patient prognosis. Moreover, 19 genes were proposed to be PATs in BTCs, with 25.4% of patients harboring these PATs. Forty-six patients received PAT-matched targeted therapies, achieving a 26.1% objective response rate; the median progression-free survival (PFS) was 5.0 months, with 56.8% of patients obtaining PFS benefits. Conclusions: Extensive genomic diversity and heterogeneity were observed among BTC patients, with contributions according to potential etiology exposures, anatomical subtypes and clinicopathological characteristics. We also demonstrated that patients with refractory BTCs who have PATs can derive considerable benefit from receiving a matched therapy, initiating further prospective clinical trials guided by molecular profiling among this aggressive cancer.
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- 2021
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