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Pathology Jun 2024Hepatocyte nuclear factors (HNF) 6 and 4α are master transcriptional regulators of development and maintenance of the liver and pancreaticobiliary tract in mice and...
HNF6 and HNF4α expression in adenocarcinomas of the liver, pancreaticobiliary tract, and gastrointestinal tract: an immunohistochemical study of 480 adenocarcinomas of the digestive system.
Hepatocyte nuclear factors (HNF) 6 and 4α are master transcriptional regulators of development and maintenance of the liver and pancreaticobiliary tract in mice and humans. However, little is known about the prevalence of HNF6 and HNF4α expression in carcinomas of the hepatobiliary tract and pancreas. We aimed to reveal the diagnostic utility of HNF6 and HNF4α immunolabelling in adenocarcinomas of these organs. We investigated HNF6 and HNF4α expression by immunohistochemistry using a total of 480 adenocarcinomas of the digestive system, including 282 of the hepatobiliary tract and pancreas and 198 of the gastrointestinal tract. HNF6 expression was primarily restricted to intrahepatic cholangiocarcinomas (CCs) (63%, n=80) and gallbladder adenocarcinomas (43%, n=88), among others. Notably, small duct intrahepatic CCs almost invariably expressed HNF6 (90%, n=42), showing stark contrast to a low prevalence in large duct intrahepatic CCs (10%, n=21; p<0.0001). HNF6 expression was infrequent in extrahepatic CCs (9%, n=55) and pancreatic ductal adenocarcinomas (7%, n=58), and it was rare in adenocarcinomas of the gastrointestinal tract [oesophagus/oesophagogastric junction (EGJ) (2%, n=45), stomach (2%, n=86), duodenum (0%, n=25), and colorectum (0%, n=42)]. In contrast, HNF4α was widely expressed among adenocarcinomas of the digestive system, including intrahepatic CCs (88%), extrahepatic CCs (94%), adenocarcinomas of the gallbladder (98%), pancreas (98%), oesophagus/EGJ (96%), stomach (98%), duodenum (80%), and colorectum (100%). HNF6 was frequently expressed in and almost restricted to intrahepatic CCs of small duct type and gallbladder adenocarcinomas, while HNF4α was expressed throughout adenocarcinomas of the digestive system. HNF6 immunolabelling may be useful in distinguishing small duct intrahepatic CCs from other types of CC as well as metastatic gastrointestinal adenocarcinomas.
PubMed: 38926048
DOI: 10.1016/j.pathol.2024.03.010 -
Anticancer Research Jul 2024Genomic examination of tumor tissue has been clinically accepted, and the identification of actionable mutations for molecular-targeted therapy may provide substantial...
BACKGROUND/AIM
Genomic examination of tumor tissue has been clinically accepted, and the identification of actionable mutations for molecular-targeted therapy may provide substantial survival benefit for patients with advanced malignancies.
CASE REPORT
A female patient in her 60s showed a stenosis of the afferent loop of the small intestine because of circumferential metastatic tumor 14 months after curative surgery for hilar cholangiocarcinoma. Chemotherapy with gemcitabine plus cisplatin was administered for 18 months. An oncopanel examination was performed during chemotherapy, and a high tumor mutation burden was revealed. At 38 months after surgery, a new recurrent tumor, 2.7 cm in size, was observed in the abdominal wall, which was histologically proven to be metastatic adenocarcinoma. Atezolizumab was administered. After three cycles of treatment, treatment was switched to pembrolizumab because of its acceptance by healthcare insurance. The recurrent tumors in the abdominal wall and small intestine disappeared 6 months after the administration of immune checkpoint inhibitor, and the patient has continued pembrolizumab, surviving for 76 months after surgery without any clinical evidence of tumor.
CONCLUSION
Immune checkpoint blockade successfully prolonged the survival of a patient with advanced hilar cholangiocarcinoma with high tumor mutation burden, although the optimal number of mutations for such a successful response needs to be clarified.
Topics: Humans; Female; Mutation; Immune Checkpoint Inhibitors; Bile Duct Neoplasms; Cholangiocarcinoma; Middle Aged; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Treatment Outcome
PubMed: 38925819
DOI: 10.21873/anticanres.17135 -
Clinics and Research in Hepatology and... Jun 2024Experimental hepatopulmonary syndrome (HPS) is best reproduced in the rat common bile duct ligation (CBDL) model. Vildagliptin (Vild) is an anti-hyperglycemic drug that...
INTRODUCTION
Experimental hepatopulmonary syndrome (HPS) is best reproduced in the rat common bile duct ligation (CBDL) model. Vildagliptin (Vild) is an anti-hyperglycemic drug that exerts beneficial anti-inflammatory, anti-oxidant and anti-fibrotic effects. Therefore, the present search aimed to explore the possible effectiveness of Vild in CBDL-induced HPS model.
METHODS
Four groups of male Wistar rats which weigh 220-270 g were used, including the normal control group, the sham control group, the CBDL group and CBDL+Vild group. The first three groups received i.p. saline, while the last group was treated with i.p. Vild (10 mg/kg/day) from the 15th to 28th day of the experiment.
RESULTS
CBDL decreased the survivability and body weight of rats, increased diameter of the pulmonary vessels, and altered the arterial blood gases and the liver function parameters. Additionally, it increased the pulmonary expressions of endothelin-1 (ET-1) and tumor necrosis factor-α (TNF-α) mRNA as well as endothelial nitric oxide synthase (eNOS), inducible nitric oxide synthase (iNOS) and vascular endothelial growth factor-A (VEGF-A) proteins. The CBDL rats also exhibited elevation of the pulmonary interleukin-6 (IL-6), dipeptidyl peptidase-4 (DPP-4) and nitric oxide (NO) levels along with reduction of the pulmonary total anti-oxidant capacity and glucagon-like peptide-1 (GLP-1) levels. Vild mitigated these alterations and improved the histopathological abnormalities caused by CBDL.
CONCLUSION
Vild effectively attenuated CBDL-induced HPS through its anti-oxidant and anti-inflammatory effects along with its modulatory effects on ET-1/NOS/NO and TNF-α/IL-6/VEGF-A signaling implicated in the regulation of intrapulmonary vasodilatation and angiogenesis, respectively.
PubMed: 38925324
DOI: 10.1016/j.clinre.2024.102408 -
Liver International : Official Journal... Jun 2024Intrahepatic cholangiocarcinoma (iCCA) has two main histological subtypes: large and small duct-type iCCA, which are characterized by different clinicopathological...
BACKGROUND & AIMS
Intrahepatic cholangiocarcinoma (iCCA) has two main histological subtypes: large and small duct-type iCCA, which are characterized by different clinicopathological features. This study was conducted with the purpose of expanding our understanding of their differences in molecular features and immune microenvironment.
METHODS
We selected 132 patients who underwent radical surgery at our department between 2015 and 2021 for clinical and survival analyses. Whole-exome sequencing was performed to analyse mutational landscapes. Bulk RNA sequencing and single-cell RNA sequencing data were used for pathway enrichment and immune infiltration analyses based on differentially expressed genes. The function of PPP1R1B was analysed both in vitro and in vivo and the gene mechanism was further investigated.
RESULTS
We found that large duct-type iCCA had worse overall survival and recurrence-free survival rates than small duct-type iCCA. Mutations in ARID1A, DOT1L and ELF3 usually occur in large duct-type iCCA, whereas mutations in IDH1 and BAP1 occur in small duct-type iCCA. Among the differentially expressed genes, we found that PPP1R1B was highly expressed in large duct-type iCCA tumour tissues. Expression of PPP1R1B promoted cell proliferation, migration and invasion and indicated a worse prognosis. A combination of USF2 with the promoter of PPP1R1B can enhance gene expression in iCCA, which may further affect the expression of genes such as AHNAK, C4BPA and activating the PI3K/AKT pathway.
CONCLUSIONS
Our findings extend our understanding of large and small duct-type iCCA. In addition, PPP1R1B may serve as a potential marker and therapeutic target for large duct-type iCCA.
PubMed: 38924592
DOI: 10.1111/liv.16015 -
PloS One 2024Cholangiocarcinoma (CCA) is an aggressive cancer originating from bile duct epithelium, particularly prevalent in Asian countries with liver fluke infections. Current...
Cholangiocarcinoma (CCA) is an aggressive cancer originating from bile duct epithelium, particularly prevalent in Asian countries with liver fluke infections. Current chemotherapy for CCA often fails due to drug resistance, necessitating novel anticancer agents. This study investigates the potential of 5'-deoxy-5'-methylthioadenosine (MTA), a naturally occurring nucleoside, against CCA. While MTA has shown promise against various cancers, its effects on CCA remain unexplored. We evaluated MTA's anticancer activity in CCA cell lines and drug-resistant sub-lines, assessing cell viability, migration, invasion, and apoptosis. The potential anticancer mechanisms of MTA were explored through proteomic analysis using LC-MS/MS and bioinformatic analysis. The results show a dose-dependent reduction in CCA cell viability, with enhanced effects on cancer cells compared to normal cells. Moreover, MTA inhibits growth, induces apoptosis, and suppresses cell migration and invasion. Additionally, MTA enhanced the anticancer effects of gemcitabine on drug-resistant CCA cells. Proteomics revealed the down-regulation of multiple proteins by MTA, affecting various molecular functions, biological processes, and cellular components. Network analysis highlighted MTA's role in inhibiting proteins related to mitochondrial function and energy derivation, crucial for cell growth and survival. Additionally, MTA suppressed proteins involved in cell morphology and cytoskeleton organization, important for cancer cell motility and metastasis. Six candidate genes, including ZNF860, KLC1, GRAMD1C, MAMSTR, TANC1, and TTC13, were selected from the top 10 most down-regulated proteins identified in the proteomics results and were subsequently verified through RT-qPCR. Further, KLC1 protein suppression by MTA treatment was confirmed through Western blotting. Additionally, based on TCGA data, KLC1 mRNA was found to be upregulated in the tissue of CCA patients compared to that of normal adjacent tissues. In summary, MTA shows promising anticancer potential against CCA by inhibiting growth, inducing apoptosis, and suppressing migration and invasion, while enhancing gemcitabine's effects. Proteomic analysis elucidates possible molecular mechanisms underlying MTA's anticancer activity, laying the groundwork for future research and development of MTA as a treatment for advanced CCA.
Topics: Cholangiocarcinoma; Humans; Proteomics; Cell Line, Tumor; Deoxyadenosines; Bile Duct Neoplasms; Apoptosis; Cell Movement; Thionucleosides; Antineoplastic Agents; Gemcitabine; Deoxycytidine; Cell Survival; Cell Proliferation; Drug Resistance, Neoplasm
PubMed: 38923999
DOI: 10.1371/journal.pone.0306060 -
Journal of Magnetic Resonance Imaging :... Jun 2024Regional lymph node metastasis (LNM) assessment is crucial for predicting intrahepatic cholangiocarcinoma (iCCA) prognosis. However, imaging assessment has limitations...
BACKGROUND
Regional lymph node metastasis (LNM) assessment is crucial for predicting intrahepatic cholangiocarcinoma (iCCA) prognosis. However, imaging assessment has limitations for identifying LNM.
PURPOSE
To investigate the association between MRI radiomics features, regional LNM status, and prognosis in iCCA.
STUDY TYPE
Retrospective.
SUBJECTS
Two hundred ninety-six patients (male = 197) with surgically confirmed iCCA.
FIELD STRENGTH/SEQUENCE
1.5 T and 3.0 T. DWI, T2WI, and contrast-enhanced T1WI.
ASSESSMENT
Clinical information, radiologic, and MRI-based radiomics features associated with LNM status were collected to establish models. Performance of MRI, PET/CT, and the combined LNM models were compared in training (N = 207) and test (N = 89) datasets. Overall survival (OS) was compared based on LNM status.
STATISTICAL TESTS
The independent features were selected by 5-fold cross-validation. The performance of MRI, PET/CT, and the models was evaluated using the area under receiver operating characteristic curve (AUC). Univariable and multivariable Cox regression were used to identify independent variables for OS. Kaplan-Meier curves were compared with the log-rank test between LNM positive and negative groups. P < 0.05 was considered statistically significant.
RESULTS
Intrahepatic duct dilatation, enhancement pattern, and CA19-9 were independent clinicoradiologic features. The radiomics model was constructed by the independent radiomics features extracted from T2WI and delay phase T1WI. The combined LNM model showed AUC of 0.888, 0.884, and 0.811 in training, validation, and test cohorts with a positive net benefit. PET/CT exhibited similar sensitivity to the combined LNM model (0.750 vs. 0.733, P > 0.999) while the combined LNM model showed higher specificity (0.703 vs. 0.630, P = 0.039) in the test cohort. High risk of regional LNM was significantly associated with worse OS (median: 24 months) than low risk (median: 30 months, P < 0.0001).
DATA CONCLUSIONS
The combined LNM model has the strongest correlation with LNM status for mass-forming iCCA patients.
EVIDENCE LEVEL
3 TECHNICAL EFFICACY: Stage 2.
PubMed: 38923735
DOI: 10.1002/jmri.29477 -
Digestive Endoscopy : Official Journal... Jun 2024This study assessed factors influencing the complete removal and recurrence of bile duct stones in patients with surgically altered anatomy (SAA) undergoing...
Factors affecting complete stone removal and bile duct stone recurrence in patients with surgically altered anatomy treated by double-balloon endoscopy-assisted endoscopic retrograde cholangiography.
OBJECTIVES
This study assessed factors influencing the complete removal and recurrence of bile duct stones in patients with surgically altered anatomy (SAA) undergoing double-balloon endoscopy-assisted endoscopic retrograde cholangiography (DBERC).
METHODS
A retrospective analysis of 289 patients with SAA treated for biliary stones with DBERC at Jichi Medical University Hospital (January 2007 to December 2022) was conducted. Evaluation of factors impacting complete stone removal was performed in 257 patients with successful bile duct cannulation. Logistic and Cox proportional hazards regression models were used to compute the odds ratios (ORs) and hazard ratios (HRs) at 95% confidence intervals (CIs).
RESULTS
Of 257 patients, 139 (54.0%) and 209 (81.3%) achieved initial and complete removal, respectively. Recurrence occurred in 55 (21.4%) patients. Factors associated with initial complete stone removal included cholangitis (P < 0.01, OR 0.48, 95% CI 0.27-0.83), number of stones (P < 0.01, OR 0.31, 95% CI 0.18-0.54), and largest stone diameter (P < 0.01, OR 0.37, 95% CI 0.20-0.67). The size of the largest stone was associated with complete removal (P = 0.01, OR 0.24, 95% CI 0.13-0.76). Recurrence was associated with cholangitis (P = 0.046, HR 0.54, 95% CI 0.29-0.99), congenital biliary dilatation (P = 0.01, HR 2.65, 95% CI 1.21-5.80), and number of stones (P = 0.02, HR 1.96, 95% CI 1.12-3.41).
CONCLUSIONS
Successful complete bile stone removal in patients with SAA depends on the stone diameter and number. Stone recurrence is influenced by the number of stones and history of congenital biliary dilatation.
PubMed: 38923022
DOI: 10.1111/den.14824 -
The Journal of Pathology Jun 2024DICER1 syndrome is a tumor predisposition syndrome caused by familial genetic mutations in DICER1. Pathogenic variants of DICER1 have been discovered in many rare...
DICER1 syndrome is a tumor predisposition syndrome caused by familial genetic mutations in DICER1. Pathogenic variants of DICER1 have been discovered in many rare cancers, including cystic liver tumors. However, the molecular mechanisms underlying liver lesions induced by these variants remain unclear. In the present study, we sought to gain a better understanding of the pathogenesis of these variants by generating a mouse model of liver-specific DICER1 syndrome. The mouse model developed bile duct hyperplasia with fibrosis, similar to congenital hepatic fibrosis, as well as cystic liver tumors resembling those in Caroli's syndrome, intrahepatic cholangiocarcinoma, and hepatocellular carcinoma. Interestingly, the mouse model of DICER1 syndrome showed abnormal formation of primary cilia in the bile duct epithelium, which is a known cause of bile duct hyperplasia and cyst formation. These results indicated that DICER1 mutations contribute to cystic liver tumors by inducing defective primary cilia. The mouse model generated in this study will be useful for elucidating the potential mechanisms of tumorigenesis induced by DICER1 variants and for obtaining a comprehensive understanding of DICER1 syndrome. © 2024 The Pathological Society of Great Britain and Ireland.
PubMed: 38922876
DOI: 10.1002/path.6320 -
Veterinary Sciences Jun 2024Platelet-derived growth factor B (PDGFB), as an important cellular growth factor, is widely involved in the regulation of cellular events such as cell growth,...
Platelet-derived growth factor B (PDGFB), as an important cellular growth factor, is widely involved in the regulation of cellular events such as cell growth, proliferation, and differentiation. Although important, the expression characteristics and biological functions in the mammalian reproductive system remain poorly understood. In this study, the PDGFB gene of Tibetan sheep was cloned by RT-PCR, and its molecular characteristics were analyzed. Subsequently, the expression of the PDGFB gene in the testes and epididymides (caput, corpus, and cauda) of Tibetan sheep at different developmental stages (3 months, 1 year, and 3 years) was examined by qRT-PCR and immunofluorescence staining. A bioinformatic analysis of the cloned sequences revealed that the CDS region of the Tibetan sheep PDGFB gene is 726 bp in length and encodes 241 amino acids with high homology to other mammals, particularly goats and antelopes. With the increase in age, PDGFB expression showed an overall trend of first decreasing and then increasing in the testis and epididymis tissues of Tibetan sheep, and the PDGFB mRNA expression at 3 months of age was extremely significantly higher than that at 1 and 3 years of age ( < 0.05). The PDGFB protein is mainly distributed in testicular red blood cells and Leydig cells in Tibetan sheep at all stages of development, as well as red blood cells in the blood vessel, principal cells, and the pseudostratified columnar ciliated epithelial cells of each epididymal duct epithelium. In addition, PDGFB protein expression was also detected in the spermatocytes of the 3-month-old group, spermatids of the 1-year-old group, spermatozoa and interstitial cells of the 3-year-old group, and loose connective tissue in the epididymal duct space in each developmental period. The above results suggest that the PDGFB gene, as an evolutionarily conserved gene, may play multiple roles in the development and functional maintenance of testicular cells (such as red blood cells, Leydig cells, and germ cells) and epididymal cells (such as red blood cells, principal cells, and ciliated epithelial cells) during testicular and epididymal development, which lays a foundation for the further exploration of the mechanisms by which the PDGFB gene influences spermatogenesis in Tibetan sheep.
PubMed: 38922013
DOI: 10.3390/vetsci11060266 -
Frontiers in Endocrinology 2024Clinically, the diagnosis and treatment of cholangiocarcinoma are generally different according to the location of occurrence, and the studies rarely consider the...
BACKGROUND
Clinically, the diagnosis and treatment of cholangiocarcinoma are generally different according to the location of occurrence, and the studies rarely consider the differences between different pathological types. Cholangiocarcinomas in large- and middle-sized intrahepatic bile ducts are mostly mucinous, while in small sized bile duct are not; mucinous extrahepatic cholangiocarcinomas are also more common than mucinous intrahepatic cholangiocarcinoma. However, it is unclear whether these pathological type differences are related to the prognosis.
METHODS
Data of total 22509 patients was analyzed from Surveillance, Epidemiology, and End Results program database out of which 22299 patients were diagnosed with common adeno cholangiocarcinoma while 210 were diagnosed with mucinous cholangiocarcinoma. Based on the propensity score matching (PSM) analysis, between these two groups' clinical, demographic, and therapeutic features were contrasted. The data were analyzed using Cox and LASSO regression analysis and Kaplan-Meier survival curves. Ultimately, overall survival (OS) and cancer specific survival (CSS) related prognostic models were established and validated in test and external datasets and nomograms were created to forecast these patients' prognosis.
RESULTS
There was no difference in prognosis between mucinous cholangiocarcinoma and adeno cholangiocarcinoma. Therefore, we constructed prognostic model and nomogram that can be used for mucinous and adeno cholangiocarcinoma at the same time. By comparing the 9 independent key characteristics i.e. Age, tumor size, the number of primary tumors, AJCC stage, Grade, lymph node status, metastasis, surgery and chemotherapy, risk scores were calculated for each individual. By integrating these two pathological types in OS and CSS prognostic models, effective prognosis prediction results could be achieved in multiple datasets (OS: AUC 0.70-0.87; CSS: AUC 0.74-0.89).
CONCLUSION
Age, tumor size, the number of primary tumors, AJCC stage, Grade, lymph node status, metastasis, surgery and chemotherapy are the independent prognostic factors in OS or CSS of the patients with mucinous and ordinary cholangiocarcinoma. Nomogram that can be used for mucinous and adeno cholangiocarcinoma at the same time is of significance in clinical practice and management of cholangiocarcinoma.
Topics: Humans; Male; Cholangiocarcinoma; Female; Prognosis; Middle Aged; Bile Duct Neoplasms; Retrospective Studies; Nomograms; Aged; SEER Program; Adult
PubMed: 38919485
DOI: 10.3389/fendo.2024.1284283