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Background: Failure of treatment with gemcitabine in most cholangiocarcinoma (CCA) patients is due to drug resistance. The therapeutic potential of natural plant secondary compounds with minimal toxicity, such as cannabidiol (CBD), is a promising line of investigation in gemcitabine-resistant CCA. We aim to investigate the effects of CBD on gemcitabine-resistant CCA (KKU-213BGemR) cells in vitro and in vivo. Materials: In vitro, cell proliferation, colony formation, apoptosis and cell cycle arrest were assessed using MTT assay, clonogenicity assay and flow cytometry. The effect of CBD on ROS production was evaluated using the DCFH-DA fluorescent probe. The mechanism exerted by CBD on ER stress-associated apoptosis was investigated by western blot analysis. A gemcitabine-resistant CCA xenograft model was also used and the expression of PCNA and CHOP were evaluated by immunohistochemical analysis. Results: The IC50 values of CBD for KKU-213BGemR cells ranged from 19.66 to 21.05 µM. For a non-cancerous immortalized fibroblast cell line, relevant values were 18.29 to 19.21 µM. CBD suppressed colony formation by KKU-213BGemR cells in a dose-dependent manner in the range of 10 to 30 µM. CBD at 30 µM significantly increased apoptosis at early (16.37%) (P = 0.0024) and late (1.8%) stages (P < 0.0001), for a total of 18.17% apoptosis (P = 0.0017), in part by increasing ROS production (P < 0.0001). Multiphase cell cycle arrest significantly increased at G0/G1 with CBD 10 and 20 µM (P = 0.004 and P = 0.017), and at G2/M with CBD 30 µM (P = 0.005). CBD treatment resulted in increased expression of ER stress-associated apoptosis proteins, including p-PERK, BiP, ATF4, CHOP, BAX, and cytochrome c. In xenografted mouse, CBD significantly suppressed tumors at 10 and 40 mg/kg·Bw (P = 0.0007 and P = 0.0278, respectively), which was supported by an increase in CHOP, but a decrease in PCNA expression in tumor tissues (P < 0.0001). Conclusion: The results suggest that CBD exhibits potent anti-cancer activity against gemcitabine-resistant CCA in vitro and in vivo, in part via ER stress-mediated mechanisms. These results indicate that clinical explorative use of CBD on gemcitabine-resistant CCA patients is warranted. [ABSTRACT FROM AUTHOR]

Background: There is a paucity of evidence supporting the use of adjuvant radiation therapy in resected biliary cancer. Supporting evidence for use comes mainly from the small SWOG S0809 trial, which demonstrated an overall median survival of 35 months. We aimed to use a large national database to evaluate the use of adjuvant chemoradiation in resected extrahepatic bile duct and gallbladder cancer. Methods: Using the National Cancer Database, we selected patients from 2004 to 2017 with pT2-4, pN0-1, M0 extrahepatic bile duct or gallbladder adenocarcinoma with either R0 or R1 resection margins, and examined factors associated with overall survival (OS). We examined OS in a cohort of patients mimicking the SWOG S0809 protocol as a large validation cohort. Lastly, we compared patients who received chemotherapy only with patients who received adjuvant chemotherapy and radiation using entropy balancing propensity score matching. Results: Overall, 4997 patients with gallbladder or extrahepatic bile duct adenocarcinoma with available survival information meeting the SWOG S0809 criteria were selected, 469 of whom received both adjuvant chemotherapy and radiotherapy. Median OS in patients undergoing chemoradiation was 36.9 months, and was not different between primary sites (p = 0.841). In a propensity score matched cohort, receipt of adjuvant chemoradiation had a survival benefit compared with adjuvant chemotherapy only (hazard ratio 0.86, 95% confidence interval 0.77–0.95; p = 0.004). Conclusion: Using a large national database, we support the findings of SWOG S0809 with a similar median OS in patients receiving chemoradiation. These data further support the consideration of adjuvant multimodal therapy in resected biliary cancers. [ABSTRACT FROM AUTHOR]

Simple Summary: The prognosis of intrahepatic cholangiocarcinoma (ICC) depends on tumor biology, morphology, and the high rates of late diagnosis and recurrence after curative-intent surgery, with high heterogeneity. Understanding the molecular landscape of ICC and its clinical implications for treatment and prognosis remains a major challenge. Several attempts have been made to classify molecular ICC subtypes, but they have produced heterogeneous results and need a clear clinical definition. This systematic review examined the evidence for the multi-omics-based classification of ICC to assess its clinical and prognostic significance. Molecular analysis of ICC can assist in decision-making by identifying patients who are suitable for targeted pre- and postoperative chemotherapy. Identifying clinical characteristics associated with specific ICC clusters resulting from multi-omics analysis could help tailor patient management. However, there are logistical, technical, and therapeutic challenges in the routine application of ICC molecular characterization. Identifying clinical characteristics commonly found in specific ICC clusters can help define high-risk ICC subtypes quickly and assist in selecting patients who may benefit the most from molecular profiling in the disease's earlier stages. Intrahepatic cholangiocarcinoma (ICC) is a heterogeneous disease characterized by a dismal prognosis. Various attempts have been made to classify ICC subtypes with varying prognoses, but a consensus has yet to be reached. This systematic review aims to gather relevant data on the multi-omics-based ICC classification. The PubMed, Embase, and Cochrane databases were searched for terms related to ICC and multi-omics analysis. Studies that identified multi-omics-derived ICC subtypes and investigated clinicopathological predictors of long-term outcomes were included. Nine studies, which included 910 patients, were considered eligible. Mean 3- and 5-year overall survival were 25.7% and 19.6%, respectively, for the multi-omics subtypes related to poor prognosis, while they were 70.2% and 63.3%, respectively, for the subtypes linked to a better prognosis. Several negative prognostic factors were identified, such as genes' expression profile promoting inflammation, mutations in the KRAS gene, advanced tumor stage, and elevated levels of oncological markers. The subtype with worse clinicopathological characteristics was associated with worse survival (Ref.: good prognosis subtype; pooled hazard ratio 2.06, 95%CI 1.67–2.53). Several attempts have been made to classify molecular ICC subtypes, but they have yielded heterogeneous results and need a clear clinical definition. More efforts are required to build a comprehensive classification system that includes both molecular and clinical characteristics before implementation in clinical practice to facilitate decision-making and select patients who may benefit the most from comprehensive molecular profiling in the disease's earlier stages. [ABSTRACT FROM AUTHOR]

The only curative treatment option for cholangiocarcinoma is surgery, making the assessment of operability a crucial step in the diagnosis. We report a case of distal common bile duct cancer in a 64-year-old male, who exhibited multiple pulmonary nodules in pre-operative chest imaging following a COVID-19 infection. As the local progression of disease was not prominent, the possibility of pulmonary metastasis was considered unlikely. A surgical biopsy was performed, which confirmed the diagnosis of pulmonary cryptococcosis. [ABSTRACT FROM AUTHOR]

Abstract Background Failure of treatment with gemcitabine in most cholangiocarcinoma (CCA) patients is due to drug resistance. The therapeutic potential of natural plant secondary compounds with minimal toxicity, such as cannabidiol (CBD), is a promising line of investigation in gemcitabine-resistant CCA. We aim to investigate the effects of CBD on gemcitabine-resistant CCA (KKU-213BGemR) cells in vitro and in vivo. Materials In vitro, cell proliferation, colony formation, apoptosis and cell cycle arrest were assessed using MTT assay, clonogenicity assay and flow cytometry. The effect of CBD on ROS production was evaluated using the DCFH-DA fluorescent probe. The mechanism exerted by CBD on ER stress-associated apoptosis was investigated by western blot analysis. A gemcitabine-resistant CCA xenograft model was also used and the expression of PCNA and CHOP were evaluated by immunohistochemical analysis. Results The IC50 values of CBD for KKU-213BGemR cells ranged from 19.66 to 21.05 µM. For a non-cancerous immortalized fibroblast cell line, relevant values were 18.29 to 19.21 µM. CBD suppressed colony formation by KKU-213BGemR cells in a dose-dependent manner in the range of 10 to 30 µM. CBD at 30 µM significantly increased apoptosis at early (16.37%) ( P = 0.0024) and late (1.8%) stages (P

Abstract Background To assess the outcome of previously untreated patients with perihilar cholangiocarcinoma who present to a cancer referral center with or without pre-existing trans-papillary biliary drainage. Methods Consecutive patients with a diagnosis of perihilar cholangiocarcinoma presenting between January 1, 2013, and December 31, 2017, were identified from a prospective surgical database and by a query of the institutional database. Of 237 patients identified, 106 met inclusion criteria and were reviewed. Clinical information was obtained from the Electronic Medical Record and imaging studies were reviewed in the Picture Archiving and Communication System. Results 73 of 106 patients (69%) presenting with a new diagnosis of perihilar cholangiocarcinoma underwent trans-papillary biliary drainage (65 endoscopic and 8 percutaneous) prior to presentation at our institution. 8 of the 73 patients with trans-papillary biliary drainage (11%) presented with and 5 developed cholangitis; all 13 (18%) required subsequent intervention; none of the patients without trans-papillary biliary drainage presented with or required drainage for cholangitis (p = 0.008). Requiring drainage for cholangitis was more likely to delay treatment (p = 0.012) and portended a poorer median overall survival (13.6 months, 95%CI [4.08, not reached)] vs. 20.6 months, 95%CI [18.34, 37.51] p = 0.043). Conclusion Trans-papillary biliary drainage for perihilar cholangiocarcinoma carries a risk of cholangitis and should be avoided when possible. Clinical and imaging findings of perihilar cholangiocarcinoma should prompt evaluation at a cancer referral center before any intervention. This would mitigate development of cholangitis necessitating additional drainage procedures, delaying treatment and potentially compromising survival.

Introduction: The peribiliary gland is an accessory bile duct gland. Hyperplasia of these tissues may lead to elevation of the mucosa in the bile ducts and bile duct stenosis. We herein report a case of peribiliary gland hyperplasia that required preoperative differentiation from bile duct cancer, with a discussion of the literature. Case Presentation: The patient had an adenomatous lesion in the ascending colon that was difficult to treat endoscopically; therefore, surgery was planned. Preoperative abdominal ultrasonography revealed a bile duct tumor, and endoscopic ultrasonography revealed a mass lesion around the confluence of the cystic duct. Computed tomography revealed localized wall thickening in the middle bile duct, and the upstream bile ducts were slightly dilated. In addition, continuous thickening of the bile duct wall from the gallbladder to the confluence of the cystic duct was observed. No distant metastases, such as liver metastases, or nearby enlarged lymph nodes were observed. Endoscopic retrograde cholangiopancreatography and magnetic resonance cholangiopancreatography revealed a papillary-like elevated lesion in the bile duct near the confluence of the cystic duct, and a biopsy and bile cytology from the same area showed no malignant findings. As a result, the possibility that the patient had gallbladder or bile duct cancer could not be ruled out; therefore, a policy of surgery together with the ascending colon tumor was decided after receiving sufficient informed consent. During surgery, the patient underwent extrahepatic bile duct resection, reconstruction of the biliary tract using the Roux-en-Y method, and right hemicolectomy. Both duodenal and hilar bile duct transects were subjected to a fast frozen section analysis during surgery, and the results were negative for cancer. A histopathological examination of the resected specimen revealed no malignant findings in the bile duct lesions, and a diagnosis of peribiliary gland hyperplasia with chronic inflammatory cell infiltration and fibrosis of the extrahepatic bile duct wall was made. Conclusions: We encountered a case of peribiliary gland hyperplasia that was difficult to distinguish from bile duct cancer.

Background: To assess the outcome of previously untreated patients with perihilar cholangiocarcinoma who present to a cancer referral center with or without pre-existing trans-papillary biliary drainage. Methods: Consecutive patients with a diagnosis of perihilar cholangiocarcinoma presenting between January 1, 2013, and December 31, 2017, were identified from a prospective surgical database and by a query of the institutional database. Of 237 patients identified, 106 met inclusion criteria and were reviewed. Clinical information was obtained from the Electronic Medical Record and imaging studies were reviewed in the Picture Archiving and Communication System. Results: 73 of 106 patients (69%) presenting with a new diagnosis of perihilar cholangiocarcinoma underwent trans-papillary biliary drainage (65 endoscopic and 8 percutaneous) prior to presentation at our institution. 8 of the 73 patients with trans-papillary biliary drainage (11%) presented with and 5 developed cholangitis; all 13 (18%) required subsequent intervention; none of the patients without trans-papillary biliary drainage presented with or required drainage for cholangitis (p = 0.008). Requiring drainage for cholangitis was more likely to delay treatment (p = 0.012) and portended a poorer median overall survival (13.6 months, 95%CI [4.08, not reached)] vs. 20.6 months, 95%CI [18.34, 37.51] p = 0.043). Conclusion: Trans-papillary biliary drainage for perihilar cholangiocarcinoma carries a risk of cholangitis and should be avoided when possible. Clinical and imaging findings of perihilar cholangiocarcinoma should prompt evaluation at a cancer referral center before any intervention. This would mitigate development of cholangitis necessitating additional drainage procedures, delaying treatment and potentially compromising survival. [ABSTRACT FROM AUTHOR]

Cholangiocarcinoma is a group of diverse invasive malignancies arising along the biliary tract. The outcomes for patients with cholangiocarcinoma remain poor but an understanding of molecular aberrations and subsequent targeted therapies to these have opened up new treatment prospects. This review describes the clinical and morphological features and classifications of intrahepatic and perihilar cholangiocarcinoma in addition to laying out the related landscape of the molecular pathology within cholangiocarcinoma. The importance of both a high index of suspicion of cholangiocarcinoma and preserving tissue whilst reporting to access molecular testing and personalised treatment pathways is emphasised. [ABSTRACT FROM AUTHOR]

Spindle and giant cell type undifferentiated carcinoma of the extrahepatic bile duct is an uncommon malignancy. We report a case involving the common bile duct in a 72-year-old male with jaundice who was admitted to our hospital. Diagnostic imaging, including abdominal computed tomography and magnetic resonance imaging, revealed a mass in the distal common bile duct, accompanied by dilatation of both intra- and extrahepatic bile ducts and regional lymph node enlargement. Endoscopic retrograde cholangiography demonstrated stenosis in the distal common bile duct, with a biopsy confirming adenocarcinoma. The patient underwent endoscopic retrograde biliary drainage followed by a subtotal stomach-preserving pancreaticoduodenectomy with regional lymphadenectomy. Microscopic examination revealed that the tumor predominantly comprised spindle and giant atypical cells within the stroma. Immunohistochemical analysis showed the tumor cells expressing cytokeratins and mesenchymal markers, confirming the diagnosis of spindle and giant cell type undifferentiated carcinoma of the common bile duct. Ki-67 labeling index was observed to be above 80%. Postoperatively, intra-abdominal lymph node recurrence was noted at two months, and multiple liver metastases were identified at three months. The patient died seven months post-surgery. The literature pertaining to this rare disease is reviewed and discussed. [ABSTRACT FROM AUTHOR]

In the current research, kaolin-decorated Au nanoparticles were produced by a green medication method by using Strawberry root’s extract as a natural coating and reducing component for capping and stabilizing Au NPs over the kaolin. The Au NPs/kaolin material was thoroughly characterized using XRD, FE-SEM, EDX-elemental mapping, TEM, and ICP. Characterization data confirmed the well-supporting of Au NPs over the kaolin. TEM images displayed the spherical shaped gold nanoparticles averaging 20–40 nm in size over the kaolin surface. The cytotoxicity and anti-bile duct cancer properties of Au NPs/kaolin were investigated through the utilization of MTT assay on three bile duct cancer cell lines, namely OCUCHLM1, EGI1, and GBCSD. Au nanoparticles (Au NPs) combined with kaolin exhibited dose-dependent anti-bile duct cancer properties and significantly reduced cell viability in OCUCHLM1, EGI1, and GBCSD cell lines. Importantly, these effects were observed without causing any cytotoxicity in the normal cell line (HUVECs). The OCUCHLM1 cell line exhibited the most significant anti-bile duct cancer effects when treated with Au NPs/kaolin, surpassing the results observed in other cell lines. Upon the successful validation of the aforementioned findings in the clinical trial investigations, Au NPs/kaolin could potentially serve as an effective chemotherapeutic agent in combating bile duct cancer.

The term cholangiocarcinoma (CCA) defines a class of epithelial malignancies originating from bile ducts. Although it has been demonstrated that CCA patients with perineural invasion (PNI) have a worse prognosis, the biological features of this phenomenon are yet unclear. Our data show that in human intrahepatic CCA specimens with documented PNI, nerve-infiltrating CCA cells display positivity of the epithelial marker cytokeratin 7, lower with respect to the rest of the tumor mass. In an in vitro 3D model, CCA cells move towards a peripheral nerve explant allowing contact with Schwann cells (SCs) emerging from the nerve. Here, we show that SCs produce soluble factors that favor the migration, invasion, survival and proliferation of CCA cells in vitro. This effect is accompanied by a cadherin switch, suggestive of an epithelial–mesenchymal transition. The influence of SCs in promoting the ability of CCA cells to migrate and invade the extracellular matrix is hampered by a specific TGFβ receptor 1 (TGFBR1) antagonist. Differential proteomic data indicate that the exposure of CCA cells to SC secreted factors induces the upregulation of key oncogenes and the concomitant downregulation of some tumor suppressors. Taken together, these data concur in identifying SCs as possible promoters of a more aggressive CCA phenotype, ascribing a central role to TGFβ signaling in regulating this process. [ABSTRACT FROM AUTHOR]

Background: The risk and prognosis of pancreatobiliary cancer and in patients with autoimmune pancreatitis (AIP) and IgG4‐related sclerosing cholangitis (IgG4‐SC) remain unclear. Therefore, we retrospectively investigated the risk of pancreatobiliary cancer and prognosis in patients with AIP and IgG4‐SC. Methods: Patients with AIP and IgG4‐SC at seven centers between 1998 and 2022 were investigated. The following data were evaluated: (1) the number of cancers diagnosed and standardized incidence ratio (SIR) for pancreatobiliary and other cancers during the observational period and (2) prognosis after diagnosis of AIP and IgG4‐SC using standardized mortality ratio (SMR). Results: This study included 201 patients with AIP and IgG4‐SC. The mean follow‐up period was 5.7 years. Seven cases of pancreatic cancer were diagnosed, and the SIR was 8.11 (95% confidence interval [CI]: 7.29–9.13). Three cases of bile duct cancer were diagnosed, and the SIR was 6.89 (95% CI: 6.20–7.75). The SMR after the diagnosis of AIP and IgG4‐SC in cases that developed pancreatobiliary cancer were 4.03 (95% CI: 2.83–6.99). Conclusions: Patients with autoimmune pancreatitis and IgG4‐SC were associated with a high risk of pancreatic and bile duct cancer. Patients with AIP and IgG4‐SC have a worse prognosis when they develop pancreatobiliary cancer. [ABSTRACT FROM AUTHOR]