The growing interest in post-translational protein modification, particularly in SUMOylation, is driven by its crucial role in cell cycle regulation. SUMOylation affects various cell cycle regulators, including oncogenes, suggesting its relevance in cancer. SUMO E3 ligases are pivotal in this process, exhibiting diverse functionalities through structural domains and subcellular localizations. A less-explored SUMO E3 ligase, RANBP2, a component of the vertebrate nuclear pore complex, emerges as a central player in cellular cycle processes, as well as in tumorigenesis. The current studies illuminate the importance of RANBP2 and underscore the need for more extensive studies to validate its clinical applicability in neoplastic interventions. Our review elucidates the significance of RANBP2 across various types of malignancies. Additionally, it delves into exploring RANBP2 as a prospective therapeutic target for cancer treatment, offering insights into the avenues that scholars should pursue in their subsequent research endeavors. Thus, further investigation into RANBP2's role in solid tumorigenesis is eagerly awaited.

Capsaicin (CAPS), a bioactive alkaloid derived from chili peppers, has garnered significant interest for its potential role as a combinatorial and chemosensitizing agent in cancer therapy. Numerous preclinical studies have demonstrated that CAPS enhanced the efficacy of various anticancer agents by promoting apoptosis, modulating autophagy and inhibiting angiogenesis, tumor growth, and metastasis. Additionally, CAPS modulated critical regulators of chemoresistance, such as P-glycoprotein (P-gp), extracellular signal-regulated kinase (ERK), nuclear factor-kappa B (NF-κB) pathway, and signal transducer and activator of transcription 3 (STAT3) pathway, thereby contributing to the reversal of multidrug resistance (MDR). Moreover, when administered in combination with chemotherapeutic agents, CAPS has been shown to improve treatment efficacy at lower drug concentrations. Given its multitargeted mechanism of action, CAPS represents a promising adjunct to conventional cancer therapies. However, due to its lipophilic nature, the development of optimized formulation strategies is essential to enhance its bioavailability and ensure consistent therapeutic outcomes. In conclusion, CAPS holds significant potential as a combinatorial and chemosensitizing agent, helping to overcome chemoresistance and enhance treatment outcomes across various malignancies. These promising findings warrant further preclinical and clinical investigations.

In this retrospective study, we evaluated the diagnostic value of [18F]FDG PET/CT in preoperative assessment of extrahepatic cholangiocarcinoma (ECC) and to develop a PET-based diagnostic algorithm for ECC.Patients with suspected ECC with biliary obstruction were included. Patients received [18F]FDG PET/CT scan and image analysis. FDG uptake was semi-quantified using the SUVmax of the suspected primary tumor, lymph nodes and metastatic lesions. Sex, age, tumor location, enhancement patterns and tumor size were analyzed using binary logistic regression for prediction of ECC on PET images.The study included 238 ECC patients and 42 patients with benign diseases. The lesion was located in the common bile duct in 67.50% patients and in the hilar region in 31.79% patients. [18F]FDG PET/CT scan showed a sensitivity of 70.6% and a specificity of 76.2% for the diagnosis of cholangiocarcinoma in patients with extrahepatic lesions, with a positive predictive value of 94.4% and a negative predictive value of 31.4% and an accuracy of 71.4%. Forced entry logistic regression analysis showed that age (OR 1.07, 95%CI, 1.03 to 1.10) and detection of ECC by [18F]FDG PET/CT scan (OR 6.15, 95% CI, 2.00 to 19.10) were predictors of ECC. A PET-based scoring algorithm had an AUC of 0.81 (95% CI, 0.75 to 0.88) and had a sensitivity of 61.3% and a specificity of 88.1% for ECC. The algorithm had a significantly better diagnostic performance than [18F]FDG PET/CT scan (Chi square test, P <0.001).The PET-based algorithm shows improved diagnostic performance for the detection of ECC and could facilitate early diagnosis and staging of ECC.

Resection of perihilar cholangiocarcinoma (pCCA) is associated with significant perioperative morbidity and mortality. We sought to evaluate surgical outcomes following resection of pCCA over time.

Patients who underwent curative-intent resection with hepatectomy for pCCA at a single institution were divided into two cohorts based on date of resection: past cohort (1996-2013), and recent cohort (2014-2023).

The study included 100 patients: 55 (55%) in the past (1996-2013) and 45 (45%) in the recent (2014-2023) cohorts. There were no differences between cohorts in age, sex, or Bismuth-Corlette classification between the two cohorts. Preoperative cholangitis was less common in the recent cohort (31% vs. 53%, p = 0.03). The proportions of right and left hepatectomies were similar in both cohorts. However, for patients with Bismuth-Corlette types I, II, and IV tumors (n = 35), left hepatectomy was more frequently performed in the recent cohort (61% vs. 13%, p = 0.005). There were trends toward lower rates of major complications (38% vs. 55%, p = 0.095) in the recent cohort. There was significantly less perioperative mortality (2% vs. 15%, p = 0.039) and no postoperative hepatic insufficiency in the recent cohort (0% vs. 20%, p = 0.001). Median recurrence-free survival was similar in the past and recent cohorts (29 vs. 37 months, respectively; p = 0.560), but median overall survival was improved in the recent cohort (33 months vs. not reached, p = 0.009).

Perioperative management to reduce preoperative cholangitis and liver insufficiency, advances in surgical technique, and consideration of left-sided hepatic resection have resulted in significantly improved outcomes in patients undergoing hepatectomy for pCCA.

Solid-tubulocystic variant of intrahepatic cholangiocarcinoma (ST-iCCA) is newly described entity characterized by two distinct histologic growth patterns: (1) solid sheets of tumor cells with focal necrosis giving pseudopapillary appearance and (2) tubular or pseudoglandular structures containing pink, colloid-like material. Tumor cells are inhibin-positive and harbor NIPBL::NACC1 fusion gene. To date, only 28 cases of ST-iCCA have been documented. While prior molecular studies provided insights into ST-iCCA, genetic profiles of individual histologic components have not been explored. This study presents first transcriptomic analysis comparing the solid/pseudopapillary and pseudoglandular components of ST-iCCA. Two cases of histologically confirmed ST-iCCA were identified for RNA sequencing which was performed on solid/pseudopapillary component, pseudoglandular component, and normal tissue. Analysis revealed distinct gene expression profiles for each pattern. Solid/pseudopapillary component uniquely overexpressed DMRTA1, NEXMIF, PRDM6, SORCS3, and NALF, while pseudoglandular component exhibited unique overexpression of HRG, ITIH3, TAT, APOA2, CP, ALDOB, CPS1, F2, KHG1, SERPINC1, HPX, C9, ADGRF1, MUC21, SAA2, SPRR2A, SAA1, FGL1, CFHR1, and LBP. These findings establish unique gene signatures for these variants of ST-iCCA, providing potential biomarkers for differential diagnosis, prognosis and targeted therapy. The distinct genetic profiles may also uncover novel therapeutic targets to address the aggressive nature of ST-iCCA.

Inflammatory markers such as C-reactive protein (CRP) and interleukin-6 (IL-6) are often elevated in liver cancer, making it difficult to monitor for bacterial infection. Hence, it is tempting to use more bacterial-specific sepsis markers such as procalcitonin (PCT) during immunosuppressive chemotherapy. This case study highlights the challenges of interpreting clinical chemistry sepsis biomarkers in patients with advanced cholangiocarcinoma (CCA).

A 55-year-old man presented with a liver mass on routine ultrasonography. MRI and CT showed multiple liver and bone metastases. The immunohistochemistry findings were consistent with an adenocarcinoma of the pancreaticobiliary system. After the diagnosis of primary hepatic CCA (NTM stage IV; FGFR2-SHROOM3 translocation) and 14 months of chemotherapy, the patient developed progressive liver lesions and new lung metastases.

During the last chemotherapy, PCT was highly elevated (>100 ng/mL), usually observed in severe sepsis or septic shock, whereas CRP was moderately elevated (<50 mg/L). The patient had mild leukopenia but no fever, systemic infection or septic shock. Blood and urine cultures were negative.

After referral to best supportive care, the patient died of liver failure. Retrospective blood analysis revealed high levels of soluble CD14 subtype, a bacterial sepsis marker known as presepsin. Calcitonin and IL-6 levels were above normal, consistent with advanced CCA, but not with a PCT/calcitonin-secreting tumor or systemic inflammation.

Oncologists are aware that CRP and IL-6 values can be elevated in liver cancer. Here, we further demonstrate that highly elevated, septic shock-like PCT values can occur even in the absence of bacterial sepsis. In addition, presepsin may be elevated, although mechanistically unrelated to PCT. Therefore, sepsis markers should be interpreted with caution and in the clinical context, not only in patients with neuroendocrine or hepatocellular carcinoma, which are known to secrete PCT and calcitonin, but also in patients with advanced CCA.

The standard regimen of gemcitabine combined with cisplatin offers limited clinical benefits in the treatment of advanced intrahepatic cholangiocarcinoma (ICC) due to intrinsic or acquired resistance. Currently, effective biomarkers to predict and improve chemotherapy resistance in ICC are lacking. Here, it is reported that a long non-coding RNA (lncRNA), PAX8-AS1, reduces the efficacy of standard chemotherapeutic drugs. Mechanistically, PAX8-AS1 activates NRF2 by binding to p62, thereby promoting GPX4 transcription, and stabilizes GPX4 mRNA through interaction with IGF2BP3. The PAX8-AS1/GPX4 axis inhibits ferroptosis and promotes resistance to gemcitabine and cisplatin. In preclinical models, the combination of the GPX4 inhibitor JKE-1674 with gemcitabine and cisplatin exhibits superior antitumor efficacy. These findings suggest a promising therapeutic strategy to improve chemotherapy efficacy in advanced ICC.

Cholangiocarcinoma (CCA) has a low survival rate of 5-17%, despite advancements in diagnosis and treatment. Liver function impacts disease prognosis, and the albumin-bilirubin (ALBI) score is a new assessment model for this purpose. While research suggests a correlation between ALBI score, liver failure and mortality in intrahepatic CCA (iCCA), predicting outcomes for extrahepatic CCA (eCCA) is challenging. Our objective was to assess the prognostic role of ALBI grade in predicting overall survival of eCCA patients.

Patients with diagnosis of eCCA who had visited Firuzgar Hospital from 2015 to 2019 were consecutively included in the study. These individuals had previously undergone Endoscopic Ultrasound-Guided Fine Needle Aspiration (EUS-FNA) or ERCP brush cytology followed by surgery. Exclusion criteria were patients with benign bile duct strictures, prior biliary tract surgery, concurrent liver disease impacting liver tests, inadequate data, or inconsistent monitoring. Clinical data of patients were collected to calculate ALBI score which was subsequently divided into three distinct grades (grade 1: ≤-2.60, grade 2: > -2.60 to ≤ - 1.39, grade 3: >-1.39). Kaplan-Meier analysis and Cox regression model were used to analyze overall survival, 1-, 3- and 5-year survival and parameters affecting patient survival.

In this study, 80 patients with diagnosis of eCCA with a median age of 67 (58.25-74) years (67.5% male) who visited Firuzgar Hospital from 2015 to 2019 were included. The average survival time of patients was 13.9 ± 16.4 months, and the 1-year, 3-year, and 5-year survival rates of patients were 36.6%, 27.1%, and 15.8%, respectively. The results showed that ALBI grade, Aspartate Aminotransferase (AST), white blood cell (WBC) and international normalized ratio (INR) have significant effects on the survival of patients (all P < 0.05). Based on the results of Cox regression, the risk of mortality due to CCA in patients with ALBI grade 3 (HR = 1.87, P = 0.0111), AST > 82.5 (HR = 1.90, P = 0.0091), WBC > 7.70 × 109/L (HR = 2.46, P = 0.0004), and INR > 1.08 (HR = 1.78, P = 0.0202) increases significantly.

We showed that ALBI grade, AST > 82.5 units/L, and INR > 1.08 can be used as predictive factors of survival in cholangiocarcinoma patients.

Cholangiocarcinoma (CCA), a neoplasm arising from biliary epithelial cells, is particularly widespread in Southeast Asia, with northeastern Thailand exhibiting the greatest prevalence attributed to Opisthorchis viverrini infection. This malignancy exhibits considerable molecular heterogeneity, leading to therapeutic resistance and recurrence. Comprehending its molecular mechanisms is essential for enhancing diagnostic and treatment approaches. Our research utilized multi-region LC-MS/MS proteomic analysis to investigate intratumor heterogeneity (ITH) in CCA. We examined 52 tumor areas and 13 neighboring tissues from 13 patients, concentrating on protein profiling, pathway analysis, differential protein expression, and the identification of shared and unique protein signatures. The findings indicated considerable inter-patient proteome variability, characterized by markedly distinct protein expressions among individuals, aligning with prior cancer research. Intra-tumor heterogeneity was apparent, with merely 18 proteins common to all tumor areas and patients, underscoring the intricacy of CCA. Significantly, the common proteins were associated with metabolic reprogramming and oxidative stress pathways, indicating possible indicators and therapeutic targets. This work highlights the significant proteome variability in CCA at both intra-tumor and inter-patient levels, underscoring the necessity for customized therapeutic approaches to tackle the disease's complexity and improve treatment outcomes.

Biliary brushing cytology during endoscopic retrograde cholangiopancreatography (ERCP) is used to assess the nature of a biliary stricture. Its low sensitivity challenges exclusion of malignancy through this technique. The aim was to evaluate the diagnostic yield of brush cytology in biliary strictures and to identify predictive factors associated with a positive diagnosis of malignancy.

Observational retrospective study in a tertiary center. All adult patients undergoing a biliary brushing during ERPC from 2016 to 2022 were included. Logistic regression analyses were performed to identify predictive factors for positive brush cytology.

A total of 5309 patients underwent ERCP within the evaluated period. Out of these, biliary brushing was performed in 518 patients including 568 cytology samples, 57.7% (299) were men, median age 74 (64-84) years old. There were 24% (126) benign strictures and 76% (392) malignant of which the most common etiology were pancreatic cancer 42.5% (220/518), followed by cholangiocarcinoma 22.6% (117/518). The sensitivity, specificity, positive predictive value, and negative predictive value were 48%, 98%, 98% and 37%, respectively. Sensitivity was 45% and 52% in pancreatic adenocarcinoma and cholangiocarcinoma, respectively. Older age (OR 1.02, 95% CI: 1.01-1.03, p=0.01) and higher bilirubin (OR 1.05, 95% CI: 1.03-1.08, p<0.001) were independent predictors for brush cytology positivity. There were 9.7% (45/518) post-ERCP complications.

Biliary brushing cytology during ERCP is a safe procedure with low sensitivity but high specificity. Older age and higher bilirubin are associated to positive biliary cytology.

Gallbladder and biliary tract cancer (GBTC) presents a worldwide health challenge with a poor prognosis. Previous studies indicated an escalating burden and potential health inequalities, necessitating an updated investigation.

This study utilized data from the Global Burden of Disease (GBD) study, covering 204 countries from 1990 to 2021. Joinpoint regression evaluated temporal trends in age-standardized incidence rates (ASIR) and age-standardized disability-adjusted life years rates (ASDR) for GBTC. The Bayesian age-period-cohort (BAPC) model projected disease burden up to 2050. Inequality analysis assessed disparities by genders across countries, and decomposition analysis determined the contributions of demographic and epidemiological factors.

From 1990 to 2021, the incident cases of GBTC increased from 107,797 to 216,768, while Disability-Adjusted Life Years (DALYs) rose from 2,326,089 years to 3,732,121. Joinpoint regression analysis revealed a global decrease in ASIR (AAPC = -0.39, 95% CI: -0.49 to -0.28) and ASDR (AAPC = -0.97, 95% CI: -1.07 to -0.88). Gender disparities were notable, with a polar reversal observed: females exhibited consistently higher ASDR levels across three decades, although both ASDR and ASIR showed continuous decreases. In contrast, males experienced a decreased ASDR but increased ASIR, with both metrics eventually surpassing those of females. The projection model also suggested diverging ASIR trends between genders. Cross-country inequality analysis revealed persistent disparities, where higher SDI countries continue to bear a greater burden, and global improvement in health equity for males remains insufficient. Decomposition analysis indicated that population growth and ageing were primary drivers of disease burden increase, whereas epidemiological changes contributed to a reduction, particularly in higher SDI quintiles.

Despite improvements, GBTC burden is still greater in high SDI regions compared to lower SDI areas, contrary to expectations. Unexpected polar reversal of gender differences warrants further attention.

Long-term prognosis after resection for intrahepatic cholangiocarcinoma (iCCA) remains poor and the preoperative oncological risk assessment is difficult. Two immune system-related plasma proteins, colony stimulating factor 1 (CSF1) and TNF-related apoptosis-inducing ligand (TRAIL), were previously indicated as prognostic factors in iCCA. This study aimed to externally validate CSF1 and TRAIL as preoperative prognostic markers for patients with resectable iCCA.

Preoperative plasma CSF1 and TRAIL concentrations (pg/mL) were determined from prospectively collected biobank samples by multiplex immunoanalysis, for patients with resectable iCCA operated at two tertiary referral centers. Primary outcome was overall survival (OS), analyzed by Kaplan-Meier method and Cox regression. Secondary outcome was disease-free survival (DFS). Discrimination was evaluated with concordance indices (C-index) and prognostic performance assessed with calibration curves.

Sixty-one patients with resection for iCCA were included. CSF1 was associated with both OS (hazard ratio [HR] 1.03, 95 % confidence interval [CI] 1.01-1.05) and DFS (HR 1.02, 95 % CI 1.00-1.04). Median OS was eight months for patients with CSF1 levels in the upper quartile (≥158 pg/mL), compared to the overall median OS of 47 months. While TRAIL was not significantly associated with OS (P = 0.216), levels in the lower quartile (≤256 pg/mL) were associated with short DFS (P = 0.004). The C-index of CSF1 for OS was 0.70, with excellent calibration for three- and five-year OS.

Preoperative plasma CSF1 was validated as a novel, well-calibrated predictor of poor survival in resectable iCCA, which could assist the preoperative risk assessment. Low plasma TRAIL was associated with early recurrence.

Recent studies indicate a potential link between female reproductive factors and the risk of biliary tract cancer (BTC). However, this association remains controversial due to conflicting results, highlighting the need for further investigation into hormonal influences on BTC development.

We conducted a nationwide cohort study using data from the Korean National Health Insurance System, following 1059,533 menopausal women aged 40-69 years (median follow-up: 9.3 years). Cox proportional hazards regression was applied to assess the risk of cholangiocarcinoma (CCA) and gallbladder cancer (GBC) in relation to reproductive factors, particularly premature menopause (before age 40) and total reproductive period (time from menarche to menopause). The primary outcome was the incidence of BTC, specifically CCA and GBC.

During 9.87 million person-years of follow-up, 4198 women (0.40 %) were diagnosed with BTC. Premature menopause was associated with a significant increase in risk for both CCA (adjusted HR 1.29, 95 % CI: 1.01-1.64) and GBC (adjusted HR 1.42, 95 % CI: 1.03-1.97). A shorter total reproductive period (<30 years) was associated with a higher risk of BTC, with an adjusted HR of 1.10 (95 % CI: 0.99-1.21) for CCA and 1.15 (95 % CI: 1.01-1.33) for GBC. Other female reproductive factors assessed showed no significant associations.

Premature menopause is associated with an increased risk of BTC, suggesting reduced lifetime exposure to female hormones as a risk factor. These results highlight the importance of considering reproductive history in identifying high-risk women and may inform targeted screening strategies for early detection.

To evaluate the safety and efficacy of 125I seed strand combined with percutaneous transhepatic biliary drainage (PTBD) and hepatic arterial infusion chemotherapy (HAIC) for unresectable Bismuth-Corlette III and IV stage hilar cholangiocarcinoma (HCCA).

From January 2018 to December 2021, a total of 128 Bismuth-Corlette III and IV stage HCCA patients with obstructive jaundice were included in this single-center retrospective study. Forty-eight patients underwent 125I seed strand combined with PTBD and HAIC (group A). The mean intended dose (r = 10 mm; z = 0; 240 days) in group A was 63.8 ± 0.6 Gy. Eighty cases underwent PTBD plus HAIC (group B). Median overall survival (OS) and median bile duct patency time (BDPT) were compared between the two groups.

In the propensity-score matched (PSM) cohort, the median OS and median BDPT were significantly longer in group A than in group B (44 PSM pairs; OS, 13.6 ± 0.4 vs. 8.7 ± 1.4 months, p < 0.001; BDPT, 12.1 ± 0.5 vs. 6.4 ± 0.7 months, p < 0.001). Multivariate analysis revealed that the treatment regimen was an independent prognostic factor of OS. There were no serious complications related to 125I seed strand implantation.

125I seed strand combined with PTBD and HAIC for unresectable Bismuth-Corlette III and IV stage HCCA is safe and effective.

Intrahepatic cholangiocarcinoma (ICC) is a highly invasive liver tumor with a poor prognosis, arises from the intrahepatic bile ducts. It is the second most common type of liver cancer. Understanding the mechanisms driving ICC progression is crucial for identification of biomarkers and therapeutic targets. Galectin-1 (Gal-1), encoded by the LGALS1 gene, is known to be upregulated in various malignancies and plays a significant role in cancer progression. However, its underlying mechanisms in ICC have yet to be fully elucidated. The study employed RNA-seq analysis, western blot, cell migration, colony forming, EdU assay, qRT-PCR, luciferase assay and mIHC to investigate the expression pattern of Gal-1 in ICC and its role in the progression of the disease. Our findings revealed a significant upregulation of Gal-1 in ICC tissues. Notably, downregulation of Gal-1inhibited ICC cell proliferation and migration. Further, Gal-1 appears to promote ICC progression through miR-21/STAT3-related pathways, playing a critical role to the tumor microenvironment. These results suggest that Gal-1 may serve as a promising molecular diagnostic marker and therapeutic target for ICC.

Cholangiocarcinoma is a common hepatic malignant tumor with an unfavorable prognosis. Therefore, we systematically evaluated the transcriptomic landscape of CHOL by whole transcriptome sequencing technology in this study and constructed a ceRNA network associated with CHOL.

First, whole transcriptome sequencing between the tumor tissues of CHOL and adjacent cancer tissues adjacent to the tumors from six patients with CHOL was performed. Then, a differential expression analysis between the CHOL group and adjacent cancer group was performed to screen significant markers. Subsequently, target gene predictive analysis and co-expression analysis were implemented to construct a ceRNA and protein-protein interaction network in CHOL, and enrichment analysis was performed to investigate gene-related molecular pathways.

The results showed that there were 761 differentially expressed mRNAs, 47 differentially expressed miRNAs, 61 differentially expressed lncRNAs, and 1481 differentially expressed circRNAs in the adjacent cancer group compared with the CHOL group, respectively. Enrichment analysis of differentially expressed mRNAs showed that the PI3K-Akt, calcium, and MAPK signaling pathways were significantly enriched. Hsa-miR-196b-5p can be a sponge to adsorb lncRNA H19 and 101 downregulated mRNAs, constructing an lncRNA-miRNA-mRNA network. Hsa_circ_0025636, hsa_circ_0057335, hsa-miR-96-5p, and hsa-miR-196b-5p were involved in the circRNA-miRNA-mRNA network. Moreover, five core genes were obtained through PPI interaction analysis, which also played an important role in the ceRNA network.

This study systematically presents a transcriptomic landscape of CHOL and identifies lncRNA/circRNA-associated ceRNA networks that could provide insights for future treatment and prognosis of CHOL, laying a certain foundation for the study of molecular mechanisms and providing novel ideas for its prognosis and treatment.

Intrahepatic cholangiocarcinoma (iCCA) is the second most prevalent primary liver cancer, and there are limited treatment options when resection is not eligible. Systemic chemotherapy (SYS) offers modest survival benefits, highlighting the need for more effective approaches. This study aimed to evaluate and compare hepatic arterial infusion chemotherapy (HAIC) with SYS in patients with unresectable iCCA in terms of efficacy and safety.

A propensity score-matched analysis was conducted on 111 patients with unresectable iCCA from March 2019 to October 2023. The cohort comprised 37 HAIC-treated and 74 SYS-treated patients. The primary endpoint was overall survival (OS), while the secondary endpoints included progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR), and adverse events (AEs).

The HAIC group demonstrated comparable survival outcomes to those of the SYS group, with a median OS of 23.7 and 19.3 months [hazard ratio (HR) =0.84, 95% confidence interval (CI): 0.53-1.35; P=0.487] and median PFS of 10.7 vs. 10.3 months (HR =0.75, 95% CI: 0.46-1.22; P=0.246), respectively. However, HAIC showed superior tumor control, achieving a significantly higher ORR (35.13% vs. 12.16%, P<0.05) and DCR (83.78% vs. 64.86%, P<0.05) as compared to SYS. Safety analysis revealed markedly lower grade 3-4 AEs in the HAIC group.

This study demonstrated that HAIC can achieve comparable survival outcomes with superior local tumor control and reduced systemic toxicity as compared to SYS, suggesting its potential as an alternative treatment option for select patients.

Cholangiocarcinoma is characterized by its high malignancy, frequent recurrence and insensitivity to conventional radiotherapy and chemotherapy. This resistance may be associated with the presence of cells in the G0/G1 arrest phase within the cancer. Cancer cells in the G0/G1 phase are resistant to therapies targeting actively dividing cells, allowing them to evade conventional adjuvant treatments and survive. When conditions become favorable, these quiescent cells can re-enter the cell cycle, proliferate and potentially contribute to cancer recurrence. However, the biomarkers for identifying cells in the G0/G1 arrest phase within cholangiocarcinoma and the molecular mechanisms inducing G0/G1 arrest remain unclear. In our study, we first identified APOC1 as a characteristic gene for G0/G1 phase arrest in cholangiocarcinoma through bulk RNA sequencing (bulkRNA-seq). We then used single-cell RNA sequencing(scRNA-seq) for cell cycle inference and localized the expression peaks of APOC1 to verify its active cell cycle phase. Our experiments demonstrated that APOC1 can induce G0/G1 phase arrest in cholangiocarcinoma cells by inhibiting the Wnt/β-catenin signaling pathway, thereby suppressing cell proliferation, migration and invasion. This suggests that APOC1 may serve as a key regulatory factor and an important biomarker for cells in the G0/G1 phase of cholangiocarcinoma.

Futibatinib is a small, potent, covalent, irreversible fibroblast growth factor receptor (FGFR) 1-4 inhibitor that has been added as a new standard of care for previously treated unresectable and/or advanced FGFR2 fusion/rearrangement-positive BTC. FGFR2 fusions/rearrangements play a key role in BTC survival, proliferation, invasion, and development of distant metastasis. The inhibition of this pathway is an important target in the treatment of BTC.

The article covers the development of futibatinib for the treatment of refractory unresectable/advanced BTC, its mechanism of action, and key pharmacodynamic/pharmacokinetic data with a focus on the safety profile. Data are based on published clinical trials, pooled analysis, and retrospective studies indexed in PubMed (2010-2024).

Futibatinib is an FDA and EMA approved FGFR2 inhibitor for the treatment of patients with refractory BTC with FGFR2 fusions/rearrangements. Ongoing drug development strategies are centered on designing new FGFR2 fusion inhibitors able to overcome on-target and off-target resistances coupled with a high target selectivity to spare the most common treatment-related adverse events (hyperphosphatemia, stomatitis, alopecia, nail toxicity, skin reactions, eye toxicity).

In this study, we explored the potential of histone deacetylase (HDAC) inhibitors, with a focus on Vorinostat, to restore the functionality of invariant natural killer T (iNKT) cells-a unique subset of T cells with potent anti-tumor activity that are often impaired within the tumor microenvironment. Using aggressive cholangiocarcinoma (CCA) cell lines lacking CD1d molecules, we observed a marked decline in iNKT cell reactivity within 48 h of exposure to CCA cells. Through a systematic approach that included the utilization of the L1000FWD search engine, Vorinostat emerged as a promising candidate for mitigating iNKT cell dysfunction. Vorinostat induced significant molecular alterations in iNKT-nonresponsive CCA cells, enhancing CD1d expression, the production of inflammatory cytokines and the activation of T cell receptor (TCR) signaling pathways. These changes effectively reactivated iNKT cells and restored their anti-tumor functionality. In the mouse xenograft model, combined treatment with Vorinostat significantly inhibited tumor growth. These findings suggest that Vorinostat may offer a novel therapeutic strategy for patients with cholangiocarcinoma who are resistant to conventional chemotherapy.

Compared to peripheral blood, bile as a microenvironment within the biliary tract is expected to contain a higher concentration of tumor-associated factors secreted directly by primary biliary tumors, making it a promising source for tumor analysis. This study explores the diagnostic and prognostic utility of exosomal miR-21-5p in bile and serum for biliary tract cancers (BTCs).

miR-21-5p expression was analyzed in 110 bile samples (55 BTC, 55 controls) collected during endoscopic retrograde cholangiopancreatography using qRT-PCR. The diagnostic and prognostic performances of miR-21-5p levels in bile and serum were evaluated. To enhance clinical applicability, we also developed a novel diagnostic parameter termed "miR-21-5p bile/serum (B/S) ratio", calculated by determining the ratio of bile to serum miR-21-5p within individuals.

miR-21-5p expression was significantly elevated in both the bile and serum of patients with BTC. Bile miR-21-5p showed superior diagnostic performance (AUC: 0.913) over serum miR-21-5p (AUC: 0.628) and CA19-9 (AUC: 0.793). Prognostically, a higher bile miR-21-5p was associated with poorer overall survival and was identified as an independent predictor (HR: 2.446, p = 0.002), whereas serum miR-21-5p lacked significant prognostic value. B/S ratio also showed high diagnostic accuracy when ≥ 2 (AUC: 0.870), and a B/S ratio ≥ 13 was associated with significantly poorer overall survival and found as an independent prognostic predictor (HR: 2.554, p = 0.008).

Bile miR-21-5p and miR-21-5p B/S ratio are promising biomarkers for BTC diagnosis and prognosis that outperform traditional markers, highlighting the potential of bile-derived miRNAs for clinical use.

Cholangiocarcinoma (CCA) is an aggressive malignancy with poor clinical outcomes. The current "gold standard" diagnostic approach, endoscopic retrograde cholangiopancreatography (ERCP)-obtained biopsy, has a relatively low sensitivity (i.e., ∼50%). Here, we developed a bile-based diagnostic system using transient stimulated Raman scattering (T-SRS). Except for the tolerance to autofluorescence inherited from traditional SRS spectroscopy, T-SRS features quantum-limit spectral line shapes and is further improved with self-calibration ability in this research. These advantages make the acquired Raman spectra insensitive to the drifting of the excitation parameters, facilitating long-term reliability. Based on the T-SRS spectra in the C-H stretching region from 76 bile samples accumulated over more than 1 year, we demonstrated high accuracy (i.e., 85 ± 3%) and sensitivity (i.e., 87 ± 9%) for classification between CCA and benign diseases. The T-SRS acquisition only requires ∼9-μL bile samples and features a drastically improved time cost. This study suggests that the self-calibrated T-SRS analysis of the bile sample offers a promising approach for rapid CCA diagnosis.

Primary liver cancer, predominantly hepatocellular carcinoma (HCC), is a major global health concern. Liver transplantation is a critical therapeutic option for HCC, offering potential tumor eradication and cure of underlying liver disease. Enhanced Recovery After Surgery (ERAS) protocols aim to improve patient outcomes by optimizing perioperative care. This study evaluates the efficacy of ERAS in elderly liver transplant recipients.

A retrospective study was conducted on elderly liver transplant patients treated from January 2016 to March 2023. Patients were divided into two groups: conventional care (n = 58) and ERAS-based care (n = 57). Propensity score matching controlled for confounding variables. Perioperative care interventions included preoperative education, intraoperative management, and postoperative strategies emphasizing early mobilization, pain management, and nutrition. Outcomes included postoperative recovery times, complication rates, and anxiety levels.

ERAS group patients showed significantly improved recovery metrics: reduced times to first oral intake (29.26 vs. 38.42 h, p = 0.011), first ambulation (3.93 vs. 5.46 days, p = 0.008), and first flatus (3.07 vs. 4.33 days, p = 0.003). ICU and total hospital stays were shorter (2.89 vs. 4.52 days, p = 0.007; 22.18 vs. 27.14 days, p = 0.014). The ERAS group had lower complication rates (31.6% vs. 56.9%, p = 0.009) and reduced anxiety levels.

ERAS protocols significantly enhance postoperative recovery and reduce complications in elderly liver transplant recipients. These findings support the integration of ERAS principles into liver transplantation care to improve patient outcomes.

The number of lymph nodes to be removed during tumor resection in patients with intrahepatic cholangiocarcinoma (ICC) has always been a subject of controversy. The correlation between examined lymph nodes (ELN) and cancer-specific mortality (CSM) in individuals with ICC was the purpose of this investigation.

Multivariable models were used to analyze data from the Surveillance, Epidemiology, and End Results database on ICC in order to ascertain the connection between ELN count and CSM. Correlation between ELN and cancer-specific survival (CSS) was evaluated by restricted cubic splines (RCS) on a continuous scale. Locally weighted scatterplot smoothing smoother was used to evaluated the hazard ratios (HRs) of ELNs for CSS with the structural breakpoints determined by Chow test.

This investigation incorporated 1335 ICC cases. Independent risk factors for CSM included median household income, race, diagnostic year, tumor grade, clinical stage, pT stage, pN stage, pM stage and ELN count. With the adjustment for covariates, ICC cases showed statistically significant improvements in CSS (HR = 0.88) as the ELN count increased. The best threshold ELN count, as determined by cut-point analysis, was 6, which allowed for accurate CSS probability discrimination.

Increasing ELN count indicated better CSS. Our results strongly suggested 6 ELNs as the optimal cut-off number for assessing the standard of lymph node inspection and prognostic classification in ICC.

Cholangiocarcinoma (CCA), which is a malignant tumor originating from the epithelial cells of the bile ducts, has witnessed an increasing incidence year by year. Owing to the dearth of effective treatments, the prognosis for CCA is rather poor. Isorhamnetin is known to possess anti-tumor, anti-inflammatory and oxidative stress modulating effects; however, its role in CCA remains unclear.

Firstly, we screened the core targets and pathways of isorhamnetin for the treatment of CCA through a network pharmacology approach. Subsequently, we verified via molecular docking that the core targets could dock stably with isorhamnetin. Finally, we verified the inhibitory effect of isorhamnetin on the malignant biological behavior of CCA in vitro and in vivo experiments.

Based on the network pharmacology analysis, we came to the conclusion that AKT1 might be a core target of isorhamnetin in the treatment of CCA. Molecular docking indicated that AKT1 was capable of binding stably to isorhamnetin. Subsequently, In vitro experiments demonstrated that isorhamnetin was able to suppress the proliferation and metastasis of CCA cells, and AKT1 played a pivotal role in this process. Mechanistically speaking, isorhamnetin exerts its inhibitory effect on tumor growth via the PI3K/AKT signaling pathway.

Our study demonstrated for the first time that isorhamnetin can inhibit the progression of CCA through PI3K/AKT, and that AKT1 may be a target of isorhamnetin for the treatment of CCA.

Intrahepatic cholangiocarcinoma (ICC) is known for its diverse cell types and resistance to standard treatments, highlighting the importance of understanding its tumor microenvironment (TME) for improved prognostic accuracy and therapeutic innovation. Our study used a multi-omics approach to analyze the ICC TME in both human and mouse samples, linking survival outcomes to the complex cellular interactions within the TME. We discovered a dedifferentiation phenomenon in ICC cells driven by the Yes-associated protein (YAP) pathway, influenced by tumor-associated macrophages (TAMs). Conversely, ICC cells promoted an immunosuppressive environment in TAMs. Targeting TAMs in a transgenic mouse model disrupted this loop, enhancing T cell responses and suggesting a novel immunotherapy avenue for ICC. Our findings reveal a reciprocal dedifferentiation-immunosuppression loop between ICC cells and TAMs, advocating TAM targeting as a promising therapy and highlighting the potential of macrophage modulation in ICC treatment.

The purpose of this review is to summarize the current knowledge of cholangiocarcinoma molecular biology and to suggest a framework for implementation of next-generation sequencing in all stages of liver transplantation. This is timely as recent guidelines recommend increased use of these technologies with promising results.

The main themes covered here address germline and somatic genetic alterations recently discovered in cholangiocarcinoma, particularly those associated with prognosis and treatment responses, and nascent efforts to translate these into contemporary practice in the peri-liver transplantation period.

Early efforts to translate molecular profiling to cholangiocarcinoma care demonstrate a growing number of potentially actionable alterations. Still lacking is a consensus on what biomarkers and technologies to adopt, at what scale and cost, and how to integrate them most effectively into care with the ambition of increasing the number of patients eligible for liver transplantation and improving their long-term outcomes.

Genetic testing and sequencing technologies offer a comprehensive understanding of cancer genetics, providing rapid and cost-effective solutions. In particular, these advanced technologies play an important role in assessing the complexities of the rare cancer types affecting several systems including the bone, endocrine, digestive, vascular, and soft tissue. This review will explore how genetic testing and sequencing technologies have contributed to the identification of biomarkers across several rare cancer types in diagnostic, therapeutic, and prognostic stages, thereby advancing PM.

A comprehensive literature search was conducted across PubMed (MEDLINE), EMBASE, and Web of Science using keywords related to sequencing technologies, genetic testing, and cancer. There were no restrictions on language, methodology, age, or publication date. Both primary and secondary research involving humans or animals were considered.

In practice, fluorescence in situ hybridization, karyotype, microarrays and other genetic tests are mainly applied to identify specific genetic alterations and mutations associated with cancer progression. Sequencing technologies, such as next generation sequencing, polymerase chain reaction, whole genome or exome sequencing, enable the rapid analysis of millions of DNA fragments. These techniques assess genome structure, genetic changes, gene expression profiles, and epigenetic variations. Consequently, they help detect main intrinsic markers that are crucial for personalizing diagnosis, treatment options, and prognostic assessments, leading to better patient prognosis. This highlights why these methods are now considered as primary tools in rare cancer research. However, these methods still face multiple limitations, including false positive results, limited precision, and high costs.

Genetic testing and sequencing technologies have significantly advanced the field of rare cancer research by enabling the identification of key biomarkers for precision diagnosis, treatment, and prognosis. Despite existing limitations, their integration into clinical and research fields continues to improve the development of personalized medicine strategies for rare and complex cancer types.

Cholangiocarcinoma (CCA) is a serious public health issue due to its insidious onset and dismal prognosis. The past few years have witnessed and highlighted the development of understanding and management of CCA. The combination of gemcitabine and cisplatin (GP) chemotherapy regimen with immunotherapy using immune checkpoint inhibitors has been considered the new standard first-line treatment alternative for advanced CCA. Notably, the proportion of patients with advanced CCA with targetable genetic mutations is approximately 40 %, and these patients may be considered for molecularly targeted therapy in the second-line treatment. In this review, we highlight the advances and progress in targeted therapies for advanced CCA, with special attention to data from Asian populations, including Chinese. In addition, we present in detail the phosphatase tension homolog (PTEN), a novel biomarker for both of first-line chemotherapy and second-line targeted therapy in advanced CCA, and its ability to forecast prognosis in patients with CCA. The mechanisms of rapid resistance to targeted agents warrant further investigation and address in light of the development of new targeted therapies. Precision medicine is gradually playing an increasing role in achieving optimal therapeutic outcomes.

BackgroundCholangiocarcinoma-with a growing incidence rate and poor prognosis-is not an uncommon cancer. Molecular profiling can reveal actionable aberrations in at least a third of the tumors. This is especially so in the case of intrahepatic cholangiocarcinoma (ICC), where mutations in the isocitrate dehydrogenase 1 and 2 genes (IDH1/2) make up 15%-20% of these tumors. IDH1/2 mutant ICC is a rare disease that has not been adequately reported. To expand the spectrum of findings seen in these patients, we present a single institution case series.Methods and resultsWe descriptively characterize the clinical, radiological, and histopathological findings of 12 such patients. IDH1/2 mutant ICC was found in elderly women, with two-thirds of patients having additional co-mutations. Anecdotally, patients who did receive systemic and/or locoregional therapies had long-term durable outcomes.ConclusionOur findings indicate an increasing need to personalize an approach for these patients with specific molecular alterations. With the advent of the IDH1 inhibitor ivosidenib and other inhibitors in this space, IDH1/2 mutation have both prognostic and predictive value. Our series builds upon the patterns and findings seen in these patients.

To clarify the short- and long-term validity of pancreatoduodenectomy in octogenarian patients with biliary tract carcinoma.

We compared 23 and 141 patients aged ≥80 and <80 years, who underwent pancreatoduodenectomy for biliary tract carcinoma (distal cholangiocarcinomas and ampullary carcinomas) and evaluated the relationship between age, clinicopathological factors, and surgical and oncological outcomes, especially in terms of recurrence.

Median overall survival time of distal cholangiocarcinoma and ampullary carcinoma was 92 and 109 months (p = 0.13). Postoperative complications, mortality, and adjuvant chemotherapy rates did not differ between the groups. Although the 5-year recurrence-free survival rate was similar, the 5-year disease-specific survival and overall survival rate were significantly shorter in octogenarians (≥80 years: 43.5, 47.1, and 35.3%; <80 years: 54.1, 69.2, and 63.0%; p = 0.41, 0.016, and 0.034, respectively). The median time from recurrence to death for octogenarian patients was significantly shorter than that of younger patients (3.3 vs. 16.1 months, p < 0.001). At recurrence, the serum albumin level, prognostic nutritional index, controlling nutritional status score, and treatment rate for recurrence were lower in octogenarians. The multivariate analysis identified age ≥80 years (hazard ratio: 3.8), low prognostic nutritional index (hazard ratio: 2.9), high serum carbohydrate antigen 19-9 (hazard ratio: 2.6), and failure to implement treatment after recurrence (hazard ratio: 3.0) as independent risk factors for a short time from recurrence to death. Furthermore, age ≥80 years (odds ratio 0.09) was an independent risk factor for treatment implementation after recurrence.

Octogenarians had a shorter survival time after recurrence, resulting from low nutritional indices and a reduced rate of treatment implementation at the time of recurrence.

The study examines Opisthorchis viverrini (OV)-related cholangiocarcinoma (CCA), a serious malignancy common in Southeast Asia. Through multi-regional whole-exome sequencing of 52 tumor samples and 13 adjacent tissues from 13 patients, significant intratumoral heterogeneity (ITH) and inter-patient heterogeneity are shown. Chronic liver fluke infection induces a distinct mutational landscape, with 48-90% of mutations concentrated in each region of the tumor. The average mutation burden is 95 non-synonymous mutations per area, exceeding previous CCA investigations. Critical driver mutations in TP53, SMAD4, and other genes underscore their significance in pathogenesis. Mutational markers elucidate mechanisms including spontaneous deamination and impaired DNA repair. Unique mutation patterns distinguish OV-associated CCA from other variants. Chromosomal instability in patient K110 signifies aggressive tumor behavior and unfavorable prognosis. Targetable mutations such as ERBB2 underscore the possibility for personalized therapeutics. These findings underscore the necessity for personalized strategies for treatment that target both trunk and branch mutations in endemic areas.

Claudins are key components of tight junctions, essential for maintaining cellular adhesion, regulating intercellular molecule transport, and preserving cell polarity. Altered claudin expression can lead to tight junction dysfunction, potentially disrupting signaling pathways and contributing to the development of epithelial cancers. This study aims to explore the understudied role of CLDN18.2 in intrahepatic cholangiocarcinoma and its relationship with clinical outcomes. We analyzed tissue samples from 182 patients who underwent curative surgery for intrahepatic cholangiocarcinoma. Our research examined the relationship between CLDN18.2 expression and various clinical factors, including patient characteristics, pathological findings, and survival metrics such as overall survival (OS), disease-free survival (DFS), metastasis-free survival (MeFS), and local recurrence-free survival (LRFS). Overexpression of CLDN18.2 showed significant associations with R1 resection (p = 0.032) and advanced T stage (p = 0.043). Univariate analysis revealed that high CLDN18.2 expression was correlated with poorer OS (p = 0.0002), DFS (p < 0.0001), LRFS (p < 0.0001), and MeFS (p < 0.0001). Multivariate analysis further confirmed that high CLDN18.2 expression was independently associated with worse OS (p = 0.015), DFS (p < 0.001), LRFS (p < 0.001), and MeFS (p < 0.001). Overexpression of CLDN18.2 was associated with unfavorable clinical prognosis and adverse pathological features in intrahepatic cholangiocarcinoma. These findings suggest that CLDN18.2 could serve as a potential prognostic biomarker for intrahepatic cholangiocarcinoma.

CCA is a highly desmoplastic malignant cancer and is the second most common primary liver malignancy after hepatocellular carcinoma (HCC), accounting for approximately 15% of all primary liver tumors. CCA has a poor prognosis, with an average five-year survival rate of 9%, which is lower than that of pancreatic cancer. Although considerable efforts have been invested into the genomics, epigenetics, and risk factors, very little is known about what might have been the key causes for the high malignancy level of CCA. In this review, we analyze the incidence and mortality of CCA in different regions based on data from 1994 to 2022 obtained from the International Agency for Research on Cancer (IARC), discuss the current status of treatment of the disease, and focus on what might be the main factors contributing to the high malignancy level of CCA: alkalosis caused by the Fenton reaction, hypoxia, and the TIME. The review includes studies published from 1979 to 2024, aiming to provide an updated synthesis of basic early classical theoretical knowledge and current knowledge about CCA. By revealing the epidemiological characteristics of CCA, the potential mechanisms of high malignancy, and the current challenges of treatment, this review aims to provide new directions for future cancer research, promote the development of personalized treatment strategies, and facilitate a deeper understanding and the more effective management of CCA worldwide.