Background: Preoperative inflammatory and nutrition-related markers—including the neutrophil-to-lymphocyte ratio (NLR), lymphocyte-to-monocyte ratio (LMR), prognostic nutritional index (PNI), and controlling nutritional status (CONUT) score—have shown prognostic relevance in various malignancies. However, their comparative utility in predicting recurrence and survival across clinically relevant subgroups in patients with intrahepatic cholangiocarcinoma (iCCA) undergoing curative-intent resection remains unclear. Methods: This retrospective study included 213 patients with histologically confirmed iCCA who underwent curative-intent resection between 2015 and 2021. Preoperative NLR, LMR, PNI, and CONUT scores were calculated from laboratory data obtained within one week before resection. Clinicopathological variables, recurrence, and survival outcomes were analyzed using Cox regression and Kaplan–Meier methods. Results: A preoperative NLR ≥ 2.4 was independently associated with poorer DFS (HR = 1.66, p = 0.025) and OS (HR = 1.94, p = 0.006). This effect remained significant in patients with R0 resection (DFS: HR = 1.66, p = 0.004; OS: HR = 2.11, p = 0.014) and in those who subsequently developed recurrence (OS: HR = 1.83, p = 0.004). The CONUT score was correlated with OS in both R0 and recurrent subgroups. Tumor morphology, consistent with prior reports, was identified as a postoperative pathological factor associated with worse prognosis. Conclusions: Preoperative NLR was associated with poorer DFS and OS in iCCA patients undergoing curative-intent resection. This association was consistently observed in subgroups with R0 resection and in those who developed recurrence. Meanwhile, the CONUT score showed limited independent significance only among patients with R0 resection who experienced recurrence.

Background/Objectives: Post-endoscopic retrograde cholangiopancreatography pancreatitis (PEP) is a frequent but insufficiently studied complication in cholangiocarcinoma (CCA). This study aimed to evaluate incidence and risk factors of PEP in CCA. Methods: We retrospectively reviewed 148 CCA patients who underwent ERCP between 2019 and 2022. Demographic, clinical, and procedural data were compared between patients with and without PEP, and logistic regression was used to identify independent predictors. Results: PEP occurred in 26.4% of patients, mostly aged ≥ 66 years, male, and with perihilar CCA. In PEP cases, metallic stents were frequently used, procedures often exceeded 60 min, and 28.2% developed post-ERCP cholangitis. Hospital stay was ≥4 days in nearly 90% of cases. PEP severity was mild (10.3%), moderate (61.5%), and severe (28.2%). Multivariate analysis showed older age, metallic stent placement, and post-ERCP cholangitis as independent risk factors, while bilirubin ≥ 15 mg/dL was protective. Conclusions: PEP occurred in over one-fourth of CCA patients, predominantly of moderate severity. Independent risk factors included older age, metallic stent placement, and post-ERCP cholangitis, whereas bilirubin ≥ 15 mg/dL was protective. Awareness of these factors may aid risk stratification and prevention in this high-risk group.

Cholangiocarcinoma (CCA) is a highly aggressive cancer of the biliary tract, distinguished by significant intratumoral heterogeneity (ITH), which contributes to therapy resistance and unfavorable clinical outcomes. Traditional genome profiling has revealed recurring driver changes in CCA; yet, genomic data alone fails to elucidate functional pathway activation, adaptive signaling, and the diverse treatment responses reported among tumor locations and disease subtypes. This review analyses the use of integrated sequencing technologies, proteogenomics, and phosphoproteomics to systematically characterize intratumoral heterogeneity in cholangiocarcinoma and convert molecular diversity into therapeutically applicable discoveries. We present evidence that the combination of genomic sequencing and mass spectrometry–based proteomics facilitates the direct correlation of genetic mutations with protein expression, post-translational modifications, and signaling system activity. Phosphoproteomic profiling specifically offers functional insights into kinase-driven networks that dictate tumor aggressiveness, therapeutic susceptibility, and adaptive resistance mechanisms, which cannot be anticipated only from DNA-level analysis. We propose that integrating proteogenomic and phosphoproteomic analyses into diagnostic and therapeutic assessments can enhance molecular classification, reveal subtype- and region-specific therapeutic dependencies, and guide rational combination treatment strategies, based on recent extensive proteogenomic studies and functional proteomic investigations in CCA. Pathway-level analysis of intratumoral heterogeneity provides a framework for selecting targeted medicines, predicting resistance, and informing personalized treatment strategies in CCA. The combination of sequencing, proteogenomics, and phosphoproteomics is essential for advancing precision oncology in cholangiocarcinoma. The implementation of this multi-layered analytical approach may better patient classification, refine therapy choices, and eventually improve clinical outcomes for individuals with this particular heterogeneous cancer.

Background: Cholangiocarcinoma (CCA) frequently recurs after curative-intent resection. Metabolic alterations and systemic inflammation may contribute to aggressive disease, but their combined prognostic relevance remains unclear. Methods: We retrospectively reanalyzed 88 patients with resected CCA and documented recurrence, including 37 with early and 51 with late recurrence. A metabolite-based risk score was developed from recurrence-associated serum metabolites identified previously. Model development and internal validation used all 88 patients, whereas analyses involving preoperative neutrophil-to-lymphocyte ratio (NLR), clinicopathological variables, and survival outcomes included 85 patients with complete clinical data. Performance was assessed using repeated nested cross-validation, bootstrap validation, discrimination, calibration, and survival analyses. Results: The 10-metabolite risk score (MRS-10) showed moderate internally validated discrimination for distinguishing early from late recurrence, with a pooled patient-level out-of-fold AUC of 0.828 (95% CI, 0.725–0.911), with limited calibration. High MRS was associated with shorter disease-free survival (DFS) and overall survival (OS) (both p < 0.001) and remained independently associated with DFS events (HR, 7.92; 95% CI, 3.94–15.92) and mortality (HR, 4.05; 95% CI, 2.08–7.89). High MRS was also associated with elevated NLR (p < 0.001). The combined MRS–NLR framework improved prognostic discrimination and stratified patients into groups with stepwise differences in DFS and OS. Exploratory subgroup analyses showed broadly consistent adverse associations across selected clinicopathological strata. Conclusions: In this retrospective exploratory analysis, a metabolite-based risk score combined with preoperative NLR was associated with recurrence and survival outcomes in resected CCA. This metabolic–inflammatory framework may provide complementary prognostic information alongside conventional clinicopathological factors. However, the findings remain hypothesis-generating and require validation in larger independent cohorts before clinical application.

Background: Cholangiocarcinoma (CCA) has the highest incidence in Northeastern Thailand, where patients generally present with late diagnosis and poor prognosis. Opisthorchis viverrini (OV) infection is the major cause of CCA, with oxidative stress driving DNA mutations and genetic instability. Microsatellite instability (MSI) is a predictive biomarker in several cancers. This study aimed to investigate MSI status and its association with clinicopathological features and survival of CCA patients. Methods: Tissue and serum samples were collected from 25 surgical CCA patients. MSI status and mismatch repair (MMR) proteins were evaluated using an MSI scanner and immunohistochemistry (IHC). Serum OV IgG was assessed by ELISA, while tumor-infiltrating lymphocytes (TILs) were evaluated by two pathologists. Associations of MSI with clinicopathological features, OV status, MMR, and survival were analyzed. Results: Among CCA patients, 66.7% were MSI-high and 33.3% were MSI-low. MSI-high significantly correlated with age < 57 years, intraductal growth pattern, OV positivity, and early-stage disease. Patients with MSI-high and high TILs showed markedly improved median survival compared to MSI-low with low TILs (94.0 vs. 16.8 and 3.0 months; HR = 6.82 and 14.10; p = 0.004 and 0.001). Incorporation of MSI and TILs remained an independent prognostic factor in multivariate analysis (p < 0.05). Conclusions: MSI-high is highly prevalent in OV-associated CCA and is associated with intraductal growth, OV infection, and early-stage disease. Combined MSI and TIL status may serve as an independent prognostic factor, warranting validation in larger cohorts.

Background/Objectives: Cholangiocarcinoma (CCA) is a very aggressive biliary carcinoma characterised by significant molecular heterogeneity and restricted treatment alternatives. Despite genomic and proteomic investigations revealing recurrent changes, the signalling dynamics influencing tumour behaviour remain inadequately comprehended. Methods: We conducted high-resolution Liquid Chromatography–Tandem Mass Spectrometry (LC–MS/MS)-based phosphoproteomics on paired tumour and surrounding tissues from 13 CCA patients in Northeast Thailand, meticulously sampling four geographically unique tumour areas for each patient. Our analysis concentrated on phosphoproteins consistently identified across all regions, delineating strong tumour-specific and cohort-wide phosphorylation signatures. Results: Notwithstanding considerable inter-patient variability, two conserved signalling modules were identified: an adhesion/Wnt axis regulated by hyperphosphorylated CTNNB1 protein (β-catenin) and a metal-handling module facilitated by metallothionein-1G (MT1G) protein and metallothionein-2A (MT2A) protein. Pathway enrichment identified focal adhesion, ECM-receptor interaction, cytoskeletal modulation, and mineral absorption as critical activities. Conclusions: This study elucidates conserved oncogenic pathways by analysing phosphoproteomic signatures across regional and patient-level variability, emphasising phosphoproteomics as a robust framework for biomarker and therapeutic development in CCA.