Cholangiocarcinoma Research Articles

Unveiling novel serum biomarkers in intrahepatic cholangiocarcinoma: a pilot proteomic exploration.

Recent advancements in proteomics have shown promise in identifying biomarkers for various cancers. Our study is the first to compare the serum proteomes of intrahepatic cholangiocarcinoma (iCCA) with cirrhosis (CIR), primary sclerosing cholangitis (PSC), and hepatocellular carcinoma (HCC), aiming to identify a proteomic signature that can effectively distinguish among these conditions. Utilizing high-throughput mass spectrometry on serum samples, we identified 845 proteins, of which 646 were suitable for further analysis. Unique clustering patterns were observed among the five groups, with significant proteomic differences. Our key findings include: S100 calcium-binding protein A9 (S100A9) and haptoglobin (HP) were more abundant in iCCA, while intercellular adhesion molecule 2 (ICAM2) was higher in HCC. Serum amyloid A1 (SAA1) and A4 (SAA4) emerged as potential biomarkers, with SAA1 significantly different in the iCCA vs healthy controls (HC) comparison, and SAA4 in the HCC vs HC comparison. Elevated levels of vascular cell adhesion molecule 1 (VCAM-1) in HCC suggested its potential as a differentiation and diagnostic marker. Angiopoietin-1 receptor (TEK) also showed discriminatory and diagnostic potential in HCC. ELISA validation corroborated mass spectrometry findings. Our study underscores the potential of proteomic profiling in distinguishing iCCA from other liver conditions and highlights the need for further validation to establish robust diagnostic biomarkers.

Serum targeted metabolomics uncovering specific amino acid signature for diagnosis of intrahepatic cholangiocarcinoma

Intrahepatic cholangiocarcinoma (iCCA) is a hepatobiliary malignancy which accounts for approximately 5–10 % of primary liver cancers and has a high mortality rate. The diagnosis of iCCA remains significant challenges owing to the lack of specific and sensitive diagnostic tests available. Hence, improved methods are needed to detect iCCA with high accuracy. In this study, we evaluated the efficacy of serum amino acid profiling combined with machine learning modeling for the diagnosis of iCCA. A comprehensive analysis of 28 circulating amino acids was conducted in a total of 140 blood samples from patients with iCCA and normal individuals. We screened out 6 differentially expressed amino acids with the criteria of |Log2(Fold Change, FC)| > 0.585, P-value < 0.05, variable importance in projection (VIP) > 1.0 and area under the curve (AUC) > 0.8, in which amino acids L-Asparagine and Kynurenine showed an increasing tendency as the disease progressed. Five frequently used machine learning algorithms (Logistic Regression, Random Forest, Supporting Vector Machine, Neural Network and Naïve Bayes) for diagnosis of iCCA based on the 6 circulating amino acids were established and validated with high sensitivity and good overall accuracy. The resulting models were further improved by introducing a clinical indicator, gamma-glutamyl transferase (GGT). This study introduces a new approach for identifying potential serum biomarkers for the diagnosis of iCCA with high accuracy.

Comprehensive genomic profiling in multiple cancer types: A comparative analysis of the National Biobank Consortium of Taiwan and clinical practice cohorts

BackgroundThis retrospective study analyzed tumor tissue profiling data to assess the potential of comprehensive genomic profiling (CGP) for patient care across diverse solid tumors. Material and methodsPatients with newly diagnosed or recurrent stage IIIB or IV lung adenocarcinoma with a null immunophenotype and esophageal, gastric, pancreatic, or bile duct cancer between January 2020 and July 2023 at two medical centers in Taiwan were included. One cohort was a part of the National Biobank Consortium of Taiwan project, whereas the other consisted of patients undergoing routine clinical practice. Tumor samples were subjected to CGP using FoundationOne®CDx, with therapeutic implications determined using OncoKB classification. ResultsFoundationOne®CDx testing of 574 patients was successful in 456 (79.4%) patients. Clinically actionable genomic alterations were detected in 21.1% (96/456) of the patients, including 17.5%, 2.9%, and 0.7% of patients with evidence levels 1, 2, and 3, respectively. Lung adenocarcinoma accounted for the largest proportion of samples with at least one actionable gene alteration (63.2%), followed by bile duct (26.9%), gastric (17.6%), esophageal (4.0%), and pancreatic (3.1%) cancers. Based on CGP results, 43 patients (9.4%) received matched targeted therapy. The median overall survival of patients who received matched therapy or not was 26.1 months (95% confidence interval (CI), 16.7–35.5 months) and 10.6 months (95% CI, 8.1–13.1 months; hazard ratio, 0.28, 95% CI, 0.14–0.55, p < 0.001), respectively. ConclusionsThis study provides comprehensive insights into the genomic profiles of diverse cancers in Taiwan, highlighting the crucial role of CGP in identifying actionable genomic alterations and guiding effective therapeutic strategies in real-world practice.

The effectiveness of combined extrahepatic bile duct resection in radically resected cases with intrahepatic cholangiocarcinoma: a SEER-based retrospective cohort study and an external validation.

To evaluate the effectiveness of the combined extrahepatic bile duct resection (EHBDR) in cases with intrahepatic cholangiocarcinoma (IHCC) in terms of clinicopathological features and long-term survival. Radically resected cases with IHCC from 2000 to 2020 were identified from Surveillance, Epidemiology, and End Results (SEER) database. Comparative analyses were performed between resected IHCC patients who received EHBDR and those without EHBDR. Moreover, an external validation was further performed based on a single-center cohort. A total of 1521 radically resected cases with IHCC (EHBDR: 189) were identified from the SEER database. Comparable age, sex, race, marital status, liver cirrhosis, differentiation status, and adjuvant chemotherapy were acquired between the two groups. EHBDR was associated with a higher incidence of adequate lymphadenectomy ( P <0.001). The incidence of cases with T3-4 or N+ disease was significantly higher in EHBDR group ( P <0.001). Adjuvant radiotherapy was more frequently performed in cases with EHBDR ( P <0.001). EHBDR failed to bring any survival benefit and was associated with a worse prognosis even after matching. Similar findings have also been revealed in the external validation cohort ( n =522, EHBDR: 117). EHBDR was associated with more extended resections, more aggressive tumor biological features, and worse prognosis. In the matched validation cohort, EHBDR was still associated with a higher incidence of early recurrence. EHBDR was an indicator of the advanced stage and failed to bring any survival benefit. It is the tumor stage that really determines the prognosis. More in-depth analyses focusing on different situations of EHBDR with more detailed clinical data are required.

Upfront surgery for intrahepatic cholangiocarcinoma: Prediction of futility using artificial intelligence

ObjectiveWe sought to identify patients at risk of “futile” surgery for intrahepatic cholangiocarcinoma using an artificial intelligence (AI)–based model based on preoperative variables. MethodsIntrahepatic cholangiocarcinoma patients who underwent resection between 1990 and 2020 were identified from a multi-institutional database. Futility was defined either as mortality or recurrence within 12 months of surgery. Various machine learning and deep learning techniques were used to develop prediction models for futile surgery. ResultsOverall, 827 intrahepatic cholangiocarcinoma patients were included. Among 378 patients (45.7%) who had futile surgery, 297 patients (78.6%) developed intrahepatic cholangiocarcinoma recurrence and 81 patients (21.4%) died within 12 months of surgical resection. An ensemble model consisting of multilayer perceptron and gradient boosting classifiers that used 10 preoperative factors demonstrated the highest accuracy, with areas under receiver operating characteristic curves of 0.830 (95% confidence interval 0.798–0.861) and 0.781 (95% confidence interval 0.707–0.853) in the training and testing cohorts, respectively. The model displayed sensitivity and specificity of 64.5% and 80.0%, respectively, with positive and negative predictive values of 73.1% and 72.7%, respectively. Radiologic tumor burden score, serum carbohydrate antigen 19-9, and direct bilirubin levels were the factors most strongly predictive of futile surgery. The artificial intelligence–based model was made available online for ease of use and clinical applicability (https://altaf-pawlik-icc-futilityofsurgery-calculator.streamlit.app/). ConclusionThe artificial intelligence ensemble model demonstrated high accuracy to identify patients preoperatively at high risk of undergoing futile surgery for intrahepatic cholangiocarcinoma. Artificial intelligence–based prediction models can provide clinicians with reliable preoperative guidance and aid in avoiding futile surgical procedures that are unlikely to provide patients long-term benefits.

Burden of Gastrointestinal Tumors in Asian Countries, 1990-2021: An Analysis for the Global Burden of Disease Study 2021.

Gastrointestinal tumors represent a significant component of the cancer burden in Asia. This study aims to evaluate the burden of gastrointestinal tumors in Asia from 1990 to 2021 using data from the Global Burden of Disease Study 2021 (GBD 2021). The absolute incidence, mortality, and disability adjusted life years (DALYs) number and rate of six gastrointestinal tumors(colon and rectum cancer (CRC), stomach cancer (SC), pancreatic cancer (PC), esophageal cancer (EC), liver cancer (LC) and gallbladder and biliary tract cancer (GBTC)) in 48 Asian countries were extracted from GBD 2021. Differences were analyzed based on gender, age, year, location and socio-demographic index (SDI). In 2021, SC accounted for the highest disease burden in Asia (DALYs=16.41million [95% UI: 13.70, 19.62]). From 1990 to 2021, the age-standardized incidence rates of EC, LC, and SC in Asia declined, while the incidence rates of CRC and PC increased significantly, with CRC showing the largest rise (AAPC=1.08 [95% CI: 1.02 to 1.12]). Gastrointestinal tumors DALY rates peaked at age 70 and above, with males generally exhibiting higher rates than females. Furthermore, East Asia bears a higher burden compared to other Asian subregions. A higher SDI correlates with increased DALY rates for PC, but no linear relationship was observed for other gastrointestinal tumors. The burden of gastrointestinal tumors in Asia remains high and may continue to increase. Therefore, effective prevention and treatment measures are essential to address the challenge posed by gastrointestinal tumors.

Efficacy of hemostasis by gastroduodenal covered metal stent placement for hemorrhagic duodenal stenosis due to pancreatobiliary cancer invasion: a retrospective study.

Advanced pancreatic and biliary tract cancers can invade the duodenum and cause duodenal hemorrhagic stenosis. This study aimed to evaluate the efficacy of covered self-expandable metal stents in the treatment of cancer-related duodenal hemorrhage with stenosis. Between January 2014 and December 2016, metal stents were placed in 51 patients with duodenal stenosis. Among these patients, a self-expandable covered metal stent was endoscopically placed in 10 patients with hemorrhagic duodenal stenosis caused by pancreatobiliary cancer progression. We retrospectively analyzed the therapeutic efficacy of the stents by evaluating the technical and clinical success rates based on successful stent placement, degree of oral intake, hemostasis, stent patency, and overall survival. The technical and clinical success rates were 100%. All 10 patients achieved a gastric outlet obstruction scoring system score of three within two weeks after the procedure and had no recurrence of melena. The median stent patency duration and overall survival after stent placement were 52 days (range, 20-220 days) and 66.5 days (range, 31-220 days), respectively. Endoscopic placement of a covered metal stent for hemorrhagic duodenal stenosis associated with pancreatic or biliary tract cancer resulted in duodenal hemostasis, recanalization, and improved quality of life.

First-in-human study of AMG 193, an MTA-cooperative PRMT5 inhibitor, in patients with MTAP-deleted solid tumors: results from phase I dose exploration

Homozygous deletion of methylthioadenosine phosphorylase (MTAP) occurs in ∼10%-15% of solid tumors. AMG 193, a CNS-penetrant methylthioadenosine-cooperative protein arginine methyltransferase 5 (PRMT5) inhibitor, selectively induces synthetic lethality in MTAP-deleted tumor cells. Here, we report results of the completed monotherapy dose exploration evaluating AMG 193 in patients with MTAP-deleted solid tumors. In this first-in-human, multicenter, open-label, phase I study, patients with advanced CDKN2A-deleted and/or MTAP-deleted solid tumors received AMG 193 orally [once (o.d.) or twice (b.i.d.) daily] continuously in 28-day cycles. Primary objectives were safety and tolerability assessed by dose-limiting toxicities and determination of the maximum tolerated dose; secondary objectives included pharmacokinetics and preliminary antitumor activity measured by RECIST v1.1. As of 23 May 2024, 80 patients in dose exploration received AMG 193 at doses 40-1600 mg o.d. or 600 mg b.i.d. The most common treatment-related adverse events were nausea (48.8%), fatigue (31.3%), and vomiting (30.0%). Dose-limiting toxicities were reported in eight patients at doses ≥240 mg, including nausea, vomiting, fatigue, hypersensitivity reaction, and hypokalemia. The maximum tolerated dose was determined to be 1200 mg o.d. Mean exposure of AMG 193 increased in a dose-proportional manner from 40 mg to 1200 mg. Among the efficacy-assessable patients treated at the active and tolerable doses of 800 mg o.d., 1200 mg o.d., or 600 mg b.i.d. (n= 42), objective response rate was 21.4% (95% confidence interval 10.3% to 36.8%). Responses were observed across eight different tumor types, including squamous/non-squamous non-small-cell lung cancer, pancreatic adenocarcinoma, and biliary tract cancer. At doses ≥480 mg, complete intratumoral PRMT5 inhibition was confirmed in paired MTAP-deleted tumor biopsies, and molecular responses (circulating tumor DNA clearance) were observed. AMG 193 demonstrated a favorable safety profile without clinically significant myelosuppression. Encouraging antitumor activity across a variety of MTAP-deleted solid tumors was observed based on objective response rate and circulating tumor DNA clearance.

55P Subsequent anticancer therapy (SAT) analysis from 3-year follow-up of the phase III TOPAZ-1 study of durvalumab plus gemcitabine and cisplatin in biliary tract cancer (BTC)

55P Subsequent anticancer therapy (SAT) analysis from 3-year follow-up of the phase III TOPAZ-1 study of durvalumab plus gemcitabine and cisplatin in biliary tract cancer (BTC)

62TiP HERIZON-BTC-302: A phase III study of zanidatamab with standard-of-care (SOC) therapy vs SOC alone for first-line (1L) treatment of human epidermal growth factor receptor 2 (HER2)-positive advanced/metastatic biliary tract cancer (BTC)

62TiP HERIZON-BTC-302: A phase III study of zanidatamab with standard-of-care (SOC) therapy vs SOC alone for first-line (1L) treatment of human epidermal growth factor receptor 2 (HER2)-positive advanced/metastatic biliary tract cancer (BTC)

57P Integrative analysis of the genomic and transcriptomic landscape identifies ciliary genes as a therapeutic target in bile duct cancer

57P Integrative analysis of the genomic and transcriptomic landscape identifies ciliary genes as a therapeutic target in bile duct cancer

47P First-line pembrolizumab (pembro) + gemcitabine and cisplatin (gem/cis) for advanced biliary tract cancer (BTC) in the China subpopulation from the phase III KEYNOTE-966 study

47P First-line pembrolizumab (pembro) + gemcitabine and cisplatin (gem/cis) for advanced biliary tract cancer (BTC) in the China subpopulation from the phase III KEYNOTE-966 study

50P Camrelizumab (Cam) combined with gemcitabine and cisplatin (GP) plus low-dose apatinib in first-line treatment of advanced biliary tract cancer (BTC)

50P Camrelizumab (Cam) combined with gemcitabine and cisplatin (GP) plus low-dose apatinib in first-line treatment of advanced biliary tract cancer (BTC)

58P Efficacy and safety of liposomal irinotecan (nal-IRI) plus fluorouracil (5-FU) and leucovorin (LV) versus 5-FU/LV alone for advanced biliary tract cancer (BTC) after progression on gemcitabine-based therapy: A pooled analysis of the NIFTY and NALIRICC trials

58P Efficacy and safety of liposomal irinotecan (nal-IRI) plus fluorouracil (5-FU) and leucovorin (LV) versus 5-FU/LV alone for advanced biliary tract cancer (BTC) after progression on gemcitabine-based therapy: A pooled analysis of the NIFTY and NALIRICC trials

Multimodal Convolutional Neural Network-Based Algorithm for Real-Time Detection and Differentiation of Malignant and Inflammatory Biliary Strictures in Cholangioscopy: a Proof of Concept Study with Video

Deep learning algorithms gained attention for detection (CADe) of biliary tract cancer (BTC) in digital single-operator cholangioscopy (dSOC). We developed a multimodal convolutional neural network (CNN) for detection (CADe) characterization and discriminating (CADx) between malignant, inflammatory and normal biliary tissue in raw dSOC videos. In addition, clinical metadata was included in the CNN algorithm to overcome limitations of image-only models. Based on dSOC videos and images of 111 patients (total of 15,158 still frames), we developed and validated a real-time CNN-based algorithm for CADe and CADx. We established an image-only model and metadata injection approach. In addition, we validated frame-wise and case-based predictions on complete dSOC video sequences. Model embeddings were visualized and class-activation maps highlighted relevant image regions. The concatenation-based CADx approach achieved a per-frame AUC of 0.871, sensitivity of 0.809 (95% CI: [0.784-0.832]), specificity of 0.773 [0.761-0.785], PPV of 0.450 [0.423-0.467], and NPV of 0.946 [0.940-0.954] with respect to malignancy on 5,715 test frames from complete videos of 20 patients. For case-based diagnosis using average prediction scores, six out of eight malignant cases and all twelve benign cases were identified correctly. Our algorithm distinguishes malignant and inflammatory bile duct lesions in dSOC videos, indicating the potential of CNN-based diagnostic support systems for both, CADe and CADx. The integration of non-image data can improve CNN based support systems, targeting current challenges in the assessment of biliary strictures.

Beyond body mass index: Body composition profiling for perioperative risk stratification in intrahepatic cholangiocarcinoma patients.

Intrahepatic cholangiocarcinoma (iCC) is an aggressive tumor, usually detected at an advanced stage. Our aim was to investigate the potential of body composition analysis (BCA) derived from presurgical staging computed tomography (CT) in predicting perisurgical complications. In this retrospective cohort study, we enrolled 86 patients who underwent CT imaging prior to liver surgery. Cox and logistic regression were performed to assess risk factors for prolonged hospital and intensive care unit (ICU) stays, as well as the occurrence of various complications. BCA parameters served as covariates besides conventional risk factors. Postoperative complications after resection of iCC significantly prolonged the overall length of hospitalization (p < .001). Presence of sarcopenia was associated with longer ICU stays. Complications were common, with 62.5% classified as Clavien-Dindo grade IIIa or lower and 37.5% as more severe. Subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT) were identified as risk factors for complications, including bile leakage (in 24 cases, p = .025), pleural effusions (in 26 cases, p = .025), and intra-abdominal abscess formation (in 24 cases, p = .043). SAT was associated with severe complications requiring interventional therapy, whereas VAT was correlated with abscess formation. Despite normal prevalence of obesity (22%), body mass index (BMI) did not have an impact on the development of perioperative complications. BCA is a useful tool for preoperative risk stratification in patients with iCC and is superior to BMI assessment. Increased SAT and VAT were associated with the risk of perisurgical complications, prolonging hospitalization. Therefore, BCA derived from routine staging CT should be considered in the preoperative assessment of patients with iCC.

Tumor Apparent Diffusion Coefficient is Associated with Early Recurrence of Intrahepatic Cholangiocarcinoma

Rationale and ObjectivesIdentifying intrahepatic cholangiocarcinoma (iCCA) patients who are at high risk for early recurrence (ER) can guide personalized treatment strategy and improve survival. This study aimed to investigate the value of preoperative MRI, especially diffusion-weighted imaging, in predicting ER, including in patients receiving neoadjuvant therapy. Materials and methodsThis study included 175 pathologically-confirmed iCCA patients who underwent curative resection (114 men, 61 women; mean age 59.0±9.56 years). MRI features, particularly apparent diffusion coefficient (ADC), were analyzed and compared between ER and non-ER cases. Survival analyses of ER were evaluated using Cox regression and Kaplan-Meier analysis. ResultsER occurred in 54.3% (95/175) of patients. Multivariate logistic regression analysis identified tumor ADC as the only independent predictor of ER (odds ratio=0.034, P<0.001), with AUCs of 0.758 (95%CI 0.664, 0.836) in the testing cohort and 0.779 (95%CI 0.622, 0.893) in the validation cohort. The optimal ADC threshold was 1.273×10-3mm2/s. Tumor ADC was comparable to the AJCC 8th staging system in predicting ER (AUC 0.758 vs 0.650 in testing cohort and 0.779 vs 0.661 in validation cohort). Multivariate Cox analysis identified high tumor burden score (HR=1.109, P=0.009), non-smooth margin (HR=2.265, P=0.008) and tumor ADC (HR=0.111, P<0.001) as independent risk factors for ER. Lower ADC values were linked to shorter RFS in both testing and validation cohorts (P<0.001 and 0.0219), as well as in patients receiving neoadjuvant therapy (P=0.003). ConclusionPreoperative MRI, particularly ADC, can help predict ER in iCCA, regardless of the application of neoadjuvant therapy, comparable to the AJCC 8th staging system.

Age and Sex Affects the Frequency and Mutation Type of FGFR2 Alterations in Cholangiocarcinoma

PURPOSE FGFR2 alterations are infrequent but currently represent the most common targetable mutation in cholangiocarcinoma. We performed a large-scale genomic analysis to assess associations between FGFR2 and other driver gene alterations in cholangiocarcinoma with patient demographics. METHODS Clinical and molecular data for patients with intrahepatic cholangiocarcinoma were abstracted from the Foundation Medicine (FMI) and Genomics, Evidence, Neoplasia, Information, Exchange (GENIE) genomic databases. The Chi-squared test was used to assess the association between sex and alterations in driver genes. FGFR2 fusion partners were analyzed using descriptive statistics. RESULTS Across both FMI (N = 7,859) and GENIE (N = 1,395) cohorts, FGFR2 rearrangements were more frequent in female than male patients with cholangiocarcinoma (odds ratio, 1.69 and 2.45). By contrast, FGFR2 missense mutations, TP53 mutations, and KRAS mutations were not associated with sex. Stratifying patients by age groups showed that FGFR2 rearrangements were specifically enriched in younger ages (&lt;45 years). Although the most common FGFR2 fusion partners were shared across both sexes, a subset of fusion partners was recurrent and uniquely associated with female or male patients. CONCLUSION FGFR2 rearrangements but not other driver alterations in cholangiocarcinoma are concentrated in young female patients, where the prevalence reached nearly 20% across two large patient cohorts. These results suggest that the molecular basis of FGFR2 rearrangements may be distinct between sexes. These results indicate the importance of genetic testing in cholangiocarcinoma, particularly for younger patients, and suggest that patient recruitment strategies in trials for FGFR2-targeting therapies should seek to reduce barriers to enhance the enrollment of young female patients.

46P The comparison outcome of GEMOX and PD-1 inhibitors combined with or without lenvatinib for advanced intrahepatic cholangiocarcinoma (ICC): A prospective, single-center, open-label, double-arm phase II trial

46P The comparison outcome of GEMOX and PD-1 inhibitors combined with or without lenvatinib for advanced intrahepatic cholangiocarcinoma (ICC): A prospective, single-center, open-label, double-arm phase II trial

Primary neuroendocrine tumor of the perihilar bile duct: A case report

Neuroendocrine tumors (NETs) arising from extrahepatic bile ducts are very rare. We present a patient with perihilar NET who was operated on with a preoperative diagnosis of Klatskin tumor. A 58-year-old female patient was admitted with abdominal pain and jaundice. Laboratory data showed elevated serum bilirubin levels and liver function tests. Computed tomography (CT) and magnetic resonance cholangiopancreatography (MRCP) findings were consistent with perihilar bile duct tumor. The patient was operated on with a diagnosis of Klatskin tumor. She underwent right hepatectomy, resection of the extrahepatic bile duct, portal lymphadenectomy and Roux-en-Y hepaticojejunostomy. The final pathologic examination of the resected specimen demonstrated a well differentiated neuroendocrine tumor (Grade 1). NETs originating from perihilar bile ducts are extremely rare, and preoperative definite diagnosis is very difficult. It should be kept in mind that NET may be one of the rare causes of perihilar bile duct obstruction.