RARE DISEASE
Rare hepatic and biliary tract tumor
Rare hepatic and biliary tract tumor
Rare hepatic and biliary tract tumor
Drug discovery
2
drugs
With orphan designations
Overview
Rare hepatic and biliary tract tumors, including cholangiocarcinoma (CCA) and gallbladder carcinoma, are aggressive malignancies with variable anatomical subtypes (intrahepatic, perihilar, extrahepatic). Risk factors include primary sclerosing cholangitis, liver fluke infections, and congenital bile duct anomalies [1][5][8]. Diagnosis is often delayed due to nonspecific symptoms, leading to advanced-stage presentation and poor prognosis [5][17].
Burden
5-year survival for advanced CCA: <10%; gallbladder cancer: median survival 3 months [6][11][12].
High morbidity from biliary obstruction (jaundice, cholangitis) and liver failure [5][8][14].
Limited clinical trial data due to rarity, necessitating multidisciplinary care at specialized centers [3][14][16].
Therapies
Curative resection for localized disease; liver transplantation for select perihilar CCA [3][8][13].
First-line chemotherapy: gemcitabine + cisplatin (median survival 11.7 months) [3][16].
Emerging targeted therapies (e.g., FGFR2 inhibitors, IDH1 inhibitors) and adjuvant capecitabine post-resection [3][16][19].
Categories: rare hepatic diseases, rare neoplastic diseases
Research Papers
126 drug discovery papers about Rare hepatic and biliary tract tumor, with 1 first-in-class and 2 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
126 drug discovery papers about Rare hepatic and biliary tract tumor, with 1 first-in-class and 2 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2026-05-27 | Dual BRAF/MEK inhibition in BRAF V600E –mutated biliary tract cancer with exploratory histology-dependent response: A systematic review and meta-analysis.
4108 Background: The BRAF V600E mutation defines an actionable subset of rare cancers. Metastatic BTC carries a poor prognosis, with median survival under one year on standard chemotherapy. Given the rarity of BRAF V600E-mutated BTC and the absence of RCTs, rigorous evidence synthesis is needed; existing data for dabrafenib plus trametinib come only from single arm basket trials such as ROAR and NCI-MATCH. The low prevalence of this mutation limits the feasibility of large randomized studies. This SRMA aimed to quantify the efficacy of dual BRAF/MEK inhibition in BTC and explore potential histology dependent differences in response. Methods: We performed a systematic review and meta-analysis (SRMA) pooling single arm Phase II basket trial cohorts (N = 53 BTC; N = 17 CNS). Seven case reports were summarized qualitatively and excluded from pooled analyses. The primary endpoint was pooled overall response rate (ORR). A random effects model was used. Subgroup and heterogeneity analyses were performed given the tissue-specific behavior of V600E-driven tumors. Histology was evaluated as an exploratory moderator and heterogeneity was quantified. Results: In the pooled cohort of 70 patients (53 BTC and 17 CNS), the overall ORR was 45.3% (95% CI: 24.5-66.9%). Heterogeneity for the BTC subgroup was moderate (I 2 = 62.6%), while overall pooled heterogeneity across all studies was low (I 2 = 14%). ORR in BTC was numerically higher than in Central nervous system (CNS) cohorts (34.9%) but subgroup differences did not reach statistical significance (P = 0.3386). The observed median OS of 13.5 months in the ROAR BTC cohort compares favourably with historical outcomes commonly reported in the 6-12 month range for advanced BTC. The consistency of pooled estimates, despite non-randomized designs, suggests a stable treatment signal while acknowledging that causality cannot be inferred from uncontrolled data. Median progression-free survival was 9.0 months in BTC and 5.5-8.0 months in CNS cohorts. Median OS in the ROAR BTC cohort was 13.5 months (95% CI: 10.4-17.6), exceeding historical expectations. The pooled rate of Grade ≥3 AEs was 59.2%, consistent with the known safety profile of dabrafenib plus trametinib; no treatment-related deaths were reported. Qualitative data from case reports confirmed regression of CNS metastases and feasibility in patients with severe hepatic dysfunction. Conclusions: Dual BRAF/MEK inhibition shows clinically meaningful activity in BRAF V600E-mutated BTC, with survival exceeding historical expectations. Exploratory analyses indicate histology-dependent differences, supporting tumor-specific therapeutic stratification. These findings align with growing tissue-agnostic evidence for MAPK inhibition and reinforce the value of routine molecular profiling, though conclusions are limited by small cohorts and single arm studies.
2026-04-20 | IgG4-sclerosing cholangitis masquerading as cholangiocarcinoma: a case report of an unresolved preoperative diagnosis.
Immunoglobulin G4-related disease (IgG4-RD) is an immune-mediated chronic fibroinflammatory condition that can affect multiple organ systems. IgG4-related sclerosing cholangitis (IgG4-SC) is its manifestation involving the biliary tract. Due to atypical clinical presentations in some cases and insufficient awareness among clinicians, IgG4-SC is frequently misdiagnosed as cholangiocarcinoma, and multiple instances of inappropriate treatment as a result have been documented. Here we report a case of IgG4-SC that presented diagnostic challenges preoperatively and was followed by rare pancytopenia after surgery. The patient was a 50-year-old man who sought medical attention due to elevated transaminases for eight months, without obvious clinical symptoms. Among serum tumor markers, the level of protein induced by vitamin K absence/antagonist-II (PIVKA-II) was elevated. Examinations including magnetic resonance cholangiopancreatography (MRCP), contrast-enhanced abdominal computed tomography (CT), and positron emission tomography-computed tomography (PET-CT) all suggested malignant stricture at the hepatic hilum. A needle biopsy indicated dysplastic changes but was inconclusive for cholangiocarcinoma. Although IgG4-SC was considered, multiple serum IgG4 measurements remained within the normal range. With an initial clinical diagnosis of cholangiocarcinoma, the patient underwent surgical resection. Intraoperative frozen section analysis indicated an inflammatory process. Postoperatively, the patient developed pancytopenia that responded poorly to conventional supportive treatment. The condition was ultimately diagnosed as IgG4-SC based on postoperative histopathology. Corticosteroid therapy led to the normalization of the patient's blood counts, transaminases, and bilirubin levels. IgG4-SC can present with a spectrum of atypical features, such as isolated biliary strictures, absence of characteristic symptoms, normal IgG4 levels, and imaging findings resembling cholangiocarcinoma. Therefore, in cases clinically suspicious for cholangiocarcinoma, differentiating IgG4-SC warrants serious consideration. Every effort should be made to complete preoperative biopsy and histopathological assessment. For cases where differentiation remains difficult despite comprehensive evaluation, surgical intervention with intraoperative frozen section biopsy is necessary to establish a definitive diagnosis and avoid delayed treatment. Furthermore, this case suggests that IgG4-SC may also involve the hematopoietic system, manifesting as pancytopenia, which can respond effectively to corticosteroid therapy.
2026-04-13 | Neoadjuvant Treatment Strategies in Unresectable Gallbladder Cancer (GBC) in a Regional Cancer Centre in India: a Prospective Cohort Study.
BACKGROUND: Since GBC usually presents as unresectable disease, we conducted a prospective observational study to evaluate the effect of neoadjuvant strategies (NAT) on radiologic downstaging and resectability. MATERIALS AND METHODS: Patients with locally advanced GBC were treated with neoadjuvant chemotherapy (NACT). Those who were unresectable after 4–6 cycles NACT were offered consolidation chemoradiotherapy [CTRT] (45 Gy along with weekly concurrent cisplatin, 5FU [prior to 2014] and thereafter concurrent capecitabine@1250mg/2). Radiological assessment of response to chemotherapy was done (by CT angiography and PET-CT) to evaluate for resectability. Features affecting resectability were evaluated. Those found suitable for resection underwent radical surgery. RESULTS: 217 patients were evaluated (January 2012 to December 2022) (NACT:60%, NACT followed by CTRT:40%,). Pretreatment CT scans revealed involvement of liver>2 cm (75%), duodenum (42%), colon (29%), CBD (36%), CHD/primary confluence (45.6%), Hepatic Artery (32%), portal vein (21%), N0 (24.5%) N1 (17%), N2 (17%), retroperitoneal LN ( 40%). After NACT considerable radiological downstaging was evident in liver, duodenum and colon involvement (52%, 40% and 37%), while downstaging in CBD, CHD/confluence was relatively rare (14%, 7%). The proportion of nodal downstaging was evident from increase in proportion of N0 and N1 (37.5%, 20%), and decrease in proportion of N2 and RPLN (8%, 20%). Only 22 patients (10%) underwent surgical resection (EC n = 21, SC n = 1, after NACT:12, after CTRT:10). All except two were R0 (91%) and 48% had ypN0 disease. The median OS of those who underwent resection is 49 months (95% CI 26.8–69 mo.) versus 9 months (95% CI 8–10 mo.) in those who did not. CONCLUSIONS: NAT in unresectable GBC results in 10% resectability rate. Patients with liver involvement, duodenal involvement and lymphadenopathy had greater possibility of resectability after NAT, whereas those with biliary tree or vessel involvement had least possibility of resection. This approach has a potential of achieving R0, node negative disease leading to improved survival rates and should be actively explored in patients without biliary and vessel involvement.
2026-02-19 | Perihilar Biliary Neuroendocrine Carcinoma Treated With Perioperative Chemotherapy and Radical Liver Surgery: A Thought-Provoking Case.
BACKGROUND Biliary neuroendocrine neoplasm (NEN) arising from the extrahepatic bile duct is rare, with an incidence of 0.2% among gastroentero-hepatopancreatobiliary NEN cases. Biliary neuroendocrine carcinoma (NEC) is an extremely rare high-grade malignancy that requires multidisciplinary treatment, including surgery, chemotherapy, and radiation. However, there have been only a few reports on the combined therapy for biliary NEC. CASE REPORT A 74-year-old man was referred to our hospital with a chief concern of obstructive jaundice. He was diagnosed with perihilar biliary NEC. The tumor primarily involved the confluence of the hepatic and left hepatic ducts. After 4 courses of systemic chemotherapy with cisplatin and etoposide (EP regimen), the tumor showed partial shrinkage. The patient underwent left and caudate hepatectomy with combined resection and reconstruction of the extrahepatic bile duct. Intraoperatively, strong adhesion between the right hepatic artery and the dorsal surface of the tumor was observed, requiring combined resection and reconstruction of the right hepatic artery. Postoperatively, the patient was treated with adjuvant chemotherapy (EP regimen) for 6 months. Ten months after surgery, he was diagnosed with multiple aggressive recurrences that were refractory to multimodal therapies. Eighteen months after the initial diagnosis and 12 months after surgery, he died of liver failure due to cholangitis. CONCLUSIONS This report presents the first case of perihilar biliary NEC that underwent perioperative chemotherapy and radical liver surgery. We believe that the introduction of perioperative chemotherapy is essential to achieve a better prognosis for perihilar biliary NEC, given its oncological malignancy and surgical invasiveness.
2025-04-08 | Embryonal biliary rhabdomyosarcoma in a 4-year-old female: a case report
Embryonal biliary rhabdomyosarcoma (EBRMS) is an exceptionally rare pediatric malignancy originating from the biliary tract. Due to its nonspecific presentation—jaundice, abdominal pain, and biliary obstruction—it often shares the clinical picture with more common hepatobiliary disorders such as hepatoblastoma or choledochal cysts, leading to diagnostic delays. A previously healthy 4-year-old girl presented with progressive jaundice, pale stools, and dark urine, initially diagnosed as amebiasis. The persistence of symptoms led to further evaluation, revealing hepatomegaly and a porta hepatis mass. Laboratory findings indicated obstructive jaundice with markedly elevated bilirubin and liver enzyme levels. Imaging included contrast-enhanced CT, which revealed a hypodense, poorly enhancing mass occupying the porta hepatis, encasing key vessels such as the main portal veins, celiac trunk, and hepatic arteries, and leading to intrahepatic biliary dilation. Multiple enlarged lymph nodes were also observed. Porta hepatic core needle biopsy and histopathological analysis confirmed EBRMS, immunohistochemically positive for desmin and myogenin. Given the severity of biliary obstruction, percutaneous biliary drainage was performed before initiating chemotherapy. The patient received 11 cycles of a modified VAC regimen (vincristine, actinomycin D, and cyclophosphamide), with initial dose adjustments made due to her unstable clinical status, including omission of vincristine, a 25 % reduction in actinomycin D, and a 50 % reduction in cyclophosphamide. Full-dose chemotherapy was resumed after her condition stabilized. She also underwent intensity-modulated radiotherapy (41.4 Gy). She achieved complete tumor regression, normalization of liver function, and long-term remission. Follow-up CT after two years showed stable residual soft tissue thickening at the porta hepatis, with no signs of recurrent or progressive disease. Despite its rarity, EBRMS and other biliary tree tumors should be considered in the differential diagnosis of children presenting with cholestasis. Early imaging studies, such as ultrasound, are critical to avoid diagnostic delays and ensure timely intervention.
oligonucleotides
2025-04-21 | Abstract 6722: OFD1 as a novel biomarker in cholangiocarcinoma: insights into ciliary dysfunction and tumor growth
Abstract Cholangiocarcinoma (CCA) is a rare and aggressive solid tumor originating from cholangiocytes lining the biliary ducts. It is the second most common primary hepatic malignancy, with an increasing global incidence and limited therapeutic options. Recent studies suggest that the primary cilium acts as a tumor suppressor in the biliary tract by regulating key cancer-related signaling pathways. Moreover, evidence links the reduction or loss of primary cilia to increased aggressiveness in various human cancers. Here, we aimed to identify and functionally characterize primary cilia-associated genes with potential translational relevance for CCA prognosis and treatment. Our study included 120 CCA patients, comprising 51% (36) with intrahepatic CCA and 49% (34) with extrahepatic CCA. Whole-transcriptome and whole-exome profiling were conducted on laser micro-dissected formalin-fixed paraffin-embedded (FFPE) tissue specimens. Bioinformatic analysis identified OFD1 as the top-ranked cilium-associated gene (fold-change ≥ 2.5, p < 0.01) among differentially expressed genes in tumor, stromal, and normal tissues. We investigated the role of OFD1 in cilia formation and cell proliferation through in vitro experiments in healthy human cholangiocytes and CCA cell lines. Immunofluorescence staining with ciliary markers revealed that OFD1 silencing promoted ciliogenesis and inhibited tumor growth in CCA cell lines. Western blot analysis confirmed a significant upregulation of ciliary proteins, including PCM1, ARL13B, and acetylated tubulin, following OFD1 silencing. Furthermore, CRISPR/Cas9-mediated OFD1 depletion in CCA cells led to a marked reduction in cell proliferation and restored ciliogenesis. Conversely, OFD1 overexpression in normal cholangiocytes resulted in increased cell proliferation and migration, along with suppression of ciliogenesis. Clinically, higher OFD1 expression was significantly associated with poorer overall survival in CCA patients (10 vs. 39 months; HR 2.33, 95% CI 1.01-5.31, p = 0.03). In conclusion, we demonstrated that OFD1 functions as an oncogene in CCA, influencing primary cilia formation and tumor cell growth. Higher OFD1 expression is a significant predictor of worse survival outcomes, identifying OFD1 as a promising biomarker and potential therapeutic target in CCA. Citation Format: Fabiola Piscopo, Anna Barbato, Massimiliano Salati, Carla Pollastro, Giorgia Gitano, Alberto Marino, Lorenzo Evangelista, Luigi Ferrante, Antonella Iuliano, Luca Reggiani-Bonetti, Maria Salatiello, Pasquale Pisapia, Umberto Malapelle, Giancarlo Troncone, Massimo Dominici, Brunella Franco, Pietro Carotenuto. OFD1 as a novel biomarker in cholangiocarcinoma: insights into ciliary dysfunction and tumor growth [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 6722.
2016-12-13 | Genetic alteration regulated by microRNAs in biliary tract cancers.
Biliary tract cancers (BTCs) constitute a relatively rare but highly malignant class of tumors with poor prognosis including gallbladder cancer, intra- and extra-hepatic cholangiocarcinoma. Recently, accumulated evidences have demonstrated that deregulated expression of microRNAs (miRNAs) is closely associated with the development, invasion, metastasis and prognosis of different cancers including BTCs. MiRNAs comprise an endogenously expressed and highly evolutionarily conserved group of small, non-coding, single-stranded RNAs which negatively regulate target genes expression by means of combining with 3' untranslated region (UTR) of corresponding mRNAs at the post-transcriptional level with significant roles in various fundamental cellular procedures including cell proliferation, differentiation, migration, cell cycle control and apoptosis. Recent studies have indicated that miRNAs could function as novel tumor-promoting genes or tumor suppressor genes to act as potential therapeutic targets in anticancer treatment because the genetic alteration regulated by miRNAs could result in tumorigenesis and tumor inhibition. Anomalous miRNAs expression patterns, acting as phenotypic signatures of distinct cancers, are promising to be used as diagnostic, prognostic, predictive biomarkers. In this review, we summarize the current findings from the studies about potential genetic alteration regulated by miRNAs and their roles in BTCs.
antibodies
2025-05-31 | PD-1 monoclonal antibody (Tislelizumab)-induced DRESS syndrome in an intrahepatic cholangiocarcinoma patient with FGFR3 mutation and elevated IgG4:A case report.
Immune-related adverse events (irAEs) include a rare, idiosyncratic but potentially life-threatening drug reaction with eosinophilia and systemic symptoms (DRESS), characterized by exanthem, fever, as well as hematologic and visceral organ involvement. We describe a 54-year-old man under the novel sequential treatment including all-trans retinoic acid (ATRA) and programmed death protein 1(PD-1) antibody (Tislelizumab) for advanced intrahepatic cholangiocarcinoma (iCCA). He was found to have Tislelizumab-induced DRESS syndrome during adjuvant therapy, and also showed the evidence of IgG4-related lymphadenopathy (IgG4-RLAD) as well as Epstein-Barr virus (EBV) infection in the absence of hemophagocytic lymphohistiocytosis (HLH) and T cell lymphoma. The patient's clinical status was successfully ameliorated through the administration of corticosteroids, intravenous immunoglobulin (IVIG), and antiviral agents, demonstrating a positive response to the treatment protocol. He was the first-ever case report of Tislelizumab-induced DRESS syndrome in the context of IgG4-RLAD with an exploration of potential mechanisms. Furthermore, we found that a somatic fibroblast growth factor receptor (FGFR) 3 p.P774L mutation at the frequency of 1.96 % was detected in his iCCA tissue. These findings indicated that this novel therapy, based on ARTA and PD-1 antibody, is more effective and could guide the clinical application of PD-1 antibody in the iCCA patients with elevated IgG4. Human leukocyte antigen (HLA) typing assay might help to screen the potential susceptible individuals to avoid immune checkpoint inhibitors (ICIs)-induced DRESS syndrome.
2024-08-31 | A Lymphoepithelioma-Like Intrahepatic Cholangiocarcinoma With Massive Multinucleated Giant Cell Reaction.
Lymphoepithelioma-like intrahepatic cholangiocarcinoma (LEL-ICC) is a rare liver tumor that appears as a hepatic nodule on imaging with a specific pathological pattern, and the definitive diagnosis relies on its pathological histomorphology, immunophenotype, and Epstein-Barr encoding region test. Radical surgical resection is the primary treatment modality, and immunotherapy is expected to be a new adjuvant treatment option. LEL-ICC with massive multinucleated giant cell infiltration has not been reported so far. In this article, we report a patient with LEL-ICC showing massive multinucleated giant cell infiltration, review the relevant literature, and analyze its clinicopathological features and prognosis to accumulate experience for the accurate diagnosis of LEL-ICC.
2024-05-02 | Efficacy of dual checkpoint inhibitors in a patient with a mixed hepatocellular cholangiocarcinoma.
A woman in her 60s was diagnosed with a metastatic, unresectable rare histological type of liver cancer; combined hepatocellular cholangiocarcinoma. She had palliative chemotherapy, initially with gemcitabine and cisplatin, and then with oxaliplatin, L-folinic acid and fluorouracil. Both treatment strategies demonstrated disease progression, and somatic mutation profiling revealed no actionable mutations. The patient was started on immuno-oncology (IO) with nivolumab and ipilimumab, followed by maintenance nivolumab. She has achieved a sustained ongoing partial response since the start of this therapy for at least 12 months. The outcome in this patient is in keeping with the growing evidence of the role that IO agents have in metastatic biliary tract cancer and also serves to highlight their importance in mixed histology liver tumours.
2022-09-08 | Clinical treatment of cholangiocarcinoma: an updated comprehensive review.
Cholangiocarcinoma (CCA) is a heterogeneous group of neoplasms of the bile ducts and represents the second most common hepatic cancer after hepatocellular carcinoma; it is sub-classified as intrahepatic cholangiocarcinoma (iCCA) and extrahepatic cholangiocarcinoma (eCCA), the latter comprising both perihilar cholangiocarcinoma (pCCA or Klatskin tumor), and distal cholangiocarcinoma (dCCA). The global incidence of CCA has increased worldwide in recent decades. Chronic inflammation of biliary epithelium and bile stasis represent the main risk factors shared by all CCA sub-types. When feasible, liver resection is the treatment of choice for CCA, followed by systemic chemotherapy with capecitabine. Liver transplants represent a treatment option in patients with very early iCCA, in referral centers only. CCA diagnosis is often performed at an advanced stage when CCA is unresectable. In this setting, systemic chemotherapy with gemcitabine and cisplatin represents the first treatment option, but the prognosis remains poor. In order to ameliorate patients' survival, new drugs have been studied in the last few years. Target therapies are directed against different molecules, which are altered in CCA cells. These therapies have been studied as second-line therapy, alone or in combination with chemotherapy. In the same setting, the immune checkpoints inhibitors targeting programmed death 1 (PD-1), programmed death-ligand 1 (PD-L1), cytotoxic T-lymphocyte antigen-4 (CTLA-4), have been proposed, as well as cancer vaccines and adoptive cell therapy (ACT). These experimental treatments showed promising results and have been proposed as second- or third-line treatment, alone or in combination with chemotherapy or target therapies.
2021-09-15 | Efficacy of pembrolizumab in microsatellite instability-high locally advanced cholangiocarcinoma: a case report.
Cholangiocarcinoma is a biliary malignant tumor which can arise at any point of biliary tree. Surgical resection is the only curative treatment and chemotherapy is used for unresectable cases, but its prognosis is poor compared with other types of cancer. Recently, pembrolizumab (PEM), an anti-programmed cell death protein 1 (PD-1) antibody, has become available for microsatellite instability (MSI)-high advanced cancers. Here, we report the use of PEM for MSI-high locally advanced cholangiocarcinoma. A 57-year-old man presented to our department with jaundice. Contrast-enhanced computed tomography showed a solitary 28-mm-diameter tumor deep in the anterior segment of the liver. Endoscopic retrograde cholangiopancreatography and intraductal ultrasonography showed narrowing of the common bile duct and absence of contrast in the right hepatic duct, and tumor invaded from hilar region of liver into left hepatic duct. We diagnosed this as double primary cancers, locally advanced intrahepatic and distal cholangiocarcinomas. The patient began gemcitabine in combination with cisplatin therapy as first-line treatment and gemcitabine in combination with S-1 therapy as second-line treatment. However, the tumor gradually grew (maximum 69 mm), intrahepatic metastasis appeared, and tumor marker increased. Because MSI-high was confirmed not only by biopsy specimens but also by liquid biopsy, the patient began PEM (200 mg per every 3 weeks). After 15 cycles of PEM were administered over about 10 months, size of tumor was reduced and tumor marker dramatically decreased. We experienced the rare case which PEM has been successfully used for MSI-high double primary cancers.
proteins
2026-01-02 | Intraductal papillary neoplasm of the biliary tract with typical clinicopathological, endoscopic features: A case report.
A literature review revealed that intraductal papillary mucinous neoplasm of the biliary tract (IPMN-B) cases with characteristic clinical, imaging, endoscopic, and pathological features are exceedingly rare. Herein, we present a case of typical IPMN-B with malignant transformation that required 4 years for a definitive diagnosis, to enhance the understanding of this disease entity. A 67-year-old male patient was referred to our hospital due to abdominal pain and jaundice. Four years before this admission, a cystic lesion and left hepatolithiasis were incidentally discovered. Laboratory tests revealed mild increases in serum white blood cell count, total bilirubin, alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, and gamma-glutamyl transferase. Tumour marker levels were within normal limits. Imaging findings demonstrated an enlargement of the cystic tumour from 41 mm to 63 mm, along with the development of numerous enhancing papillary nodules within it, which showed hyperenhancement during the arterial phase. Duodenoscopy revealed an enlarged major duodenal papilla with a fish-mouth appearance and dilated orifice, exuding translucent jelly-like mucus. Endoscopic retrograde cholangiography demonstrated multiple cloudy, irregular filling defects within the dilated extrahepatic bile duct. Following the diagnosis of IPMN-B, left hepatectomy was performed. Postoperative histopathological examination and immunohistochemistry confirmed IPMN-B with high-grade intraepithelial neoplasia and associated invasive carcinoma. Heightened vigilance and recognition of IPMN-B are essential when "hepatic cysts" or "biliary stones" are incidentally detected.
2023-08-21 | Phase 2 trial of bintrafusp alfa as second-line therapy for patients with locally advanced/metastatic biliary tract cancers.
Biliary tract cancers are rare, heterogeneous cancers with poor prognoses. Bintrafusp alfa, a first-in-class bifunctional fusion protein composed of the extracellular domain of TGF-βRII (a TGF-β "trap") fused to a human IgG1 monoclonal antibody blocking programmed death ligand 1, was evaluated in patients with locally advanced/metastatic chemorefractory biliary tract cancers. This multicenter, single-arm, open-label, phase 2 study (NCT03833661) enrolled adults with locally advanced or metastatic biliary tract cancer that was intolerant to or had failed first-line systemic platinum-based chemotherapy. Patients received 1200 mg bintrafusp alfa intravenously Q2W. The primary endpoint was confirmed objective response according to Response Evaluation Criteria in Solid Tumors 1.1 assessed by IRC. Secondary endpoints included duration of response, durable response rate, safety, progression-free survival, and overall survival.Between March 2019 and January 2020, 159 patients were enrolled. Median follow-up was 16.1 (range, 0.0-19.3) months; 17 patients (10.7%; 95% CI: 6.4%-16.6%) achieved an objective response. Median duration of response was 10.0 (range, 1.9-15.7) months; 10 patients (6.3%; 95% CI: 3.1%-11.3%) had a durable response (≥6 mo). Median progression-free survival was 1.8 months (95% CI: 1.7-1.8 mo); median overall survival was 7.6 months (95% CI: 5.8-9.7 mo). Overall survival rates were 57.9% (6 mo) and 38.8% (12 mo). Grade ≥3 adverse events occurred in 26.4% of patients, including one treatment-related death (hepatic failure). Frequent grade ≥3 adverse events included anemia (3.8%), pruritus (1.9%), and increased alanine aminotransferase (1.9%). Although this study did not meet its prespecified primary endpoint, bintrafusp alfa demonstrated clinical activity as second-line treatment in this hard-to-treat cancer, with durable responses and a manageable safety profile.
other
2026-04-03 | Abstract 2667: TM4SF1 as a novel tumor-associated antigen in biliary tract cancers targetable by immune effector cell therapy
Abstract Biliary tract cancers (BTC) are a rare set of genetically heterogeneous and aggressive malignancies associated with late presentation, poor prognosis and limited effective therapies. Thus, there is an unmet clinical need for the development of novel therapeutic strategies. Identification of uniquely expressed cell-surface tumor-associated antigens (TAA) holds promise in epithelial tumors more generally, as they can serve as ligands for a variety of therapeutics, including CAR-T cell therapy. However, TAA identification in BTCs has been limited by expression in normal liver tissue. Here, we identify the cell-surface protein transmembrane 4 L six family member 1 (TM4SF1) as a potential BTC TAA targetable by CAR-T therapy. We find TM4SF1 expression is upregulated in BTC relative to normal hepatic/biliary tissue at the mRNA level in the TCGA dataset. Correspondingly, we find that TM4SF1 in primary BTC archival tissue is upregulated at the protein level using immunohistochemistry. To validate TM4SF1 as a targetable TAA in BTC, we show that TM4SF1-directed CAR-T cells demonstrate robust, dose-dependent growth inhibition of human-derived BTC cell lines in vitro and significant anti-tumor activity in a heterotopic BTC cell line-derived xenograft model in vivo. Together, our data provide support for TM4SF1 as a promising TAA in BTCs that can be used for the rational development of therapeutic modalities targeting TM4SF1, including CAR-T cells, in a patient population with significant unmet need. Citation Format: Lorraine Nuniz, Franklin Huang. TM4SF1 as a novel tumor-associated antigen in biliary tract cancers targetable by immune effector cell therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 2667.
2025-06-26 | A proposed staging system for intrahepatic cholangiocarcinoma involving the hilar.
Intrahepatic cholangiocarcinoma involving the hepatic hilum (h-ICC) is a rare and aggressive malignancy with heterogeneous clinical outcomes. Current staging systems are often inadequate for prognostic prediction in this subgroup. This study aimed to identify key prognostic factors and develop a novel, clinically applicable survival classification model for patients with h-ICC undergoing surgery. We retrospectively analyzed 333 patients with h-ICC at West China Hospital from 2003 to 2023. Baseline clinical, laboratory, and imaging data were collected. Univariate and multivariate Cox regression analyses identified independent prognostic factors. A classification and regression tree (CART) model was constructed to stratify patients based on overall survival. Model performance was assessed using ROC curves and Brier scores. Intrahepatic metastasis (HR = 1.569, P = 0.0489) and regional lymph node metastasis (HR = 2.227, P < 0.001) were identified as independent prognostic factors. A CART-based survival model stratified patients into four risk groups based on regional lymphatic metastasis, local organ metastasis, intrahepatic metastasis, total bilirubin level (cutoff: 192.6 μmol/L), and tumor size (cutoff: 4.65 cm). Based on these variables, we constructed a nomogram to improve clinical availability. After verification, the proposed model demonstrated good discriminatory ability and calibration. Intrahepatic and lymphatic metastases are critical prognostic indicators in h-ICC. The newly developed CART-based staging system offers improved survival stratification and may guide personalized treatment planning in this patient population.
small molecules
2026-05-27 | Dual BRAF/MEK inhibition in BRAF V600E –mutated biliary tract cancer with exploratory histology-dependent response: A systematic review and meta-analysis.
4108 Background: The BRAF V600E mutation defines an actionable subset of rare cancers. Metastatic BTC carries a poor prognosis, with median survival under one year on standard chemotherapy. Given the rarity of BRAF V600E-mutated BTC and the absence of RCTs, rigorous evidence synthesis is needed; existing data for dabrafenib plus trametinib come only from single arm basket trials such as ROAR and NCI-MATCH. The low prevalence of this mutation limits the feasibility of large randomized studies. This SRMA aimed to quantify the efficacy of dual BRAF/MEK inhibition in BTC and explore potential histology dependent differences in response. Methods: We performed a systematic review and meta-analysis (SRMA) pooling single arm Phase II basket trial cohorts (N = 53 BTC; N = 17 CNS). Seven case reports were summarized qualitatively and excluded from pooled analyses. The primary endpoint was pooled overall response rate (ORR). A random effects model was used. Subgroup and heterogeneity analyses were performed given the tissue-specific behavior of V600E-driven tumors. Histology was evaluated as an exploratory moderator and heterogeneity was quantified. Results: In the pooled cohort of 70 patients (53 BTC and 17 CNS), the overall ORR was 45.3% (95% CI: 24.5-66.9%). Heterogeneity for the BTC subgroup was moderate (I 2 = 62.6%), while overall pooled heterogeneity across all studies was low (I 2 = 14%). ORR in BTC was numerically higher than in Central nervous system (CNS) cohorts (34.9%) but subgroup differences did not reach statistical significance (P = 0.3386). The observed median OS of 13.5 months in the ROAR BTC cohort compares favourably with historical outcomes commonly reported in the 6-12 month range for advanced BTC. The consistency of pooled estimates, despite non-randomized designs, suggests a stable treatment signal while acknowledging that causality cannot be inferred from uncontrolled data. Median progression-free survival was 9.0 months in BTC and 5.5-8.0 months in CNS cohorts. Median OS in the ROAR BTC cohort was 13.5 months (95% CI: 10.4-17.6), exceeding historical expectations. The pooled rate of Grade ≥3 AEs was 59.2%, consistent with the known safety profile of dabrafenib plus trametinib; no treatment-related deaths were reported. Qualitative data from case reports confirmed regression of CNS metastases and feasibility in patients with severe hepatic dysfunction. Conclusions: Dual BRAF/MEK inhibition shows clinically meaningful activity in BRAF V600E-mutated BTC, with survival exceeding historical expectations. Exploratory analyses indicate histology-dependent differences, supporting tumor-specific therapeutic stratification. These findings align with growing tissue-agnostic evidence for MAPK inhibition and reinforce the value of routine molecular profiling, though conclusions are limited by small cohorts and single arm studies.
2026-04-20 | IgG4-sclerosing cholangitis masquerading as cholangiocarcinoma: a case report of an unresolved preoperative diagnosis.
Immunoglobulin G4-related disease (IgG4-RD) is an immune-mediated chronic fibroinflammatory condition that can affect multiple organ systems. IgG4-related sclerosing cholangitis (IgG4-SC) is its manifestation involving the biliary tract. Due to atypical clinical presentations in some cases and insufficient awareness among clinicians, IgG4-SC is frequently misdiagnosed as cholangiocarcinoma, and multiple instances of inappropriate treatment as a result have been documented. Here we report a case of IgG4-SC that presented diagnostic challenges preoperatively and was followed by rare pancytopenia after surgery. The patient was a 50-year-old man who sought medical attention due to elevated transaminases for eight months, without obvious clinical symptoms. Among serum tumor markers, the level of protein induced by vitamin K absence/antagonist-II (PIVKA-II) was elevated. Examinations including magnetic resonance cholangiopancreatography (MRCP), contrast-enhanced abdominal computed tomography (CT), and positron emission tomography-computed tomography (PET-CT) all suggested malignant stricture at the hepatic hilum. A needle biopsy indicated dysplastic changes but was inconclusive for cholangiocarcinoma. Although IgG4-SC was considered, multiple serum IgG4 measurements remained within the normal range. With an initial clinical diagnosis of cholangiocarcinoma, the patient underwent surgical resection. Intraoperative frozen section analysis indicated an inflammatory process. Postoperatively, the patient developed pancytopenia that responded poorly to conventional supportive treatment. The condition was ultimately diagnosed as IgG4-SC based on postoperative histopathology. Corticosteroid therapy led to the normalization of the patient's blood counts, transaminases, and bilirubin levels. IgG4-SC can present with a spectrum of atypical features, such as isolated biliary strictures, absence of characteristic symptoms, normal IgG4 levels, and imaging findings resembling cholangiocarcinoma. Therefore, in cases clinically suspicious for cholangiocarcinoma, differentiating IgG4-SC warrants serious consideration. Every effort should be made to complete preoperative biopsy and histopathological assessment. For cases where differentiation remains difficult despite comprehensive evaluation, surgical intervention with intraoperative frozen section biopsy is necessary to establish a definitive diagnosis and avoid delayed treatment. Furthermore, this case suggests that IgG4-SC may also involve the hematopoietic system, manifesting as pancytopenia, which can respond effectively to corticosteroid therapy.
2026-04-13 | Neoadjuvant Treatment Strategies in Unresectable Gallbladder Cancer (GBC) in a Regional Cancer Centre in India: a Prospective Cohort Study.
BACKGROUND: Since GBC usually presents as unresectable disease, we conducted a prospective observational study to evaluate the effect of neoadjuvant strategies (NAT) on radiologic downstaging and resectability. MATERIALS AND METHODS: Patients with locally advanced GBC were treated with neoadjuvant chemotherapy (NACT). Those who were unresectable after 4–6 cycles NACT were offered consolidation chemoradiotherapy [CTRT] (45 Gy along with weekly concurrent cisplatin, 5FU [prior to 2014] and thereafter concurrent capecitabine@1250mg/2). Radiological assessment of response to chemotherapy was done (by CT angiography and PET-CT) to evaluate for resectability. Features affecting resectability were evaluated. Those found suitable for resection underwent radical surgery. RESULTS: 217 patients were evaluated (January 2012 to December 2022) (NACT:60%, NACT followed by CTRT:40%,). Pretreatment CT scans revealed involvement of liver>2 cm (75%), duodenum (42%), colon (29%), CBD (36%), CHD/primary confluence (45.6%), Hepatic Artery (32%), portal vein (21%), N0 (24.5%) N1 (17%), N2 (17%), retroperitoneal LN ( 40%). After NACT considerable radiological downstaging was evident in liver, duodenum and colon involvement (52%, 40% and 37%), while downstaging in CBD, CHD/confluence was relatively rare (14%, 7%). The proportion of nodal downstaging was evident from increase in proportion of N0 and N1 (37.5%, 20%), and decrease in proportion of N2 and RPLN (8%, 20%). Only 22 patients (10%) underwent surgical resection (EC n = 21, SC n = 1, after NACT:12, after CTRT:10). All except two were R0 (91%) and 48% had ypN0 disease. The median OS of those who underwent resection is 49 months (95% CI 26.8–69 mo.) versus 9 months (95% CI 8–10 mo.) in those who did not. CONCLUSIONS: NAT in unresectable GBC results in 10% resectability rate. Patients with liver involvement, duodenal involvement and lymphadenopathy had greater possibility of resectability after NAT, whereas those with biliary tree or vessel involvement had least possibility of resection. This approach has a potential of achieving R0, node negative disease leading to improved survival rates and should be actively explored in patients without biliary and vessel involvement.
2026-02-19 | Perihilar Biliary Neuroendocrine Carcinoma Treated With Perioperative Chemotherapy and Radical Liver Surgery: A Thought-Provoking Case.
BACKGROUND Biliary neuroendocrine neoplasm (NEN) arising from the extrahepatic bile duct is rare, with an incidence of 0.2% among gastroentero-hepatopancreatobiliary NEN cases. Biliary neuroendocrine carcinoma (NEC) is an extremely rare high-grade malignancy that requires multidisciplinary treatment, including surgery, chemotherapy, and radiation. However, there have been only a few reports on the combined therapy for biliary NEC. CASE REPORT A 74-year-old man was referred to our hospital with a chief concern of obstructive jaundice. He was diagnosed with perihilar biliary NEC. The tumor primarily involved the confluence of the hepatic and left hepatic ducts. After 4 courses of systemic chemotherapy with cisplatin and etoposide (EP regimen), the tumor showed partial shrinkage. The patient underwent left and caudate hepatectomy with combined resection and reconstruction of the extrahepatic bile duct. Intraoperatively, strong adhesion between the right hepatic artery and the dorsal surface of the tumor was observed, requiring combined resection and reconstruction of the right hepatic artery. Postoperatively, the patient was treated with adjuvant chemotherapy (EP regimen) for 6 months. Ten months after surgery, he was diagnosed with multiple aggressive recurrences that were refractory to multimodal therapies. Eighteen months after the initial diagnosis and 12 months after surgery, he died of liver failure due to cholangitis. CONCLUSIONS This report presents the first case of perihilar biliary NEC that underwent perioperative chemotherapy and radical liver surgery. We believe that the introduction of perioperative chemotherapy is essential to achieve a better prognosis for perihilar biliary NEC, given its oncological malignancy and surgical invasiveness.
2025-04-08 | Embryonal biliary rhabdomyosarcoma in a 4-year-old female: a case report
Embryonal biliary rhabdomyosarcoma (EBRMS) is an exceptionally rare pediatric malignancy originating from the biliary tract. Due to its nonspecific presentation—jaundice, abdominal pain, and biliary obstruction—it often shares the clinical picture with more common hepatobiliary disorders such as hepatoblastoma or choledochal cysts, leading to diagnostic delays. A previously healthy 4-year-old girl presented with progressive jaundice, pale stools, and dark urine, initially diagnosed as amebiasis. The persistence of symptoms led to further evaluation, revealing hepatomegaly and a porta hepatis mass. Laboratory findings indicated obstructive jaundice with markedly elevated bilirubin and liver enzyme levels. Imaging included contrast-enhanced CT, which revealed a hypodense, poorly enhancing mass occupying the porta hepatis, encasing key vessels such as the main portal veins, celiac trunk, and hepatic arteries, and leading to intrahepatic biliary dilation. Multiple enlarged lymph nodes were also observed. Porta hepatic core needle biopsy and histopathological analysis confirmed EBRMS, immunohistochemically positive for desmin and myogenin. Given the severity of biliary obstruction, percutaneous biliary drainage was performed before initiating chemotherapy. The patient received 11 cycles of a modified VAC regimen (vincristine, actinomycin D, and cyclophosphamide), with initial dose adjustments made due to her unstable clinical status, including omission of vincristine, a 25 % reduction in actinomycin D, and a 50 % reduction in cyclophosphamide. Full-dose chemotherapy was resumed after her condition stabilized. She also underwent intensity-modulated radiotherapy (41.4 Gy). She achieved complete tumor regression, normalization of liver function, and long-term remission. Follow-up CT after two years showed stable residual soft tissue thickening at the porta hepatis, with no signs of recurrent or progressive disease. Despite its rarity, EBRMS and other biliary tree tumors should be considered in the differential diagnosis of children presenting with cholestasis. Early imaging studies, such as ultrasound, are critical to avoid diagnostic delays and ensure timely intervention.
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2025-04-21 | Abstract 6722: OFD1 as a novel biomarker in cholangiocarcinoma: insights into ciliary dysfunction and tumor growth
Abstract Cholangiocarcinoma (CCA) is a rare and aggressive solid tumor originating from cholangiocytes lining the biliary ducts. It is the second most common primary hepatic malignancy, with an increasing global incidence and limited therapeutic options. Recent studies suggest that the primary cilium acts as a tumor suppressor in the biliary tract by regulating key cancer-related signaling pathways. Moreover, evidence links the reduction or loss of primary cilia to increased aggressiveness in various human cancers. Here, we aimed to identify and functionally characterize primary cilia-associated genes with potential translational relevance for CCA prognosis and treatment. Our study included 120 CCA patients, comprising 51% (36) with intrahepatic CCA and 49% (34) with extrahepatic CCA. Whole-transcriptome and whole-exome profiling were conducted on laser micro-dissected formalin-fixed paraffin-embedded (FFPE) tissue specimens. Bioinformatic analysis identified OFD1 as the top-ranked cilium-associated gene (fold-change ≥ 2.5, p < 0.01) among differentially expressed genes in tumor, stromal, and normal tissues. We investigated the role of OFD1 in cilia formation and cell proliferation through in vitro experiments in healthy human cholangiocytes and CCA cell lines. Immunofluorescence staining with ciliary markers revealed that OFD1 silencing promoted ciliogenesis and inhibited tumor growth in CCA cell lines. Western blot analysis confirmed a significant upregulation of ciliary proteins, including PCM1, ARL13B, and acetylated tubulin, following OFD1 silencing. Furthermore, CRISPR/Cas9-mediated OFD1 depletion in CCA cells led to a marked reduction in cell proliferation and restored ciliogenesis. Conversely, OFD1 overexpression in normal cholangiocytes resulted in increased cell proliferation and migration, along with suppression of ciliogenesis. Clinically, higher OFD1 expression was significantly associated with poorer overall survival in CCA patients (10 vs. 39 months; HR 2.33, 95% CI 1.01-5.31, p = 0.03). In conclusion, we demonstrated that OFD1 functions as an oncogene in CCA, influencing primary cilia formation and tumor cell growth. Higher OFD1 expression is a significant predictor of worse survival outcomes, identifying OFD1 as a promising biomarker and potential therapeutic target in CCA. Citation Format: Fabiola Piscopo, Anna Barbato, Massimiliano Salati, Carla Pollastro, Giorgia Gitano, Alberto Marino, Lorenzo Evangelista, Luigi Ferrante, Antonella Iuliano, Luca Reggiani-Bonetti, Maria Salatiello, Pasquale Pisapia, Umberto Malapelle, Giancarlo Troncone, Massimo Dominici, Brunella Franco, Pietro Carotenuto. OFD1 as a novel biomarker in cholangiocarcinoma: insights into ciliary dysfunction and tumor growth [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 6722.
2016-12-13 | Genetic alteration regulated by microRNAs in biliary tract cancers.
Biliary tract cancers (BTCs) constitute a relatively rare but highly malignant class of tumors with poor prognosis including gallbladder cancer, intra- and extra-hepatic cholangiocarcinoma. Recently, accumulated evidences have demonstrated that deregulated expression of microRNAs (miRNAs) is closely associated with the development, invasion, metastasis and prognosis of different cancers including BTCs. MiRNAs comprise an endogenously expressed and highly evolutionarily conserved group of small, non-coding, single-stranded RNAs which negatively regulate target genes expression by means of combining with 3' untranslated region (UTR) of corresponding mRNAs at the post-transcriptional level with significant roles in various fundamental cellular procedures including cell proliferation, differentiation, migration, cell cycle control and apoptosis. Recent studies have indicated that miRNAs could function as novel tumor-promoting genes or tumor suppressor genes to act as potential therapeutic targets in anticancer treatment because the genetic alteration regulated by miRNAs could result in tumorigenesis and tumor inhibition. Anomalous miRNAs expression patterns, acting as phenotypic signatures of distinct cancers, are promising to be used as diagnostic, prognostic, predictive biomarkers. In this review, we summarize the current findings from the studies about potential genetic alteration regulated by miRNAs and their roles in BTCs.
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2025-05-31 | PD-1 monoclonal antibody (Tislelizumab)-induced DRESS syndrome in an intrahepatic cholangiocarcinoma patient with FGFR3 mutation and elevated IgG4:A case report.
Immune-related adverse events (irAEs) include a rare, idiosyncratic but potentially life-threatening drug reaction with eosinophilia and systemic symptoms (DRESS), characterized by exanthem, fever, as well as hematologic and visceral organ involvement. We describe a 54-year-old man under the novel sequential treatment including all-trans retinoic acid (ATRA) and programmed death protein 1(PD-1) antibody (Tislelizumab) for advanced intrahepatic cholangiocarcinoma (iCCA). He was found to have Tislelizumab-induced DRESS syndrome during adjuvant therapy, and also showed the evidence of IgG4-related lymphadenopathy (IgG4-RLAD) as well as Epstein-Barr virus (EBV) infection in the absence of hemophagocytic lymphohistiocytosis (HLH) and T cell lymphoma. The patient's clinical status was successfully ameliorated through the administration of corticosteroids, intravenous immunoglobulin (IVIG), and antiviral agents, demonstrating a positive response to the treatment protocol. He was the first-ever case report of Tislelizumab-induced DRESS syndrome in the context of IgG4-RLAD with an exploration of potential mechanisms. Furthermore, we found that a somatic fibroblast growth factor receptor (FGFR) 3 p.P774L mutation at the frequency of 1.96 % was detected in his iCCA tissue. These findings indicated that this novel therapy, based on ARTA and PD-1 antibody, is more effective and could guide the clinical application of PD-1 antibody in the iCCA patients with elevated IgG4. Human leukocyte antigen (HLA) typing assay might help to screen the potential susceptible individuals to avoid immune checkpoint inhibitors (ICIs)-induced DRESS syndrome.
2024-08-31 | A Lymphoepithelioma-Like Intrahepatic Cholangiocarcinoma With Massive Multinucleated Giant Cell Reaction.
Lymphoepithelioma-like intrahepatic cholangiocarcinoma (LEL-ICC) is a rare liver tumor that appears as a hepatic nodule on imaging with a specific pathological pattern, and the definitive diagnosis relies on its pathological histomorphology, immunophenotype, and Epstein-Barr encoding region test. Radical surgical resection is the primary treatment modality, and immunotherapy is expected to be a new adjuvant treatment option. LEL-ICC with massive multinucleated giant cell infiltration has not been reported so far. In this article, we report a patient with LEL-ICC showing massive multinucleated giant cell infiltration, review the relevant literature, and analyze its clinicopathological features and prognosis to accumulate experience for the accurate diagnosis of LEL-ICC.
2024-05-02 | Efficacy of dual checkpoint inhibitors in a patient with a mixed hepatocellular cholangiocarcinoma.
A woman in her 60s was diagnosed with a metastatic, unresectable rare histological type of liver cancer; combined hepatocellular cholangiocarcinoma. She had palliative chemotherapy, initially with gemcitabine and cisplatin, and then with oxaliplatin, L-folinic acid and fluorouracil. Both treatment strategies demonstrated disease progression, and somatic mutation profiling revealed no actionable mutations. The patient was started on immuno-oncology (IO) with nivolumab and ipilimumab, followed by maintenance nivolumab. She has achieved a sustained ongoing partial response since the start of this therapy for at least 12 months. The outcome in this patient is in keeping with the growing evidence of the role that IO agents have in metastatic biliary tract cancer and also serves to highlight their importance in mixed histology liver tumours.
2022-09-08 | Clinical treatment of cholangiocarcinoma: an updated comprehensive review.
Cholangiocarcinoma (CCA) is a heterogeneous group of neoplasms of the bile ducts and represents the second most common hepatic cancer after hepatocellular carcinoma; it is sub-classified as intrahepatic cholangiocarcinoma (iCCA) and extrahepatic cholangiocarcinoma (eCCA), the latter comprising both perihilar cholangiocarcinoma (pCCA or Klatskin tumor), and distal cholangiocarcinoma (dCCA). The global incidence of CCA has increased worldwide in recent decades. Chronic inflammation of biliary epithelium and bile stasis represent the main risk factors shared by all CCA sub-types. When feasible, liver resection is the treatment of choice for CCA, followed by systemic chemotherapy with capecitabine. Liver transplants represent a treatment option in patients with very early iCCA, in referral centers only. CCA diagnosis is often performed at an advanced stage when CCA is unresectable. In this setting, systemic chemotherapy with gemcitabine and cisplatin represents the first treatment option, but the prognosis remains poor. In order to ameliorate patients' survival, new drugs have been studied in the last few years. Target therapies are directed against different molecules, which are altered in CCA cells. These therapies have been studied as second-line therapy, alone or in combination with chemotherapy. In the same setting, the immune checkpoints inhibitors targeting programmed death 1 (PD-1), programmed death-ligand 1 (PD-L1), cytotoxic T-lymphocyte antigen-4 (CTLA-4), have been proposed, as well as cancer vaccines and adoptive cell therapy (ACT). These experimental treatments showed promising results and have been proposed as second- or third-line treatment, alone or in combination with chemotherapy or target therapies.
2021-09-15 | Efficacy of pembrolizumab in microsatellite instability-high locally advanced cholangiocarcinoma: a case report.
Cholangiocarcinoma is a biliary malignant tumor which can arise at any point of biliary tree. Surgical resection is the only curative treatment and chemotherapy is used for unresectable cases, but its prognosis is poor compared with other types of cancer. Recently, pembrolizumab (PEM), an anti-programmed cell death protein 1 (PD-1) antibody, has become available for microsatellite instability (MSI)-high advanced cancers. Here, we report the use of PEM for MSI-high locally advanced cholangiocarcinoma. A 57-year-old man presented to our department with jaundice. Contrast-enhanced computed tomography showed a solitary 28-mm-diameter tumor deep in the anterior segment of the liver. Endoscopic retrograde cholangiopancreatography and intraductal ultrasonography showed narrowing of the common bile duct and absence of contrast in the right hepatic duct, and tumor invaded from hilar region of liver into left hepatic duct. We diagnosed this as double primary cancers, locally advanced intrahepatic and distal cholangiocarcinomas. The patient began gemcitabine in combination with cisplatin therapy as first-line treatment and gemcitabine in combination with S-1 therapy as second-line treatment. However, the tumor gradually grew (maximum 69 mm), intrahepatic metastasis appeared, and tumor marker increased. Because MSI-high was confirmed not only by biopsy specimens but also by liquid biopsy, the patient began PEM (200 mg per every 3 weeks). After 15 cycles of PEM were administered over about 10 months, size of tumor was reduced and tumor marker dramatically decreased. We experienced the rare case which PEM has been successfully used for MSI-high double primary cancers.
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2026-01-02 | Intraductal papillary neoplasm of the biliary tract with typical clinicopathological, endoscopic features: A case report.
A literature review revealed that intraductal papillary mucinous neoplasm of the biliary tract (IPMN-B) cases with characteristic clinical, imaging, endoscopic, and pathological features are exceedingly rare. Herein, we present a case of typical IPMN-B with malignant transformation that required 4 years for a definitive diagnosis, to enhance the understanding of this disease entity. A 67-year-old male patient was referred to our hospital due to abdominal pain and jaundice. Four years before this admission, a cystic lesion and left hepatolithiasis were incidentally discovered. Laboratory tests revealed mild increases in serum white blood cell count, total bilirubin, alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, and gamma-glutamyl transferase. Tumour marker levels were within normal limits. Imaging findings demonstrated an enlargement of the cystic tumour from 41 mm to 63 mm, along with the development of numerous enhancing papillary nodules within it, which showed hyperenhancement during the arterial phase. Duodenoscopy revealed an enlarged major duodenal papilla with a fish-mouth appearance and dilated orifice, exuding translucent jelly-like mucus. Endoscopic retrograde cholangiography demonstrated multiple cloudy, irregular filling defects within the dilated extrahepatic bile duct. Following the diagnosis of IPMN-B, left hepatectomy was performed. Postoperative histopathological examination and immunohistochemistry confirmed IPMN-B with high-grade intraepithelial neoplasia and associated invasive carcinoma. Heightened vigilance and recognition of IPMN-B are essential when "hepatic cysts" or "biliary stones" are incidentally detected.
2023-08-21 | Phase 2 trial of bintrafusp alfa as second-line therapy for patients with locally advanced/metastatic biliary tract cancers.
Biliary tract cancers are rare, heterogeneous cancers with poor prognoses. Bintrafusp alfa, a first-in-class bifunctional fusion protein composed of the extracellular domain of TGF-βRII (a TGF-β "trap") fused to a human IgG1 monoclonal antibody blocking programmed death ligand 1, was evaluated in patients with locally advanced/metastatic chemorefractory biliary tract cancers. This multicenter, single-arm, open-label, phase 2 study (NCT03833661) enrolled adults with locally advanced or metastatic biliary tract cancer that was intolerant to or had failed first-line systemic platinum-based chemotherapy. Patients received 1200 mg bintrafusp alfa intravenously Q2W. The primary endpoint was confirmed objective response according to Response Evaluation Criteria in Solid Tumors 1.1 assessed by IRC. Secondary endpoints included duration of response, durable response rate, safety, progression-free survival, and overall survival.Between March 2019 and January 2020, 159 patients were enrolled. Median follow-up was 16.1 (range, 0.0-19.3) months; 17 patients (10.7%; 95% CI: 6.4%-16.6%) achieved an objective response. Median duration of response was 10.0 (range, 1.9-15.7) months; 10 patients (6.3%; 95% CI: 3.1%-11.3%) had a durable response (≥6 mo). Median progression-free survival was 1.8 months (95% CI: 1.7-1.8 mo); median overall survival was 7.6 months (95% CI: 5.8-9.7 mo). Overall survival rates were 57.9% (6 mo) and 38.8% (12 mo). Grade ≥3 adverse events occurred in 26.4% of patients, including one treatment-related death (hepatic failure). Frequent grade ≥3 adverse events included anemia (3.8%), pruritus (1.9%), and increased alanine aminotransferase (1.9%). Although this study did not meet its prespecified primary endpoint, bintrafusp alfa demonstrated clinical activity as second-line treatment in this hard-to-treat cancer, with durable responses and a manageable safety profile.
other
2026-04-03 | Abstract 2667: TM4SF1 as a novel tumor-associated antigen in biliary tract cancers targetable by immune effector cell therapy
Abstract Biliary tract cancers (BTC) are a rare set of genetically heterogeneous and aggressive malignancies associated with late presentation, poor prognosis and limited effective therapies. Thus, there is an unmet clinical need for the development of novel therapeutic strategies. Identification of uniquely expressed cell-surface tumor-associated antigens (TAA) holds promise in epithelial tumors more generally, as they can serve as ligands for a variety of therapeutics, including CAR-T cell therapy. However, TAA identification in BTCs has been limited by expression in normal liver tissue. Here, we identify the cell-surface protein transmembrane 4 L six family member 1 (TM4SF1) as a potential BTC TAA targetable by CAR-T therapy. We find TM4SF1 expression is upregulated in BTC relative to normal hepatic/biliary tissue at the mRNA level in the TCGA dataset. Correspondingly, we find that TM4SF1 in primary BTC archival tissue is upregulated at the protein level using immunohistochemistry. To validate TM4SF1 as a targetable TAA in BTC, we show that TM4SF1-directed CAR-T cells demonstrate robust, dose-dependent growth inhibition of human-derived BTC cell lines in vitro and significant anti-tumor activity in a heterotopic BTC cell line-derived xenograft model in vivo. Together, our data provide support for TM4SF1 as a promising TAA in BTCs that can be used for the rational development of therapeutic modalities targeting TM4SF1, including CAR-T cells, in a patient population with significant unmet need. Citation Format: Lorraine Nuniz, Franklin Huang. TM4SF1 as a novel tumor-associated antigen in biliary tract cancers targetable by immune effector cell therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 2667.
2025-06-26 | A proposed staging system for intrahepatic cholangiocarcinoma involving the hilar.
Intrahepatic cholangiocarcinoma involving the hepatic hilum (h-ICC) is a rare and aggressive malignancy with heterogeneous clinical outcomes. Current staging systems are often inadequate for prognostic prediction in this subgroup. This study aimed to identify key prognostic factors and develop a novel, clinically applicable survival classification model for patients with h-ICC undergoing surgery. We retrospectively analyzed 333 patients with h-ICC at West China Hospital from 2003 to 2023. Baseline clinical, laboratory, and imaging data were collected. Univariate and multivariate Cox regression analyses identified independent prognostic factors. A classification and regression tree (CART) model was constructed to stratify patients based on overall survival. Model performance was assessed using ROC curves and Brier scores. Intrahepatic metastasis (HR = 1.569, P = 0.0489) and regional lymph node metastasis (HR = 2.227, P < 0.001) were identified as independent prognostic factors. A CART-based survival model stratified patients into four risk groups based on regional lymphatic metastasis, local organ metastasis, intrahepatic metastasis, total bilirubin level (cutoff: 192.6 μmol/L), and tumor size (cutoff: 4.65 cm). Based on these variables, we constructed a nomogram to improve clinical availability. After verification, the proposed model demonstrated good discriminatory ability and calibration. Intrahepatic and lymphatic metastases are critical prognostic indicators in h-ICC. The newly developed CART-based staging system offers improved survival stratification and may guide personalized treatment planning in this patient population.
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Drug Discovery Landscape
2 orphan drug designations for Rare hepatic and biliary tract tumor.
2 orphan drug designations for Rare hepatic and biliary tract tumor.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
humanized IgG1 monoclonal antibody against annexin-A1 | antibodies | FDA | 2025-09-26 | — | Medannex Ltd |
transforming growth factor beta trap/anti-programmed death ligand-1 antibody bifunctional fusion protein | antibodies | FDA | 2018-12-07 | — | EMD Serono Research & Development Institute, Inc. |
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