Gemcitabine combined with cisplatin is the first-line chemotherapy for advanced cholangiocarcinoma, but drug resistance remains a challenge, leading to unsatisfactory therapeutic effect. Here, we elucidate the possibility of chemotherapy regimens sensitized by inhibiting succinylation in patients with cholangiocarcinoma from the perspective of post-translational modification. Our omics analysis reveals that succinylation of PDHA1 lysine 83, a key enzyme in the tricarboxylic acid cycle, alters PDH enzyme activity, modulates metabolic flux, and leads to alpha-ketoglutaric acid accumulation in the tumor microenvironment. This process activates the OXGR1 receptor on macrophages, triggering MAPK signaling and inhibiting MHC-II antigen presentation, which promotes immune escape and tumor progression. Moreover, we show that inhibiting PDHA1 succinylation with CPI-613 enhances the efficacy of gemcitabine and cisplatin. Targeting PDHA1 succinylation may be a promising strategy to improve treatment outcomes in cholangiocarcinoma and warrants further clinical exploration.

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

A prospective study was started in May 2016 to evaluate the efficacy and safety of particle therapy for intrahepatic cholangial carcinoma (ICC). To compare treatment modalities, we also conducted a meta-analysis of literature data and a systematic comparison using registry data.

Patients who received particle therapy for ICC from May 2016 to June 2018 were registered. Nineteen manuscripts (4 particle therapy, 8 3D-CRT, 7 SBRT) were selected for the meta-analysis.

A total of 85 cases (proton beam therapy 59, carbon therapy 26) were registered. The median overall survival (OS) of the 85 patients was 22.1 months (95% CI: 12.9-31.3); the 1-, 2-, 3-, and 4-year OS rates were 70.9% (95% CI: 61.1-80.7%), 47.6% (36.8-58.4%), 37.7% (26.7-48.7%), and 22.7% (10.2-35.2%), respectively; and the 1-, 2-, 3-, and 4-year local recurrence rates were 8.2% (1.1-15.3%), 21.6% (9.3-33.9%), 33.4% (16.7-50.1%), and 33.4% (16.7-50.1%), respectively. In the meta-analysis and registry data, the 1-year OS for particle therapy, SBRT and 3D-CRT were 71.8% (95% CI: 64.6-77.8%), 59.2% (53.0-64.9%, p = 0.0573), and 47.2% (36.8-56.9%, p = 0.0004), respectively. The incidence of grade 3 or higher late non-hematological toxicity in the meta-analysis and registry data were 7.4-12% for particle therapy, 6.7-16.7% for SBRT, and 8.1-14.3% for 3D-CRT.

Particle therapy achieved a good therapeutic effect for ICC, and a meta-analysis indicated that particle therapy is a better treatment modality than SBRT and 3D-CRT.

Gallbladder cancer is characterized by a dismal prognosis, with a limited number of biological markers currently identified for the carcinogenesis, progression and prognosis of gallbladder cancers (GBCs). The discovery of efficacious biomarkers is crucial for enhancing the prognosis of gallbladder cancer.

Analysis of RNAseq datasets from gallbladder cancer allowed the identification of differential genes between gallbladder cancer and adjacent tissues. Subsequent application of Mendelian randomization extracted target gene known to promote gallbladder cancer from these differentially expressed genes. Immunohistochemistry was then conducted to evaluate the expression of these target gene in a cohort of 215 patients with gallbladder cancer, utilizing follow-up information to determine their prognostic value. Moreover, single-cell sequencing data of gallbladder cancer elucidated the role of target genes within the immune microenvironment of this cancer type. The Genomics of Therapeutics Response Portal (CTRP) database enabled the assessment of the impact of target genes on the IC50 of chemotherapy drugs. Lastly, network pharmacology and analytical methodologies were employed to investigate the effects of traditional Chinese medicine active ingredients targeting these specific genes.

ASPH expression is notably elevated in gallbladder cancer tissues, correlating with an unfavorable prognosis for patients afflicted with this disease. Results from Mendelian randomization studies suggest that heightened ASPH levels play a significant role in the development of gallbladder polyps and stones, which are established clinical risk factors in gallbladder cancer. Analysis of clinical samples demonstrates a positive association between ASPH expression and indicators of poor differentiation, increased tumor size, advanced TNM stage, lymph node metastasis, and invasion. The single-cell immune microenvironment reveals that ASPH not only enhances the expression of immune checkpoints, namely PDL1 and PVR, in the gallbladder cancer epithelium, resulting in immune evasion, but also triggers epithelial-mesenchymal transition and migration, promoting metastasis. Furthermore, ASPH contributes to heightened tumor drug metabolism, hence raising the IC50 values for gemcitabine and paclitaxel. Utilizing network pharmacology and molecular docking techniques, this study pinpointed six bioactive compounds derived from traditional Chinese medicine with a targeted effect on the ASPH protein, comprising Sebacic acid, Suberic acid, Azelaic acid, Dimelic acid, Succinic acid, and D-Asparaginsaeure.

ASPH plays a role in promoting the development of gallbladder cancer and resistance to chemotherapeutic agents, rendering it a promising target for therapeutic interventions. Active therapeutic compounds targeted on ASPH can be identified among the active ingredients present in traditional Chinese medicine.

Intrahepatic cholangiocarcinoma (iCCA) is a malignant liver tumor with a rising global incidence and poor prognosis, largely due to late-stage diagnosis and limited effective treatment options. Standard chemotherapy regimens, including cisplatin and gemcitabine, often fail because of the development of multidrug resistance (MDR), leaving patients with few alternative therapies. Doxycycline, a tetracycline antibiotic, has demonstrated antitumor effects across various cancers, influencing cancer cell viability, apoptosis, and stemness. Based on these properties, we investigated the potential of doxycycline to overcome gemcitabine resistance in iCCA.

We evaluated the efficacy of doxycycline in two MDR iCCA cell lines, MT-CHC01R1.5 and 82.3, assessing cell cycle perturbation, apoptosis induction, and stem cell compartment impairment. We assessed the in vivo efficacy of combining doxycycline and gemcitabine in mouse xenograft models.

Treatment with doxycycline in both cell lines resulted in a significant reduction in cell viability (IC50 ~15 µg/mL) and induction of apoptosis. Doxycycline also diminished the cancer stem cell population, as indicated by reduced cholangiosphere formation. In vivo studies showed that while neither doxycycline nor gemcitabine alone significantly reduced tumor growth, their combination led to marked decreases in tumor volume and weight at the study endpoint. Additionally, metabolic analysis revealed that doxycycline reduced glucose uptake in tumors, both as a monotherapy and more effectively in combination with gemcitabine.

These findings suggest that doxycycline, especially in combination with gemcitabine, can restore chemotherapy sensitivity in MDR iCCA, providing a promising new strategy for improving outcomes in this challenging disease.

To compare overall survival (OS), toxicity, and quality of life (QOL) in patients with metastatic gallbladder cancer receiving oral capecitabine (X) with best supportive care (BSC) and BSC alone.

Patients with metastatic gallbladder cancer and Karnofsky Performance Status (KPS) ≥70 were accrued and assigned to either arm A or B. Assignment to these two arms was based on physician/patient discretion. Arm A received oral capecitabine 825 mg/m2 twice a day d1-14, repeated every 3 weeks for six cycles with BSC, and arm B received BSC alone. The Kaplan-Meier method computed OS and comparison was using a log-rank test. QOL was measured using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire C30 administered at baseline, 3 months, and 6 months. The linear mixed-effects model was used for the longitudinal analysis of QOL.

Between December 2020 and April 2022, 64 patients diagnosed with metastatic gallbladder carcinoma and KPS ≥70 were accrued in the study, and 32 patients were assigned to each arm. In arm A versus B, the median age was 52 versus 55 (P = .21); the median KPS was 80 versus 70 (P = .008). The median OS in arm A versus B was 3.4 versus 2 months (P = .001). Grade 1-2 vomiting and diarrhea were seen in 50% versus 78% (P = .041) and 59% versus 9.3% (P = .01) patients in arm A versus B, respectively. Grade 1-2 hand-foot syndrome was seen in 12 (37.5%) patients in arm A. Dynamic changes showed an improvement in pain in the linear mixed model with a significant difference between the arms (P = .011); arm A experienced a significant improvement in pain over time (arm × time P = .020). Global QOL improved over time (P = .038) with parallel improvement between arms (arm × time P = .490).

Compared with BSC alone, patients who receive X + BSC experience an OS improvement of 1.4 months and better pain control without grade 3 toxicities or negative impact on QOL.

Despite a rising incidence, biliary tract cancers (BTCs) are still considered a rare tumor entity. The disease's subtle clinical presentation and lack of effective early detection strategies often lead to a diagnosis at an advanced or unresectable stage, where curative options are limited.

This review provides an overview of current systemic therapies and emerging novel approaches for BTC. For decades, the combination of gemcitabine with cisplatin (GemCis) has been the standard of care for palliative treatment. However, since 2020, the diagnostic and therapeutic landscape for BTC has evolved considerably, not only in the first-line setting but also beyond, driven by the development of clinical trials exploring immunotherapy and molecularly targeted agents. Due to the high frequency of targetable genetic alterations in BTC patients, there is a growing emphasis on obtaining tissue or liquid biopsy samples to identify markers like microsatellite instability and other actionable oncogenic driver genes.

Early initiation of systemic therapies in combination with multimodal approaches is essential for maximizing survival outcomes in patients with BTC.

Cholangiocarcinoma (CCA), a malignancy that arises from biliary epithelial cells, has a dismal prognosis, and few targeted therapies are available. Aurora B, a key mitotic regulator, has been reported to be involved in the progression of various tumors, yet its role in CCA is still unclarified.

Human CCA tissues and murine spontaneous CCA models were used to assess Aurora B expression in CCA. A loss-of-function model was constructed in CCA cells to determine the role of Aurora B in CCA progression. Subcutaneous and liver orthotopic xenograft models were used to assess the therapeutic potential of Aurora B inhibitors in CCA.

In murine spontaneous CCA models, Aurora B was significantly upregulated. Elevated Aurora B expression was also observed in 62.3% of human specimens in our validation cohort (143 CCA specimens), and high Aurora B expression was positively correlated with pathological parameters of tumors and poor survival. Knockdown of Aurora B by siRNA and heteroduplex oligonucleotide (HDO) or an Aurora B kinase inhibitor (AZD1152) significantly suppressed CCA progression via G2/M arrest induction. An interaction between Aurora B and c-Myc was found in CCA cells. Targeting Aurora B significantly reduced this interaction and accelerated the proteasomal degradation of c-Myc, suggesting that Aurora B promoted the malignant properties of CCA by stabilizing c-Myc. Furthermore, sequential application of AZD1152 or Aurora B HDO drastically improved the efficacy of gemcitabine in CCA.

Aurora B plays an essential role in CCA progression by modulating c-Myc stability and represents a new target for treatment and chemosensitization in CCA.

Intrahepatic cholangiocarcinoma (iCCA) is the second most common malignant primary liver cancer. iCCA may develop on an underlying chronic liver disease and its incidence is growing in relation with the epidemics of obesity and metabolic diseases. In contrast, perihilar cholangiocarcinoma (pCCA) may follow a history of chronic inflammatory diseases of the biliary tract. The initial management of CCAs is often complex and requires multidisciplinary expertise. The French Association for the Study of the Liver wished to organize guidelines in order to summarize the best evidence available about several key points in iCCA and pCCA. These guidelines have been elaborated based on the level of evidence available in the literature and each recommendation has been analysed, discussed and voted by the panel of experts. They describe the epidemiology of CCA as well as how patients with iCCA or pCCA should be managed from diagnosis to treatment. The most recent developments of personalized medicine and use of targeted therapies are also highlighted.

Cholangiocarcinoma (CCA) is a rare and aggressive cancer, mostly diagnosed at advanced or metastatic stage, at which point systemic treatment represents the only therapeutic option. Chemotherapy has been the backbone of advanced CCA treatment. More recently, immunotherapy has changed the therapeutic landscape, as immune checkpoint inhibitors have yielded the first improvement in survival and currently, the addition of either durvalumab or pembrolizumab to standard of care cisplatin plus gemcitabine represents the new first-line treatment option. However, the use of immunotherapy in subsequent lines has not demonstrated its efficacy and therefore, it is not approved, except for pembrolizumab in the selected microsatellite instability-high population. In addition, advances in comprehensive genomic profiling have led to the identification of targetable genetic alterations, such as isocitrate dehydrogenase 1 (IDH1), fibroblast growth factor receptor 2 (FGFR2), human epidermal growth factor receptor 2 (HER2), proto-oncogene B-Raf (BRAF), neurotrophic tropomyosin receptor kinase (NTRK), rearranged during transfection (RET), Kirsten rat sarcoma virus (KRAS), and mouse double minute 2 homolog (MDM2), thus favoring the development of a precision medicine approach in previously treated patients. Despite these advances, the use of molecularly driven agents is limited to a subgroup of patients. This review aims to provide an overview of the newly approved systemic therapies, the ongoing studies, and future research challenges in advanced CCA management.

Immune checkpoint blockade (ICB)-based immunotherapy has inspired new hope for advanced biliary tract cancer (BTC) treatment; however, there are no prior studies that primarily focus on different anatomical types of unresectable BTCs reacting differently to ICB.

We retrospectively collected data on advanced BTC patients who received anti-programmed cell death protein 1 (anti-PD1) therapy from two affiliated hospitals of Sun Yat-Sen university. The effects of anti-PD1 were compared for different anatomical sites. The GSE32225 and GSE132305 datasets were used to further analyze differences in the immune microenvironments between intrahepatic cholangiocarcinoma (ICC) and extrahepatic cholangiocarcinoma (ECC).

A total of 198 advanced BTC patients were enrolled in this study, comprising 142 patients with ICC and 56 with other cancer types ("Others" group), including ECC and gallbladder cancer. In the anti-PD1 treated patients, the ICC group (n = 90) achieved longer median progression-free survival (mPFS) (9.5 vs. 6.2 months, p = 0.02) and median overall survival (mOS) (15.1 vs. 10.7 months, p = 0.02) than the Others group (n = 26). However, chemotherapy did not show different effects between the two groups (mOS: 10.6 vs. 12.1 months, p = 0.20; mPFS: 4.9 vs. 5.7 months, p = 0.83). For the first-line anti-PD1 therapy, the ICC group (n = 70) achieved higher mOS (16.0 vs. 11.8 months, p = 0.04) than the Others group (n = 19). Moreover, most chemokines, chemokine receptors, major histocompatibility complex molecules, immunostimulators, and immunoinhibitors were stronger in ICC than ECC; furthermore, CD8+ T cells and M1 macrophages were higher in ICC than ECC for most algorithms. The immune differential genes were mainly enriched in antigen processing and presentation as well as the cytokine receptors.

This study shows that the efficacy of anti-PD1 therapy was higher in ICC than in other types of BTCs. Differences in the immune-related molecules and cells between ICC and ECC indicate that ICC could benefit more from immunotherapy.

Existing clinical biomarkers do not reliably predict treatment response or disease progression in patients with advanced intrahepatic cholangiocarcinoma (ICC). Circulating neoplastic-immune hybrid cells (CHCs) have great promise as a blood-based biomarker for patients with advanced ICC. Peripheral blood specimens were longitudinally collected from patients with advanced ICC enrolled in the HELIX-1 phase II clinical trial (NCT04251715). CHCs were identified by co-expression of pan-cytokeratin (CK) and CD45, and levels were correlated to patient clinical disease course. Unsupervised machine learning was then performed to extract their morphological features to compare them across disease courses. Five patients were included in this study, with a median of nine specimens collected per patient. A median of 13.5 CHCs per 50,000 peripheral blood mononuclear cells were identified at baseline, and levels decreased to zero following the initiation of treatment in all patients. Counts remained undetectable in three patients who demonstrated end-of-trial clinical treatment response and conversely increased in two patients with evidence of therapeutic resistance. In the post-trial surveillance period, interval counts increased prior to or at the time of clinical progression in three patients and remain undetectable in one patient with continued long-term disease stability. Using our machine learning platform, treatment-resistant CHCs exhibited upregulation of CK and downregulation of CD45 relative to treatment-responsive CHCs. CHCs represent a promising blood-based biomarker to supplement traditional radiographic and biochemical measures.

Despite the recent advances in cancer treatment, the therapeutic options for patients with biliary tract cancer are still very limited and the prognosis very poor. More than 50% of newly diagnosed patients with biliary tract cancer are not amenable to curative surgical treatment and thus treated with palliative systemic treatment. Malignant bile duct obstructions in patients with perihilar and/or ductal cholangiocarcinoma (CCA) represents one of the most important challenges in the management of these patients, owning to the risk represented by developing life-threatening cholangitis which, in turn, limits the use of systemic treatment. For this reason, endoscopic stenting and/or bile duct decompression is the mainstay of treatment of these patients. Data on efficacy and safety of adding radiofrequency ablation (RFA) to biliary stenting is not conclusive. The aim of this multicenter, randomized trial is to evaluate the effect of intraductal RFA prior to bile duct stenting in patients with unresectable perihilar or ductal CCA undergoing palliative systemic therapy.

ACTICCA-2 is a multicenter, randomized, controlled, open-label, investigator-initiated trial. 120 patients with perihilar or ductal CCA with indication for biliary stenting and systemic therapy will be randomized 1:1 to receive either RFA plus bile duct stenting (interventional arm) or bile duct stenting alone (control arm). Patients will be stratified by trial site and tumor location (perihilar vs. ductal). Both arms receive palliative systemic treatment according to the local standard of care determined by a multidisciplinary tumorboard. The primary endpoint is time to first biliary event, which is determined by an increase of bilirubin to > 5 mg/dl and/or the occurrence of cholangitis leading to premature stent replacement and/or disruption of chemotherapy. Secondary endpoints include overall survival, safety according to NCI CTCAE v5, quality of life assessed by questionnaires (EORTC QLQ-C30 and QLQ-BIL21), clinical event rate at 6 months after RFA and total days of over-night stays in hospital. Follow-up for the primary endpoint will be 6 months, while survival assessment will be continued until end of study (maximum follow-up 30 month). All patients who are randomized and who underwent endoscopic stenting will be used for the primary endpoint analysis which will be conducted using a cause-specific Cox proportional hazards model with a frailty for trial site and fixed effects for the treatment group, tumor location, and stent material.

ACTICCA-2 is a multicenter, randomized, controlled trial to assess efficacy and safety of adding biliary RFA to bile duct stenting in patients with CCA receiving palliative systemic treatment.

The study is registered with ClinicalTrials.gov (NCT06175845) and approved by the local ethics committee in Hamburg, Germany (2024-101232-BO-ff). This manuscript reflects protocol version 1 as of January 9th, 2024.

Cholangiocarcinoma (CCA) features highly desmoplastic stroma that promotes structural and functional resistance to therapy. Lysyl oxidases (LOX, LOXL1-4) catalyze collagen cross-linking, thereby increasing stromal rigidity and facilitating therapeutic resistance. Here, we evaluate the role of lysyl oxidases in stromal desmoplasia and the effects of pan-lysyl oxidase (pan-LOX) inhibition in CCA.

Resected CCA and normal liver specimens were analyzed from archival tissues. Spontaneous and orthotopic murine models of intrahepatic CCA (iCCA) were used to assess the impact of the pan-LOX inhibitor PXS-5505 in treatment and correlative studies. The functional role of pan-LOX inhibition was interrogated through in vivo and ex vivo assays.

All 5 lysyl oxidases are upregulated in CCA and reduced lysyl oxidase expression is correlated with an improved prognosis in resected patients with CCA. Spontaneous and orthotopic murine models of intrahepatic cholangiocarcinoma upregulate all 5 lysyl oxidase isoforms. Pan-LOX inhibition reversed mechanical compression of tumor vasculature, resulting in improved chemotherapeutic penetrance and cytotoxic efficacy. The combination of chemotherapy with pan-LOX inhibition increased damage-associated molecular pattern release, which was associated with improved antitumor T-cell responses. Pan-LOX inhibition downregulated macrophage invasive signatures in vitro, rendering tumor-associated macrophages more susceptible to chemotherapy. Mice bearing orthotopic and spontaneously occurring intrahepatic cholangiocarcinoma tumors exhibited delayed tumor growth and improved survival following a combination of pan-LOX inhibition with chemotherapy.

CCA upregulates all 5 lysyl oxidase isoforms, and pan-LOX inhibition reverses tumor-induced mechanical forces associated with chemotherapy resistance to improve chemotherapeutic efficacy and reprogram antitumor immune responses. Thus, combination therapy with pan-LOX inhibition represents an innovative therapeutic strategy in CCA.

The prognosis of patients with perihilar-cholangiocarcinoma (PHC) is poor, with the majority presenting with unresectable disease at diagnosis. Palliative chemotherapy (CHT) is the standard treatment for unresectable PHC. Irreversible electroporation (IRE) has been introduced as a novel ablation technique, working predominantly nonthermal. This review aims to analyse the efficacy and safety of IRE in treating unresectable PHC.

This systematic review and meta-analysis was performed according to a specific protocol designed a priori, and reported according to the PRISMA. PubMed/MEDLINE, Scopus, and Cochrane CENTRAL were searched up to December 2023. Primary Outcome of interest of our meta-analysis was the mean Overall Survival (OS). Secondary outcomes were progression-free survival (PFS) and adverse event rate (AE).

The mean OS was estimated at 25.49 months (CI, 21.47-38.72, I2 81.37%), PFS 17.86 (CI, 13.00-22.72, I2 11.42%), with an AE incidence of 12% (CI, 7%-31%, I2 83.57%). High heterogeneity was found among studies, with no single study fully responsible for it, suggesting high variability among facilities/populations.

IRE is effective and relatively safe for unresectable PHC. However, the lack of prospective studies and randomized trials comparing chemotherapy or locoregional treatment with IRE prevents drawing sufficiently robust conclusions.

IRE appears a safe and effective technique for treating unresectable perihilar cholangiocarcinoma.

Cholangiocarcinoma is the most common malignancy of the biliary tree and has a poor prognosis. Adenocarcinoma is the most common pathological type of cholangiocarcinomas, but rare squamous, adenosquamous, and mucinous variants have been reported without adequate clinical data.

This report describes a rare case of primary squamous cell carcinoma (SCC) of the intrahepatic bile duct. The patient was admitted with a tumor in the hepatic caudate lobe with no obvious clinical symptoms. Examination revealed hepatitis B surface antigen positivity, a slight increase in alfa-fetoprotein to 16.34 ng/mL, and an irregular slightly heterogeneous enhancing lesion in the hepatic caudate lobe, which was initially thought to be hepatocellular carcinoma. Laparoscopic resection was performed, and the final pathology suggested a rare primary SCC of the intrahepatic bile duct. Immunohistochemistry indicated positivity for villin, partial positivity for p63, and negativity for hepatocyte, CK7, CK8, CK19, and CK20. The Ki-67 index was approximately 60%. The patient received six cycles of Tegio chemotherapy. A new lesion was detected in the liver after 15 months. The surgery was performed, and the patient was followed-up at a local hospital. To date, no new lesions have been observed.

Surgery is the first choice for resectable lesions, and combined chemotherapy based on pathology is essential for increasing overall survival.

The locally advanced unresectable intrahepatic cholangiocarcinoma (ICC) has detrimental oncological outcomes. In this study, we aimed to investigate the efficacy of radiotherapy in patients with locally advanced unresectable ICC.

Between 2001 and 2021, 116 patients were identified through medical record who underwent radiotherapy for locally advanced unresectable ICC. The resectability of ICC is determined by the multidisciplinary team at each institution. Overall survival (OS) were analyzed using the Kaplan-Meier method, and prognostic factors were analyzed using the Cox proportional hazards model.

The median equivalent radiotherapy dose in 2 Gy fractions (EQD2) was 52 Gy (range, 30 to 110 Gy). Forty-seven patients (40.5%) received sequential gemcitabine-cisplatin based chemotherapy (GEM-CIS CTx). Multivariate analysis identified two risk factors, EQD2 of ≥ 60 Gy and application of sequential GEM-CIS CTx for OS. Patients were grouped by these two risk factors: group 1, EQD2 ≥ 60 Gy with sequential GEM-CIS CTx (n=25); group 2, EQD2 < 60 Gy with sequential GEM-CIS CTx or fluoropyrimidine-based concurrent chemoradiotherapy (n=70); and group 3, radiotherapy alone (n=21). Curative resection was more frequently undergone in group 1 than in groups 2 or 3 (28% vs. 8.6% vs. 0%, respectively). Consequently, OS was significantly better in group 1 than in groups 2 and 3 (p < 0.05).

Combined high-dose radiotherapy with sequential GEM-CIS CTx improved oncologic outcomes in patients with locally advanced unresectable ICC. Further prospective studies are required to validate these findings.

For biliary tract cancer (BTC), the addition of immunotherapy (durvalumab or pembrolizumab) to gemcitabine and cisplatin (GemCis) significantly improved overall survival (OS) in phase 3 clinical trials (RCTs). However, the interpretation and magnitude of the treatment effect is challenging because OS Kaplan-Meier curves violate the proportional hazards (PH) assumption. Analysis using restricted mean survival time (RMST) allows quantification of the benefits in the absence of PH. This systematic review and meta-analysis aims to assess the benefit of immunotherapy-based regimens for OS at 24 months using RMST analysis.

A systematic review was conducted using studies published up to 8 November 2023. Only phase 3 RCTs evaluating the use of anti-PD-1/PD-L1 combined with GemCis and reporting OS were included. KM curves for OS were digitized, and the data were reconstructed. A meta-analysis for OS by RMST at 24 months was performed.

A total of 1754 participants from the TOPAZ-1 and KEYNOTE-966 trials were included. In TOPAZ-1, RMSTs at 24 months were 13.52 (7.92) and 12.21 (7.22) months with GemCis plus durvalumab and GemCis alone, respectively. In KEYNOTE-966, RMSTs at 24 months were 13.60 (7.76) and 12.45 (7.73) months with GemCis plus pembrolizumab and GemCis alone, respectively. Immunotherapy-based regimens showed a mean OS difference at 24 months by an RMST of 1.21 months [(95% CI: 0.49-1.93), p < 0.001, I2 = 0%].

Immunotherapy-based regimens improve OS in advanced BTC. Given this magnitude of benefit, it is essential to weigh up individual patient factors, preferences, and potential risks. RMST analysis provides valuable information to patients and physicians, facilitating decision-making in a value-based medical environment.

The aim of this study is to investigate the role of CFHR1 in bile duct carcinoma (BDC) and its mechanism of action, and we hope that our analysis and research will contribute to a better understanding of cholangiocarcinoma (BDC) disease genesis, progression and the development of new therapeutic strategies. The prognostic receiver operating characteristic curve of CFHR1 was generated using survival ROC. The ROC curve for CFHR1 showed that there is a correlation between CFHR1 expression and clinicopathological parameters and has an impact on poor prognosis. STRING was used to predict the protein-protein interaction network of the identified genes, and the Microenvironment Cell Populations counter algorithm was used to analyze immune cell infiltration within the BDC. The combined analysis showed that CFHR1 was found to be upregulated in BDC tissues, along with a total of 20 related differentially expressed genes (DEGs) (8 downregulated and 12 upregulated genes). Also, the results showed that the expression of CFHR1 is correlated with immune cell infiltration in tumor and immune cell markers in BDC (P < 0.05). In addition, we have verified experimentally the biological function of CFHR1. These findings suggest that CFHR1 may be a prognostic marker and a potential therapeutic target for BDC. Information regarding the detailed roles of CFHR1 in BDC could be valuable for improving the diagnosis and treatment of this rare cancer.

To study which radiographic features were associated with recurrence and adverse outcome in patients undergoing surgical resection of perihilar cholangiocarcinoma (PCCA), as well as to evaluate the imaging patterns that signify recurrence after the resection of PCCA.

This study was conducted in a solitary tertiary center and utilized a retrospective, analytical, case-control design. The study population consisted of patients with pathologically confirmed PCCA who underwent surgical resection and were subsequently followed up from January 2009 to December 2017. A total of 77 patients were enrolled in the study and were categorized into two distinct groups, namely recurrent and non-recurrent. The analysis encompassed the examination of demographic data and recurrence patterns. Additionally, survival and multivariate analyses were employed to assess radiographic imaging data and surgical information.

Seventy-seven patients diagnosed with PCCA based on pathological evidence were included in the study. Among the participants, there were 28 females and 49 males, with ages ranging from 41 to 81 years (mean age of 60.65 ± 7.66). A noteworthy finding was the recurrence rate of 65 % observed following surgical resection. The presence of regional lymph node (LN) metastasis, adjacent organ invasion, and surgical margin emerged as the three independent factors that exhibited a significant association with recurrence after post-operative resection (p = 0.023, p = 0.028, and p = 0.010, respectively). The patients with PCCA who experienced regional LN metastasis had a median overall survival (OS) of 22 months, which was significantly lower than the 46 months observed in those without regional LN metastasis (p < 0.018). Furthermore, the individuals with regional LN metastasis had a death rate that was 2.08 times higher than those without (p = 0.040). In addition, those with adjacent organ invasion had an OS duration of 21 months compared with 52 months in those without (p = 0.008), and the rate of death was 2.39 times higher (p = 0.018). Patients with an R1 resection margin had an OS duration of 36 months compared with 51.56 months in those with an R0 resection margin (p = 0.006), as well as a 2.13 times higher rate of recurrence (p = 0.010) and a 2.43 times higher mortality rate (p = 0.013).

The presence of regional LN metastasis, invasion of adjacent organs, and R1 resection margin were identified as distinct factors that are linked to both disease recurrence and reduced OS. Local recurrence, as well as the spread of cancer to distant organs such as the lungs and liver, were frequently observed patterns of recurrence. To enhance the precision of staging, prognosis, and treatment, the inclusion of periductal fat or invasion of adjacent organs should be considered in the staging system for PCCA.

The incidence of intrahepatic cholangiocarcinoma (IHCCA) is rising around the world. The disease is becoming a major global health issue. Conventionally, most patients with cholangiocarcinoma present with advanced disease and systemic therapy is the mainstay of treatment. This review discusses recent advances in systemic treatments for patients with IHCCA.

The addition of durvalumab to a gemcitabine plus cisplatin regimen has significantly improved overall survival in the phase 3 TOPAZ-1 trial and is currently recommended as a standard first-line treatment. The phase 3 ABC-06 and phase 2b NIFTY trials have shown the benefit of second-line fluoropyrimidine plus oxaliplatin, and fluoropyrimidine plus nanoliposomal irinotecan, respectively. They have provided a treatment option for patients without actionable alterations who progressed to first-line therapy. For patients with actionable genomic alterations, including FGFR2 rearrangement, IDH1 mutation, BRAF mutation, and ERBB2 amplification, targeted agents have shown encouraging efficacy in several phase 2-3 trials, and are recommended as subsequent treatments. Immune checkpoint inhibitors are being investigated for the treatment of previously treated patients, although only a small proportion of patients showed durable responses.

Recent advances in systemic treatments have improved clinical outcomes in patients with advanced IHCCA. However, most patients eventually show resistance to the treatment, and tumor progression occurs within a year. Indeed, there should be further efforts to improve the outcomes of patients with advanced IHCCA.

Intrahepatic cholangiocarcinoma (ICC) can be treated with chemotherapy in unresectable cases, but outcomes are poor. Proton beam therapy (PBT) may provide an alternative treatment and has good dose concentration that may improve local control.

Fifty-nine patients who received initial PBT for ICC from May 2016 to June 2018 at nine centers were included in the study. The treatment protocol was based on the policy of the Japanese Society for Radiation Oncology. Forty patients received 72.6-76 Gy (RBE) in 20-22 fr, 13 received 74.0-76.0 Gy (RBE) in 37-38 fr, and 6 received 60-70.2 Gy (RBE) in 20-30 fr. Overall survival (OS) and progression-free survival (PFS) were estimated by Kaplan-Meier analysis.

The 59 patients (35 men, 24 women; median age: 71 years; range: 41-91 years) had PS of 0 (n = 47), 1 (n = 10), and 2 (n = 2). Nine patients had hepatitis and all 59 cases were considered inoperable. The Child-Pugh class was A (n = 46), B (n = 7), and unknown (n = 6); the median maximum tumor diameter was 5.0 cm (range 2.0-15.2 cm); and the clinical stage was I (n = 12), II (n = 19), III (n = 10), and IV (n = 18). At the last follow-up, 17 patients were alive (median follow-up: 36.7 months; range: 24.1-49.9 months) and 42 had died. The median OS was 21.7 months (95% CI: 14.8-34.4 months). At the last follow-up, 37 cases had recurrence, including 10 with local recurrence. The median PFS was 7.5 months (95% CI: 6.1-11.3 months). In multivariable analyses, Child-Pugh class was significantly associated with OS and PFS, and Child-Pugh class and hepatitis were significantly associated with local recurrence. Four patients (6.8%) had late adverse events of grade 3 or higher.

PBT gives favorable treatment outcomes for unresectable ICC without distant metastasis and may be particularly effective in cases with large tumors.

Patients with advanced biliary tract cancer (BTC) have a poor survival. We aim to evaluate the efficacy and safety of nab-paclitaxel plus gemcitabine and cisplatin regimen in Chinese advanced BTC patients.

Eligible patients with locally advanced or metastatic BTC administrated intravenous 100 mg/m2 nab-paclitaxel, 800 mg/m2 gemcitabine, and 25 mg/m2 cisplatin every 3 weeks. The primary endpoint was progression-free survival (PFS). The secondary endpoints included overall survival (OS) and adverse events, while exploratory endpoint was the association of biomarkers with efficacy.

After the median follow-up of 25.0 months, the median PFS and OS of 34 enrolled patients were 7.1 months (95% confidence interval [CI], 5.4 to 13.7) and 16.4 months (95% CI, 10.9 to 23.6), respectively. The most common treatment-related adverse events at ≥ 3 grade were neutropenia (26.5%) and leukopenia (26.5%). Survival analyses demonstrated that carcinoembryonic antigen (CEA) levels could monitor patients' survival outcomes. A significant increase in the number of infiltrating CD4+ cells (p=0.008) and a decrease in programmed death-1-positive (PD-1+) cells (p=0.032) were observed in the response patients.

In advanced BTC patients, nab-paclitaxel plus gemcitabine and cisplatin regimen showed therapeutic potential. Potential prognostic factors of CEA levels, number of CD4+ cells and PD-1+ cells may help us maximize the efficacy benefit.

Recently, anti-programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) immunotherapy offers promising results for advanced biliary tract cancer (BTC). However, patients show highly heterogeneous responses to treatment, and predictive biomarkers are lacking. We performed a systematic review and meta-analysis to assess the potential of PD-L1 expression as a biomarker for treatment response and survival in patients with BTC undergoing anti-PD-1/PD-L1 therapy.

We conducted a comprehensive systematic literature search through June 2023, utilizing the PubMed, EMBASE, and Cochrane Library databases. The outcomes of interest included objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), and overall survival (OS) according to PD-L1 expression. Subgroup analyses and meta-regression were performed to identify possible sources of heterogeneity.

A total of 30 studies was included in the final analysis. Pooled analysis showed no significant differences in ORR (odds ratio [OR], 1.56; 95% confidence intervals [CIs], 0.94-2.56) and DCR (OR, 1.84; 95% CIs, 0.88-3.82) between PD-L1 (+) and PD-L1 (-) patients. In contrast, survival analysis showed improved PFS (hazard ratio [HR], 0.54, 95% CIs, 0.41-0.71) and OS (HR, 0.58; 95% CI, 0.47-0.72) among PD-L1 (+) patients compared to PD-L1 (-) patients. Sensitivity analysis excluding retrospective studies showed no significant differences with the primary results. Furthermore, meta-regression demonstrated that drug target (PD-1 vs. PD-L1), presence of additional intervention (monotherapy vs. combination therapy), and PD-L1 cut-off level (1% vs. ≥5%) significantly affected the predictive value of PD-L1 expression.

PD-L1 expression might be a helpful biomarker for predicting PFS and OS in patients with BTC undergoing anti-PD-1/PD-L1 therapy. The predictive value of PD-L1 expression can be significantly influenced by diagnostic or treatment variables.

https://www.crd.york.ac.uk/PROSPERO, identifier CRD42023434114.

Biliary tract cancer (BTC) is a relatively rare but aggressive gastrointestinal cancer with a high mortality rate. Cancer stem cell (CSC) populations play crucial roles in tumor biology and are responsible for the low response to anti-cancer treatment and the high recurrence rate. This study investigated the role of Transgelin-2 (TAGLN2), overexpressed in CSC in BTC cells, and analyzed its expression in patient tissues and serum to identify potential new targets for BTC.

TAGLN2 expression was suppressed by small-interfering or short hairpin RNAs, and its effects on tumor biology were assessed in several BTC cell lines. Furthermore, the effects of TAGLN2 silencing on gemcitabine-resistant BTC cells, differentially expressed genes, proteins, and sensitivity to therapeutics or radiation were assessed. TAGLN2 expression was also assessed using western blotting and immunohistochemistry in samples obtained from patients with BTC to validate its clinical application.

Suppression of TAGLN2 in BTC cell lines decreased cell proliferation, migration, invasion, and tumor size, in addition to a reduction in CSC features, including clonogenicity, radioresistance, and chemoresistance. TAGLN2 was highly expressed in BTC tissues, especially in cancer-associated fibroblasts in the stroma. Patients with a low stromal immunohistochemical index had prolonged disease-free survival compared to those with a high stromal immunohistochemical index (11.5 vs. 7.4 months, P = 0.013). TAGLN2 expression was higher in the plasma of patients with BTC than that in those with benign diseases. TAGLN2 had a higher area under the curve (0.901) than CA19-9, a validated tumor biomarker (0.799; P < 0.001).

TAGLN2 plays a critical role in promoting BTC cell growth and motility and is involved in regulating BTC stemness. Silencing TAGLN2 expression enhanced cell sensitivity to radiation and chemotherapeutic drugs. The expression of TAGLN2 in patient tissue and plasma suggests its potential to serve as a secretory biomarker for BTC. Overall, targeting TAGLN2 could be an appropriate therapeutic strategy against advanced cancer following chemotherapy failure.

DNA crosslinking agents such as cisplatin and related platinum(II) analogs are effective drugs to treat solid tumors. However, these therapeutics can cause high toxicity in the body, and tumors can develop resistance to them. To develop less toxic and more effective DNA crosslinkers, medicinal chemists have focused on tuning the ligands in square planar platinum(II) complexes to modulate their bioavailability, targeted cell penetration, and DNA binding rates. Unfortunately, linking in vitro DNA binding capacity of DNA crosslinkers with their in vivo efficacy has proven challenging. Here we report an electrochemical biosensor strategy that allows the study of platinum(II)-DNA binding in real time. Our biosensors contain a purine-rich deoxynucleotide sequence, T6 (AG)10 , modified with a 5' hexylthiol linker for easy self-assembly onto gold electrodes. The 3' terminus is functionalized with the redox reporter methylene blue. Electron transfer from methylene blue to the sensor is a function of platinum(II) compound concentration and reaction time. Using these biosensors, we resolve DNA binding mechanisms including monovalent and bivalent binding, as well as base stacking. Our approach can measure DNA binding kinetics in buffers and in 50 % serum, offering a single-step, real-time approach to screen therapeutic compounds during drug development.

Intrahepatic cholangiocarcinoma is the second most frequent primary liver cancer after hepatocellular carcinoma. According to International Classification of Diseases-11 (ICD-11), intrahepatic cholangiocarcinoma is identified by a specific diagnostic code, different with respect to perihilar-CCA or distal-CCA. Intrahepatic cholangiocarcinoma originates from intrahepatic small or large bile ducts including the second-order bile ducts and has a silent presentation that combined with the highly aggressive nature and refractoriness to chemotherapy contributes to the alarming increasing incidence and mortality. Indeed, at the moment of the diagnosis, less than 40% of intrahepatic cholangiocarcinoma are suitable of curative surgical therapy, that is so far the only effective treatment. The main goals of clinicians and researchers are to make an early diagnosis, and to carry out molecular characterization to provide the patient with personalized treatment. Unfortunately, these goals are not easily achievable because of the heterogeneity of this tumor from anatomical, molecular, biological, and clinical perspectives. However, recent progress has been made in molecular characterization, surgical treatment, and management of intrahepatic cholangiocarcinoma and, this article deals with these advances.