Broadening the therapeutic horizon of advanced biliary tract cancer through molecular characterisation

Biliary tract cancers (BTC) comprise a group of rare and heterogeneous poor-prognosis tumours with the incidence of intrahepatic cholangiocarcinoma increasing over recent years. Combination chemotherapy with gemcitabine and cisplatin is the established first-line treatment for advanced BTC with a significant but modest survival advantage over monotherapy. There remains no accepted standard treatment in the second-line setting, although recent results from a randomised study have shown a survival benefit with 5-fluorouracil and oxaliplatin chemotherapy. Historically, clinical trials investigating targeted therapies in unselected BTC have failed to demonstrate significant clinical benefit. More recently, advancement in molecular exploration of BTC has shed light on the complex biological heterogeneity within these tumours and has also identified actionable genomic aberrations, such as fibroblast growth factor receptor 2 (FGFR2) gene fusions, isocitrate dehydrogenase (IDH) and BRAF mutations, which offer promise with the anticipation of increased responses and durable clinical benefit in selected patients. Several targeted drugs have now entered clinical development with some encouraging results being seen. Here we review the current and rapidly evolving therapeutic landscape of advanced BTC, including targeted therapies and immunotherapy. We also discuss how recent efforts and successes in BTC are overcoming the obstacles typically associated with precision medicine in rare cancers. Ultimately, the management of advanced BTC is likely to become molecularly selected in the near future with the hope of finally improving the bleak prognosis of patients with this disease.     

晚期胆道系统肿瘤内科治疗进展

胆道系统肿瘤是一类具有遗传多样性的恶性肿瘤, 主要包括肝内胆管癌、肝外胆管癌和胆囊癌。多数患者确诊时多无法手术切除或发生转移, 预后较差。手术和放疗在晚期胆系恶性肿瘤中的作用有限。化疗作为主要的治疗选择, 研究显示传统化疗的有效率可达10%~40%。吉西他滨联合顺铂的化疗方案可显著延长患者的生存期, 被认为是标准的治疗方案。分子靶向治疗在晚期胆系肿瘤中效果令人欣悦, 但仍需进一步深入研究。 < /span >      

胆系肿瘤化疗及其分子靶向治疗

 胆系肿瘤是一种起源于胆管上皮的恶性肿瘤。多数患者发病时已达局部晚期或已发生远处转移。尽管系统化疗方案层出不穷,但是无法行手术切除的患者预后极差。吉西他滨与顺铂联合方案化疗可显著延长患者的生存期,是目前局部晚期或转移性胆系肿瘤化疗的标准方案。应用分子靶向药物治疗进展期胆系肿瘤是临床研究的新趋势。     

A real-world study of the efficacy and safety of anti-programmed cell death-1 therapy combined with chemotherapy or targeted therapy in patients with advanced biliary tract cancer

BackgroundImmune checkpoint inhibitors (ICIs) represent a breakthrough in cancer treatment. However, they have rarely been used to treat biliary tract cancer (BTC). In the current study, we aimed to evaluate and compare the efficacy and safety of anti-programmed cell death-1 (PD-1) therapy used alone or in combination with chemotherapy or targeted therapy in the treatment of advanced BTC.MethodsPatients with advanced BTC who were treated either with anti-PD-1 therapy alone or anti-PD-1 therapy plus chemotherapy or targeted therapy between December, 2015 and October, 2017 were retrospectively screened for eligibility. Patients who had previously received treatment with any agent targeting T-cell co-stimulation or immune checkpoints were excluded. Overall survival (OS), progression-free survival (PFS), objective response rate (ORR), and safety were evaluated.ResultsA total of 37 patients were included in this study (15 cases in the monotherapy group and 22 cases in the combination group). Patients in the combination group had significantly longer OS [median, 8.2 vs. 3.6 months, HR 0.47 (0.20–1.10), P=0.011] and PFS (median, 3.9 vs. 2.0 months, HR 0.58 (0.28–1.19), P=0.034) than patients in the monotherapy group. The ORR was 18.2% (4/22) and 0% in the combination group and monotherapy group, respectively, and the difference was not significant (P=0.131). Furthermore, no significant difference was found between the two groups with respect to the incidence of grade 3–4 treatment-related adverse events (P=0.388).ConclusionsAnti-PD-1 therapy plus chemotherapy or targeted therapy is an effective and tolerable treatment for patients with advanced BTC and is promising as a first-line treatment or beyond.     

Immunotherapy as a treatment for biliary tract cancers: A review of approaches with an eye to the future

Biliary tract cancers (BTC) are aggressive malignancies associated with resistance to chemotherapy and poor prognostic rates. Therefore, novel treatment approaches are in need. Immunotherapy represents a promising breakthrough that uses a patient’s immune system to target a tumor. This treatment approach has shown immense progress with positive results for selected cancers such as melanoma and nonsmall cell lung cancer. Initial preclinical data and preliminary clinical studies suggest encouraging mechanistic effects for immunotherapy in BTC offering the hope for an expanding therapeutic role for this disease. These approaches include targeted tumor antigen therapy via peptide and dendritic cell-based vaccines, allogenic cell adoptive immunotherapy, and the use of inhibitory agents targeting the immune checkpoint receptor pathway and multiple components of the tumor microenvironment. At this time demonstrating efficacy in larger clinical trials remains imperative. A multitude of ongoing trials aim to successfully translate mechanistic effects into antitumor efficacy and ultimately aim to incorporate immunotherapy into the routine management of BTC. With further research efforts, the optimization of dosing and therapeutic regimens, the identification of novel tumor antigens and a better understanding of alternative checkpoint pathway receptor expression may provide additional targets for rational combinatorial therapies which enhance the effects of immunotherapy and may offer hope for further advancing treatment options. Ultimately, the challenge remains to prospectively identify the subsets of patients with BTC who may respond to immunotherapy, and devising alternative strategies to sensitize those that do not with the hopes of improving outcomes for all with this deadly disease.     

Current Progress in Immunotherapy for the Treatment of Biliary Cancers

Purpose

Biliary tract cancers (BTC) remain one of the poorest groups of malignancies in terms of long-term survival, with only limited success in improvements by the use of systemic chemotherapy and our current repertoire of molecularly targeted therapies. Treatments that aim to adapt the patient’s own immune system to target cancer cell have shown tremendous promise in treating solid tumors such as melanoma and non-small cell lung cancer, and there are many recently completed and ongoing studies looking to move immunotherapy into the treatment of BTC. We review here both preclinical and early clinical studies of immune therapies for BTC, including autologous cell transfer, vaccinations, and immunomodulatory approaches (e.g., immune checkpoint inhibitors).

Methods

Published abstracts and articles from peer-reviewed journals as well as ongoing trial information were obtained from PubMed, Google Scholar, and Clinicaltrials.gov.

Results

The use of immune-mediated or immunomodulatory therapies in BTC are supported by observations that many chronic inflammatory states are associated with their development. Although success in treating BTC by the active manipulation of the immune system has been limited to date, we note many recent and ongoing areas of preclinical and clinical investigation that may translate to further clinical trials.

Conclusions

As we continue to follow subgroup analyses and results from specific studies that include BTC patients, we will hopefully be able to combine these with focused preclinical investigations providing further rationale for future trial success in treating BTC.

     

Paradigm shift of chemotherapy and systemic treatment for biliary tract cancer

Biliary tract cancers (BTC) are frequently identified at late stages and have a poor prognosis due to limited systemic treatment regimens. For more than a decade, the combination of gemcitabine and cis-platin has served as the first-line standard treatment. There are few choices for second-line chemo-therapy. Targeted treatment with fibroblast growth factor receptor 2 inhibitors, neurotrophic tyrosine receptor kinase inhibitors, and isocitrate dehydrogenase 1 inhibitors has had important results. Immune checkpoint inhibitors (ICI) such as pembrolizumab are only used in first-line treatment for microsatellite instability high patients. The TOPAZ-1 trial's outcome is encouraging, and there are several trials underway that might soon put targeted treatment and ICI combos into first-line options. Newer targets and agents for existing goals are being studied, which may represent a paradigm shift in BTC management. Due to a scarcity of targetable mutations and the higher toxicity profile of the current medications, the new category of drugs may occupy a significant role in BTC therapies.     

Immunotherapy of biliary tract cancer

Biliary tract cancers (BTCs), which encompass intra- and extrahepatic cholangiocarcinomas as well as gallbladder carcinomas, are one of the most aggressive malignancies. Although the development of systemic chemotherapy approaches has made progress, the prognosis of BTC remains poor. Chronic inflammation plays an important role in the carcinogenesis of BTC, highlighting the immune etiology of this disease. Immunotherapy has emerged as a promising new modality of treatment for BTC. Here, we summarize the relevant tumor immunology of BTC and recently completed and ongoing clinical trials of immunotherapy for BTC.     

Phase II Trial of Erlotinib and Docetaxel in Advanced and Refractory Hepatocellular and Biliary Cancers: Hoosier Oncology Group GI06-101

Background Patients with advanced hepatocellular (HCC) and biliary tract carcinomas (BTC) have poor prognosis. While the EGFR pathway is overactive in HCC and BTC, single agent anti-EGFR therapies confer modest activity. Preclinical data showed synergistic antiproliferative and proapoptotic effects between anti-EGFR therapies and taxanes. We conducted a phase I study of erlotinib and docetaxel in solid tumors, and noted good tolerability and sustained complete (5 years +) and partial responses in patients with HCC and BTC. This trial evaluated the efficacy of erlotinib with docetaxel in refractory hepatobiliary cancers. Methods Eligible patients were allowed to have two prior systemic therapies. Docetaxel 30 mg/m(2) i.v. was administered on days 1, 8, 15, and erlotinib 150 mg was dosed orally on days 2-7, 9-14, 16-28 of each 28-day cycle. The primary endpoint was 16 weeks progression-free survival (PFS), and secondary endpoints included response, stable disease, and overall survival. Tumor samples were analyzed for KRAS gene mutations and E-cadherin expression by immunohistochemistry (IHC). Patients with BTC and HCC were accrued and assessed in separate strata for the efficacy endpoints, but for the two-stage initial design of the study, combined PFS was considered. A Simon optimal two-stage design tested the hypothesis that the 16-week PFS is < 15% (clinically inactive) versus the alternative of ≥ 30% (warranting further study). Results Twenty-five patients, 14 with HCC and 11 with BTC, were enrolled. Common toxicities were rash (76%), diarrhea (56%), and fatigue (52%), mostly grade 1 or 2. No objective responses were seen. Seven BTC (64%) and 6 HCC patients (46%) had stable disease as best response, with a median duration of 16.1 weeks (95% CI 3.7-56.3) for BTC, and 17.6 weeks (95% CI 8.1-49.8) for HCC. The 16-week PFS was 64% for BTC (95% CI 29.7-84.5), and 38% for HCC (95% CI 14.1-62.8). Median overall survival was 5.7 and 6.7 months for BTC and HCC patients, respectively. BTC patients with grade ≥ 2 rash had higher median PFS (6.2 vs 2.2 months) and OS (14.2 vs 4.2 months). HCC patients with negative/low E-cadherin expression had higher median PFS (6.7 vs 2.1 months) and OS (14.5 vs 4 months). Conclusions Erlotinib with docetaxel met the 16-week PFS ≥ 30% endpoint, but overall survival was comparable to that seen with single-agent erlotinib. With the limitation of small numbers of patients, grade ≥ 2 rash (in BTC), and negative/low E-cadherin expression (HCC) were associated with higher PFS and OS. Discussion Refractory biliary tract and hepatocellular cancers are difficult to treat, and no chemotherapy or biologically targeted therapies have impacted survival. Based on preclinical synergism and prior phase I data, we conducted a multi-institutional study sequentially combining the EGFR-targeted agent erlotinib with docetaxel. Results from this study show that the primary endpoint, 16-week PFS of ≥ 30%, was met for the combined group of BTC and HCC patients (as originally planned in the study design), as well as in each disease category: 63.6% for BTC and 38.5% for HCC patients. Nevertheless, no patients attained an objective response and the median survival of 5.7 months for BTC, and 6.7 months for HCC patients (while heavily pretreated), is comparable to that seen with single-agent EGFR-targeted therapies. Safety analysis shows that this regimen was generally well tolerated, and most adverse events were grade 1 or 2. Few patients had reversible grade 3 transaminase elevation (8%), and severe anorexia, fatigue, and rash were uncommon. As expected, patients with grade ≥ 2 rash experienced higher PFS and OS, but this was noted only among the BTC group, likely because too few HCC patients had grade ≥ 2 rash. KRAS is an important predictive marker for anti-EGFR therapies for lung and colorectal cancers, but for HCC or the heterogeneous group of BTC (with 10-50% KRAS mutations) no significant correlations have been established. We were not able to identify a correlation between KRAS and benefit from erlotinib-based therapy, as all but one HCC patient had KRAS wild type gene status. Preclinical data in multiple tumor types showed that E-cadherin, a signature marker for an "epithelial" tumor phenotype when overexpressed, predicts EGFR pathway activation and determines sensitivity to EGFR-targeted agents. E-cadherin is often seen as a poor prognostic marker when downregulated, as noted during cancer progression. Not all studies demonstrate beneficial effects from E-cadherin overexpression, possibly due to histological expression variability or tumor type specificity for this biomarker. Six BTC and 8 HCC patients had evaluable tumor samples for E-cadherin analysis. While the numbers were small and conclusions should be viewed with caution, negative/low E-cadherin expression was associated with improved PFS and OS for hepatobiliary cancers (most significant in HCC) in this refractory patient population where we expected lower expression levels. In conclusion, the combination of erlotinib with docetaxel provided a 16-week PFS of ≥ 30% but showed no appreciable differences in overall survival from historical data with single-agent erlotinib. While EGFR represents an important target in this group of malignancies, it is clear that hepatobiliary cancers are heterogeneous, thus a meaningful improvement in survival most likely will require careful treatment selection based on patient tumor's molecular and genetic profiling.     

Auto-induction and growth stimulatory effect of betacellulin in human pancreatic cancer cells

Betacellulin (BTC) was identified in mouse pancreatic beta cell tumors as a member of the epidermal growth factor (EGF) family, and was found to bind and activate the EGF receptor. BTC is also expressed in some human malignancies and may have an important role in tumor growth progression. We examined whether BTC and EGF have a growth stimulatory effect on human pancreatic cancer cell lines both in vitro and in vivo. We also investigated the BTC expression and autonomous induction of BTC in pancreatic cancer cells. in vitro, both BTC and EGF had almost the same proliferative effect on Panc-1, MIA PaCa-2 and AsPC-1. in vivo, in a Panc-1 inoculated athymic mice model, BTC-treated tumors grew approximately five times larger than in control. Immunocytochemistry showed that BTC expression occurred in three pancreatic cancer cell lines, with MIA PaCa-2 showing the strongest intensity. Semi-quantitative RT-PCR of MIA Paca-2 showed that mRNA levels of BTC gradually increased after treatment with 1 nM BTC. Immunocytochemistry also demonstrated that the intensity of BTC-like immunoreactivity was increased when treated with 1 nM BTC but was reduced after treatment with 100 nM of AG1478, an EGF receptor tyrosine kinase inhibitor. BTC has thus a significant growth stimulatory effect on pancreatic cancer cells and might function as an autocrine and paracrine growth factor. BTC expression in pancreatic cancer cells is, at least in part, controlled by an auto-induction mechanism.     

Novel therapeutic strategy targeting the Hedgehog signalling and mTOR pathways in biliary tract cancer

Background:

Activation of the PI3K/mTOR and Hedgehog (Hh) signalling pathways occurs frequently in biliary tract cancer (BTC). Crosstalk between these pathways occurs in other gastrointestinal cancers. The respective signalling inhibitors rapamycin and vismodegib may inhibit BTC synergistically and suppress cancer stem cells (CSCs).

Methods:

Gene expression profiling for p70S6k and Gli1 was performed with BTC cell lines. Tumour and pathway inhibitory effects of rapamycin and vismodegib were investigated in BTC preclinical models and CSCs.

Results:

Rapamycin and vismodegib synergistically reduced BTC cell viability and proliferation. This drug combination arrested BTC Mz-ChA-1 cells in the G1 phase but had no significant effect on the cell cycle of BTC Sk-ChA-1 cells. Combined treatment inhibited the proliferation of CSCs and ALDH-positive cells. Nanog and Oct-4 expression in CSCs was decreased by the combination treatment. Western blotting results showed the p-p70S6K, p-Gli1, p-mTOR, and p-AKT protein expression were inhibited by the combination treatment in BTC cells. In an Mz-ChA-1 xenograft model, combination treatment resulted in 80% inhibition of tumour growth and prolonged tumour doubling time. In 4 of 10 human BTC specimens, tumour p-p70S6K and Gli1 protein expression levels were decreased with the combination treatment.

Conclusions:

Targeted inhibition of the PI3K/mTOR and Hhpathways indicates a new avenue for BTC treatment with combination therapy.     

Immunotherapeutic approaches in biliary tract carcinoma: Current status and emerging strategies

For biliary tract carcinoma (BTC), complete surgical resection of tumor is only feasible in a minority of patients, and the treatment options for patients with unresectable or metastatic disease are limited. Advances in cancer immunology have led to identification of tumor-infiltrating immune cells as indicators of prognosis and response to treatment in BTC. This has also facilitated development of immunotherapy that focuses on enhancing the immune system against biliary tumors. This includes peptide- and dendritic cell-based vaccines that stimulate in-vivo immune responses against tumor-specific antigens. Adoptive immunotherapy, which entails the ex-vivo expansion of tumor-infiltrating immune cells for subsequent reintroduction, and cytokine-based therapies have been developed in BTC. Clinical studies indicate that this type of therapy is generally well tolerated. Combination therapy with dendritic cell-based vaccines and adoptive immunotherapy has shown particularly good potential. Emerging strategies through discovery of novel antigen targets and by reversal of tumor-associated immunosuppression are expected to improve the efficacy of immunotherapy in BTC. Collaborative efforts by integration of targeted immunotherapeutics with molecular profiling of biliary tumor will hopefully make a positive impact on advancing towards the goal of developing precision treatment of patients with this highly lethal disease.     

Establishment of six new human biliary tract carcinoma cell lines and identification of MAGEH1 as a candidate biomarker for predicting the efficacy of gemcitabine treatment

The aim of this study was to establish new biliary tract carcinoma (BTC) cell lines and identify predictive biomarkers for the potential effectiveness of gemcitabine therapy. Surgical specimens of BTC were transplanted directly into immunodeficient mice to establish xenografts, then subjected to in vitro cell culture. The gemcitabine sensitivity of each cell line was determined and compared with the genome‐wide gene expression profile. A new predictive biomarker candidate was validated using an additional cohort of gemcitabine‐treated BTC cases. From 55 BTC cases, we established 19 xenografts and six new cell lines. Based on their gemcitabine sensitivity, 10 BTC cell lines (including six new and four publicly available ones) were clearly categorized into two groups, and MAGEH1 mRNA expression in the tumor cells showed a significant negative correlation with their sensitivity to gemcitabine. Immunohistochemically, MAGEH1 protein was detected in three (50%) out of six sensitive cell lines, and four (100%) out of four resistant cell lines. In the validation cohort of gemcitabine‐treated recurrence cases, patients were categorized into “effective” and “non‐effective” groups according to the RECIST guidelines for assessment of chemotherapeutic effects. MAGEH1 protein expression was detected in two (40%) out of five “effective” cases and all four (100%) “non‐effective” cases. We have established a new BTC bioresource that covers a wide range of biological features, including drug sensitivity, and is linked with clinical information. Negative expression of MAGEH1 protein serves as a potential predictive marker for the effectiveness of gemcitabine therapy in BTC. (Cancer Sci 2010; 101: 882–888)     

Chemopreventive and therapeutic efficacy of orally active tyrosine kinase inhibitors in a transgenic mouse model of gallbladder carcinoma.

Biliary tract cancer (BTC) is the second most common primary hepatobiliary cancer after hepatocellular cancer. At the time of diagnosis, most BTC are at an advanced stage and are unresectable. There is presently no effective curative treatment of the advanced disease nor is there any effective clinical therapy that will prevent the development of BTC. All of these factors render gallbladder cancer nearly incurable with a poor survival rate. The aim of our study was to provide a better understanding of the mechanisms involved in the development of gallbladder carcinoma as the advancement of more effective treatment options would significantly improve prognosis. In the present study, we examined the effect of gefitinib, a selective epidermal growth factor receptor/tyrosine kinase inhibitor (EGFR/TKI), on the development of gallbladder carcinoma in BK5.erbB2 mice. In addition, we examined the effect of another quinazoline derivative, GW2974, which is able to block the activation of both the EGFR and erbB2, in this model. Animals were treated with either 400 ppm gefitinib or 200 ppm GW2974 as a supplement in the diet using either a chemopreventive or therapeutic protocol. The results show that both compounds were potent chemopreventive and therapeutic agents in this mouse model of human BTC. The results also suggest that activation of the EGFR plays an important role in development of BTC in this model and that targeting both the EGFR and erbB2 may be an effective strategy for treatment of this disease.     

Geographic Clustering Patterns in Mortality from Biliary Tract Cancer in Japan

We calculated the standardized mortality ratios (SMRs) of biliary tract cancer (BTC) in Japan from 1981 to 1990 and statistically analyzed the results according to 333 Secondary Areas of Medical Care, as well as sex and subsite [gallbladder cancer (GBC) and extrahepatic bile duct cancer (BDC)], in order to examine geographic clustering patterns of BTC. In GBC in both sexes, the Secondary Areas of Medical Care with high SMRs were clustered in the eastern part of Japan. In BDC in both sexes, the Areas with high SMRs were clustered between the northern and eastern parts of Japan. In comparison with GBC, this clustering favored the northern part of Japan. In males, the clustering pattern in mortality from BTC was mainly due to the occurrence of BDC. In females, the clustering pattern in mortality from BTC reflected that of GBC. The clustering of BTC, especially GBC, seems to be related to the distribution of plains, basins, and rivers.     

Potent in vitro and in vivo antitumor activity of interleukin-4-conjugated Pseudomonas exotoxin against human biliary tract carcinoma

Targeting cytotoxins or immunotoxins to tumor cell surface receptors represents a new approach for the treatment of cancers. We tested the antitumor activity of a cytotoxin (IL-4-PE) composed of an interleukin-4 (IL-4) targeting moiety and a truncated form of Pseudomonas exotoxin A against human biliary tract carcinoma (BTC). Immunohistochemical analysis showed that cultured BTC cell lines and cancerous epithelia in BTC tissue (e.g., gallbladder carcinoma, extrahepatic cholangiocarcinoma, and intrahepatic cholangiocarcinoma) expressed receptors for IL-4 in situ at high densities. However, normal epithelial cells in gallbladder and bile duct tissues did not express these IL-4 receptors. Eight BTC cell lines expressed IL-4R on the cell surface as determined by radiolabeled ligand binding assays. When these cells were treated with IL-4-PE, significant cytotoxicity was observed as determined by the inhibition of protein synthesis. The concentration of agent causing 50% inhibition of protein synthesis (IC(50)) was found to be less than 10 ng/mL in 4 of the 8 BTC cell lines studied. The antitumor activity of IL-4-PE was assessed for human BTC cells implanted subcutaneously in immunodeficient mice. By intratumoral injection of IL-4-PE, complete disappearance of the established tumors was observed in 40% of animals. Intraperitoneal administration of IL-4-PE at tolerated doses to animals with peritoneally disseminated BTC exhibited significantly prolonged survival compared to untreated animals (>14 weeks vs. 5 weeks in treated and untreated mice, respectively). These results indicate that IL-4 receptor-targeted cytotoxin is a potent agent that may provide a new therapeutic option for BTC.     

Confounded association between proton pump inhibitor use and risk of biliary tract cancer: Result from three cohorts

Recent epidemiological studies suggested that proton pump inhibitor (PPI) use was associated with an increased risk of biliary tract cancer (BTC), however, confounders were not adequately controlled. Our study aimed to evaluate PPI use and subsequent risk of BTC and its subtypes in three well-established cohorts. We conducted a pooled analysis of the subjects free of cancers in UK Biobank (n = 463 643), Nurses' Health Study (NHS, n = 80 235) and NHS II (n = 95 869). Propensity score weighted Cox models were used to estimate marginal HRs of PPIs use on BTC risk, accounting for potential confounders. We documented 284 BTC cases in UK Biobank (median follow-up: 7.6 years), and 91 cases in NHS and NHS II cohorts (median follow-up: 15.8 years). In UK biobank, PPI users had a 96% higher risk of BTC compared to nonusers in crude model (HR 1.96, 95% CI 1.44-2.66), but the effect was attenuated to null after adjusting for potential confounders (HR 0.95, 95% CI 0.60-1.49). PPI use was not associated with risk of BTC in the pooled analysis of three cohorts (HR 0.93, 95% CI 0.60-1.43). We also observed no associations between PPI use with risk of intrahepatic (HR 1.00, 95% CI 0.49-2.04), extrahepatic bile duct (HR 1.09, 95% CI 0.52-2.27) and gallbladder cancers (HR 0.66, 95% CI 0.26-1.66) in UK Biobank. In summary, regular use of PPIs was not associated with the risk of BTC and its subtypes.     

Lung tumor induction in strain A mice with benzotrichloride

Benzotrichloride (BTC) is used in the synthesis of benzoyl chloride and benzoyl peroxide. Epidemiological data suggest that BTC is a human lung carcinogen. In the present study, BTC was evaluated for its ability to induce lung adenomas in strain A/J mice. Four groups of 15 male and 15 female A/J mice were injected i.p. with either tricaprylin or BTC in tricaprylin three times a week for 8 weeks. BTC groups received doses totaling 1440 mg/kg, 719 mg/kg or 287 mg/kg. The mean number of lung tumors per mouse was 127 87 +/- 5.81, 43 +/- 2.44, and 17.73 +/- 1.09 in the groups treated with either 1440 mg/kg, 719 mg/kg, or 287 mg/kg, respectively. Tricaprylin-vehicle controls had a mean number of 0.46 +/- 0.15 lung tumors per mouse. Therefore, BTC produced a significant (P less than 0.001) and dose-related increase in the lung tumor response when compared to tricaprylin controls and is a potent carcinogen in the strain A mouse lung tumor bioassay.     

Survival benefits of chemotherapy for unresectable biliary tract cancer--a multicenter retrospective analysis

There is no agreement on the standard chemotherapeutic regimen for biliary tract cancer(BTC), although multi-drug regimens such as gemcitabine and/or S-1 have been tested in clinical trials. This study retrospectively reviewed data from patients with BTC who were seen at hospitals in the Kitakyushu and Fukuoka areas between 2005 and 2006, and examined the effect of systemic chemotherapy regimen on survival benefits in patients with unresectable BTC. Chemotherapy may benefit patients with BTC any age group, regardless of the primary site.