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Background/objectives To assess the association between processed meat and the risk of selected digestive tract and laryngeal cancers. Subjects/methods We conducted a series of case-control studies between 1985 and 2007 in Italy. The studies included a total of 1475 cases of cancer of the oral cavity and pharynx, 1077 of the larynx, 716 of the esophagus, 999 of the stomach, 684 of the liver, 159 of the biliary tract, 688 of the pancreas, and a total of 9720 controls. Odds ratios (ORs), and the corresponding 95% confidence intervals (CIs), were estimated by unconditional logistic regression models, including terms for socio-demographic factors, tobacco smoking, and alcohol intake. Results Compared to the lowest tertile of processed meat consumption, the ORs for subjects in the highest one were 1.18 (95% CI 0.98–1.43) for oral cavity and pharyngeal, 1.51 (95% CI 1.18–1.91) for esophageal, 1.19 (95% CI 0.96–1.47) for laryngeal, 0.98 (95% CI 0.81–1.18) for stomach, 0.85 (95% CI 0.51–1.40) for biliary tract, 1.20 (95% CI 0.94–1.54) for liver, and 1.46 (95% CI 1.15–1.85) for pancreatic cancers. Conclusions Our findings support the hypothesis that high processed meat consumption increases esophageal and pancreatic cancers risk. Residual confounding by socio-demographic factors, tobacco smoking, and alcohol intake may, partly or largely, account for these associations. We found no overall association with other digestive tract and laryngeal cancers.

This study evaluated the clinical use of serum metabolomics to discriminate malignant cancers including pancreatic cancer (PC) from malignant diseases, such as biliary tract cancer (BTC), intraductal papillary mucinous carcinoma (IPMC), and various benign pancreaticobiliary diseases. Capillary electrophoresismass spectrometry was used to analyze charged metabolites. We repeatedly analyzed serum samples (n = 41) of different storage durations to identify metabolites showing high quantitative reproducibility, and subsequently analyzed all samples (n = 140). Overall, 189 metabolites were quantified and 66 metabolites had a 20% coefficient of variation and, of these, 24 metabolites showed significant differences among control, benign, and malignant groups (p < 0.05; Steel–Dwass test). Four multiple logistic regression models (MLR) were developed and one MLR model clearly discriminated all disease patients from healthy controls with an area under receiver operating characteristic curve (AUC) of 0.970 (95% confidential interval (CI), 0.946–0.994, p < 0.0001). Another model to discriminate PC from BTC and IPMC yielded AUC = 0.831 (95% CI, 0.650–1.01, p = 0.0020) with higher accuracy compared with tumor markers including carcinoembryonic antigen (CEA), carbohydrate antigen 19-9 (CA19-9), pancreatic cancer-associated antigen (DUPAN2) and s-pancreas-1 antigen (SPAN1). Changes in metabolomic profiles might be used to screen for malignant cancers as well as to differentiate between PC and other malignant diseases.

Cholangiocarcinomas (CCAs) comprise of a heterogeneous group of cancers arising in the biliary tract (intrahepatic or iCCA, perihilar or pCCA and distal or dCCA; the latter are known under the collective term of eCCA), each subtype having its own particularities in carcinogenesis, management and prognosis. The increasing incidence in recent decades, limited treatment options and high mortality rates, even in the early stages, have led to an imperious need for more in-depth understanding and development of tailored treatments for this type of aggressive tumour. The wide use of molecular profiling has increased the understanding of biology and identified key molecular drivers, for example, IDH1 mutations or FGFR2 fusions for iCCA, or BRAF mutations in eCCA. Most recently, the FDA approved pemigatinib, an FGFR inhibitor and ivosidenib, an IDH1 inhibitor, but even though progress has been made to better understand the mechanisms of tumorigenesis, genetic make-up, and tumour resistance to standard chemotherapy and targeted therapies, cholangiocarcinomas still represent an important challenge in the daily clinical practice of oncology. The purpose of this review is to highlight the recent progress in the systemic treatment of advanced/metastatic CCAs with a focus on targeted drugs and their biomarkers currently evaluated in early-phase clinical trials.

The standard treatment of unresectable biliary tract cancer (BTC) has shown an insufficient response rate (RR). Our retrospective setting revealed that a combination therapy consisting of intra-arterial chemotherapy plus radiation therapy (IAC + RT) provided a high RR and long-term survival benefits in unresectable BTC. This prospective study aimed to test the effectiveness and safety of IAC + RT as the first-line therapy. The regimen included one-shot IAC with cisplatin, 3–6 months of reservoir IAC (5-FU and cisplatin, q/week), and 50.4 Gy of external radiation. The primary endpoints include the RR, disease control rate, and adverse event rate. This study included seven patients with unresectable BTC without distant metastasis, with five cases classified as stage 4. RT was completed in all cases, and the median number of reservoir IAC sessions was 16. The RR was 57.1% for imaging and 71.4% for clinical assessment, and the disease control rate was 100%, indicating a high antitumor efficacy, which allowed two cases to be transferred to surgery. Five cases of leukopenia and neutropenia; four cases of thrombocytopenia; and two cases of hemoglobin depletion, pancreatic enzyme elevation, and cholangitis were observed, but with no treatment-related deaths. This study revealed a very high antitumor effect with IAC + RT for some unresectable BTC, and it could be useful for conversion therapy.

Background: Although surgery is the mainstay of curative-intent treatment for extrahepatic biliary tract cancer (EBTC), recurrence following surgery can be high and prognosis poor. The impact of neoadjuvant therapy (NAT) relative to upfront surgery (US) among patients with EBTC remains unclear. Methods: The Surveillance, Epidemiology, and End Results (SEER) databases was utilized to identify patients who underwent surgery from 2006 to 2017 for EBTC, including gallbladder cancer (GBC) and extrahepatic cholangiocarcinoma (ECC). Trends in NAT utilization were investigated, and the impact of NAT on prognosis was compared with US using a propensity score-matched (PSM) analysis. Results: Among 6582 EBTC patients (GBC, n = 4467, ECC, n = 2215), 1.6% received NAT; the utilization of NAT for EBTC increased over time (Ptrend = 0.03). Among patients with lymph node metastasis, the lymph node ratio was lower among patients with NAT (0.18 vs. 0.40, p < 0.01). After PSM, there was no difference in overall survival (OS) and cancer-specific survival (CSS) among patients treated with NAT versus US (5-year OS: 24.0% vs. 24.6%, p = 0.14, 5-year CSS: 38.0% vs. 36.1%, p = 0.21). A subgroup analysis revealed that NAT was associated with improved OS and CSS among patients with stages III–IVA of the disease (OS: HR 0.65, 95%CI 0.46–0.92, p = 0.02, CSS: HR 0.62, 95%CI 0.41–0.92, p = 0.01). Conclusions: While NAT did not provide an overall benefit to patients undergoing surgery for EBTC, individuals with advanced-stage disease had improved OS and CSS with NAT. An individualized approach to NAT use among patients with EBTC may provide a survival benefit.

We previously established mouse models of biliary tract cancer (BTC) based on the injection of cells with biliary epithelial stem cell properties derived from KRAS(G12V)-expressing organoids into syngeneic mice. The resulting mouse tumors appeared to recapitulate the pathological features of human BTC. Here we analyzed images of hematoxylin and eosin (H&E) staining for both the mouse tumor tissue and human cholangiocarcinoma tissue by pixel-level clustering with machine learning. A pixel-clustering model that was established via training with mouse images revealed homologies of tissue structure between the mouse and human tumors, suggesting similarities in tumor characteristics independent of animal species. Analysis of the human cholangiocarcinoma tissue samples with the model also revealed that the entropy distribution of cancer regions was higher than that of noncancer regions, with the entropy of pixels thus allowing discrimination between these two types of regions. Histograms of entropy tended to be broader for noncancer regions of late-stage human cholangiocarcinoma. These analyses indicate that our mouse BTC models are appropriate for investigation of BTC carcinogenesis and may support the development of new therapeutic strategies. In addition, our pixel-level clustering model is highly versatile and may contribute to the development of a new BTC diagnostic tool.

Background: In 2013, an unusually high incidence of biliary tract cancer among current or former workers of the offset color proof printing department of a printing company in Osaka, Japan, was reported. The purpose of this study was to examine whether distance from the printing factory was associated with incidence of biliary tract cancer and whether incident biliary tract cancer cases clustered around the printing factory in Osaka using population-based cancer registry data. Methods: We estimated the age-standardized incidence ratio of biliary tract cancer according to distance from this printing factory. We also searched for clusters of biliary tract cancer incidence using spatial scan statistics. Results: We did not observe statistically significantly high or low standardized incidence ratios for residents in each area categorized by distance from the printing factory for the entire sample or for either sex. The scan statistics did not show any statistically significant clustering of biliary tract cancer incidence anywhere in Osaka prefecture in 2004-2007. Conclusions: There was no statistically significant clustering of biliary tract cancer incidence around the printing factory or in any other areas in Osaka, Japan, between 2004 and 2007. To date, even if some substances have diffused outside this source factory, they do not appear to have influenced the incidence of biliary tract cancer in neighboring residents.

Purpose S-1 chemotherapy is effective against advanced biliary tract cancer. The purpose was to evaluate the efficacy and safety of S-1-based concurrent chemoradiotherapy in patients with advanced biliary tract cancer. Methods Patients with pathologically-proven advanced biliary tract cancer were eligible. S-1 was orally administered at a dose of 40 mg/m 2 , twice daily from day 1 to 14 and from day 22 to 35; concurrent radiotherapy of 180–200 cGy per fraction was delivered in 25–28 fractions. After treatment completion, tumor response was evaluated by computed tomography. In the first stage of the optimal two-stage phase II design, 18 patients were required. Results Twenty patients were enrolled between August 2006 and February 2009. The median age was 62.5 years (range 45–77 years). The median follow-up time was 11.6 months (range 1.9–49.1 months). Fifteen patients (75 %) had extrahepatic cholangiocarcinoma, two patients (10 %) had intrahepatic cholangiocarcinoma, and three patients (15 %) had gallbladder cancer. After treatment, a partial response was achieved in three patients (15 %), and stable disease was achieved in 14 patients (70 %). The overall response rate was 15 %, and the disease stabilization rate was 85 %. There was no grade 4 toxicity or treatment-related death. The common grade 3 toxicities were thrombocytopenia (15 %), neutropenia (10 %), and nausea (10 %). The median progression-free survival and median overall survival were 5.9 months (range 2.2–9.5 months) and 10.8 months (range 1.1–20.4 months), respectively. Conclusions This study shows that S-1-based concurrent chemoradiotherapy is feasible and tolerable in patients with advanced biliary tract cancer. It will be further confirmed in a following large-scale phase II study.

Background Metastatic biliary tract cancer (BTC) has poor prognosis. Recently, patients with metastatic BTC who respond well to systemic chemotherapy can be treated by radical resection or “conversion surgery.” Case presentation A 67-year-old male patient was diagnosed with intrahepatic cholangiocarcinoma with para-aortic metastases [cT2N1M1, stage IVB]. He was enrolled in our phase II study for unresectable BTC consisting of cisplatin (25 mg/m 2 i.v. for 30 min) followed by gemcitabine (1000 mg/m 2 i.v. for 30 min) on days 1 and 8 and oral S-1 on alternate days. After 8 courses of this regimen, marked regression of para-aortic lymph metastases was achieved, and we performed extended left hepatic lobectomy with the caudate lobe, concomitant portal vein resection, and lymph node dissection including the para-aortic region. The patient made a satisfactory recovery and was discharged on postoperative day 25. Histopathological examination revealed more than 50% of the tumor area replaced with fibrosis, and curative resection was achieved (ypT2N1M1, stage IVB, Evans criteria IIb). The patient received adjuvant chemotherapy using S-1 for 12 months and remains well with no evidence of tumor recurrence as of 48 months after surgery. Conclusions We herein report a successfully treated case of advanced BTC with para-aortic lymph node metastases by conversion surgery after combination chemotherapy using gemcitabine, cisplatin, and S-1.

Biliary tract cancer (BTC) represents the second most frequently diagnosed primary liver cancer worldwide following hepatocellular carcinoma, and the overall survival of patients with unresectable disease remains poor. In recent years, the advent of immune checkpoint inhibitors (ICIs) has revolutionized the therapeutic landscape of several malignancies with these agents, which have also been explored in advanced BTC, as monotherapy or in combination with other anticancer agents. However, clinical trials evaluating ICIs in BTC have shown conflicting results, and the clinical benefit provided by immunotherapy seems limited to a small subgroup of BTC patients. Thus, the identification of reliable predictors of the response to immunotherapy represents a significant challenge in this setting. This review provides an overview of the available evidence on the biomarkers predictive of the response to ICIs in patients with advanced BTC, especially focusing on programmed death-ligand 1 (PD-L1), tumor mutational burden (TMB), microsatellite instability (MSI), and other emerging biomarkers.