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IntroductionPrognosis of biliary tract cancers (BTC) remains dismal and novel treatment strategies are needed to improve survival. BRCA mutations are known to occur in BTC but their frequency and the molecular landscape in which they are observed in distinct sites of BTC remain unknown.Material and methodsTumour samples from 1292 patients with BTC, comprising intrahepatic cholangiocarcinoma (IHC, n=746), extrahepatic cholangiocarcinoma (EHC, n=189) and gallbladder cancer (GBC, n=353), were analysed using next-generation sequencing (NGS). Tumour mutational burden (TMB) was calculated based on somatic non-synonymous missense mutations. Determination of tumour mismatch repair (MMR) or microsatellite instability (MSI) status was done by fragment analysis, immunohistochemistry and the evaluation of known microsatellite loci by NGS. Programmed death ligand 1 expression was analysed using immunohistochemistry.ResultsOverall, BRCA mutations were detected in 3.6% (n=46) of samples (BRCA1: 0.6%, BRCA2: 3%) with no significant difference in frequency observed based on tumour site. In GBC and IHC, BRCA2 mutations (4.0% and 2.7%) were more frequent than BRCA1 (0.3% and 0.4%, p<0.05) while in EHC, similar frequency was observed (2.6% for BRCA2 vs 2.1% for BRCA1). BRCA mutations were associated with a higher rate in subjects with MSI-H/deficient mismatch repair (19.5% vs 1.7%, p<0.0001) and tumours with higher TMB, regardless of the MMR or MSI status (p<0.05).ConclusionsBRCA mutations are found in a subgroup of patients with BTC and are characterised by a distinct molecular profile. These data provide a rationale testing poly(ADP-ribose)polymeraseinhibitors and other targeted therapies in patients with BRCA-mutant BTC.

Cancer immunotherapy is a success story of translational medicine that has led to improved survival in patients with different difficult-to-treat types of cancer, such as metastasized melanoma, non-small cell lung cancer or renal cell carcinoma. These novel therapeutic agents exert their antitumor effects by activating the patients' immune system against cancer cells. Immunotherapy can be divided into active agents, such as anti-tumour vaccines or adoptive T-cell transfer, and passive immunotherapies like monoclonal antibodies, checkpoint inhibitors, cytokine therapy, bispecific T-cell engagers. After initial experimental use, broad clinical application revealed a number of important cardiovascular side effects of immunotherapeutics, which limit treatment options and decrease patients' prognosis and quality of life. With the rising rate of new immunotherapeutics at a hand, the number of patients receiving cancer immunotherapy will constantly increase, resulting in improved long-term survival rates. This review aims to summarize available cancer immunotherapies, their mechanism of action, currently known cardiovascular toxicities and their treatment. Further optimization of patient care will depend on the combined efforts by oncologists, cardiologists and cardiac surgeons to identify patients at risk and the implementation of interdisciplinary screening and treatment strategies. It is therefore crucial to familiarize heart specialists with novel cancer therapeutics and their potential adverse effects.

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IntroductionPatients with refractory metastatic cancer have been shown to benefit from molecular profiling of tumor tissue. The ONCO-T-PROFILE project was launched in March 2014 at the Innsbruck Medical University. Within 2 years our project aims to recruit 110 patients with stage IV cancer refractory to standard therapy. Our data presented here are based on an interim-analysis.MethodsTumor tissue specimens were submitted for molecular profiling to the certified laboratory (Caris Life Science, USA). Druggable tumor targets were selected based on biomarker status to agents with potential clinical benefit. Clinical benefit was defined as a PFS ratio (=PFS upon treatment according to the molecular profile/ PFS upon the last prior therapy) ≥ 1.3.ResultsAs of April 2015, tumors from 50 patients have been molecularly profiled and one or more targets were detectable in 48 specimens (98%). So far, 19 (38%) patients have been treated according to their molecular tumor profile. To date, 8 (42%) patients have reached a PFS ratio of ≥ 1.3.ConclusionsWe could show that molecular profiling is feasible in the clinical routine. A proportion of patients might benefit from an individualized treatment approach based on molecular profiling. As a result, we will proceed to enroll patients in ONCO-T-PROFILE.

Regulated intramembrane proteolysis (RIP) has been shown to be an important mechanism for oncogenic activation of EpCAM through nuclear translocation of the intracellular domain EpICD. Recently, we identified two different membranous EpCAM variants namely EpCAM MF (full-length) and EpCAM MT (truncated) to be expressed in the majority of human epithelial tumors. The aim of our study was to evaluate the potential role of these two protein variants as additional prognostic biomarkers in colorectal cancer. In most studies only one antibody targeting the extracellular domain of EpCAM (EpEX) has been used, whereas in the present study additionally an antibody which detects the intracellular domain (EpICD) was applied to discriminate between different EpCAM variants. Colorectal cancer (CRC) is a common cause of cancer-related mortality worldwide and approximately 30% of patients present with advanced disease at diagnosis.

Aims Anaemia and iron deficiency (ID) are frequently found in patients with chronic heart failure (CHF) and associated with adverse outcome. However, it is unclear whether absolute [transferrin saturation (TSAT) <20%, ferritin <100 μg/L] or inflammation-driven functional ID (TSAT <20%, ferritin >100 μg/L) with and without anaemia had similar or different consequences for such patients. Methods and results Within this retrospective cohort study, 2223 patients (1601 men and 622 women) with CHF, referred to our department, between 2000 and 2018, were followed for a median time of 84 months. Anaemia was found in 393 patients and was an independent predictor for an adverse outcome [HR 2.164 (95% CI 1.865-2.512), P < 0.001]. In 674 patients with available parameters of iron metabolism, ID was present in 228 patients and was associated with an unfavourable outcome [HR 1.499 (95% CI 1.158-1.940), P = 0.002]. ID was best predicting an adverse outcome in men ≤59 years, with heart failure with reduced ejection fraction, preserved kidney function, no inflammation, and a body mass index (BMI) ≥25.5 kg/ m 2. Functional ID in women and absolute ID in men were associated with poor prognosis. Of note, TSAT <20% but not low ferritin levels were predictive for an adverse outcome. Anaemic patients with high ferritin levels, advanced inflammation, older age, low BMI, male gender, and reduced glomerular filtration rate had the worst prognosis. Conclusions Anaemia and low tissue iron availability as reflected by TSAT <20% are negative predictors of outcome in patients with CHF. Systemic inflammation, renal function, BMI, age, and gender are important contributors for the clinical course.

Aims Amyloid cardiomyopathy is an underappreciated cause of morbidity and mortality. Recent evidence suggests that ATTR wild-type cardiomyopathy (ATTRwt-CM) is probably much more common than widely appreciated. So far, no data are available on comparison of mortality from ATTRwt-CM and other heart failure aetiologies. Methods and results This was a retrospective, observational, cohort study of 2251 patients and their data collected prospectively from May 2000 to June 2018. Long-term mortality was the main outcome measure. Underlying cardiomyopathies were classified as amyloid CM (6.1%) [ATTRwt 3.0%; light-chain amyloidosis (AL) 3.1%], dilated CM (dCMP) (46.4%), ischaemic heart disease (IHD) (24.4%), hypertensive heart disease (HHD) (14.6%), hypertrophic CM (HCM) (5.1%), and valvular heart disease (VHD) (3.4%). Median duration of follow-up was 7.1 years (interquartile range 3.4-11.3). Five-year overall survival in the whole cohort was 80.1%. In multivariate analysis, individuals with amyloid CM were 3.74 times [95% confidence interval (CI) 2.72-5.14; P < 0.001] more likely to die of any reason than were individuals with dCMP. Mortality was higher in AL-CM compared with ATTRwt-CM [hazard ratio (HR) 2.88; 95% CI 1.48-5.58; P = 0.002]. Mortality rates in patients with ATTRwt-CM were higher than in patients with dCMP (