Prostate cancers harboring DNA repair gene alterations are particularly sensitive to PARP inhibitor treatment. We report a case of an advanced prostate cancer patient profiled within the NCT-MASTER (Molecularly Aided Stratification for Tumor Eradication Research) precision oncology program using next-generation sequencing. Comprehensive genomic and transcriptomic analysis identified a pathogenic germline PALB2 variant as well as a mutational signature associated with disturbed homologous recombination together with structural genomic rearrangements. A molecular tumor board identified a potential benefit of targeted therapy and recommended PARP inhibition and platinum-based chemotherapy. Single-agent treatment with the PARP inhibitor olaparib as well as subsequent combination with platinum-based chemotherapy resulted in disease stabilization and substantial improvement of clinical symptoms. Upon progression, we performed whole-exome and RNA sequencing of a liver metastasis, which demonstrated up-regulation of several genes characteristic for the neuroendocrine prostate cancer phenotype as well as a novel translocation resulting in an in-frame, loss-of-function fusion of RB1. We suggest that multidimensional genomic characterization of prostate cancer patients undergoing PARP inhibitor therapy will be necessary to capture and understand predictive biomarkers of PARP inhibitor sensitivity and resistance.

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BackgroundAdvanced liver diseases are associated with profound alterations of the coagulation system increasing the risk not only of bleeding, but also of thromboembolic complications. A recent milestone study has shown that prophylactic anticoagulation in liver cirrhosis patients results in a reduced frequency of hepatic decompensation. Yet, INR measurement, one of the most widely applied tests to assess liver function, only inaccurately predicts the risk of hepatic decompensation related to alterations of the coagulation system. To assess the relationship between selected coagulation factors / natural anticoagulants with INR, MELD score, and hepatic decompensation, we performed the present pilot study. A total number of 92 patients with various stages of liver cirrhosis were included and prospectively followed for at least 6 months. We found that important natural anticoagulants, namely antithrombin and protein C, as well as factor XI (which may also serve as an anticoagulant) decreased earlier and by a larger magnitude than one would expect from classical coagulation test results. The correlation between these factors and INR was only moderate. Importantly, reduced plasma activities of natural anticoagulants but not INR or MELD score were independent predictors of hepatic encephalopathy (P = 0.013 and 0.003 for antithrombin and protein C, respectively).ConclusionIn patients with liver cirrhosis plasma activities of several natural anticoagulants are earlier and stronger affected than routine coagulation tests. Reduced activities of natural anticoagulants may be predictive for the development of hepatic encephalopathy.

Aims Diabetes mellitus (DM) has a negative impact on prognosis in patients with heart failure (HF). The role impact of DM in HF patients with implantable cardioverter defibrillator (ICD) or cardiac resynchronization therapy (CRT) devices might differ and remains unclear. The aim of our study was to investigate the impact of DM on periprocedural complications and clinical outcome in HF patients undergoing ICD or CRT implantation. Methods and results Within the German Device Registry, data from 50 German centres were collected between January 2007 and February 2014. A retrospective analysis of n = 5329 patients undergoing ICD implantation was conducted. Patients' characteristics, procedural data, periprocedural complications, and post-procedural clinical outcome, including a composite clinical endpoint of all-cause mortality, stroke, and myocardial infarction (MACCE), were analysed. Subgroup analysis were performed for ICD and CRT implantations. Median follow-up was 15.7 (12.9; 20.0) and 16.2 (12.8; 21.2) months in DM and non-DM patients. Of 5329 patients enrolled, n = 1448 (27.2%) had a diagnosis of DM. Within the cohort, 94% of DM and 90% of non-DM patients had a diagnosis of HF. Patients with DM were older, had higher body mass index, and higher rate of cardiovascular comorbidities compared with non-DM patients. Unadjusted and adjusted analyses revealed similar all-over intrahospital periprocedural complication rates in both groups (4.1% vs 3.9%). Unadjusted Kaplan-Meier survival analysis showed higher all-cause mortality after 1 year (9.0% vs 6.3%; log-rank P = 0.001) with higher MACCE rates (10.0% vs 7.3%; P < 0.001) in the DM group versus non-DM patients. After multivariable adjustment for relevant covariates, the association of DM to MACCE disappeared [HR 1.11 (0.89-1.38)]. Because chronic kidney disease (CKD) was clearly associated with increased 1 year MACCE after multivariate adjustment [odds ratio (OR) 2.11 (1.68-2.64)], a subgroup analysis was performed showing a strong trend towards more perioperative complications in DM patients with CKD [OR 2.16 (0.9-5.21)], while no effect of DM was observed in patients without CKD [OR 0.73 (0.42-1.28)]. Conclusions The overall risk of periprocedural complications and short-term (1 year) clinical outcome in patients with DM and HF undergoing ICD or CRT defibrillator (CRT-D) implantation was not increased. In contrast, CKD was associated with an increased risk of 1 year MACCE in HF patients undergoing ICD/CRT-D implantation.

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