FET PET-based target volume delineation for the radiotherapy of glioblastoma: A pictorial guide to help overcome methodological pitfalls.

PET is increasingly used for target volume definition in the radiotherapy of glioblastoma, as endorsed by the 2023 ESTRO-EANO guidelines. In view of its growing adoption into clinical practice and upcoming PET-based multi-center trials, this paper aims to assist in overcoming common pitfalls of FET PET-based target delineation in glioblastoma.

Early and Sustained Symptom Control with Mirikizumab in Patients with Ulcerative Colitis in the Phase 3 LUCENT Program.

BACKGROUND AND AIMS: Ulcerative colitis (UC), a chronic inflammatory bowel disease, may manifest with symptoms of increased stool frequency (SF), rectal bleeding (RB), bowel urgency (BU), abdominal pain (AP), and fatigue. Mirikizumab, an anti-IL-23p19 antibody, demonstrated efficacy and safety in patients with moderately to severely active UC in the LUCENT Phase 3 trials. We evaluated mirikizumab's efficacy in achieving symptom control and time to symptom improvement during induction, maintenance of sustained symptom control, "comprehensive symptom control", defined according to a combination of individual patient-reported outcomes, and prognostic baseline indicators of early symptomatic remission at week 4. METHODS: The results of LUCENT-1/-2 have previously been reported. Treatment differences for symptomatic endpoints were compared over 52 weeks versus placebo (PBO) and comprehensive symptomatic endpoints at 12 and 52 weeks of continuous treatment. Subgroup analyses were conducted for prior biologic or tofacitinib treatment failure. Prognostic analyses were run using regression analysis. RESULTS: By Week (W)2, mirikizumab-treated patients achieved greater reductions in SF, RB, BU, and fatigue versus PBO. At W4, there was a higher rate of AP improvement. At W12, a greater proportion of mirikizumab-treated patients achieved symptomatic remission, RB remission, SF remission, and BU remission/clinically meaningful improvement. Mirikizumab-treated patients sustained symptom control versus placebo patients in maintenance until W52. This treatment effect was shown in patients regardless of prior biologic or tofacitinib failure. Additionally, mirikizumab achieved comprehensive symptom control versus PBO at W12 and W52. CONCLUSIONS: Mirikizumab demonstrated efficacy in achieving and sustaining symptom control and comprehensive symptom control over 52 weeks. [NCT03518086; NCT03524092].

Dummy run for planning of isotoxic dose-escalated radiation therapy for glioblastoma used in the PRIDE trial (NOA-28; ARO-2024-01; AG-NRO-06).

Background: The PRIDE trial (NOA-28; ARO-2024-01; AG-NRO-06; NCT05871021) is designed to determine whether a dose escalation with 75.0 Gy in 30 fractions can enhance the median overall survival (OS) in patients with methylguanine methyltransferase (MGMT) promotor unmethylated glioblastoma compared to historical median OS rates, while being isotoxic to historical cohorts through the addition of concurrent bevacizumab (BEV). To ensure protocol-compliant irradiation planning with all study centers, a dummy run was planned and the plan quality was evaluated. Methods: A suitable patient case was selected and the computed tomography (CT), magnetic resonance imaging (MRI) and O-(2-[18F]fluoroethyl)-L-tyrosine (FET) positron emission tomography (PET) contours were made available. Participants at the various intended study sites performed radiation planning according to the PRIDE clinical trial protocol. The treatment plans and dose grids were uploaded as Digital Imaging and Communications in Medicine (DICOM) files to a cloud-based platform. Plan quality and protocol adherence were analyzed using a standardized checklist, scorecards and indices such as Dice Score (DSC) and Hausdorff Distance (HD). Results: Median DSC was 0.89, 0.90, 0.88 for PTV60, PTV60ex (planning target volume receiving 60.0 Gy for the standard and the experimental plan, respectively) and PTV75 (PTV receiving 75.0 Gy in the experimental plan), respectively. Median HD values were 17.0 mm, 13.9 mm and 12.1 mm, respectively. These differences were also evident in the volumes: The PTV60 had a volume range of 219.1-391.3 cc (median: 261.9 cc) for the standard plans, while the PTV75 volumes for the experimental plans ranged from 71.5-142.7 cc (median: 92.3 cc). The structures with the largest deviations in Dice score were the pituitary gland (median 0.37, range 0.00-0.69) and the right lacrimal gland (median 0.59, range 0.42-0.78). Conclusions: The deviations revealed the necessity of systematic trainings with appropriate feedback before the start of clinical trials in radiation oncology and the constant monitoring of protocol compliance throw-out the study. Trial registration: NCT05871021.

Dosimetric feasibility analysis and presentation of an isotoxic dose-escalated radiation therapy concept for glioblastoma used in the PRIDE trial (NOA-28; ARO-2022-12).

Background and purpose: The PRIDE trial (NOA-28; ARO-2022-12; NCT05871021) is scheduled to start recruitment in October 2023. Its primary objective is to enhance median overall survival (OS), compared to historical median OS rates, in patients with methylguanine methlyltransferase (MGMT) promotor unmethylated glioblastoma by incorporating isotoxic dose escalation to 75 Gy in 30 fractions. To achieve isotoxicity and counteract the elevated risk of radiation necrosis (RN) associated with dose-escalated regimens, the addition of protective concurrent bevacizumab (BEV) serves as an innovative approach. The current study aims to assess the dosimetric feasibility of the proposed concept. Materials and methods: A total of ten patients diagnosed with glioblastoma were included in this dosimetric analysis. Delineation of target volumes for the reference plans adhered to the ESTRO-EANO 2023 guideline. The experimental plans included an additional volume for the integrated boost. Additionally, the 60 Gy-volume was reduced by using a margin of 1.0 cm instead of 1.5 cm. To assess the risk of symptomatic RN, the Normal Tissue Complication Probability (NTCP) was calculated and compared between the reference and experimental plans. Results: Median NTCP of the reference plan (NTCPref) and of the experimental plan (NTCPex) were 0.24 (range 0.11-0.29) and 0.42 (range 0.18-0.54), respectively. NTCPex was a median of 1.77 (range 1.60-1.99) times as high as the NTXPref. In a logarithmic comparison, the risk of RN is enhanced by a factor of median 2.00 (range 1.66-2.35). The defined constraints for the organs at risk were feasible. Conclusion: When considering the potential protective effect of BEV, which we hypothesized might reduce the risk of RN by approximately two-fold, achieving isotoxicity with the proposed dose-escalated experimental plan for the PRIDE trial seems feasible.

Stereotactic Radiosurgery of Multiple Brain Metastases: A Review of Treatment Techniques.

The advancement of systemic targeted treatments has led to improvements in the management of metastatic disease, particularly in terms of survival outcomes. However, brain metastases remain less responsive to systemic therapies, underscoring the significance of local interventions for comprehensive disease control. Over the past years, the threshold for treating brain metastases through stereotactic radiosurgery has risen. Yet, as the number of treated metastases increases, treatment complexity and duration also escalate. This trend has made multi-isocenter radiosurgery treatments, such as those with the Gamma Knife, challenging to plan and lengthy for patients. In contrast, single-isocenter approaches employing linear accelerators offer an efficient and expeditious treatment option. This review delves into the literature, comparing different linear-accelerator-based techniques with each other and in relation to dedicated systems, focusing on dosimetric considerations and feasibility.

Tumor-Specific Delivery of 5-Fluorouracil-Incorporated Epidermal Growth Factor Receptor-Targeted Aptamers as an Efficient Treatment in Pancreatic Ductal Adenocarcinoma Models.

BACKGROUNDS & AIMS: Fluoropyrimidine c (5-fluorouracil [5FU]) increasingly represents the chemotherapeutic backbone for neoadjuvant, adjuvant, and palliative treatment of pancreatic ductal adenocarcinoma (PDAC). Even in combination with other agents, 5FU efficacy remains transient and limited. One explanation for the inadequate response is insufficient and nonspecific delivery of 5FU to the tumor. METHODS: We designed, generated, and characterized 5FU-incorporated systematic evolution of ligands by exponential enrichment (SELEX)-selected epidermal growth factor receptor (EGFR)-targeted aptamers for tumor-specific delivery of 5FU to PDAC cells and tested their therapeutic efficacy in vitro and in vivo. RESULTS: 5FU-EGFR aptamers reduced proliferation in a concentration-dependent manner in mouse and human pancreatic cancer cell lines. Time-lapsed live imaging showed EGFR-specific uptake of aptamers via clathrin-dependent endocytosis. The 5FU-aptamer treatment was equally effective in 5FU-sensitive and 5FU-refractory PDAC cell lines. Biweekly treatment with 5FU-EGFR aptamers reduced tumor burden in a syngeneic orthotopic transplantation model of PDAC, in an autochthonously growing genetically engineered PDAC model (LSL-KrasG12D/+;LSL-Trp53flox/+;Ptf1a-Cre [KPC]), in an orthotopic cell line-derived xenograft model using human PDAC cells in athymic mice (CDX; Crl:NU-Foxn1nu), and in patient-derived organoids. Tumor growth was significantly attenuated during 5FU-EGFR aptamer treatment in the course of follow-up. CONCLUSIONS: Tumor-specific targeted delivery of 5FU using EGFR aptamers as the carrier achieved high target specificity; overcame 5FU resistance; and proved to be effective in a syngeneic orthotopic transplantation model, in KPC mice, in a CDX model, and in patient-derived organoids and, therefore, represents a promising backbone for pancreatic cancer chemotherapy in patients. Furthermore, our approach has the potential to target virtually any cancer entity sensitive to 5FU treatment by incorporating 5FU into cancer cell-targeting aptamers as the delivery platform.

Patient delay and benefit of timely reperfusion in ST-segment elevation myocardial infarction.

BACKGROUND: In patients with ST-segment elevation myocardial infarction (STEMI), it is unknown how patient delay modulates the beneficial effects of timely reperfusion. AIMS: To assess the prognostic significance of a contact-to-balloon time of less than 90 min on in-hospital mortality in different categories of symptom-onset-to-first-medical-contact (S2C) times. METHODS: A total of 20 005 consecutive patients from the Feedback Intervention and Treatment Times in ST-segment Elevation Myocardial Infarction (FITT-STEMI) programme treated with primary percutaneous coronary intervention (PCI) were included. RESULTS: There were 1554 deaths (7.8%) with a J-shaped relationship between mortality and S2C time. Mortality was 10.0% in patients presenting within 1 hour, and 4.9%, 6.0% and 7.3% in patient groups with longer S2C intervals of 1-2 hours, 2-6 hours and 6-24 hours, respectively. Patients with a short S2C interval of less than 1 hour (S2C<60 min) had the highest survival benefit from timely reperfusion with PCI within 90 min (OR 0.27, 95% CI 0.23 to 0.31, p<0.0001) as compared with the three groups with longer S2C intervals of 1 hour

Hemodynamic monitoring by intracardiac impedance measured by cardiac resynchronization defibrillators: Evaluation in a controlled clinical setting (BIO.Detect HF II study).

BACKGROUND: In patients with cardiac resynchronization therapy defibrillators (CRT-Ds), intracardiac impedance measured by dedicated CRT-D software may be used to monitor hemodynamic changes. We investigated the relationship of hemodynamic parameters assessed by intracardiac impedance and by echocardiography in a controlled clinical setting. METHODS: The study enrolled 68 patients (mean age, 66 ± 9 years; 74% males) at 12 investigational sites. The patients had an indication for CRT-D implantation, New York Heart Association class II/III symptoms, left ventricular ejection fraction 15%-35%, and a QRS duration ≥150 ms. Two months after a CRT-D implantation, hemodynamic changes were provoked by overdrive pacing. Intracardiac impedance was recorded at rest and at four pacing rates ranging from 10 to 40 beats/min above the resting rate. In parallel, echocardiography measurements were performed. We hypothesized that a mean intra-individual correlation coefficient (rmean) between stroke impedance (difference between end-systolic and end-diastolic intracardiac impedance) measured by CRT-D and the aortic velocity time integral (i.e., stroke volume) determined by echocardiography would be significantly larger than 0.65. RESULTS: The hypothesis was evaluated in 40 patients with complete data sets. The rmean was 0.797, with a lower confidence interval bound of 0.709. The study hypothesis was met (p = 0.007). A stepwise reduction of stroke impedance and stroke volume was observed with increasing heart rate. CONCLUSIONS: Intracardiac impedance measured by implanted CRT-Ds correlated well with the aortic velocity time integral (stroke volume) determined by echocardiography. The impedance measurements bear potential and are readily available technically, not requiring implantation of additional material beyond standard CRT-D system.

Distribution and impact of age in patients with implantable cardioverter-defibrillators regarding early complications and 1-year clinical outcome: results from the German Device Registry.

BACKGROUND: Patients receiving implantable-cardioverter-defibrillators (ICD) in clinical practice are often older or younger than in clinical trials. Whether older patients benefit from ICD-therapy in a similar way as younger patients is under debate. The objective of this study was to provide real-world data regarding outcomes with respect to age in a large cohort in the German Device Registry. METHODS: Within the registry data from 50 German centers were collected between January 2007 and February 2014. RESULTS: Our analysis included 3239 ICD patients representing a group of young (28%; group I: < 58 years), intermediate aged (50%; group II: 58-74 years), and elderly patients (22%; group III: 75-92 years). Intergroup comparison of all groups was performed followed by individual comparison vs. group II serving as age-reference group. Procedure-related complications did not differ between all groups. Analysis of the primary endpoint, 1-year all-cause mortality, revealed an increased mortality in the elderly and a decreased mortality in the young cohort vs. the reference group II (group I 2.1%, group II 6.2%, group III 13.2%; p < 0.001). While all-cause rehospitalizations did not differ, we observed a difference in reported device revisions showing more device revisions required in younger patients (group I 8.9%, group II 6.8%, group III 4.0%; p = 0.001). CONCLUSIONS: One-year mortality was doubled in elderly ICD patients probably due to non-cardiac causes. These results further underpin the need for re-evaluating the primary prevention ICD indication in octo- and nonagenarians. Young patients show lower mortality rates but seem to bear higher risk of device-related complications, which highlights the need for improved measures to reduce device-related complications in the young.

Long-term effects of a standardized feedback-driven quality improvement program for timely reperfusion therapy in regional STEMI care networks.

AIMS: Current European Society of Cardiology guidelines state that repetitive monitoring and feedback should be implemented for ST-elevation myocardial infarction (STEMI) treatment, but no evidence is available supporting this recommendation. We aimed to analyze the long-term effects of a formalized data assessment and systematic feedback on performance and mortality within the prospective, multicenter Feedback Intervention and Treatment Times in STEMI (FITT-STEMI) study. METHODS: Regular interactive feedback sessions with local STEMI management teams were performed at six participating German percutaneous coronary intervention (PCI) centers over a 10-year period starting from October 2007. RESULTS: From the first to the 10th year of study participation, all predefined key-quality indicators for performance measurement used for feedback improved significantly in all 4926 consecutive PCI-treated patients - namely, the percentages of patients with pre-hospital electrocardiogram (ECG) recordings (83.3% vs 97.1%, p < 0.0001) and ECG recordings within 10 minutes after first medical contact (41.7% vs 63.8%, p < 0.0001), pre-announcement by telephone (77.0% vs 85.4%, p = 0.0007), direct transfer to the catheterization laboratory bypassing the emergency department (29.4% vs 64.2%, p < 0.0001), and contact-to-balloon times of less than 90 minutes (37.2% vs 53.7%, p < 0.0001). Moreover, this feedback-related continuous improvement of key-quality indicators was linked to a significant reduction in in-hospital mortality from 10.8% to 6.8% (p = 0.0244). Logistic regression models confirmed an independent beneficial effect of duration of study participation on hospital mortality (odds ratio = 0.986, 95% confidence interval = 0.976-0.996, p = 0.0087). In contrast, data from a nationwide PCI registry showed a continuous increase in in-hospital mortality in all PCI-treated STEMI patients in Germany from 2008 to 2015 (n = 398,027; 6.7% to 9.2%, p < 0.0001). CONCLUSIONS: Our results indicate that systematic data assessment and regular feedback is a feasible long-term strategy and may be linked to improved performance and a reduction in mortality in STEMI management.

Impact of diabetes on clinical outcome of patients with heart failure undergoing ICD and CRT procedures: results from the German Device Registry.

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.

Single chamber implantable cardioverter defibrillator compared to dual chamber implantable cardioverter defibrillator: less is more! Data from the German Device Registry.

BACKGROUND: In patients with high risk for sudden cardiac death the implantation of a defibrillator is an established treatment. However the benefits and risks for patients in accordance to the number of the leads are not clear. Even in the current guidelines a recommendation to this question is missing. We analyzed advantage and disadvantages of single-chamber implantable cardioverter defibrillators (VVI-ICD) versus dual-chamber implantable cardioverter defibrillators (DDD-ICD) in the prospective German Device Registry. METHODS: The data of 2240 patients who underwent ICD implantation in 45 German Centers between January 2007 and March 2011 were included in a prospective device registry (VVI: n = 1629, male = 1358, EF = 34% ± 13%; DDD: n = 611, male = 491, EF = 35% ± 14%). RESULTS: The in-hospital complications were significantly higher in the DDD-ICD group with higher revision/device complication rates (3.0% vs. 1.2%; p = 0.003) but also higher mortality rate (1.0% vs. 0.1%; p < 0.001). Regarding the adjusted data at 1-year follow-up DDD-ICD caused more device revisions, but no difference in rehospitalization and mortality. CONCLUSION: It is still unclear whether DDD-ICD may be beneficial for patients with preserved sinus and atrioventricular nodal function. Our data show that the decision of the operator to choose a DDD-ICD in these patients must be taken very carefully. By choosing a DDD-ICD the patient is exposed to a significantly higher periprocedural complication rate and higher in-hospital mortality. In absence of relevant bradycardias implantation of a DDD-ICD is not justified.

Prognostic significance of emergency department bypass in stable and unstable patients with ST-segment elevation myocardial infarction.

BACKGROUND: In ST-segment elevation myocardial infarction (STEMI) patients treated with percutaneous coronary intervention, direct transport from the scene to the catheterisation laboratory bypassing the emergency department has been shown to shorten times to reperfusion. The aim of this study was to investigate the effects of emergency department bypass on mortality in both haemodynamically stable and unstable STEMI patients. METHODS: The analysis is based on a large cohort of STEMI patients prospectively included in the German multicentre Feedback Intervention and Treatment Times in ST-Elevation Myocardial Infarction (FITT-STEMI) trial. RESULTS: Out of 13,219 STEMI patients who were brought directly from the scene by emergency medical service transportation and were treated with percutaneous coronary intervention, the majority were transported directly to the catheterisation laboratory bypassing the emergency department (n=6740, 51% with emergency department bypass). These patients had a significantly lower in-hospital mortality than their counterparts with no emergency department bypass (6.2% vs. 10.0%, P<0.0001). The reduced mortality related to emergency department bypass was observed in both stable (n=11,594, 2.8% vs. 3.8%, P=0.0024) and unstable patients presenting with cardiogenic shock (n=1625, 36.3% vs. 46.2%, P<0.0001). Regression models adjusted for the Thrombolysis In Myocardial Infarction (TIMI) risk score consistently confirmed a significant and independent predictive effect of emergency department bypass on survival in the total study population (odds ratio 0.64, 95% confidence interval 0.56-0.74, P<0.0001) and in the subgroup of shock patients (OR 0.69, 95% CI 0.54-0.88, P=0.0028). CONCLUSION: In STEMI patients, emergency department bypass is associated with a significant reduction in mortality, which is most pronounced in patients presenting with cardiogenic shock. Our data encourage treatment protocols for emergency department bypass to improve the survival of both haemodynamically stable patients and, in particular, unstable patients. Clinical Trial Registration: NCT00794001 ClinicalTrials.gov: NCT00794001.

Long-term effects of a standardized feedback-driven quality improvement program for timely reperfusion therapy in regional STEMI care networks.

AIMS: Current European Society of Cardiology guidelines state that repetitive monitoring and feedback should be implemented for ST-elevation myocardial infarction (STEMI) treatment, but no evidence is available supporting this recommendation. We aimed to analyze the long-term effects of a formalized data assessment and systematic feedback on performance and mortality within the prospective, multicenter Feedback Intervention and Treatment Times in STEMI (FITT-STEMI) study. METHODS: Regular interactive feedback sessions with local STEMI management teams were performed at six participating German percutaneous coronary intervention (PCI) centers over a 10-year period starting from October 2007. RESULTS: From the first to the 10th year of study participation, all predefined key-quality indicators for performance measurement used for feedback improved significantly in all 4926 consecutive PCI-treated patients - namely, the percentages of patients with pre-hospital electrocardiogram (ECG) recordings (83.3% vs 97.1%, p < 0.0001) and ECG recordings within 10 minutes after first medical contact (41.7% vs 63.8%, p < 0.0001), pre-announcement by telephone (77.0% vs 85.4%, p = 0.0007), direct transfer to the catheterization laboratory bypassing the emergency department (29.4% vs 64.2%, p < 0.0001), and contact-to-balloon times of less than 90 minutes (37.2% vs 53.7%, p < 0.0001). Moreover, this feedback-related continuous improvement of key-quality indicators was linked to a significant reduction in in-hospital mortality from 10.8% to 6.8% (p = 0.0244). Logistic regression models confirmed an independent beneficial effect of duration of study participation on hospital mortality (odds ratio = 0.986, 95% confidence interval = 0.976-0.996, p = 0.0087). In contrast, data from a nationwide PCI registry showed a continuous increase in in-hospital mortality in all PCI-treated STEMI patients in Germany from 2008 to 2015 (n = 398,027; 6.7% to 9.2%, p < 0.0001). CONCLUSIONS: Our results indicate that systematic data assessment and regular feedback is a feasible long-term strategy and may be linked to improved performance and a reduction in mortality in STEMI management.

Response to olaparib in a PALB2 germline mutated prostate cancer and genetic events associated with resistance.

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.

Evaluation of thoracic impedance trends for implant-based remote monitoring in heart failure patients - Results from the (J-)HomeCARE-II Study.

AIMS: Remote monitoring by implantable devices substantially improves management of heart failure (HF) patients by providing diagnostic day-to-day data. The use of thoracic impedance (TI) as a surrogate measure of fluid accumulation is still strongly debated. The multicenter HomeCARE-II study evaluated clinically apparent HF events in the context of remote device diagnostics, focusing on the controversial role of TI. METHODS AND RESULTS: We followed 497 patients (66.6 ±â€¯10.1 years, 77% male, QRS 139.8 ±â€¯36.0 ms, ejection fraction 26.8 ±â€¯7.0%) implanted with a CRT-D (67%) or an ICD (33%) for 21.4 ±â€¯8.1 months. An independent event committee confirmed 171 HF events of which 82 were used to develop a TI-based algorithm for the prediction of imminent cardiac decompensation. Highly inter-individual variations in patterns of TI trends were observed. The algorithm resulted in a sensitivity of 41.5% (50.0%) with 0.95 (1.34) false alerts per patient year, and a positive predictive value of 7.9% overall and 27.9% in the HF event group of patients. Averaged ratio statistics showed a significant pre-hospital decrease and a highly significant in-hospital increase in TI after intensified diuresis. Recurrent decompensations turned out to be preceded by a significantly stronger decrease of TI compared to first events with a higher chance for detection (63.6% sensitivity, p < 0.05). CONCLUSIONS: Overall performance in predicting imminent decompensation by monitoring TI alone is limited due to its high inter-patient variability. TI stand-alone applications should be redirected towards a target population with more advanced symptoms where post-hospital observation aimed to maintain the patient's discharge status might be the most valuable approach. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov Identifier NCT00711360 (HomeCARE-II) and NCT01221649 (J-HomeCARE-II).

Can we rely on Danish? Real-world data on patients with nonischemic cardiomyopathy from the German Device Registry.

According to current guidelines prophylactic implantable cardioverter-defibrillator (ICD) therapy is recommended in patients with significantly impaired left ventricular systolic function. However, the recently published DANISH trial did not find a significantly lower long-term rate of death from any cause compared with usual clinical care in patients with non-ischemic cardiomyopathy. We investigated whether registry data from a multi-center 'real-life' registry on patients with non-ischemic cardiomyopathy are similar to this trial. The German Device Registry (DEVICE) is a nationwide, prospective registry with one-year follow-up investigating 5451 patients receiving device implantations in 50 German centers. The present analysis of DEVICE focused on patients with non-ischemic cardiomyopathy and a left ventricular ejection fraction ≤35% who received a prophylactic ICD. Out of 779 patients with symptomatic heart failure and nonischemic cardiomyopathy, 33.1% received a single chamber ICD (VVI), while 11.0% were implanted with a dual-chamber ICD (DDD), and 55.8% received a defibrillator system for cardiac resynchronization therapy. Median follow-up was 16.1 months. 90.7% were alive at follow-up, 9.3% had died during this period. Overall mortality after one year was 5.4%. Overall mortality one year after implantation was significantly increased in patients 68 years and older(7.9%) as compared to younger patients (59-68 years: 2.5%; < 59 years: 3.8%; p < 0.015). Data from the present registry support the recently published results of the DANISH trial. In particular the influence of an increased age as proven in the DANISH trial might also play a role in the present collective. This limits the potential beneficial effect of ICD therapy in particular in the elderly population.

Impact of treatment delay on mortality in ST-segment elevation myocardial infarction (STEMI) patients presenting with and without haemodynamic instability: results from the German prospective, multicentre FITT-STEMI trial.

Aims: The aim of this study was to investigate the effect of contact-to-balloon time on mortality in ST-segment elevation myocardial infarction (STEMI) patients with and without haemodynamic instability. Methods and results: Using data from the prospective, multicentre Feedback Intervention and Treatment Times in ST-Elevation Myocardial Infarction (FITT-STEMI) trial, we assessed the prognostic relevance of first medical contact-to-balloon time in n = 12 675 STEMI patients who used emergency medical service transportation and were treated with primary percutaneous coronary intervention (PCI). Patients were stratified by cardiogenic shock (CS) and out-of-hospital cardiac arrest (OHCA). For patients treated within 60 to 180 min from the first medical contact, we found a nearly linear relationship between contact-to-balloon times and mortality in all four STEMI groups. In CS patients with no OHCA, every 10-min treatment delay resulted in 3.31 additional deaths in 100 PCI-treated patients. This treatment delay-related increase in mortality was significantly higher as compared to the two groups of OHCA patients with shock (2.09) and without shock (1.34), as well as to haemodynamically stable patients (0.34, P < 0.0001). Conclusions: In patients with CS, the time elapsing from the first medical contact to primary PCI is a strong predictor of an adverse outcome. This patient group benefitted most from immediate PCI treatment, hence special efforts to shorten contact-to-balloon time should be applied in particular to these high-risk STEMI patients. Clinical Trial Registration: NCT00794001.

Severity of coronary artery disease is associated with non-alcoholic fatty liver dis-ease: A single-blinded prospective mono-center study.

BACKGROUND AND AIMS: Liver steatosis has shown to be associated with coronary artery disease (CAD). The aim of our study was to evaluate the association between the presence and severity of CAD and Non-alcoholic fatty liver disease (NAFLD) assessed by transient elastography (TE) and controlled attenuation parameter (CAP). METHODS: 576 Patients undergoing coronary angiography were enrolled in this prospective study, receiving at least 10 TE and CAP measurements using the FibroScan® M-probe. Clinically relevant CAD (CAD 3) was defined as stenosis with ≥75% reduction of the luminal diameter. NAFLD was determined by CAP ≥234 dB/m. NAFLD with advanced fibrosiswas determined by TE-values ≥7.9kPa in the presence of NAFLD and absence of congestive or right-sided heart failure. Rates and 95% confidence intervals are shown. RESULTS: 505 patients were available for analysis of NAFLD. However, only 392 patients were available for analysis of NAFLD with advanced fibrosis, since 24 patients had to be excluded due to non valid TE-measurements and 89 patients due to congestive or right-sided heart failure or suspected concomitant liver disease, respectively. 70.5% (66.3%-74.4%) of patients had CAD 3, 71.5% (67.3%-75.4%) were diagnosed with NAFLD, and 11.2% (8.3%-14.8%) with NAFLD with advanced fibrosis. Patients with CAD 3 had higher median CAP-values (273±61 vs. 260±66 dB/m; p = 0.038) and higher degrees of steatosis as compared to patients without CAD 3. While NAFLD was significantly more often diagnosed in patients with CAD 3 (75.0% vs. 63.1%, p = 0.0068), no significant difference was found for NAFLD with advanced fibrosis (10.7% vs. 12.5%, p = 0.60). CONCLUSIONS: Clinically relevant CAD is frequently associated with the presence of NAFLD, but not NAFLD with advanced fibrosis.