Klinikum Ludwigsburg

Abstract Background Heart failure (HF) is one of the leading public health issues worldwide. Current guidelines recommend HF treatment using different drug classes depending on ejection fraction (EF) and underlying cause of HF. Sodium-glucose co-transporter 2 inhibitors (SGLT2i) are a drug class with a class IA recommendation in the current ESC-guidelines for HF treatment independent of EF. The SGLT2i dapagliflozin is approved for treatment of HF across the entire spectrum of EF in Germany. However, real-world data are limited. Purpose The aim of EVOLUTION-HF DEallEF is to generate data on real-world dapagliflozin use in HF patients independently of EF in Germany under the multinational umbrella EVOLUTION-HF study protocol. Methods EVOLUTION-HF DEallEF is a non-interventional, prospective, longitudinal cohort study. It is planned to enrol a total of 1000 patients with chronic HF in Germany, including 40% patients with preserved (HFpEF; EF ≥ 50%), 20% with mildly reduced (HFmrEF; EF 41-49%), and 40% with reduced EF (HFrEF; EF ≤ 40%). Patients willing to participate, aged ≥18 years, who started dapagliflozin treatment 14 to 90 days prior to enrolment according to the local product label, are eligible for participation. Among reasons for exclusion is previous SGLT2i treatment (including dapagliflozin). Data on medical history, clinical symptoms, previous and concomitant medication and patient-reported outcomes (PROs) are collected. EVOLUTION-HF DEallEF has included its first patient in 04/2024 and is currently open for enrolment. Interim analyses (IA) were planned at predefined timepoints (after 250, 500 enrolled patients and enrolment completion). The three different EF cohorts (HFpEF, HFmrEF, HFrEF) are analysed separately and as a total population. Only descriptive statistical methods are used. Results This 1st IA (data cutoff: 02/12/2024) included 249 patients in the safety set (all patients received at least one dose of dapagliflozin, one patient refused data usage) and 244 patients who fulfilled all eligibility criteria in the full analysis set (FAS). Patients were enrolled in 31 study sites, mainly in office-based cardiologic practices. In the FAS, distribution of patients to HF cohorts was 51% with HFpEF (n=125), 30% with HFmrEF (n=73), and 19% with HFrEF (n=46). Conclusions Patients’ and disease characteristics observed at the time of the first IA are in range with previously published data indicating that a representative cohort of patients newly treated with dapagliflozin for HF are enrolled in EVOLUTION-HF DEallEF. Dysbalance in expected enrolment proportion per EF cohort is mainly caused by exclusion of patients with SGLT2i-pretreatment. The study aims to provide further insights into real-world dapagliflozin treatment for HF in Germany, focussing on clinical and patients’ perspective.

Merkel cell carcinoma (MCC) is an aggressive tumor mostly related to Merkel cell polyomavirus genomic integration. MCC can present either as a primary cutaneous tumor or as a lymph node metastasis without a primary skin tumor (MCCWOPT). The distinction between MCCWOPT and lymph node metastases of non-cutaneous neuroendocrine carcinomas remains challenging. The present study aims to determine whether the methylation profile can distinguish MCCWOPT from lymph node metastases of extracutaneous neuroendocrine carcinomas. Methylation profiles of twenty MCCWOPT were compared to 23 cutaneous MCC, 37 small-cell lung carcinomas, 17 and 34 well-differentiated neuroendocrine tumors of the ileum and pancreas. Among the controls, cutaneous MCC cases formed a cluster distinct from other extracutaneous neuroendocrine tumors. MCCWOPT clustered together with cutaneous MCC cases. Methylation profiling represents a promising additional tool for the diagnosis of MCCWOPT.

Extracorporeal Life Support (ECLS) has evolved into an established treatment for severe cardiogenic shock. As most patients have residual antegrade left ventricular output toward the descending aorta that meets the retrograde blood flow from the arterial ECLS cannula, they may develop differential hypoxemia. The location of the mixing cloud is critical for coronary and brain oxygenation. We analyzed the effects of the development of differential hypoxemia on morbidity and mortality of ECLS patients. Moreover, we analyzed the impact of two different treatment options for this phenomenon, including the administration of beta-blockers and the provision of a supplementary arterial cannula, on survival. We performed a retrospective review of patient demographics, outcomes, laboratory, and respiratory parameters during and after ECLS support for 76 ECLS patients treated at our institution. Overall, 38 ECLS patients developed differential hypoxemia. Treatment of this phenomenon included either the administration of beta-blockers (n = 18) or the introduction of a second arterial ECLS cannula (n = 20). There were no significant differences in median SOFA-Scores (Sequential Organ Failure Assessment Scores) between groups (p = 0.072; ECLS vs. ECLS with differential hypoxemia patients). Under all respiratory and laboratory values analyzed, only bilirubin levels were significantly different (p = 0.020). Development of differential hypoxemia was associated with significantly decreased survival rates (p = 0.05). Moreover, insertion of a second arterial ECLS cannula was a risk factor for mortality (OR: 3.68, 95% CI 1.18-11.47, p = 0.025). Development of differential hypoxemia is associated with significantly increased mortality rates among ECLS patients and should therefore be prevented as far as possible. Non-invasive administration of beta-blockers seems to be the more effective treatment option for differential hypoxemia, as the introduction of a second arterial ECLS cannula was a risk factor for mortality.

To compare online MR-guided SBRT (MRgRT) of liver metastases with state-of-the-art ITV-based SBRT (ITV-SBRT) and assess which patients benefit most from MRgRT. In a prospective randomized trial (MAESTRO study, NCT05027711), patients were randomized to either gated and online adaptive MRgRT or ITV-SBRT if a biologically effective dose (BED10) of 100Gy was feasible with ITV-SBRT. Otherwise, patients were treated with MRgRT. In this subgroup analysis of 20 patients, a dosimetric comparison of MRgRT and ITV-SBRT plans was performed. Tumor control and normal tissue complication probabilities were calculated. In 40% of all patients, MRgRT enabled SBRT with less fractions and/or higher prescription BED10. Almost all target volume metrics were improved with MRgRT. MRgRT PTV D95% was significantly higher in the overall cohort (91.0±22.9Gy vs. 79.5±27.2Gy, p=0.001), in uncritical (111.3±6.2Gy vs. 104.7±4.1Gy, p=0.022) and in critical cases with limited healthy liver volume or nearby gastrointestinal organs at risk (74.1±16.9Gy vs. 58.5±18.5Gy, p=0.041). Target volume V100% was also superior with MRgRT. Calculated 2-year tumor control probability was significantly superior with MRgRT overall (73.0±6.2% vs. 69.7±7.9%, p=0.002), in uncritical cases (78.3±1.4% vs. 76.8±1.0%, p=0.022) and in critical cases (68.5±4.8% vs. 63.8±5.8%, p=0.041), without elevated normal tissue complication probability. Dosimetrically, gated MRgRT was beneficial for virtually all the hepatic metastases analyzed in this study. Patients with metastases located critically near gastrointestinal OAR or with limited healthy liver volume should be allocated to centers providing MRgRT.

ABSTRACTBackgroundOver the past years, some studies in amyotrophic lateral sclerosis (ALS) have provided heterogeneous findings regarding demographic and clinical data as well as the impact of various prognostic factors. It is well known that these inconsistencies might be caused by a selection bias in hospital‐based data sets. In this study, we sought to further characterize this selection bias.MethodsWe compared hospital‐based data from the ALS center at Ulm University (UC; n = 3833; 1997–2021) with the population‐based ALS registry Swabia (SR; n = 852; 2010–2020).ResultsPatients from UC were younger (age of onset 60.9 [IQR 52.4–68.9] vs. 65.0 [57.0–72.7]), had a higher share of males (60.5% vs. 56.3%), a longer diagnostic delay (10.5 [IQR 6.4–18.4] months vs. 6.9 [IQR 3.4–12.1] months), a higher prevalence of the “definite” category according to El Escorial diagnostic criteria (60.9% vs. 11.2%), a higher share of familial cases (12.9% vs. 6.3%), a slower progression rate (points of ALS functional rating scale revised lost per month −0.54 [IQR −1.02 to −0.28] vs. −0.79 [IQR −1.47 to −0.43]), and (among all deceased patients) a higher share of percutaneous endoscopic gastrostomy (26.7% vs. 17.7%) and non‐invasive ventilation (34.3% vs. 25.3%).ConclusionsThe observed differences likely indicate a selection bias in hospital‐based data, which may be attributed, among others, to the willingness to travel large distances to a specialized center, the desire to participate in clinical studies, and the attitude toward life‐prolonging measures. These differences must be considered when interpreting and generalizing study results from hospital‐based populations.

Introduction: The rapid identification of acute intracerebral hemorrhage (ICH) in patients with symptoms of acute stroke is decisive for prehospital triage and initiation of targeted therapies. Glial fibrillary acidic protein (GFAP) is a highly promising blood biomarker indicating ICH. In this study we investigated the potential of a new GFAP point-of-care test for rapidly distinguishing ICH from ischemic stroke (IS) and stroke mimics in the prehospital phase. Methods: Acute stroke patients admitted within 6 hours of symptom onset were enrolled. Blood samples were collected in the prehospital phase. Plasma GFAP measurements were performed on the i-STAT Alinity® (Abbott) device (duration of analysis 15 min). The gold standard was the final diagnosis at hospital discharge categorized as ICH, IS or stroke mimics. Results: 353 patients were enrolled (mean age 74.6 ±13.4, years). GFAP concentrations were strongly elevated in ICH patients (n=76; median 208 pg/mL [IQR 60 – 5907]) compared to IS patients (n=258; median 30 pg/mL [IQR 29-51]) and stroke mimics (n=19; median 48 pg/mL [IQR 29-97]; p<0.001). Patients with anticoagulation-associated ICH had higher GFAP values compared to non-anticoagulated patients. Cut-off points were determined allowing diagnosis of ICH across distinct age groups with high positive predictive values (90.0 to 95.5%). Vice versa, in patients with a moderate to severe neurological deficit (NIHSS > 6), GFAP values below 30 pg/mL ruled out ICH with a negative predictive value of 100.0 %. Conclusion: Prehospital GFAP measurements on a point-of-care platform allow a reliable identification of patients with ICH. This opens the potential for optimized triage as well as the initiation of blood pressure lowering therapy and anticoagulation reversal in earlier time frames.