Abstract Background Depression associated with occupational stress is highly prevalent, causing high rates of sick leave and thus posing significant societal and economic burden. Meta-analyses of the few studies on psychological and work-focused interventions for common mental disorders including depression report small effects on depressive symptomatology and occupational outcomes. There is an urgent need for more controlled studies on work-directed interventions assessing work outcomes. Methods This is an interventional, multicentre, active-controlled, cluster-randomised, observer-blinded clinical trial with two parallel groups conducted in 6 clinical centres throughout Germany over the course of 3 years. A sample of 144 outpatients with work stress related depression will be cluster-randomised to either a specific interpersonal group intervention for depression and work stress (IPT-Work) or a nonspecific supportive group psychotherapy (SP). Each group consists of 10 sessions over 8 weeks of 90 min duration with 4–6 participants. Patients will be assessed at baseline, post-treatment and at 3 months follow-up. The primary endpoint is the relative change in HRSD-24 score from baseline to follow-up 3 months after end of treatment. Secondary outcome measures include the Occupational Depression Inventory (ODI), the Work Ability Index (WAI), the Return to Work Attitude (RTW-SE), the Effort-Reward-Imbalance (ERI), the Job Content Questionnaire 2 (JCQ2), and the Connor-Davidson Resilience Scale (CD-RISC). In addition, Quality of Life (WHOQOL-BREF) and days of sick leave throughout the study period will be assessed. Effects of treatment will be analysed with a linear mixed model for repeated measures including randomised arm, time point and their interaction as well as HRSD-24 baseline scores and their interaction with time point as fixed effects. Discussion Results will provide a comparison of a nonwork-directed psychological intervention and a specific, work-directed approach with respect to symptom improvement and increase in work ability. The aim is to improve quality of mental health care for depressed employees to facilitate recovery, improve work ability, and reduce the risk of long-term occupational incapacity. Ultimately, findings will inform the practice of the efficiency of using psychological group treatment in depressed individuals with work stress. Trial registration German Clinical Trials Register (DRKS00035259); prospectively registered on 15th January 2025.

BACKGROUND:O-(2-[18F]fluoroethyl)-L-tyrosine (FET)-PET has a higher specificity than contrast-enhanced T1-weighted MRI (CE-T1MRI) in diagnosing recurrent glioblastoma. We aimed to evaluate whether a FET-PET-based target volume delineation, compared with CE-T1MRI, improves outcomes in patients with recurrent glioblastoma scheduled for re-irradiation. METHODS:GLIAA was a multicentre, open-label, parallel randomised study done in 15 radiation oncology centres in Germany. Patients aged 18 years or older with a Karnofsky performance score greater than 60% and a macroscopic WHO grade IV recurrent glioblastoma (1-6 cm) were randomly assigned (1:1) to receive either FET-PET-based or CE-T1MRI-based target volume delineation followed by re-irradiation with 39 Gy in 13 fractions. Randomisation was performed centrally, using a minimisation technique with a random element and a computer-assisted randomisation tool, stratified by time since first radiotherapy, previous chemotherapy, tumour diameter, MGMT status, and planned chemotherapy. The primary endpoint was progression-free survival from randomisation, assessed in the per-protocol population (patients who initiated treatment per their assigned group). Adverse events were systematically assessed in all patients who commenced therapy. The trial was registered with ClinicalTrials.gov (NCT01252459), German Clinical Trials Registry (DRKS00000634), and European Clinical Trials Database (EudraCT 2012-001121-27), and is completed. FINDINGS:Between Nov 22, 2013, and Aug 18, 2021, 271 patients were recruited and screened for eligibility, 200 of whom were randomly assigned to re-irradiation based on FET-PET (n=100) or CE-T1MRI (n=100). 85 (43%) participants were female and 115 (58%) were male. 98 patients in the FET-PET group and 97 in the CE-T1MRI group were treated per protocol. Median follow-up for censored patients was 12·2 months (IQR 6·6-20·7). Median progression-free survival was 4·0 months (95% CI 3·7-5·2) in the FET-PET group and 4·9 months (3·7-6·0) in the CE-T1MRI group (one-sided stratified log-rank p=0·98; adjusted hazard ratio 1·14 [95% CI 0·85-1·52]; p=0·39; median follow-up for six censored patients 4·1 months [IQR 2·3-6·6]). The most common grade 3-4 adverse event was radionecrosis (eight [8%] of 99 in the FET-PET group vs seven [7%] of 99 in the CE-T1MRI group). Acute and subacute serious adverse events occurred in 15 (15%) of 99 patients in each group; possibly re-irradiation-related late serious adverse events occurred in ten (10%) of 97 patients in the FET-PET group and 18 (19%) of 96 in the CE-T1MRI group. There were no treatment-related deaths. INTERPRETATION:FET-PET-based target volume delineation for re-irradiation did not lead to a significant clinical benefit compared with CE-T1MRI-based treatment in patients with recurrent glioblastoma. Thus, CE-T1MRI remains the preferred delineation method in this setting. FUNDING:Deutsche Krebshilfe.

2038 Background: The HIPPORAD trial aimed to evaluate a new method of whole brain radiation therapy (WBRT) with simultaneous integrated boost (SIB) to the metastases, with versus without hippocampal avoidance in patients with brain metastases. Methods: We conducted a prospective, multicentre, randomised, double-blind trial (DRKS00004598). Patients with 4-10 brain metastases > = 5mm were randomised at 13 centres in Germany 1:1 between WBRT+SIB with hippocampus avoidance (HA-WBRT+SIB) (arm A) and WBRT+SIB (arm B). Patients and assessors of outcome were blinded to the randomised arm. All patients received WBRT with 30 Gy and SIB with 51 Gy or 42 Gy in 12 fractions, 5x/week. The primary endpoint was the change in neurocognitive function (assessed by the Verbal Learning and Memory Test [VLMT]) 3 months after treatment. Secondary endpoints included neurocognitive changes at 9 and 18 months, development of anxiety and depression, quality of life and measures of oncological outcome. Results: Between August 2 nd , 2016 and September 7 th , 2021, 170 patients were recruited and 136 were randomised between HA-WBRT+SIB (n = 67) and WBRT+SIB (n = 69). Of these, 38 patients in arm A and 42 in arm B were known to be alive 3 months after treatment and were included in the primary endpoint analysis. The change in overall learning performance at 3 months was not significantly different between arms (p = 0.83). VLMT-scores decreased after 3 months, but improved at 9 and 18 months, with HA-WBRT+SIB showing an overall superior trend over WBRT+SIB. At 18 months, VLMT-scores improved to values above baseline in both arms. Patients treated with HA-WBRT+SIB had significantly less depression compared to patients treated with WBRT+SIB at 3 (p = 0.047) and 18 months (p = 0.048). The 12-month-tumor control for boosted metastases was 96% in Arm A and 88% in Arm B, while for the WBRT area it was 78% in both arms. Time to hippocampal tumour progression was comparable between arms (p = 0.98). After 12 months, 4% of patients in arm A and 12% in arm B had suffered neurological death. Conclusions: To our knowledge, this is the first prospective trial to show that hippocampal avoidance during WBRT leads to significantly lower rates of depression. The development of VLMT values after HA-WBRT+SIB and WBRT+SIB with 30 Gy in 2.5 Gy-fractions was comparable and a good recovery was observed at 18 months in both arms. The method showed a considerably higher intracerebral tumour control with lower neurological mortality rates compared to historical cohorts. Clinical trial information: DRKS00004598 .

Amyloid PET imaging is an established diagnostic tool for Alzheimer's disease, but its successful integration into clinical practice requires a comprehensive understanding of its impact on patients and the healthcare system. In 2022, the coverage with evidence development (CED) ENABLE study has been approved by the German Federal Joint Committee (trial registration: DRKS00030839). The study is scheduled to start in early 2024. Primary outcome of ENABLE is the change in patients' functional abilities at 18 months after diagnosis with amyloid PET versus without amyloid-PET. Here we describe the design of an ENABLE sub-study aimed at performing a process evaluation. We will conduct an outcome and process evaluation using a pre-post descriptive design nested in ENABLE (Figure), based on the Medical Research Council's Process Evaluation (PE) framework. The PE will focus on acceptability and reach of the target groups of patients and care providers, as well as fidelity of delivery (% of adherence to protocol, study duration), contextual changes and mechanisms (e.g., ability to mirror routine care). We will collect patients’ data independently, but in parallel with ENABLE, using interviews, surveys and checklists to assess acceptance of the intervention, fidelity of adherence to the follow-up procedures, perceived benefits and challenges. Healthcare providers and administrators will be interviewed to identify implementation hurdles and facilitators, contextual factors influencing uptake and underlying mechanisms. For data analysis we will employ a mixed-methods approach. Expected outcomes will include acceptability and adherence, barriers and facilitators to implementation, contextual factors influencing implementation, perceived utility of the intervention by patients and providers, and mechanisms by which the intervention can be delivered as part of normal care. This process evaluation can inform researchers on how to design future CED studies to be implemented into clinical care. The lessons learned during the development and approval process of the ENABLE project in Germany, as well as its process evaluation, can benefit other European CED studies and policy-makers stakeholders in making informed decisions. Likewise, these findings can be generalized beyond the context of amyloid PET to other diagnostic biomarkers, ultimately improving the diagnosis and management of Alzheimer's disease.

We prospectively evaluated the effects of stereotactic body radiotherapy (SBRT) on circulating immune cells. Patients with oligo-metastatic and oligo-progressive pulmonary lesions were treated with SBRT with (cSBRT) or without (SBRT group) concurrent systemic treatment (chemotherapy or immune checkpoint blockade) using different fractionation regimes. Immunoprofiling of peripheral blood cells was performed at baseline, during, at the end of SBRT, and at the first and second follow-ups. The study accrued 100 patients (80 with evaluable samples). The proportion of proliferating CD8+ T-cells significantly increased after treatment. This increase remained significant at follow-up in the SBRT group, but not in the cSBRT group and was not detected with doses of >10Gy per fraction indicating that lower doses are necessary to increase proliferating T-cells' frequency. We detected no favorable impact of concurrent systemic treatment on systemic immune responses. The optimal timing of systemic treatment may be post-SBRT to leverage the immune-modulating effects of SBRT.

Background:Informal caregivers of depressed individuals often report extensive psychological distress with detrimental consequences for their own health and for the course of the depressed person's disease. An online self-help programme was developed involving focus groups of caregivers, affected individuals and clinical experts. Methods:In this randomised, controlled, open-label superiority trial with three parallel groups (prospective registration: DRKS00025241), stratified randomisation allocated caregivers (≥18 years) of depressed individuals in a 2:2:1 ratio to receiving the programme with either individualised (IND, three weekly e-mails by trained psychologists) or automated (AUT) support messages, or to treatment as usual (TAU; information material, no online programme, no messages). The primary outcome was the change from baseline to four weeks after randomisation in the Kessler Psychological Distress Scale (K-10). Findings:The trial was conducted between 01 March 2020 and 29 February 2024. In 1640 (IND: n = 651; AUT: n = 659; TAU: n = 330) caregivers (mean[SD] age m age = 42·8 [12·89] years; n = 1300 [79%] female; baseline K-10 score m K-10 = 23·4 [6·09]), both IND and AUT reduced psychosocial distress significantly more than TAU at four weeks after randomisation (adjusted difference m IND/TAU [95%-CI] = -1·45 [-2·19,-0·72], p = 0·0001; m AUT/TAU [95%-CI] = -0·89 [-1·63,-0·14], p = 0·0205; dropout rate: 34%, n = 562). No study-related harms were reported. Interpretation:Psychological online support for caregivers of depressed individuals with either individualised or automated messages is effective in decreasing their psychosocial distress and could be offered as part of integrated services. Funding:German Innovation Fund (Federal Joint Committee, 01VSF19054).

OBJECTIVES:Structured Early detection of Asymptomatic Liver fibrosis and cirrhosis (SEAL) is a population-based screening programme using non-invasive tests for the early detection of liver fibrosis. This study evaluates the cost implications if the SEAL programme were to be implemented in routine care in Germany. DESIGN:This study models cost differences with and without the SEAL screening programme. We regress costs of care on patient characteristics (age, comorbidities, sex, liver diseases, liver cancer and liver fibrosis and cirrhosis (LCI) stage) using statutory health insurance (SHI) data from routine care patients with LCI (n=4177). Based on these results, we predict per-patient costs for the patients newly diagnosed with LCI by SEAL (n=45). Costs with and without screening are estimated using patient age and LCI stage distributions from either SEAL or routine care. SETTING:SEAL was conducted in two German states. Initial screening was performed by patients' primary care physicians. PARTICIPANTS:Individuals insured by SHI without a prior diagnosis of LCI, eligible for Check-up 35, a general health check-up programme primarily targeting adults aged 35 and older, conducted by primary care physicians. INTERVENTIONS:Screening via aspartate aminotransferase to platelet ratio index in primary care, for further evaluation serological diagnostics and ultrasound examinations in secondary care and specific assessment for definite diagnosis including transient elastography and liver biopsy for selected cases in tertiary care. PRIMARY AND SECONDARY OUTCOME MEASURES:Primary outcome measures: expected 5-year cost changes for SEAL patients diagnosed with fibrosis or cirrhosis compared to costs without a screening programme. SECONDARY OUTCOME MEASURES:case mix of leading chronic liver disease and LCI stages among patients diagnosed with advanced fibrosis or cirrhosis in SEAL versus routine care without screening. RESULTS:Screening leads to fewer decompensated cases at initial diagnosis (4.6% in SEAL vs 22.8% in routine care) and thus savings in the costs of care within the first years of diagnosis: total expected costs per case were €2175 lower (bias-corrected bootstrap CIs (BCI): €527 to 3734), and LCI-associated costs were reduced by €1218 (BCI: €296 to 2164). Comparing the savings to the additional costs of diagnosis (range: €1575-1726 per detected LCI case) reveals that average changes in costs with screening range from moderate savings to moderate extra costs. CONCLUSIONS:SEAL liver screening identifies patients in less advanced stages of LCI. If only costs were considered that are directly attributable to LCI, savings within 5 years are unlikely to fully outweigh the costs of screening. However, since this approach might miss additional LCI-related costs, SEAL appears to be cost-neutral compared with routine care when considering total healthcare costs. REGISTRATION NUMBER:The SEAL registration number is DRKS00013460. This study relates to its results.

BACKGROUND:The advancement of Artificial Intelligence, particularly Large Language Models (LLMs), is rapidly progressing. LLMs, such as OpenAI's GPT, are becoming vital in scientific and medical processes, including text production, knowledge synthesis, translation, patient communication and data analysis. However, the outcome quality needs to be evaluated to assess the full potential for usage in statistical applications. LLMs show potential for all research areas, including teaching. Integrating LLMs in research, education and medical care poses opportunities and challenges, depending on user competence, experience and attitudes. OBJECTIVE:This project aims at exploring the use of LLMs in supporting statistical consulting by evaluating the utility, efficiency and satisfaction related to the use of LLMs in statistical consulting from both advisee and consultant perspective. Within this project, we will develop, execute and evaluate a training module for the use of LLMs in statistical consulting. In this context, we aim to identify the strengths, limitations and areas for potential improvement. Furthermore, we will explore experiences, attitudes, fears and current practices regarding the use of LLMs of the staff at the Medical Center and the University of Freiburg. MATERIALS AND METHODS:This multimodal study includes four study parts using qualitative and quantitative methods to gather data. Study part (I) is designed as mixed mode study to explore the use of LLMs in supporting statistical consulting and to evaluate the utility, efficiency and satisfaction related to the use of LLMs. Study part (II) uses a standardized online questionnaire to evaluate the training module. Study part (III) evaluates the consulting sessions using LLMs from advisee perspective. Study part (IV) explores experiences, attitudes, fears and current practices regarding the use of LLMs of the staff at the Medical Center and the University of Freiburg. This study is registered at the Freiburg Registry of Clinical Studies under the ID: FRKS004971.

To investigate the efficacy of bilirubin reduction by hemoadsorption with CytoSorb® in patients with acute-on-chronic liver failure (ACLF) receiving continuous renal replacement therapy (CRRT). A prospective, randomized, single-center, open-label, controlled pilot trial. Patients with ACLF, acute kidney injury, and serum bilirubin ≥5 mg/dL were assigned 1:1:1 to one of three study groups (CRRT with or without hemoadsorption, no CRRT). In the hemoadsorption group, the CytoSorb adsorber was incorporated into the CRRT system, replaced after 12, 24, and 48 h, and removed after 72 h. The primary endpoint was the serum bilirubin level after 72 h. CYTOHEP was terminated early due to difficulties in recruiting patients and ethical concerns. Three of 9 patients (33%) were treated in each group. Comparing the three groups, mean bilirubin levels after 72 h were lower by −8.0 mg/dL in the “CRRT with hemoadsorption” group compared to “CRRT without hemoadsorption” (95% CI, −21.3 to 5.3 mg/dL; p  = 0.17). The corresponding mean difference between “CRRT without hemoadsorption” and “no CRRT” was −1.4 mg/dL (95% CI, −14.2 to 11.5 mg/dL; p  = 0.78). Comparing “CRRT with hemoadsorption” and “no CRRT,” it was −9.4 mg/dL (95% CI, −20.8 to 2.1 mg/dL; p  = 0.0854). Only 1/9 patients (11%, “no CRRT” group) survived day 30 after study inclusion but died on day 89. IL-6, liver function parameters, and clinical scores were similar between the study groups. CYTOHEP failed to demonstrate that extracorporeal hemoadsorption combined with CRRT can reduce serum bilirubin in ACLF patients with acute kidney failure.

2021 Background: Re-irradiation is an important treatment option for recurrent glioblastoma (rGBM). Here, we aimed to compare the oncological outcome of a re-irradiation target volume delineation based on O-(2-[18F]fluoroethyl)-L-tyrosine (FET) positron emission tomography (PET) with the one of a treatment based on contrast enhanced T1-weighted magnetic resonance imaging (T1Gd-MRI). Methods: GLIAA was a prospective, multicenter, randomized trial (NOA 10/ARO 2013-1, DKTK-a.). Patients with rGBM recurrence of 1-6 cm following initial radiotherapy were recruited at 14 centers in Germany and randomized 1:1 between a FET-PET- (arm A) and a T1Gd-MRI-based target volume delineation (arm B). The treatment consisted in a high-precision stereotactic re-irradiation with 39 Gy in 13 fractions. The primary endpoint was progression-free survival (PFS) from randomization. Secondary endpoints included overall survival (OS), local tumor control, and toxicity. Results: From November 26, 2013, to September 2, 2021, 271 patients were assessed for eligibility and 200 were randomized. 98 patients in the FET-PET arm and 97 patients in the T1Gd-MRI arm were treated per protocol. Median PFS was 4.0 months (95% confidence interval [CI] 3.7-5.2) in the FET-PET arm and 4.9 months (95% CI 3.7-6.0) in the GdT1-MRI arm (one-sided stratified log-rank test p=0.98; adjusted HR for the experimental versus the control arm 1.14 [95% CI 0.85-1.52], p=0.39). Median OS was 9.4 months (95% CI 7.8-11.1) in arm A and 9.0 months (95% CI 7.6-10.5) in arm B (HR 1.01 [95% CI 0.75-1.37], p=0.92). Local control rate at 12 months was 22% in the FET-PET arm (95% CI 14%-31%) and 20% in the GdT1-MRI arm (95% CI 12%-29%). Radiation necrosis as adverse event was documented in 25.5% of cases in arm A and in 21.6% in arm B. Of the 239 patients who received the FET tracer, 3 reported 5 severe adverse events in the timespan of 7 days after PET. No event was related to the application of the tracer. Conclusions: In this trial, FET-PET-based re-irradiation of rGBM was not superior to the GdT1-MRI-based treatment. Consequently, both options remain valid in this setting. Stereotactic re-irradiation with 39 Gy in 3 Gy fractions was shown to be safe and the FET-PET investigation was well tolerated in all cases. Due to the inclusion of FET-PET-positive patients only, our results do not impact the known diagnostic role of FET-PET in differentiating rGBM progression from post-therapeutic changes. Clinical trial information: NCT01252459 .

Objectives Early diagnosis of inflammatory arthritis is critical to prevent joint damage and functional incapacities. However, the discrepancy between recommendations of early diagnosis and reality is remarkable. The Rheuma-VOR study aimed to improve the time to diagnosis of patients with early arthritis by coordinating cooperation between primary care physicians, specialists and patients in Germany. Methods This prospective non-randomised multicentre study involved 2340 primary care physicians, 72 rheumatologists, 4 university hospitals and 4 rheumatology centres in 4 German Federal States. The two coprimary endpoints (time to diagnosis and screening performance of primary care physicians) were evaluated for early versus late implementation phase. Additionally, time to diagnosis and secondary endpoints (decrease of disease activity, increase in quality of life and overall well-being, improvement of fatigue, depression, functional ability, and work ability, reduction in drug and medical costs and hospitalisation) were compared with a reference cohort of the German Rheumatism Research Centre (DRFZ) reflecting standard care. Results A total of 7049 patients were enrolled in the coordination centres and 1537 patients were diagnosed with a rheumatic disease and consented to further participation. A follow-up consultation after 1 year was realised in 592 patients. The time to diagnosis endpoint and the secondary endpoints were met. In addition, the calculation of cost-effectiveness shows that Rheuma-VOR has a dominant cost–benefit ratio compared with standard care. Discussion Rheuma-VOR has shown an improvement in rheumatological care, patient-reported outcome parameters and cost savings by coordinating the cooperation of primary care physicians, rheumatologists and patients, in a nationwide approach.

The utility of amyloid positron emission tomography (PET) for the etiological diagnosis of dementia and its impact on functional status of patients in routine care are currently unclear. Here, we describe the design of ENABLE, a randomized controlled two-armed coverage with evidence development (CED) study in Germany. Approximately 1126 patients with mild to moderate dementia of unclear etiology will be randomly assigned to either an amyloid PET or a no amyloid PET group. Patients will be followed-up for 24 months. The study has been registered at the German Clinical Trials Register () with the registration code DRKS00030839. The primary endpoint of ENABLE is the ability to perform functional activities of daily living at 18 months. Secondary endpoints include change in diagnosis, diagnostic confidence, and cognitive and clinical outcomes of patients. We expect that the CED study ENABLE will inform about patient relevant effects of amyloid PET in routine care. Furthermore, we anticipate that ENABLE will support physicians' and payers' decisions on provision of health care for patients with dementia. HighlightsStudy design focuses on the usefulness of amyloid positron emission tomography (PET) in routine care.Study design addresses the patient-relevant effect of amyloid PET.Patient representatives were involved in the creation of the study design.The study will help improve routine care for people with dementia.