Abstract Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a potentially curative treatment, which carries a high risk of complications and mortality, highlighting the necessity of discussions about life threat. This study explores the perspectives of patients, informal caregivers (ICs), and healthcare professionals (HCPs) regarding the timing, content, and challenges of these discussions. Multicenter cross-sectional survey in comprehensive care centers across Germany, involving patients with allo-HSCT, ICs, and HCPs. Questionnaires assessed perceived concerns about life threat, communication needs, and attitudes toward death. Statistical analyses included descriptive statistics, group comparisons, and multivariate logistic regressions. A total of 61 patients, 31 ICs and 125 HCPs participated in this study. Patients and ICs had a high need for discussion about life threat at diagnosis, which was corroborated by HCPs. At further time points in the transplant trajectory, there were more discrepancies between patients‘/ICs‘ and HCPs’ perceptions towards conversations about life threat. While 61.7% of patients preferred having their ICs present during discussions, ICs often felt overlooked, with only 50% finding conversations with HCPs helpful. HCPs’ avoidance of death was associated with a reduced likelihood of reporting a need for conversation in patients in the event of severe complications. These findings highlight a discrepancy between patients’ and ICs’ preferred timing for conversations about life threat and HCPs’ perceptions of when patients actually express such a need. To bridge this gap, earlier and ongoing conversations are essential. Training programs should address HCPs’ discomfort in discussing prognosis and improve interdisciplinary teamwork to standardize end-of-life communication. Trial registration number: DRKS00027290 (German Clinical Trials Register) on 10.01.2022.

Focal breast lesions are observed in up to 5.8% of CT examinations performed in female patients for a wide variety of indications not affecting the breast. To simplify and standardize the further procedure in the case of breast masses visualized by computed tomography (CT), an easy and robust diagnostic approach in assigning surely benign findings, uncertain findings and probably malignant findings is warranted. We aimed (1) to determine the diagnostic gain of quantitative measurements of the iodine content in breast masses visualized in contrast-enhanced dual energy (DE) CT examinations additional to the assessment of qualitative image features; and (2) to generate an interactive hierarchical decision tree allowing to assess the individual probability of benign or malignant findings. All contrast-enhanced DECT examinations performed in adult females from January 2018 to December 2020 were retrospectively screened for solid breast masses. Subsequently, the DECT images with confirmed breast masses were evaluated independently by 3 radiologists experienced in breast imaging using a structured questionnaire. First, the image characteristics of the ACR-BIRADS atlas on MRI were queried, and an assessment of the probability of benignancy or malignancy was requested. Second, the iodine content in the breast masses was interactively measured, and the readers were asked to provide a further assessment of the biological identity. Third, a decision tree was developed using a nonparametric supervised (machine) learning algorithm. During the survey period, 5.591 contrast-enhanced DECT examinations of the chest were carried out in adult female patients. Six hundred eighty-seven DECTs (12.3%) displayed breast masses. The study group comprised 415 female patients (7.4%) with a benign or malignant breast mass confirmed by histology (155, 37.4%), a constant CT-course of ≥2 years without interfering therapy (202, 48.8%) and/or noninvasive breast imaging (57, 13.8%). Neither in the first step nor in the second step of the evaluations a cancer confirmed in the reference standard was classified as certainly benign. Subgroup analyses showed that the combined qualitative and quantitative approach was diagnostically superior compared with the sole descriptor-based assessments in 757 assessments of DECT evaluations with ACR 1+2 breast densities (AUC = 0.961 vs 0.924, lower bound 0.940 vs 0.893, upper bounds 0.982 vs 0.956, P = 0.001) and for the 541 assessments of DECT examinations visualizing masses in denser ACR 3+4 parenchyma (AUC = 0.972 vs 0.948, lower bound 0.953 vs 0.923, upper bound 0.991 vs 0.974, P = 0.043). Including iodine content into the descriptive image evaluations proved to be superior to the solely descriptor-based assessments in 456 assessments of lesions with >5 to 10 mm diameter and in 370 assessments of lesions with >10 to 20 mm (P = 0.002, 0.002 and 0.018, respectively). Mass contour proved to be the first hierarchical decision level of the interactive classification tree for the differentiation of benign and malignant lesions developed in step 3. In the second hierarchical level, automatically generated classifications of the iodine content allowed to generate 3 diagnostic predictors analogous to the BIRADS classification with a depth of 2 ramifications. Information on the iodine content of breast masses detected by DECT increases diagnostic certainty in the assessment of the biological significance of the lesions. The presented nonparametric decision tree may be helpful in interactively combining semantic and quantitative image data in clinical routine diagnostics of breast masses in spectral CT examinations.

The ESTIMABL2-trial demonstrated non-inferiority of avoiding radioiodine therapy in low-risk differentiated thyroid cancer (DTC, i.e. papillary- and follicular thyroid cancer (PTC, FTC)). Yet, follow-up duration was limited and FTC were underrepresented. We therefore assessed long-term relative survival by comparing observed and expected cancer-free survival. This robust measure of net survival was used to evaluate the long-term effects of radioiodine therapy, including in previously underrepresented histological subgroups. Using the SEER-database, we identified 18,645 patients with DTC according to the criteria in the ESTIMABL2-trial (low risk PTC and FTC with pT1am-pT1b, N0-NX). Long-term relative survival (> 10 years) was analysed retrospectively, subdivided based on histology (PTC and FTC) and TNM-status, and additionally in 5,171 patients with lymph node involvement (N1). Relative survival was compared at 3 -, 5 -, and 10-years follow-up with and without radioiodine. Radioiodine therapy was associated with higher long-term relative survival in specific subgroups: Among FTC patients, relative survival was higher with radioiodine after 5- and, 10-years by 0.3

BACKGROUND:Lipoedema is a painful, chronic disease of the subcutaneous adipose tissue, predominantly affecting women. Conservative complex decongestive therapy is the standard of care but offers limited symptom relief. Liposuction appears to be a promising approach but lacks evidence of effectiveness and safety. The aim of this trial was to show superiority of liposuction compared with conservative therapy regarding relevant pain reduction with reasonable safety. METHODS:In this multicentre, randomised controlled trial at 11 German centres, eligible women with stage I, II, or III lipoedema and leg pain of at least 4 points on a 0-10 numeric rating scale received conservative therapy for up to 7 months and then were randomly assigned to liposuction or conservative therapy (2:1) stratified by lipoedema stage and study site. For all visits involving an assessment, patches were applied to the legs of all patients, and patients were instructed not to reveal the treatment they had received, in order to mask the assessor. The primary endpoint was reduction of patient-reported leg pain by at least 2 points after 12 months, and missing assessment was considered non-successful.The primary outcome was analysed in the intention-to-treat population which included all randomly assigned patients, and safety analysis included all enrolled patients. A long-term follow-up of 36 months is ongoing. This study is registered at ClinicalTrials.gov, NCT04272827. FINDINGS:Of 1973 patients screened between Jan 19, 2021, and June 7, 2022, 453 were enrolled, and 410 were randomly assigned to the liposuction group (n=278) or to the conservative therapy group (n=132). All 410 patients were included in the intention-to-treat analysis (mean age 42·9 [ SD 10·6]; ethnicity data were not collected). After 12 months, 190 (68%) of 278 randomisly assigned patients undergoing liposuction achieved the primary endpoint of pain reduction versus ten (8%) of 132 randomly assigned to conservative therapy (odds ratio 26·2 [95% CI 13·1-52·5]; p<0·0001). Adverse events occurred in 124 (47%) of 265 patients undergoing liposuction, and 20 (8%) of 265 were rated as serious. In the conservative therapy group, 30 (21%) of 145 patients reported adverse events, and five (3%) 145 were rated as serious. Secondary endpoints regarding quality of life showed greater improvement in the liposuction group. INTERPRETATION:Liposuction was superior to conservative therapy in reducing leg pain and improving quality of life in patients with lipoedema, but was associated with a higher rate of serious adverse events. Liposuction has the potential to be a promising treatment option for patients with lipoedema. FUNDING:The Federal Joint Committee, Germany.

OBJECTIVE:Randomised controlled trials (RCTs) are considered the gold standard in clinical research. However, randomization isn't always feasible, e.g., due to ethical considerations. As a result, quasi-experimental designs, such as the regression-discontinuity design (RDD), have been advocated as valuable alternatives and are increasingly employed in health sciences. So far, however, there is no way to take repeated measures into account in an RDD analysis, although repeated measures are not uncommon in medical research. This article proposes an extension of the RDD methodology to incorporate repeated measures within the statistical analysis. METHODS:The article introduces consistent mathematical notation for combining a univariate RDD with a linear mixed model (LMM) to account for repeated measures. The application is presented using data from the nFC-isPO (N = 1,417), where the Hospital Anxiety and Depression Scale (HADS) was employed to assess anxiety and depression in newly diagnosed cancer patients over a 12-month treatment period. The HADS scores were measured at baseline (T1), after 4 months (T2) and after 12 months (T3). Patients were assigned to control (psychosocial care) or treatment (psycho-oncological-psychotherapeutic care) group based on a predetermined HADS threshold at T1. RESULTS:The average treatment effect (ATE) was similar in both univariate RDD and LMM-RDD when applied to complete cases. Including all available data (T2 and/or T3), univariate RDD analyses were based on different samples for each time point. At T2, the ATE sign reversed from negative to positive, suggesting a change in discontinuity direction. At T3, the ATE magnitude nearly doubled compared to the complete case analysis. LMM-RDD estimated treatment effects were higher than those from univariate RDD. Nevertheless, none reached statistical significance. The time effect ([Formula: see text]), representing the difference in treatment effects between two time points (complete case: [Formula: see text]=0.577; T2 and/or T3 available: [Formula: see text]=0.491), was not significant (p = 0.855; 95%-CI: [-5.589; 6.743]; p = 0.869, 95%-CI: [-5.328; 6.310]). CONCLUSION:Extending the RDD to incorporate repeated measures within a linear mixed model (LMM-RDD) provides a more robust and comprehensive analytical approach when an RCT is not feasible. This approach not only addresses the challenges of missing data and an unbalanced number of outcome measures, but also allows for the identification of time-varying treatment effects that may not be discernible using traditional RDD. TRIAL REGISTRATION:The study was registered in the German Clinical Trials Registry on 30 October 2018 under the ID "DRKS00015326".

4083 Background: Anti-PD-(L)1 is effective in esophageal adenocarcinoma (EGA). The phase II RICE trial (NCT04159974) evaluated the addition of neoadjuvant and adjuvant durvalumab, with or without tremelimumab, to neoadjuvant chemoradiotherapy (CROSS). Methods: Patients with locally advanced (≥uT3/Nx or uT2/N+) non-metastatic EGA received two doses of neoadjuvant durvalumab in addition to CROSS, followed by surgery. Adjuvant therapy was randomized 1:1 to durvalumab (12 doses) alone (arm A) or durvalumab plus one dose of tremelimumab (arm B). Translational analyses included HLA-I genotyping, immunohistochemistry, whole-exome sequencing and RNA-sequencing. Clinical outcomes were analyzed in patients who received at least one neoadjuvant dose (mITT) and in those who were randomized and received at least one adjuvant dose (R-mITT). Results: In the mITT set (n=56), 95% completed neoadjuvant therapy and 93% underwent resection. The rate of grade ≥3 non-hematologic adverse events during neoadjuvant treatment was 25% (13/56 G3, 1/56 G4). Surgery was feasible with a rate of anastomotic leakage of 6%. Major pathological response (MPR, <10% viable tumor cells) was achieved in 54% (30/56) including a 23% (13/56) pathological complete response rate (pCR, ypT0/ypN0). The rate of MPR was higher than in propensity-based comparisons with FLOT (25%) and CROSS (37%). Two-year overall (OS) and progression-free (PFS) survival of the mITT set were 72.7% and 53.1%, respectively. After completion of Stage I of the trial (safety run in), 38 patients were included in the R-mITT set. 80% in arm A (durvalumab monotherapy, n=20) and 44% in arm B (durvalumab plus tremelimumab, n=18) completed at least 80% of adjuvant immunotherapy. Combined immunotherapy in the R-mITT set was associated with higher grade ≥3 toxicity (22% G3/ 22% G4 in Arm B vs. 15% G3 / 0% G4 in arm A) and did not improve survival (2-year OS/PFS 95.0%/80.0% [arm A] vs. 82.4%/54.2% [arm B]). Tumor mutational burden, heterozygosity of HLA-I, expression of genes related to antigen presentation and T-cell abundance were associated with pathological response. However, discordant cases across all biomarkers underscore the complexity of tumor-immune interactions underlying response to immunotherapy. Conclusions: RICE demonstrates safety and feasibility of adding anti-PD-L1 to neoadjuvant CROSS in EGA and shows promising response rates. While CROSS is no longer considered standard of care, our results support efficacy of durvalumab, consistent with results for FLOT plus durvalumab in the MATTERHORN trial. Addition of tremelimumab to durvalumab is not supported by our study. Clinical trial information: NCT04159974 .

Patients with glioblastoma represent a highly vulnerable cohort as they often experience rapid health deterioration with severe symptom burden including neurological, (neuro)psychological, and psychiatric symptoms. The aim of this sub-analysis of the “Early Palliative Care for Patients with Glioblastoma” (EPCOG) trial was to investigate the specific challenges of conducting a multicenter, randomized, controlled, clinical trial in glioblastoma patients testing a specialized palliative care (PC) intervention. We analyzed screening protocols and protocol deviations with respect to number and reasons for non-participation, skipped/delayed visits and attrition using descriptive statistics and content analysis of free-text comments. In total, 41.5

Abstract Background Multiple sclerosis is associated with complex individual disease trajectories with a high symptom burden affecting physical, psychological and social life, accompanied by fractured biographies and increased suicide rates. In this complex situation coordinating and providing necessary health and social services and treatments by themselves is often perceived as unmanageable. Care and case management (CCM) aims to ensure optimal care in all dimensions of life. The aim of this sub-study of the COCOS-MS (Communication, coordination and security for people with severe Multiple Sclerosis) trial was to evaluate the CCM intervention at the individual and overall level. Methods The analysis of the long-term cross-sectoral CCM intervention included: descriptive statistical analysis of the individually defined goals and actions taken together with the CCM and the statistical evaluation of the evolution of unmet needs of people with severe MS (PwsMS) and caregivers considering physical health, mental health, self-sufficiency, social situation and participation utilizing the sign test (α < 0.05) and cross tables. The data were analyzed in accordance with the modified intention-to-treat principle. Results Compliant to protocol, a total of 40 PwsMS were randomized to the intervention group; 18 caregivers of these PwsMS also participated. In 80% the individually set goals were realized during the CCM intervention. They were mostly related to healthcare, organizational issues or general aspects like: receiving information). The participants benefited from the CCM in all assessed dimensions, which was especially reflected in a significant reduction of unmet needs in relation to: MS related physical health (p = 0.039), medical, nursing and therapeutic care (p = 0.008), and increased autonomy regarding the pursuit of hobbies and interests (p = 0.002). Across 30 sub-domains, on average 6.3 improvements and 1.6 deteriorations per sub-domains were recorded on PwsMSs’ side. Conclusions The CCM is a worthwhile approach to the comprehensive networking of health and social structures. It helps PwsMS to manage their disease and its associated problems more effectively and broadly. Thereby, they gain resources for their life outside their illness. Improved self-sufficiency and social participation lead to a consolidated identity. This could increase feelings of dignity and counteract life-denying thoughts. Trial registration German Register for Clinical Studies (DRKS) (DRKS00022771, 11th January 2021).

Objective Cognitive remediation therapy (CRT) is an evidence-based behavioral intervention that enhances functional outcomes in schizophrenia patients by improving cognition. However, not all patients benefit equally from CRT, and predictors of real-world functional improvement are poorly understood. This study aimed to identify patient-related baseline predictors of functional improvement by evaluating two distinct CRT approaches targeting different types of cognition: social cognition (Integrated Social Cognition and Social Skills Training, ISST) and neurocognition (Neurocognitive Remediation Therapy, NCRT). Methods This secondary analysis used data from a large, multicenter randomized controlled trial. Participants with schizophrenia (N = 174) were randomly assigned to ISST or NCRT for six months. Multiple linear regression analyses were performed to determine whether baseline demographic, cognitive, clinical, or functional characteristics predicted changes in real-world functioning, as measured by the Social and Occupational Functioning Assessment Scale. Results The Digit Symbol Substitution Test was the strongest and most consistent predictor of functional improvement. Lower baseline functioning also predicted greater gains, although only in multivariable models. Domain-specific predictors were identified for each intervention: better affect recognition predicted better outcomes in ISST, whereas verbal memory did so in NCRT. Conclusion The CRT approaches studied here appear to be most effective for individuals with a more preserved baseline level of cognitive performance, especially in terms of processing speed. These findings support the use of brief cognitive assessments to guide CRT implementation and suggest that tailoring interventions to individual cognitive profiles may enhance treatment efficacy.

BACKGROUND:Positive effects of early integration of palliative care (EIPC) have been shown for systemic solid malignant tumors. We tested the hypothesis that EIPC improves quality of life (QoL), palliative care (PC) problems and mood in glioblastoma patients and reduces caregiver burden. METHODS:This randomized, rater-blinded, controlled trial conducted in six German university medical centers included glioblastoma patients within four weeks after diagnosis (first/recurrent) and their caregivers. Patients received standard care (control) or standard care and EIPC (intervention) for 12 months. Primary outcome was change in QoL after six months measured by the trial outcome index of the FACT-Br. Data were assessed 3-monthly for up to 24 months. RESULTS:Between 05/2019 and 04/2021 patients were enrolled and randomized to the intervention (n = 109) or control group (n = 108). QoL at month six was in favor of the intervention, however not statistically significant (mean difference 4.1 with 95% CI, -4.4 to 12.6, P = .34; intervention: n = 98 (m = 54/f = 44); control: n = 89 (m = 50/f = 39)). In an analysis adjusted for time of death, performed because of a significant survival difference (control superior to intervention, P = .018), QoL was better in the intervention group (P = .041). Secondary outcomes showed that patients significantly benefited from EIPC regarding PC problems and mood especially after intervention ended, while caregivers did not seem to benefit. CONCLUSIONS:Provided that the survival difference is included in the analysis, EIPC improves QoL in glioblastoma patients. This, in addition to improved mood and PC problems, demonstrates that EIPC sustainably improves 'how to live' but not 'length of life'.

ABSTRACT Aim Extrauterine placental perfusion (EPP) may be a feasible cord clamping strategy in very low birth weight (VLBW) infants to support neonatal transition. However, the impact of EPP on neurodevelopment remains unclear. The study aimed to compare the effects of EPP with time‐based delayed cord clamping (DCC) on neurodevelopmental outcomes. Methods This follow‐up study of the randomised controlled EXPLAIN (Extrauterine Placental Transfusion in Resuscitation of Very Low Birth Weight Infants) trial ( ClinicalTrials.gov Identifier: NCT03916159) was conducted at a tertiary perinatal centre from 2021 to 2023. Antenatally randomised VLBW infants received either EPP or DCC (> 30 s). Neurodevelopment was assessed at 24 months of corrected age using the Bayley Scales of Infant and Toddler Development, Third Edition. Data analysis was intention‐to‐treat. Results Of 59 infants enrolled, 54 (92%) participated in the follow‐up (27 EPP, 27 DCC). Median age at assessment was 24.3 months (range 23.5–25.0); 28 (52%) were male. Infant characteristics and short‐term outcomes were similar between groups. No relevant differences were observed in median cognitive, motor or language scores or in rates of cerebral palsy, hearing, or visual impairment. Conclusion The neurodevelopment of the VLBW infants who received EPP and DCC was comparable, suggesting that EPP may be a viable alternative.

OBJECTIVE:This study investigates the association of loneliness during the COVID-19 pandemic and the course of depressive, anxiety and sleep symptoms after psychological treatment in older adults. METHODS:During the first wave of the pandemic in 2020, we assessed additional, original data of 132 participants aged ≥60 years who had completed psychological treatment for late-life depression (LLD) in the context of a multicenter, randomized controlled trial (CBT-late). We measured loneliness using the UCLA Loneliness Scale. Depression, anxiety and sleep symptoms were assessed using the Geriatric Depression Scale (GDS), Geriatric Anxiety Inventory (GAI), and Insomnia Severity Index (ISI). RESULTS:Participants with higher loneliness scores (n = 44) experienced a significant worsening of depressive and anxiety symptoms during the pandemic (estimated marginal mean difference (emmd) of change in GDS between post-treatment and COVID-19 visit: GDSemmd= -4.61, [95% CI: -6.97 to -2.26], GAIemmd= -2.21, [95% CI: -3.76 to -0.65]), while those with low to moderate loneliness (n = 72) maintained stable mild symptoms (GDSemmd= -1.39, [95% CI: -3.00 to 0.22], GAIemmd= -0.49, [95% CI: -1.69 to 0.72]). All patients reported increased sleep disturbances during the pandemic regardless of loneliness, while remaining in the range for sub-threshold insomnia. CONCLUSIONS:Our results suggest an association of significant loneliness during the COVID-19 pandemic and a clinically relevant worsening of depressive and anxiety symptoms in older adults. Loneliness assessments and interventions may be incorporated into treatments for LLD, particularly during pandemics or other crises.