University Hospital Frankfurt

Introduction Accurate and reproducible measures of factor activity are required to guide clinical decision‐making following gene therapy for haemophilia B (HB). Highly significant discrepancies have been observed in measurements of various factor IX (FIX) concentrates that carry molecular modifications to extend their half‐life, arguing for the need for careful analysis of new HB treatment modalities with respect to FIX assay performance. Aim To further characterise variability in FIX activity measured using different one‐stage assays (OSAs) and chromogenic assays (CAs) in patients with HB receiving gene therapy utilising the FIX Padua variant and to assess whether assay differences were due to the FIX‐Padua variant. Methods FIX activity was assessed centrally (OSA and CA) and locally (OSA only) using plasma samples collected from a phase 2b and phase 3 study of etranacogene dezaparvovec and in an in vitro study of wild‐type (wt) recombinant human FIX (rhFIX) and rhFIX‐Padua. Results Lower CA than OSA FIX activity for plasma samples from the phase 3 trial was observed (CA:OSA ratio: 0.408 [±0.049]–0.547 [±0.062]). Local OSA:central OSA FIX activity ratios were 0.789 (±0.314)–1.021 (±0.159). Local OSA:central OSA FIX activity ratios across methods and/or reagents were 0.81 (±0.02)–1.28 (±0.04) for rhFIX‐wt‐spiked samples and 0.67 (±0.02)–1.13 (±0.09) for rhFIX‐Padua‐spiked samples. Conclusion FIX activity differences between central and local OSAs were modest; similar differences were observed in vitro with rhFIX‐wt versus rhFIX‐Padua. Commonly available OSAs can be used to monitor patients post‐etranacogene dezaparvovec administration; we recommend using the same assay platform throughout the post‐treatment period.

The scaffolding protein NEDD9 coordinates signaling downstream of integrins by interacting with focal adhesion kinase (FAK) and thereby promotes cell migration. NEDD9 expression is altered in a number of clinical conditions such as cancer, but its role in innate immunity against infections remains elusive. Transcriptome analysis of Salmonella Typhimurium ( S T)-infected murine macrophages showed downregulation of NEDD9 and genes belonging to its signaling network. Bacterial infections induced host-mediated lysosomal degradation of NEDD9 in macrophages and PBMCs isolated from patients suffering from bloodstream infection. However, S T induced translocation of NEDD9 from the cytoplasm to S T-containing phagosomes and prevented their phagolysosome-mediated clearance by FAK/AKT activation, reflecting a bacterial evasion mechanism. Complete loss of NEDD9 significantly reduced bacterial burden and enhanced inflammation upon S T infection both in vitro and in vivo. Mechanistically, we show that NEDD9 activates the FAK-AKT pathway allowing phosphorylation of FAK and AKT to impair phagolysosomal-mediated clearance of bacteria. Our study has thus identified NEDD9 as a critical regulator of lysosomal function in macrophages and a potential host-directed therapeutic target to treat bacterial infections. Classification: Biological Sciences, Microbiology

Mental disorders represent a major global health challenge, with an estimated lifetime prevalence approaching 30%. Despite the availability of effective treatments, access to mental health care remains inadequate. Computational psychiatry, leveraging advancements in artificial intelligence (AI) and machine learning (ML), has shown potential for transforming mental health care by improving diagnosis, prognosis, and the personalization of treatment. However, integrating these technologies into routine clinical practice remains limited due to technical and infrastructure challenges. While ongoing computational developments will enhance AI’s precision, many studies focus on its broad potential without providing specific, clinician-informed guidance for immediate application. To address this gap and the urgent need for clinically actionable AI tools, we surveyed 53 psychiatrists and clinical psychologists to identify their priorities for AI in mental health care. Our findings reveal a strong preference for tools enabling continuous monitoring and predictive modeling, particularly in outpatient settings. Clinicians prioritize accurate predictions of symptom trajectories and proactive patient monitoring over interpretability and explicit treatment recommendations. Self-reports, third-party observations, and sleep quality and duration emerged as key data inputs for effective models. Together, this study provides a clinician-driven roadmap for AI integration, emphasizing predictive models based on ecological momentary assessment (EMA) data to forecast disorder trajectories and support real-world practice. Supplementary Information The online version contains supplementary material available at 10.1186/s12888-025-06957-3.

Cultivating three-dimensional spiral ganglion explants is a well-established in-vitro assay for assessing the neurotrophic potential of compounds. The manual neurite measurement remains common but hinders high-throughput experimentation. The present study aimed to automate this process, comparing two methods, Sholl and Gray Value analysis, with manual neurite measurement to enhance this time-consuming and labor-intensive evaluation. The explants were cultured with brain-derived neurotrophic factor (BDNF), and both neurons and neurites were marked immunohistochemically. The comparison of methods included significance of treatment group differences, accuracy, precision, time and interference. Sholl analysis outperformed manual measurements in time and precision, exhibiting fewer interferences compared to Gray Value analysis. It effectively distinguished between control and BDNF concentrations, paralleling manual tracing outcomes. The Sholl intersections per radius analysis, employing repeated measures (rm) ANOVA across 31 measurement points, exhibited the smallest deviation from manual measurement. Gray Value analysis introduced inner explant brightness as a parameter that parallels neuronal survival within the explant. The present study demonstrates, that Sholl analysis with rm ANOVA emerged as the most efficient, with reduced time and manpower requirements. This positions the improved Sholl analysis as a potent tool for high-throughput, automated assessments of neurotrophic potential, marking a significant advancement in the field.

The cytogenetic risk category retains a pivotal role in the prediction of prognosis in acute myeloid leukemia (AML) patients undergoing hematopoietic stem cell transplantation (HSCT), however, its impact on secondary AML (sAML) is less established. We assessed whether the ELN 2022 cytogenetic risk score predicts outcomes in sAML patients in remission undergoing HSCT from HLA-matched donors performed between 2010 and 2022. Among 1119 patients, 829 had intermediate and 284 had adverse cytogenetics (6 with favorable risk were excluded). Engraftment rates was 72.4% vs. 99.5%. Acute graft-versus-host disease (GVHD) incidence did not differ, but 2-years all grades and extensive chronic GVHD were higher in the intermediate vs. adverse cytogenetics risk groups, hazard ratio (HR) = 0.72; p = 0.034 and HR = 0.58; p = 0.027, respectively. Two-year non-relapse mortality (NRM) was similar. All other HSCT outcomes were inferior in the adverse risk vs. intermediate-risk patients: The HR for 2-year relapse incidence (RI) was 2.48 (95% CI 1.95–3.15, p < 0.001). The HRs for 2-year leukemia-free survival (LFS), overall survival (OS), and GVHD-free/relapse-free survival (GRFS) were 1.62 (95% CI 1.34–1.95, p < 0.001), 1.59 (95% CI 1.3–1.93, p < 0.001) and 1.38 (95% CI 1.15–1.65, p < 0.001), respectively. We conclude that cytogenetic risk score predicts HSCT outcomes in sAML patients.

Background Mesial temporal lobe epilepsy (mTLE) infrequently presents with isolated amygdala enlargement (AE), but its relevance remains ambiguous. We therefore investigated clinical, imaging, and histopathological findings in mTLE‐AE compared to non‐lesional mTLE (mTLE‐NL) patients, and additionally strategies for identifying AE. Methods We detected AE by automated volumetry of otherwise unremarkable magnetic resonance images of mTLE patients, compared with a healthy comparator. Autoimmune inflammation as an AE cause was excluded using the Graus criteria. We compared clinical and neuropsychological variables between mTLE‐AE and mTLE‐NL. Secondary assessment of AE was by neuroradiologist visual detection. Results Of 63 mTLE patients, 15 had mTLE‐AE. In these, normalized mean volume was 1857.58 mm³ (SD = 207.38) for the left, 1973.09 mm³ (SD = 214.91) for the right amygdala, 2003.34 mm³ (SD = 218.85) for the larger and 1827.34 mm³ (SD = 179.85) for the smaller amygdala. Mean volume in the healthy control subjects was 1853.4 mm³ for the left (SD = 212.44) and 1895.2 mm³ for the right amygdala (SD = 224.29). Clinical parameters including age, sex, epilepsy duration, history of febrile convulsions, drug resistance, neuropsychological performance, surgical outcome, and medications did not differ significantly between mTLE‐AE and mTLE‐NL. Histopathological findings in mTLE‐AE included dysmorphic neurons, potential tumors, and focal cortical dysplasia. Neuroradiologists independently described AE in 37 of 63 mTLE patients. Conclusions mTLE‐AE has no specific clinical profile compared to non‐lesional mTLE and features diverse underlying pathologies. Volumetric detection appears more conservative than conventional qualitative visual analysis, but may miss cases of subtle AE. Combining automated volumetry with visual assessment may improve AE detection.

Background Late effects can occur years to decades after cancer therapy, resulting in morbidity and reduced health-related quality of life. Clinical long-term follow-up (LTFU) enables timely diagnosis and treatment of these sequelae. So far, only a minority of childhood cancer survivors (CCS) in Germany regularly visit LTFU care facilities. The LE-Na study aims to: 1. implement and/or improve LTFU care structures for adult CCS in Germany, 2. inform former patients about late effects and LTFU care centers, 3. create a basis for future research by building up a central database, consent management and infrastructure, 4. establish a clinical LTFU cohort of adult CCS in Germany, 5. evaluate the implementation of the LFTU care, 6. enable the expansion of LTFU care structures nationwide, 7. integrate the developed LTFU care structures into the standard health care system. Methods Within five years, approximately 5000 CCS will be invited to visit one of the 10 LTFU centers in Germany. Study participants are either contacted by the German Childhood Cancer Registry (GCCR), transitioned from the local pediatric oncology care unit, or recruited via media. They are assigned to one of three different risk groups based on an evidence-based risk stratification and receive standardized multidisciplinary follow-up care. Primary outcomes are satisfaction with the LTFU care offer as well as degree of health-related self-efficacy expectation. They will be assessed at two time points. A scientific evaluation of the implemented LTFU care will be enabled by a waitlist control group. The harmonized outcome data are documented in a standardized database. Discussion By addressing CCS in Germany who have not received standardized LTFU care yet, the LE-Na study expects to improve nationwide LTFU care and therewith patient’s satisfaction with the LTFU care offer as well as their health-related self-efficacy expectation.

The use of digital technologies is becoming increasingly important in medicine and is having a significant impact on developments in the surgical field. However, there is a great need to improve and implement those new techniques in surgical education and training in order to adequately prepare young surgeons for associated challenges. The aim of this study is to analyze the importance, use, and influence of digital technology on the success of future surgical training in Germany. An online survey was conducted from April–September 2024 with a total of 12 open (n = 2) and standardized (n = 10) questions. The closed questions could be answered on a Likert scale from 1 (strongly agree) to 5 (strongly disagree). The questionnaire was sent out via the email distribution list of the German Society of Surgery and its social media channels. A total of 97 response datasets were analyzed. At the time of analysis, the majority of participants were working in general surgery (n = 54, 64%) and at a nonuniversity clinic (n = 49, 58%). In all, 19% of the respondents were residents. When choosing their current workplace, 44% prioritized advanced digitalization, while 61% stated that they had not yet used generative AI at all. Only 9% of trainees had access to curricular training on robotic systems. A change to a location with more advanced medical technology was considered by 19%. While 26% of study participants would consider being operated on by an AI-assisted robotic system, 46% of the participants could imagine using this technology on their patients. This analysis provides insight into the importance and use of digital technology in surgery in Germany. In particular, it reveals deficits in the use of AI-based methods, comprehensive provision of digital technologies, and the access of trainees to innovative training. The results also confirm the need to further raise awareness of the topic.

Standard of care first‐line systemic treatment for advanced biliary tract cancer includes chemo‐immunotherapy with gemcitabine, cisplatin, and durvalumab, followed by maintenance durvalumab monotherapy. The present work aims to investigate the differences in baseline clinical and molecular characteristics between patients with early progression during chemo‐immunotherapy and those who reach durvalumab maintenance therapy. The study population included patients with unresectable, locally advanced, or metastatic BTC who received treatment at 38 clinical Institutions in 12 countries from July 2021 to December 2023. The primary objective of the study was to investigate whether baseline clinical and molecular characteristics differed between patients with early progression during chemo‐immunotherapy versus those reaching durvalumab maintenance therapy. Four hundred forty‐eight patients were included in this study. Two hundred twenty‐seven patients (50.7%) received maintenance with durvalumab monotherapy, whereas 221 (49.3%) did not receive maintenance therapy due to PD during first‐line chemo‐immunotherapy before completing 8 cycles. Results show that patients who received maintenance were more likely to be older (≥70 years), have an ECOG = 0, locally advanced disease, and a neutrophil‐to‐lymphocyte ratio (NLR) <3. A higher proportion of patients with BAP1 mutations received maintenance, while TP53 mutations were more common in those who progressed early. According to the present analysis, a substantial proportion of patients (50.7%) with advanced BTC who were treated with chemotherapy plus durvalumab proceeded to receive maintenance therapy with durvalumab monotherapy, with a median treatment duration of 4.4 cycles. Patients ≥70 years, with ECOG PS 0, with locally advanced disease, and with NLR <3 had a higher likelihood of receiving maintenance therapy.

Background The need for postoperative permanent pacemaker implantation (PPMI) remains one of the most frequent complications after transcatheter aortic valve implantation (TAVI). This study aimed to develop a novel, 2‐step risk score to predict PPMI probability after TAVI and implement it into a user‐friendly website. Our risk score addresses the data gap on current prosthesis generations and provides a new, clinically motivated approach to calculating PPMI risk. Methods and Results Between January 2019 and December 2020, 1039 patients underwent TAVI at our institution. We retrospectively evaluated clinical, electrocardiographic, echocardiographic, computed tomographic, and periprocedural data. Patients with prior PPMI were excluded. We developed a prediction model for PPMI occurrence, using 55 patient and procedural characteristics. With exclusion criteria applied, 836 patients (mean age 80.3±9.1 years; 50.6% female) were included. Of these, 149 (17.8%) required PPMI within 30 days after TAVI. Fourteen preprocedural parameters, including preexisting right bundle‐branch block, atrioventricular block, left bundle‐branch block, bradycardia, interventricular septum thickness, New York Heart Association class, and aortic annulus perimeter, were identified as PPMI risk factors and used to calculate the baseline risk in the first step of the TAVI PACER score. The second step includes intraprocedural variables to demonstrate how PPMI risk can vary based on valve type and implantation depth. The TAVI PACER score predicts PPMI with a sensitivity of 76% and specificity of 72% (area under the curve=0.8). Conclusions The TAVI PACER score provides a novel tool for daily clinical practice, predicting individual PPMI risk after TAVI based on various patient and procedural characteristics.

Seasonal Influenza A/B vaccination is routinely administered in patients with Multiple Myeloma (MM) given their disease-and therapy-associated immunosuppression and risk of infection. Previous data show poor seroconversion rates after one vaccination with an increase to ~ 60% after boosting while the impact of multiple lines of therapy remains unclear. Accordingly, we performed a retrospective single-center study assessing immune responses after single or prime-boosting vaccination in 71 patients with MM treated at our institution during the 2019/20 season. Overall, 63.3% of patients with MM achieved sufficient responses after one or two Influenza A/B vaccinations. In patients receiving a prime-boost approach, significantly higher serological titers but no significant increase in responder rates were observed after the boost vaccination. Complete or very good partial remission and no immunoparesis were identified as independent predictors of sufficient serological response by multivariate regression analysis and responders were characterized by high CD19⁺ B-cell and CD4⁺ T-cell counts. Patients achieving a sufficient response only after the prime-boost approach showed significantly shorter time since high-dose chemotherapy and autologous stem-cell transplantation (HDC-ASCT). Together, this study suggests that single vaccination against Influenza A/B might be sufficient for patients with MM while a prime-boost approach might be necessary for patients with recent HDC-ASCT. Supplementary Information The online version contains supplementary material available at 10.1007/s00277-025-06367-1.

To date, there are no age-appropriate instruments for assessing the subjective impact of pediatric traumatic brain injury (TBI) sequelae on multiple domains of health-related quality of life (HRQoL) in young children. The present study therefore aims to develop and examine the psychometric properties of a new disease-specific, self-reported HRQoL instrument, the Quality of Life after Brain Injury for children aged 6–7 years (QOLIBRI-KIDDY). Questionnaire development included focus group interviews, cognitive debriefings, and Delphi expert panels. The pilot version of the instrument was tested in 72 children (6.00–7.92 years of age; 60% boys; 86% after mild TBI). After item reduction based on a confirmatory scale analysis considering the six-factor structure of the questionnaire versions for older children, adolescents, and adults (Cognition, Self, Daily Life & Autonomy, Social Relationships, Emotions, Physical Problems), its reliability and validity were investigated. The final version of the QOLIBRI-KIDDY comprises 23 items. Psychometric analyses indicated internal consistency to be satisfactory ( ɑ = 0.49–0.72; ω = 0.57–0.78). Construct validity suggested the expected overlap between generic HRQoL and TBI-specific HRQoL ( r = 0.17–0.36). There were small ( r > 0.2) to moderate ( r > 0.3) correlations between lower TBI-specific HRQoL and participants with lower learning rates, anxiety, depression, and post-concussion symptoms, particularly on the Cognition, Social Relationships, Emotions, and Physical Problems scales. The comparison of known groups revealed significant moderate and significant effects for lower HRQoL in children with depressive symptoms on the Emotions scale ( d = − 0.46) and with post-concussion symptoms on the Cognition ( d = − 0.42) and Social Relationships scales ( d = − 0.56). The QOLIBRI-KIDDY is a comprehensive, yet economical tool, comparable in content and items to the other age-adapted QOLIBRI versions. Its application has the potential to provide longitudinal data on subjects after TBI from childhood to older age, with a subjective perspective that can contribute to improving the therapy, rehabilitation, and daily life of young children.

Background Effective management of scalp psoriasis needs treatment with high patient preference and treatment satisfaction. Clinical trials show promising results for calcipotriene and betamethasone dipropionate cream based on polyaphron dispersion (PAD) technology (CAL/BDP PAD‐cream). However, real‐world data are scarce. Objectives To evaluate patient‐ and clinician‐reported outcomes and impact of adherence on treatment outcomes of CAL/BDP PAD‐cream in adults with mild‐to‐moderate scalp psoriasis in real‐world settings in Europe. Methods PRO‐SCALP is an ongoing observational, multicentre cohort study, collecting data primarily at baseline and Week 8 (end of the study, EOS). Patient self‐assessments included Treatment Satisfaction Questionnaire for Medication Version 9 (TSQM‐9), Scalpdex questionnaire, Worst Itch‐Numerical Rating Scale (WI‐NRS), sleep patterns, personal preferences and adherence to CAL/BDP PAD‐cream using a visual analogue scale (VAS). Clinicians' assessments included physician global assessment of scalp (scalp‐PGA) and S‐mPASI. Results Of 152 patients included in this interim analysis, 134 patients (mean age: 48.4 years; 69.4% females) had evaluable outcome data. At EOS, mean (SD) patient satisfaction scores (TSQM‐9) were—effectiveness: 76.0 (23.9), convenience of use: 70.2 (21.3), global satisfaction: 76.1 (22.5). At Week 8, 79.0% of patients attained a scalp‐PGA score of 0 (clear) or 1 (almost clear), and 71.0% attained scalp‐PGA success, defined as a scalp PGA score of 0/1 and ≥ 2‐points improvement in scalp‐PGA score change from baseline (CFB). CFB of S‐mPASI scores, patient‐reported symptoms, emotions, functioning and overall Scalpdex scores as well as WI‐NRS scores improved significantly (p < 0.0001) at EOS, within both low‐adherence (VAS < 80) and high‐adherence (VAS: 80−100) groups. Across key outcome measures, CFB of treatment outcomes was found to be better in patients with higher adherence. Conclusions Findings of the study indicate high treatment satisfaction, significant improvement in clinical outcomes and patients' quality of life associated with CAL/BDP PAD‐cream, especially in patients with higher adherence.

Background Pulmonary metastasectomy (PM) is the most frequently performed local ablative therapy for leiomyosarcoma (LMS), synovial sarcoma (SyS), and undifferentiated pleomorphic sarcoma (UPS). This study aimed to assess surgical feasibility, outcome, and clinical prognostic factors, as well as the value of a peri-interventional systemic therapy. Methods This multicenter retrospective study enrolled 77 patients with LMS, SyS, or UPS who underwent first-time complete resection of isolated lung metastases between 2009 and 2021. Disease-free survival (DFS), overall survival (OS), and clinical prognostic factors were analyzed. Results After the first PM, the median DFS was 7.4 months, and the median OS was 58.7 months. A maximal lesion diameter greater than 2 cm was associated with reduced DFS in both the univariable (hazard ratio [HR], 2.29; p = 0.006) and multivariable (HR, 2.60; p = 0.005) analyses. The univariable analysis identified a maximal lesion diameter greater than 2 cm as an adverse prognostic factor for OS (HR, 5.6; p < 0.001), whereas a treatment-free interval longer than 12 months was associated with improved OS (HR, 0.42; p = 0.032). The addition of systemic therapy was associated with a trend toward improved DFS for patients with lesions larger than 2 cm (HR, 0.29; p = 0.063). Severe postoperative complications (grade ≥IIIa) occurred in 2 % of the patients. Conclusion The size of resected lung metastases might be a more relevant prognostic factor than their number for patients with LMS, SyS, or UPS. For patients with lung metastases larger than 2 cm in maximal diameter, additional systemic therapy may be warranted.

Purpose Polycystic ovary syndrome (PCOS) is a metabolic and hormonal disorder that affects physical and emotional well-being. The aim of this cross-sectional study was to assess associated factors like sleep disturbance, obstructive sleep apnea (OSA), anxiety and depression in a German-speaking population with PCOS. Methods We designed an anonymous online survey with items from validated questionnaires, including the Hospital Anxiety and Depression Scale (HADS), the Generalized Anxiety Disorder (GAD-7), the Pittsburgh Sleep Quality Index (PSQI) and the STOP-Bang questionnaire to screen for OSA. The survey was mainly distributed via social media in Austria, Germany and Switzerland. Data from 587 questionnaires were analyzed. Results Based on the STOP Bang questionnaire, 19.5% of women had a high probability for OSA. BMI and insulin resistance were identified as independent associated factors with OSA (both p < 0.001). Overall, the median anxiety score (GAD-7) was in the moderate range (Median 10.0, Interquartile range (IQR) 8.0). According to the HADS, association with moderate to severe anxiety (HADS-A) was 52.0% and with moderate to severe depression (HADS-D) 27.8%. There was a significant positive correlation between HADS-A/ HADS-D and BMI (r = 0.122, (HADS-A)/ r = 0.223 (HADS-D), both p < 0.01). According to the PSQI, 60.5% had mild sleep disturbance and 29.7% had chronic sleep disturbance. Chronic sleep disturbance was associated with anxiety disorders and depression, as well as a high probability of OSA (p < 0.001) after adjustment for age. Conclusion Our study highlights the probability of depression, anxiety and sleep disorders, including OSA, in women with PCOS and their association with BMI and insulin resistance.

Purpose To examine the long‐term results of the Press‐Fit‐Hybrid fixation technique in anterior cruciate ligament (ACL) reconstruction on self‐reported knee function, sport ability, return to sport (RTS) success, quality of life and re‐rupture rates. Methods Adults with ACL rupture which was reconstructed between 2011 and 2013 using the Press‐Fit‐Hybrid fixation technique were included. Participants completed questionnaires before surgery and at 6‐month, 1‐year, 2‐year, 3‐year and 10‐year follow‐ups. Subjective knee function was self‐reported using the International Knee Documentation Committee (IKDC) and Lysholm scores. The level of sport activities was assessed using the Tegner Activity Scale (TAS), and quality of life was evaluated with the Knee injury and Osteoarthritis Outcome Score Quality of Life subscale (KOOS‐QoL). RTS success rates were categorised into return to participation, RTS and return to performance. Results Participants (N = 135) (81 males, 54 females; aged 32.3 years [SD 11.7]) were included. Mean scores at 2, 3 and 10 years were for IKDC 87.6 (SD 10.5), 89.2 (SD 11.0) and 86.5 (SD 14.8), while for Lysholm 92.1 (SD 8.4), 93.3 (SD 7.8) and 90.6 (SD 12.3). The KOOS‐QoL averaged 80.4; 70.0% scored above 80.0. After 3 years, 73% returned to their pre‐injury TAS‐level; 52% still performed at the pre‐injury level after 10 years. Average return to participation was within 5.9 months. 96% returned to sport within 9.6 months on average. 72% returned to performance within a mean of 12.2 months. Re‐rupture rates were 2.85% in the first 3 years and 5% between 3 and 10 years post‐surgery. Conclusion Press‐Fit‐Hybrid leads to low re‐rupture and high RTS rates, restoring knee functionality and improved quality of life. Preliminary results need validation in a randomised controlled trial. Level of Evidence Level III.

Objective Among women with uterine fibroids (UFs), we assess the extent to which the linzagolix effect on pain alleviation is explained by its effect on reducing heavy menstrual bleeding (HMB) and fibroid volume (FV). Design Post hoc analysis on the pooled data from two randomised double‐blind placebo‐controlled phase 3 trials. Setting 94 sites in the US (PRIMROSE 1 trial) and 95 sites in Europe/US (PRIMROSE 2 trial). Population Women aged ≥ 18 years with ultrasound‐confirmed UFs and HMB (n = 1012). Methods Participants were randomised to linzagolix (100 mg and 200 mg, with and without hormonal add‐back therapy) versus placebo. A post hoc mediation analysis was conducted on the pooled PRIMROSE 1 and PRIMROSE 2 data. The effect of linzagolix versus placebo on pain reduction was divided into three components (effect explained by HMB reduction associated with linzagolix, FV reduction associated with linzagolix, and remaining [not yet explained] treatment effect), with proportions of each component reported. Main Outcome Measures The mediation analysis outcome was clinically significant pain reduction, defined as a change of ≥ 2 pain categories from baseline to Week 24 using the Numeric Rating Scale (pain categories: no pain (0), and mild (1–3), moderate (4–6), severe pain (7–10)). Results In the mediation analysis, 28%–51% (depending on treatment arm) of linzagolix effect on pain reduction was explained by its effect on HMB reduction, while 2%–8% was explained by its effect on FV reduction. The residual proportion ranged between 44% and 67%, depending on treatment arm, and was statistically significant only in the linzagolix 200 mg without add‐back therapy arm (p = 0.002). Conclusions This analysis showed that reductions in pain were significantly mediated by reductions in HMB (all doses) and FV (200 mg alone) in linzagolix‐treated women with UFs. Further research is needed to identify additional mediating factors. Trial Registration ClinicalTrials.gov: NCT03070899 and NCT03070951