Rare genetic factors have been shown to substantially contribute to mental illness, but so far, no precision treatments for mental disorders have been described. It was recently identified that rare variants in GRIN2A encoding the GluN2A subunit of the N-methyl-D-aspartate receptor (NMDAR) confer a substantial risk for schizophrenia. To determine the prevalence of mental disorders among individuals with GRIN2A-related disorders, we enquired the presence of psychiatric symptoms in 235 individuals with pathogenic variants in GRIN2A who had previously enrolled in our global GRIN registry. We identified null variants in GRIN2A (GRIN2Anull) to be significantly associated with a broad spectrum of mental disorders including schizophrenia compared to a longitudinal population cohort (FinRegistry) as well as missense variants (GRIN2Amissense). In our cohort, GRIN2Anull-related mental disorders manifest in early childhood or adolescence, which is substantially earlier than the average adult onset in the general population. In 68% of co-incident epilepsy and mental disorder, mental disorders start after epilepsy offset and the age of epilepsy offset correlated with mental disorder onset. GRIN2Anull-related phenotypes appear to occasionally even manifest as isolated mental disorder, i.e. as schizophrenia or mood disorder without further GRIN2A-specific symptoms, such as intellectual disability and/or epilepsy. As L-serine is known to mediate co-agonistic effects on the NMDAR, we applied it to four individuals with GRIN2Anull-related mental disorders, all of whom experienced improvements of their neuropsychiatric phenotype. GRIN2Anull appears to be the first monogenic cause of early-onset and even isolated mental disorders, such as early-onset schizophrenia. Genetic testing should be considered in the diagnostic work-up of affected individuals to improve diagnosis and potentially offer personalized treatment as increasing brain concentrations of NMDAR co-agonists appears to be a promising precision treatment approach successfully targeting deficient glutamatergic signaling in individuals with mental disorders, i.e. due to GRIN2Anull.
Abstract INTRODUCTION The German Hodgkin Study Group (GHSG) HD21 trial for adult patients with newly diagnosed advanced-stage classical Hodgkin lymphoma (AS-cHL) was designed to reduce treatment-related morbidity (TRMB) and improve efficacy by comparing the novel BrECADD regimen (brentuximab vedotin, etoposide, cyclophosphamide, doxorubicin, dacarbazine, dexamethasone) to the standard eBEACOPP protocol. Here, we report the final efficacy and safety including long-term progression-free survival (PFS), overall survival (OS), and late toxicity outcomes. METHODS This open-label, international, randomized phase III trial included adults aged 18-60 with newly diagnosed AS-cHL, randomized 1:1 to treatment with 4–6 cycles of eBEACOPP or BrECADD, guided by positron emission tomography after two cycles (PET2). The trial was registered at clinicaltrials.gov (NCT02661503) and conducted according to ICH-GCP guidelines. Co-primary objectives were reduction of TRMB and superiority of PFS with BrECADD vs. eBEACOPP, both of which were met previously. The final analysis focused on long-term PFS, overall survival (OS), and second primary malignancies (SPMs). Kaplan-Meier estimates and Cox regression were used for time-to-event analysis in the intention-to-treat (ITT) population. Additionally, we describe prognostic factors for PET2 response among baseline characteristics including metabolic tumor volume (MTV) and the prognostic value of international prognostic score (IPS) variables and MTV at baseline for PFS, respectively, in the BrECADD arm. Univariate logistic regressions were used to identify associations with interim PET response (p<=.001), which were then compared using multivariate analyses. RESULTS A total of 1,500 patients were enrolled between July 2016 and August 2020 across 233 sites in nine countries. Baseline demographics and disease characteristics were well balanced between arms. After 2 cycles of BrECADD, 235/664 patients (35%) with centrally reviewed PET2 were classified as PET-positive. ECOG > 0 (Odds Ratio [OR] 1.62, 95% CI 1.03-2.55) and higher MTV (OR 1.14 per 100 mL, 95% CI 1.06-1.22) at baseline were associated with positive PET after 2x BrECADD in multivariate analysis. Median follow-up for this final analysis was 60 months and seven new PFS-events occurred after the previous analysis at 48 months: Five in the eBEACOPP arm and two in the BrECADD arm. Confirming earlier analysis, the hazard ratio (HR) for PFS was 0.64 (95% CI 0.44–0.93) favoring BrECADD. The absolute 5-year PFS for BrECADD was 93.6% (95% CI 91.7–95.5) vs. 90.6% (95% CI 88.4-92.8) with eBEACOPP, with a particularly pronounced 5y PFS benefit in PET2-negative patients of 96.2% vs. 92.4% (HR 0.46, 95% CI 0.25–0.83;). Among the IPS variables, male sex (HR 2.68, CI 95% 1.37-5.27) and hemoglobin < 10.5 g/dL (HR 2.41, 95% CI 1.25-4.68) were associated with higher risk for PFS events in multivariate cox regression, whereas MTV at baseline in univariate cox regression was not (HR 0.95 per 100 mL, 95% CI 0.81-1.11). Salvage therapies were similar across treatment arms: most patients with progression or relapse received autologous stem cell transplantation (52/61 (82%) after eBEACOPP vs 29/38 (76%) after BrECADD). With four (two in each treatment group) new death events since the previous analysis, OS remained at 98% in both arms. The cumulative incidence of SPMs at 60 months was 2.1% after eBEACOPP and 2.8% after BrECADD, with differing patterns: more secondary MDS/AML occurred in the eBEACOPP arm (six vs. one), while more secondary NHL cases were observed in the BrECADD arm (two vs. eight). No new sMDS/AML events occurred beyond the primary analysis. CONCLUSION With 5 years follow-up, this analysis confirms the unprecedented primary cure-rate and long-term safety profile of BrECADD. While higher baseline lymphoma burden associates with incomplete remission at PET2, the risk for treatment failure seems mitigated through response-adaptation. Taken together, our results establish individualized BrECADD as a standard treatment option for adult patients with newly diagnosed AS-cHL.
ABSTRACT:Beyond cure, major goals in patients with Hodgkin lymphoma (HL) are tailoring treatment to a patient's individual risk for relapse to reduce acute and late toxicities, identifying candidates for early incorporation of novel agents, and making treatment affordable on a global level. Minimal residual disease (MRD) assessment by circulating tumor DNA (ctDNA) sequencing emerged as a promising strategy to achieve these goals; however, previous studies differed in sampling time points, assay validation, and definitions for MRD negativity. Here, we applied LymphoVista, a validated ctDNA sequencing assay for genotyping and MRD monitoring in lymphoma, to samples obtained from the German Hodgkin Study Group (GHSG) HD21 trial after 2 cycles of treatment (MRD-2) using a case-cohort design. Patients with positive MRD-2 result were at higher risk for relapse, progression, or death compared with MRD-2-negative patients (4-year progression-free survival [PFS], 36.7% vs 82.2%; hazard ratio, 5.3; 95% confidence interval, 2.0-13.8; P = .0008). After inverse probability weighting accounting for the number of events in the full reference set, patients with positive and negative MRD-2 results had 4-year PFS rates of 72.2% vs 95.3%. Combining MRD-2 with positron emission tomography after 2 cycles of BrECADD/eBEACOPP (PET-2) can identify patients at very low and patients at very high risk of relapse, progression, or death. In summary, these results suggest that MRD-2 assessment by LymphoVista allows for early outcome prognostication in patients with HL and could be used as a tool to improve treatment guidance on its own or in conjunction with PET-2.
BACKGROUND AND AIMS:Stereotactic arrhythmia radioablation (STAR) is increasingly used for refractory ventricular tachycardia (VT), yet prospective multicentre outcome data remain limited. Here, the planned interim analysis of the prospective Standardized Treatment and Outcome Platform for Stereotactic Therapy Of Re-entrant tachycardia by a Multidisciplinary (STOPSTORM) registry is reported. METHODS:STOPSTORM is a European prospective, international, multicentre registry of patients treated with STAR. The primary efficacy endpoint was the change in sustained VT episode burden comparing the 6 months before versus the 6 months after STAR. The primary safety endpoint was the occurrence of serious adverse events (SAEs) adjudicated as possibly or probably treatment-related. Overall survival was assessed using time-to-event methods. RESULTS:Across 28 centres, 193 patients were included (mean age 68±9 years; 88% male; 53% non-ischaemic cardiomyopathy). Median follow-up was 19 months. Among 107 evaluable patients with ≥6-month follow-up, the median VT episode burden was reduced by 80% after STAR. Among patients surviving ≥6 months, 72% were free from implantable cardioverter-defibrillator (ICD) shock. In the full cohort, 12 SAEs were adjudicated as possibly or probably treatment-related, including pericardial effusion, coronary events, and early post-treatment ventricular arrhythmia. Overall survival probability was 77% at 12 months. CONCLUSIONS:In the largest prospective multicentre cohort reported to date, STAR was associated with a substantial reduction in VT burden and ICD shocks, with a low frequency of possibly or probably treatment-related SAEs.
Background Adjuvant chemotherapy provides limited benefit in unselected stage II colon cancer. Post-operative circulating tumour DNA (ctDNA) has higher prognostic value than classical clinical markers, with ctDNA positivity indicating an unfavourable outcome. Patients and methods Patients with Union for International Cancer Control stage II, mismatch repair proficient/microsatellite stable colon cancer were tested for ctDNA using an academic, tumour-informed, next-generation sequencing-based test. ctDNA-positive patients were randomly assigned 2:1 to CHEMO (capecitabine ± oxaliplatin) or observation (OBS). ctDNA-negative patients were randomly assigned 1:4 to OBS or OFF-STUDY. ctDNA results were not disclosed in the OBS group. The primary endpoint was disease-free survival (DFS) in ctDNA-positive patients. All differences were tested using one-sided log-rank tests. The trial ended early due to funding expiry. Results From June 2020 to July 2025, 2126 patients were screened in Germany and Austria. Overall, 1396 patients (2.9% ctDNA-positive) were randomly assigned: 1083 to OFF-STUDY, 287 to OBS, and 26 to CHEMO, of whom 81% started therapy. DFS and overall survival (OS) were significantly worse in ctDNA-positive versus ctDNA-negative patients [3-year DFS 52% versus 87%, hazard ratio (HR) 4.28, 95% confidence interval (CI) 2.32-7.93, P < 0.001; 3-year OS 88% versus 98%, HR 5.48, 95% CI 1.64-18.28, P = 0.001]. In the intention-to-treat (ITT) cohort, the between-arm differences were not significant (3-year recurrence 36% versus 62%, HR 0.48, 95% CI 0.17-1.33, P = 0.075; 3-year DFS 61% versus 38%, HR 0.55, 95% CI 0.21-1.48, P = 0.12). In the per-protocol analysis (excluding untreated CHEMO patients), time to recurrence and DFS were improved with CHEMO compared with OBS (3-year recurrence 19% versus 62%, HR 0.23, 95% CI 0.06-0.87, P = 0.009; 3-year DFS 77% versus 38%, HR 0.31, 95% CI 0.09-1.03, P = 0.021). Conclusion The primary ITT endpoint was not met, potentially related to the reduced power due to premature trial closure. The per-protocol analysis suggests a benefit from adjuvant therapy in ctDNA-positive patients, supporting ctDNA testing for adjuvant decision making in the future.
