Background:Alzheimer's disease (AD) is a continuum between normal health and dementia with a long preclinical phase, during which AD pathologies start to emerge, but where there are not yet any overt symptoms. The hallmark pathologies of AD are extracellular β-amyloid (Aβ) plaques and intra-neuronal neurofibrillary tangles (NFTs). Aβ deposition is present at the preclinical stage. Additionally, raised microglial activation is a key factor in AD. However, its exact timing and role is still unclear. This exploratory study investigated the prevalence of microglial activation and its association with Aβ deposition and memory impairment in preclinical AD. Methods:A total of 19 preclinical AD subjects with no cognitive complaints but abnormal Aβ deposition present on 11C-Pittsburgh Compound B (11C-PiB PET) and 10 healthy subjects with no cognitive complains or abnormal Aβ deposition on 11C-PiB PET underwent 11C-PK11195 PET (11C-PK). Additionally, the preclinical AD subjects underwent formal cognitive testing with sensitive memory tests, including the Rey Auditory Verbal Learning Test, the Rey Complex Figure Test, and the Face-Name Associative Memory Exam. Results:Microglial activation was raised in occipital and parietal cortices in preclinical AD subjects compared to healthy controls (p < 0.01). In the preclinical subjects there were significant positive correlations between Aβ load and microglial activation in parietal areas (p < 0.01). Finally, in the preclinical subjects, there were significant negative correlations between microglial activation and memory test performance in selected cortical areas (p < 0.01). Conclusion:Microglial activation was significantly raised in preclinical AD cases with no cognitive complaints and associated with impaired memory test performance. This suggests that microglial activation is present before overt clinical symptoms emerge and may be detrimental to cognition even at this early stage.
Abstract Both the phase 3 MAIA and ALCYONE studies demonstrated significant survival benefit with the addition of daratumumab to standard-of-care Rd (Revlimid [lenalidomide] and dexamethasone; D-Rd) or to VMP (Velcade [bortezomib], melphalan, and prednisone; D-VMP), respectively, vs Rd or VMP alone in transplant-ineligible newly diagnosed multiple myeloma (NDMM). Patients with NDMM are highly susceptible to infection; therefore, gaining a greater understanding of infection incidence may help to mitigate future risk. We conducted a pooled analysis of infection incidence, timing, and management strategies from MAIA and ALCYONE. The median (range) age of the pooled population was 72 (40-93) years. Incidence was higher with D-Rd/D-VMP vs Rd/VMP for grade 3/4 (36.9% vs 22.4%) and grade 5 (3.0% vs 1.5%) infections; however, exposure-adjusted incidence rates were generally comparable between groups. Any-grade infections led to the discontinuation of study treatment in ∼2% of patients across treatment groups. Of the timing intervals explored, the highest incidence of grade 3/4 infection occurred within the first 6-month interval of study treatment initiation in both groups. Median time to the first onset of grade 3/4 infections (per Kaplan-Meier estimates) was 83.3 months and not estimable in the D-Rd/D-VMP and Rd/VMP groups, respectively. Although the rates of D-Rd/D-VMP treatment discontinuation due to infection remained low in MAIA and ALCYONE, clinicians should remain vigilant about infections throughout treatment and follow local guidelines and International Myeloma Working Group recommendations to minimize the risk of infection. These trials were registered at www.ClinicalTrials.gov as NCT02252172 (MAIA) and NCT02195479 (ALCYONE).
Introduction PRELUCA is a randomised, intervention, non-inferiority study designed to use real-time, longitudinal circulating tumour DNA (ctDNA) measurements to evaluate the efficacy of immunotherapy in patients with advanced non-small cell lung cancer (NSCLC). The primary outcome is overall survival between the two groups: the standard of care group (computer tomography scan evaluation) and intervention group (ctDNA evaluation).Methods and analysis The inclusion and exclusion criteria align with European Society for Medical Oncology treatment guidelines and permit broad inclusion of NSCLC patients, ensuring ‘real-world’ representativeness. The study uses a tumour-informed method, using baseline next generation sequencing analyses to design patient-specific droplet digital PCR assays, which are run with collected blood samples 1 week prior to the intended treatment, enabling real-time evaluation via ctDNA Response Evaluation Criteria in Solid Tumours.Ethics and dissemination Inclusion began in July 2023 and patients are now being actively included in five locations across Denmark. Approval by The Committee on Health Research Ethics of Region Zealand was gained on 4 May 2023.Trial registration number NCT05889247.
Teclistamab is the first approved anti-B-cell maturation antigen (BCMA) bispecific antibody for patients with triple-class exposed relapsed/refractory multiple myeloma (RRMM), based on the results of the MajesTEC-1 clinical trial. Here, we first report the findings from REALiTEC, a retrospective observational study of patients who received teclistamab outside of clinical trials in Europe and Israel. The study included 113 patients from 23 sites in eight countries, with most (88.5%) accessing the medication through pre-approval access programs. The median age was 66 years, and patients had a median of 6 prior lines of therapy. Notably, 78.8% were triple-class refractory, 44.2% penta-class refractory, and 35.4% had previous anti-BCMA treatment. Overall response rate (ORR) was 60.2%, with 52.2% of patients achieving a very good partial response or better (≥VGPR). After a median follow-up of 20.7 months, median duration of response (DOR) was 20.3 months, median progression-free survival (PFS) was 9.7 months, and median overall survival (OS) was 26.3 months. Patients attaining ≥VGPR experienced longer DOR (median 26.1 months), with 12-month PFS and OS rates of 71.2% and 83.1%, respectively. Subgroup analyses demonstrated consistent outcomes across different patient groups, even in those with historically poorer outcomes. Most common adverse events were infections (all grades 70.8%), cytokine release syndrome (55.8%), neutropenia (35.4%), and anemia (25.7%), with no new safety signals identified. Infection rates decreased over time, and immunoglobulin replacement therapy was used in up to 60% of patients. REALiTEC corroborates the efficacy observed in the MajesTEC-1 study, supporting teclistamab as an effective treatment option in heavily pre-treated RRMM patients.
