Despite previous reports of hippocampal alterations in breast cancer patients, the structural evolution of hippocampal subfields in relationship with memory remains to be characterized in this population. We aimed to measure hippocampal subfield volumes and their links with memory performances before and after chemotherapy in breast cancer patients compared to healthy controls. Forty-two middle aged women were evaluated, including 19 patients assessed before (T1), one-month (T2) and one-year (T3) after chemotherapy, and 23 controls assessed at T1 and T3. Using high-resolution MRI, hippocampal subfields were automatically segmented. Derived volumetric measures were compared between groups at T1 and T3 and within the patient group (T1, T2, T3). Both encoding and retrieval memory performances were measured using a dedicated task. At T1 and globally (i.e., T1 and T3 together), patients showed lower retrieval performance and larger subiculum and whole hippocampal volumes compared to controls. Volumes of the whole hippocampus and of the Cornu Ammonis (CA) 4-Dentate gyrus increased over time in controls. Longitudinal comparisons within the patients’ group did not yield significant changes. Volumes were negatively associated with age in controls, and positively with education level in patients. Our results highlight structural differences in the subiculum and whole hippocampus of breast cancer patients both post-surgery and over the adjuvant treatment course. These modifications may reflect a combination of cancer-related and early perioperative factors, while the lack of subsequent longitudinal changes in patients prevents conclusions regarding the specific impact of chemotherapy. Additional studies with larger sample sizes will be of help to further our findings.
The randomized controlled multicentre APACH2 trial showed that first-line [18F]F-choline (FCH1) PET/CT is superior to [99mTc]Tc-sestaMIBI (MIBI1) SPECT/CT for referring patients with primary hyperparathyroidism (pHPT) to effective minimally invasive parathyroidectomy (MIP). The aim of this study was to weigh this clinical gain against the increase in imaging costs. The effectiveness criterion per imaging strategy was the rate of normocalcemia at one month post true-positive first-line imaging-guided MIP. The medico-economic analysis, carried out from the payer’s perspective, integrated direct hospital costs up to 6 months after randomization. The result of the cost-effectiveness analysis was calculated in the form of an incremental cost-effectiveness ratio (ICER), establishing the average cost necessary to cure an additional person by switching from the usual MIBI1 strategy to the new FCH1 strategy. Sensitivity analyses were used to test the robustness of the ICER. The APACH2 trial enrolled 57 patients from November 2019 to May 2022 in four centres, randomized between FCH1 (n = 29) or MIBI1 (n = 28). The differential cost between FCH1 and MIBI1 strategies was €136.5 (average cost FCH1 €3,843.5 (95
INTRODUCTION:Increasing evidence suggests that dolutegravir (DTG), endorsed by the WHO since 2018 for first-line antiretroviral therapy (ART), is associated with significant weight gain and potentially also with cardiometabolic disorders. In an effort to expand therapeutic options for people living with HIV (PLHIV), the EvaLuating the non-inferiority of DORAvirine vs DOlutegravir trial aims to compare the virologic efficacy of doravirine (DOR) and DTG-based regimens and to assess their safety, including a focus on cardiometabolic effects. METHODS AND ANALYSIS:This is an international, phase III, multicentre, open-label, non-inferiority, randomised trial that will enrol 610 ART-naïve PLHIV (HIV RNA≥1000 copies/mL at screening) across six countries (Brazil, Cameroon, France, Côte d'Ivoire, Mozambique and Thailand) spanning four continents. Key inclusion criteria include age ≥18 years, confirmed HIV-1 infection with plasma RNA levels ≥1000 copies/mL, indication for ART initiation and no prior ART exposure. Participants will be randomised in a 1:1 ratio to receive either DOR 100 mg once daily in combination with tenofovir disoproxil fumarate (TDF) (300 mg daily) plus lamivudine (3TC) (300 mg daily) or DTG (50 mg daily) in combination with TDF (300 mg once daily) plus either emtricitabine (FTC) (200 mg daily) or 3TC (300 mg daily). Randomisation will be stratified by screening HIV-1 RNA load (≤100 000 or >100 000 copies/mL) and by country. The primary outcome is virological efficacy, defined as the proportion of participants achieving HIV-1 RNA <50 copies/mL at week 48 on the assigned treatment (FDA Snapshot algorithm). Secondary outcomes include cardiometabolic safety endpoints (ie, weight gain, insulin resistance, hypertension, diabetes, waist and hip circumferences, waist-to-hip ratio, fasting glycaemia, insulin and fasting serum lipids), along with mental health, quality of life, virological and immunological parameters. Final data collection is expected by July 2028. ETHICS AND DISSEMINATION:Primary outcome results (week 48) are expected in early 2028. The project was submitted to and approved by national ethics committees and pharmaceutical regulatory authorities in all participating countries: Brazil (CEP INI FIOCRUZ (21.040-900)/CEP HGNI (26.030-380)); Cameroon (CNERSH (2024/09/1717/CE/CNERSH/SP)/Ministry of Public Health (D30-1464/AAR/MINSANTE/SG/DROS/CRC); Côte d'Ivoire: (CNESVS (0018224/MSHPCMU/CNESVS-km)/AIRP (1329/AIRP/DISMP/Om/kbaag); France (CTIS CPP/ANSM (2023-508626-10-00)); Mozambique (CNBS (20/CNBS/25)/ANARME (4635/380/ANARME)); Thailand: (IHRP (08/1944)/Thai FDA: ongoing on 19 January 2026). The trial received authorisation from the French National Commission for Data Protection and Liberties (CNIL) under approval number 924 302. Written informed consent is obtained from all participants prior to any study-specific procedures and trial enrolment, in accordance with the Declaration of Helsinki and applicable national regulations. Study findings will be disseminated through publication in peer-reviewed journals and presentations at national and international scientific conferences. Results will also be communicated to policymakers, healthcare professionals, community stakeholders and study participants through appropriate dissemination activities, including policy briefs, stakeholder meetings and lay summaries on dedicated and easily accessible platforms. TRIAL REGISTRATION NUMBERS:NCT06203132; EU-CT, 2023-508626-10-00.
Poly (ADP-ribose) polymerase inhibitors (PARPi) are approved for the treatment of HER2-negative metastatic breast cancer (MBC) in germline (g)BRCA1/2 pathogenic alteration (m) carriers. Olaparib and talazoparib showed efficacy in MBC patients with somatic (s)BRCA1/2m and/or gPALB2m in phase 2 trials. We aimed to investigate the effectiveness of PARPi in this setting in the real-life ESME cohort. ESME-MBC, a nationwide observational cohort, gathers data on MBC patients treated in 18 French Cancer Centers from 2008 on. We selected all patients treated with PARPi and who had either sBRCA1/2m or gPALB2m MBC. The primary endpoint was progression-free survival (PFS). Secondary endpoints included overall survival (OS) from treatment initiation, PFS and OS according to type of mutation, type of PARPi and line of treatment. The Kaplan-Meier method was used to assess survival. Among 35,687 patients included in the ESME database from 2008 to 2022, 57 were eligible for the present analysis (46 with sBRCA1/2m;11 gPALB2m). Median age at treatment was 54 years [31-83]). 39% were triple negative MBC (17 sBRCA1/2m and 5 gPALB2m), 60% HR-positive/HER2-negative (28 sBRCA1/2m and 6 gPALB2m). The median number of treatment lines prior PARPi, including endocrinotherapy, was two [0-9]. PARPi was initiated in first- or second line for 24 patients, representing 64% of triple-negative patients and 42% of HR-positive/HER2-negative patients. 32 patients (56%) received olaparib, 22 talazoparib (39%, all with sBRCA1/2m) and 3 another PARPi. A clinical trial was the context for 36.8% of prescriptions. In the whole population, median PFS and OS were 5.4 [95%CI: 4.3; 8.3] and 13.2 months [11.2; 19.7] respectively. For patients bearing sBRCA1/2m and gPALB2m, median PFS were 4.9 [3.0; 8.2] and 8.3 [3.0; not achieved (NA)] months respectively, and median OS 12.1 [10.4; 19.7] and 17.6 [2.4; NA] months respectively. Median PFS was 4.9 [2.8; 6.7] and 8.2 months [3.9; 13.1] for talazoparib and olaparib respectively; and median OS 12.1 [7.2; 24.3] and 15.0 months [10.1; 26.6]. In this multicenter real-life cohort of MBC patients with a sBRCA1/2 or a gPALB2 mutation, effectiveness of PARPi appeared in line with phase II trials. These data further support the use of olaparib or talazoparib in gPALB2m, and possibly in sBRCA1/2m. P. ROTTIER, L. CHALTIEL, Z. NEVIERE, W. JACOT, A. MAILLIEZ, F. DALENC, T. BACHELOT, E. BRAIN, V. MASSARD, B. SAUTEREY, T. GRINDA, C. BAILLEUX, M. ARDENOS, L. BOSQUET, G. EMILE. Parp inhibitors use in patients in germline palb2 or somatic brca1/2 mutations carriers with metastatic breast cancer: real life data from the esme database [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS2-04-29.
Constitutional epimutations of the MLH1 gene are an alternative cause of Lynch syndrome, in which inactivation of an allele of a mismatch repair (MMR) gene results from MLH1 promoter methylation, rather than a pathogenic genetic variant. These epimutations are often mosaic, and methylation levels ranging from ~50% monoallelic methylation to low-level methylation (1%-5%) are observed in the blood of MLH1 epimutation carriers. Using a specific and highly sensitive droplet digital methyl-specific PCR (ddMSP) assay, six patients with very low methylation levels (< 1%) were identified in a series of 142 patients with a MLH1-methylated tumor diagnosed before age 61, who had been referred to the clinical lab between 2020 and 2024. These patients were initially missed by standard pyrosequencing assay, emphasizing the need for highly sensitive assays for constitutional epimutation screening. To confirm that methylated DNA molecules detected by ddMSP did not correspond to circulating tumor DNA rather than germline DNA, multiple validation analyses were performed, including validation of the constitutional origin of methylation on other sources of germline DNA and tumoral analysis. Taking into account the other patients identified as epimutation carriers by pyrosequencing during the same 5-year period, 13.1% of patients with a MLH1-methylated tumor before age 61 were diagnosed as Lynch syndrome patients, which changed their clinical follow-up. These findings highlight the relevance of recommendations for systematic MLH1 epimutation screening using highly sensitive assays in patients with MLH1-methylated tumors diagnosed before age 61. Such screening will increase the number of patients diagnosed with Lynch syndrome caused by a MLH1 constitutional epimutation, improving patient care and outcomes, as well as genetic counseling.
