Karolinska Development (Sweden)

Pilocytic astrocytomas (PAs) are rare primary brain tumors in adults and exhibit worse outcomes compared with pediatric cases. Surgery is the primary therapeutic approach, whereas radiation therapy (RT) is reserved for symptomatic recurrence but is associated with substantial long-term toxicity. PAs are characterized by the activation of the mitogen-activated protein kinase (MAPK) signaling pathway and Mitogen-activated protein kinase kinase (MEK) inhibitors have demonstrated effectivity in pediatric populations, though data in adults remain limited. We retrospectively analyzed data of five adult patients (ages 30-79), four with PAs and one with PA with anaplastic transformation, that were administered trametinib, a MEK1/2 inhibitor. All tumors harbored somatic NF-1 mutations, with one germline NF-1 case. According to RANO 2.0 criteria, three patients achieved partial responses and two had stable disease, with neurological improvement in two cases. Median progression-free survival was 16.65 months, supporting MEK inhibition as an effective treatment strategy in adult PAs.

Abstract Background The association between inflammatory bowel disease (IBD) and venous thromboembolism (VTE) is well-studied in the adult population. However, in paediatric-onset IBD (PIBD; < 18 years) data are scarce. Most studies are limited in size, as pointed out by the recently published ESPGHAN-ECCO guidelines for the treatment of paediatric acute severe ulcerative colitis. Several studies have indicated an increased risk of cerebral venous sinus thrombosis (CSVT). Assessing the risk among children and adolescents across clinical characteristics is crucial to guide clinical decisions about prophylactic treatment. Methods We used data from nationwide population-based registers to identify patients diagnosed with PIBD in Denmark (1996-2022) and Sweden (2006-2023). Patients with PIBD were matched on the date of first IBD diagnostic listing with up to 10 reference individuals from the general population by age, sex, and place of residence. Occurrence of VTE was compared in absolute (incidence rate difference, IRD) and relative terms (hazard ratios, HR) with 95% confidence intervals (95%CI). Data from Denmark and Sweden were combined using random effects meta-analyses. Comparisons included VTE overall, by VTE subtypes, sex, age, IBD subtypes, and time since diagnosis; and in the data from Sweden only, by disease activity (steroid prescriptions or addition/change of immunomodulators or advanced therapies, hospitalisation or surgery for IBD) and hospitalisation. Results We included 4,009 (Denmark) + 6,781 (Sweden) patients with PIBD and 39,096 + 64,497 reference individuals. Median follow-up time was 9.6 and 8.9 years, respectively. The incidence rate of VTE among patients with IBD was 1.3 per 1,000 person-years (95%CI: 1.1-1.5), and 0.4 (95%CI: 0.2-0.7) among reference individuals, with an IRD of 0.9 (95%CI: 0.7-1.2) per 1,000 person-years and an HR of 3.3 (95%CI: 1.8-6.3) (Table 1). The HR within the first 2 years of IBD was 18.8 (95%CI: 10.3-34.1). While CSVT and other thrombotic events had the highest HRs among VTE subtypes, the absolute risk of CSVT was low, at 1 per 10,000 person-years. In Sweden, disease activity, and hospitalisation, particularly hospitalisation for IBD, were strongly associated with VTE. Conclusion PIBD was associated with a substantially increased relative risk of VTE compared to the general population, although the absolute risk, including that for CSVT, was very low. Clinicians should carefully consider the risk of VTE in this population, in particular early on in the disease course, and during disease activity and hospitalisation. Conflict of interest: Dr. Bröms, Gabriella: Dr Bröms has served as a speaker for Takeda and Janssen and worked on projects at Karolinska Institute, partly financed by Janssen, Pfizer and UCB, unrelated to this study. Trudu, Beatrice: None. Modin, Frederikke Agerbo: None. Moshtaghi-Svensson, John: None. Burisch, Johan: Dr. Burisch reports grants from AbbVie, Janssen-Cilag, MSD, Takeda, Tillots Pharma, Bristol Myers Squibb, and Novo Nordisk Foundation personal fees from AbbVie, Janssen-Cilag, Celgene, MSD, Pfizer, Takeda, Tillots Pharma, Bristol Myers Squibb, Samsung Bioepis, Pharmacosmos, Ferring, Galapagos, Eli Lilly, Dr Falk Pharma, Celltrion, Zealand Pharma and Orion Pharma. Forss, Anders: Served as speaker/advisory board member for Janssen Cilag AB, Pfizer and Tillotts Pharma. Jansson, Sabine: Dr Jansson has received travel support from Ferring Pharmaceuticals and research grants from Takeda Pharma A/S, and Ferring Pharmaceuticals. Unrelated to the work submitted. Ludvigsson, Jonas: Dr Ludvigsson has received financial support from Merck/MSD for a study on inflammatory bowel disease and fibrosis and for developing a paper reviewing national healthcare registers in China. Dr Ludvigsson also has an ongoing research collaboration on celiac disease with Takeda. Earlier support includes a grant from Janssen for an unrelated study on behalf of the Swedish IBD quality register (SWIBREG). Mårild, Karl: Dr Mårild has received payment for two lectures for Pfizer Osooli, Mehdi: Dr Osooli participated in projects at Karolinska institute partly financed by pharmaceutical companies. All unrelated to this study. de Ridder, Lissy: Non-financial Support: Pfizer Other: Abbvie, Pfizer, Janssen, Eli Lilly, Takeda, Medtronic, Alvotech Wewer, Vibeke: None. SWIBREG Study Group, Swibreg: None Malham, Mikkel: None. Olen, Ola: Dr Olén has led projects at Karolinska Institutet financed by grants from Pfizer, Janssen, Alfasigma, AbbVie, Takeda, Bristol Myers Squibb, and Ferring. OO has served as speaker for lectures organized by Janssen, Pfizer, Takeda, and Bristol Myers Squibb.

Abstract MET-FINGER is the first randomized controlled trial combining healthy lifestyle changes with a putative disease-modifying drug (metformin) for the prevention of cognitive impairment, in an APOEε4-enriched at-risk population of older adults. The potential benefits of metformin repurposing are based on the link between Type-II Diabetes (T2D) and Alzheimer’s Disease (AD), and emerging evidence of independent neuro-protective effects. Findings will provide crucial information for innovative precision-prevention strategies aimed at cognitive impairment and dementia risk-reduction. 600 participants are randomly allocated to the FINGER 2.0 intervention (lifestyle for all + metformin, where appropriate; active arm), or regular health advice (control arm). Participants in the FINGER 2.0 group and at increased risk of T2D, are further randomised to 2000mg/day metformin, 1000mg/day metformin, or placebo (double-blind). The multimodal lifestyle intervention is an optimised version of the FINGER model. Metformin is administered as Glucophage®XR/SR 500, (Merck Healthcare KGaA, Darmstadt, Germany; 500mg oral tablets). Primary outcome is change in global cognition (combined z-score of a neuropsychological test battery). Secondary outcomes are changes in individual cognitive domains; functional ability; and risk factors for AD/dementia. The feasibility, potential lifestyle-metformin interaction, and disease-modifying effects of the lifestyle-metformin combination are exploratory outcomes. 489 eligible participants have been identified; 365 have been randomised. The main challenges experienced are linked to balancing APOEε4-carriers enrichment and the eligibility rate for metformin treatment (e.g., APOEε4-carriers were less likely to fulfil some eligibility criteria for metformin). Lessons learned, pertaining to trial design, set-up, recruitment, and delivery, for future combination-therapy studies, will be presented.

Many oral health-related quality of life instruments have been developed but few have undergone a comprehensive psychometric assessment. One commonly used measure is the Oral Impact on Daily Performance (OIDP). This study revised the configural and metric properties as well as the performance of items based on Item Response Theory (IRT) of a dichotomous-item version of OIDP in Brazil. The nine-item dichotomous version of the OIDP was analysed using data from a nationally representative sample from the Oral Health Survey (SBBrasil 2010). It consisted of 30 064 individuals aged 12 to 75 and was split into two partitions comprising n1 = 20 040 and n2 = 10 024, respectively. Confirmatory factor analyses (CFA) were conducted on the larger partition and cross-validated on the smaller to assess configural and metric properties. The item performance was evaluated using a 2-parameter item response theory (IRT) model. Sampling weights were used in all analyses. The unidimensional model presented two violations of conditional independence, one between items i5 (practising sports) and i4 (going out) and another between items i6 (trouble in speaking) and i7 (shame of speaking or smiling). A CFA of the most parsimonious model (removing i5, i6 and i7) yielded a RMSEA = 0.02, WRMR = 1.42, CFI = 0.99 and TLI = 0.99. The IRT analyses showed that three pairs of items had very similar levels of difficulty and discrimination suggesting redundancy. A shorter dichotomous version of the OIDP scale has acceptable configural and metric properties. Being more concise and thus efficient, it may be better suited for large-scale population surveys than the version currently in use.

Background: Heart failure with preserved ejection fraction (HFpEF) is a heterogeneous condition with high morbidity and mortality. Risk stratification of patients with HFpEF is important for advancing therapeutic development and improving clinical care. Research Question: Predicting overall mortality and heart failure (HF) Hospitalization in real world HFpEF population Aims : to leverage machine learning model to develop prognostic models based on real-world data, with the potential to support risk stratification in routine clinical practice Methods: CONFIDENT is an observational, multi-cohort study across three centers in Europe and the US. Patients with HFpEF, according to the HFA-PEFF criteria with ≥ 2 years of follow-up, were included from 2013 to 2022. The dataset included multimodal data from electronic health records, lab tests, echocardiography, and electrocardiography, with 82 baseline candidate variables. We developed machine learning-based prognostic models to predict all-cause mortality and HF hospitalization. Model performance was compared to conventional risk score in an external validation cohort. Results: A total of 1208 patients were included in the study. The mean age was 72±12. The 2-year risk of HF hospitalization and all-cause mortality ranged from 13 to 44% and 9 to 19% respectively. The all-cause mortality prognostic model achieved good discrimination with a C-index of 0.67 [95%CI, 0.66-0.68], and 0.68 [95%CI 0.66-0.69] in the training cohorts, and 0.72 [95%CI 0.65-0.78] in the validation cohort, and performed better than the PREDICT-HFpEF score (C-index: 0.66 [95%CI 0.65-0.68], p-value =0.012; 0.60, [95%CI 0.59-0.62],p-value < 0.01 and 0.67 [95%CI 0.58-0.73], p-value =0.013 respectively. Similar results were observed when compared to the Meta-Analysis Global Group In Chronic Heart Failure Risk Score (MAGGIC). Similarly, the model derived for HF hospitalization outperformed PREDICT-HFpEF and MAGGIC + natriuretic peptide. Conclusion: CONFIDENT prognostic models for all-cause mortality and HF hospitalization using routinely collected variables can reliably predict outcomes and facilitate personalized care and trial recruitment strategies in HFpEF.

Brain metastases following esophagectomy for cancer are rare but can greatly affect quality of life. To date, risk factors for, time to development of, and treatment strategies for brain metastasis are not well defined. Consecutive patients treated with esophagectomy for clinical stage I-IVA esophageal cancer from 2010 to 2021 across five centers were included. Logistic regression analyses were performed to identify risk factors for development of solitary brain metastases. Overall survival was assessed using Kaplan-Meier analysis. Of 3191 included patients, 91 (2.9%) developed solitary brain metastasis. Multivariable analysis identified increasing clinical nodal stage, adenocarcinoma (adjusted odds ratio [aOR] 4.00; 95% confidence interval [CI] 1.91-10), neoadjuvant chemoradiotherapy (aOR 2.18; 95% CI 1.19-4.28), and adjuvant therapy (OR 2.48; 95% CI 1.10-5.18) as risk factors for developing solitary brain metastases. Complete pathological responders were more likely to develop brain metastases than distant metastases (aOR 2.43; 95% CI 1.23-4.55). Patients with early solitary brain metastasis had the worst median overall survival (4.4 months, 95% CI 2.2-17) compared with classic (11 months, 95% CI 8.3-18) or late (7.4 months, 95% CI 2.1-not reached) (p = 0.20). Treatment involving surgery combined with radiation (adjusted hazard ratio [aHR] 0.10; 95% CI 0.05-0.20) resulted in better median overall survival (18 months, 95% CI 13-26) than did radiation (aHR 0.20; 95% CI 0.11-0.36) (10 months, 95% CI 6.1-14) or best supportive care (1.3 months, 95% CI 0.39-2.8) (p < 0.001). After esophagectomy for cancer, nodal involvement, adenocarcinoma, neoadjuvant and adjuvant therapy, and complete pathologic response appear to be risk factors for developing solitary brain metastases. Survival of selected patients with solitary brain metastasis is possible, especially if they are able to undergo surgery combined with radiation therapy.

BackgroundAlzheimer’s disease (AD) exhibits sex differences in prevalence, symptoms and risk factors. Understanding the effect of sex in AD cerebrospinal fluid (CSF) biomarkers and their association with amyloid-beta (Aβ) pathology in preclinical stages have important implications for their use in prevention trials. The objective of this study was to examine sex differences in core AD CSF biomarkers used in early diagnosis and prevention trials, as well as in CSF biomarkers reflecting downstream pathophysiological mechanisms, and in their associations with Aβ pathology as measured by Positron Emission Tomography (PET).MethodsCognitively Unimpaired (CU) participants from the ALFA + (N = 400) and the WRAP/WADRC (N = 548) cohorts were included in the study. CSF biomarkers for core AD pathology (Aβ42, Aβ42/40, p-tau181/Aβ42, p-tau181, p-tau217 and p-tau231), neurodegeneration (NfL, t-tau), synaptic dysfunction (neurogranin, GAP-43, SNAP25, synaptotagmin-1, α-synuclein), glial reactivity (GFAP, S100B, sTREM2, YKL-40), neuroinflammation (IL-6, MCP-1), and vascular dysregulation (sICAM-1, sVCAM-1) were measured. Participants underwent Aβ PET at baseline and follow-up visit. We used Analyses of Covariance (ANCOVA) to evaluate sex differences in CSF biomarker levels and performed sex-stratified Receiver-Operating Characteristic (ROC) analyses to test their performance to identify Aβ PET-positive individuals. Additionally, we run linear regression models to study the modifying effect of sex on the association of baseline CSF biomarkers with cross-sectional and longitudinal Aβ PET uptake.ResultsMen had higher CSF NfL, glial reactivity and vascular dysregulation biomarkers (Cohen’s d ranging from -0.22 to -0.44, P < 0.05), and lower synaptic biomarkers (Cohen’s d ranging from 0.18 to 0.30, P < 0.05) compared to women at baseline. There were no sex differences in the core AD CSF biomarkers’ performance to identify Aβ PET-positive individuals (DeLong's test P values > 0.05), with CSF p-tau181/Aβ42 and p-tau217 showing the highest performance in both sexes (Areas Under the Curve (AUCs) ranging from 87.1 to 96.3). However, sex modified the associations of baseline CSF biomarkers with Aβ PET uptake, which were more pronounced in women than in men.ConclusionsOur results suggest that tailoring core AD CSF biomarkers by sex is not necessary for detecting Aβ PET positivity in CU individuals. However, sex differences in their association with Aβ deposition could influence their prognostic or monitoring applications.Supplementary InformationThe online version contains supplementary material available at 10.1186/s13195-025-01844-1.

To assess risks of adverse pregnancy outcomes (APOs) in a contemporary cohort of women with systemic sclerosis (SSc) in relation to the timing of SSc diagnosis and by parity. From the nationwide Swedish Medical Birth Register, we assembled pregnancies with births in women with SSc and in comparator women from the general population (1998-2021). We classified pregnancies according to the timing of SSc diagnosis at birth: post-SSc (after SSc diagnosis [n = 94]) and pre-SSc (zero to three years [n = 39] or more than three years [n = 839] before diagnosis of SSc). We used regression models estimating relative risks (RRs) and odds ratios of APOs with 95% confidence intervals (CIs) in post-SSc and pre-SSc pregnancies, respectively. For post-SSc pregnancies, RRs of preeclampsia (3.8, 95% CI 1.8-7.8), preterm birth (3.3; 95% CI 1.8-6.1), and cesarean delivery (2.5; 95% CI 1.8-3.5) were increased. By contrast, there were no indications of increased proportions of maternal or neonatal death or stillbirth. Stratifying on parity, risks were considerably higher among primiparous post-SSc women (preeclampsia RR 7.5, 95% CI 3.5-16.1; preterm birth RR 5.1, 95% CI 2.5-10.5). We also noted increased odds of APOs in pre-SSc pregnancies, with the highest estimates in the zero to three years' pre-SSc pregnancies. Contemporary women with SSc displayed markedly increased risks of several APOs after SSc diagnosis; the risks of some APOs were already increased before diagnosis, particularly within three years. Our findings suggest that both preclinical and overt SSc have a substantial impact on pregnancy outcomes, especially in the first pregnancy, highlighting the importance of specialized care and close monitoring.

[This corrects the article DOI: 10.3389/fphar.2025.1532022.].