Citations

Abstract Objectives Polymyalgia rheumatica (PMR) is the second most frequent inflammatory rheumatic disease in older adults, after rheumatoid arthritis. Recommendations for the management of PMR, developed by the German, Austrian and Swiss societies of rheumatology and other organizations were published in 2018. Methods These recommendations are now updated based on a systematic literature search that covered the evidence published between July 2016 and January 2024 on therapeutic interventions and prognostic factors for PMR. The search string followed that used in the original recommendations, with an extension for targeted synthetic disease-modifying antirheumatic drugs (DMARDs). Based on evidence and expert opinions, the task force (12 physicians, two healthcare professionals and two patients from three countries) developed a set of four overarching principles and seven specific recommendations. Results The current update reiterates previous guideline recommendations for glucocorticoids (15–25 mg prednisone equivalents per day) as initial treatment for PMR once diagnosis has been confirmed, with subsequent tapering over 4–12 months (depending on whether a glucocorticoid sparing agent is used), with monitoring of disease activity and treatment-related adverse effects. Interleukin-6 receptor blocking agents should be considered in addition to glucocorticoids in patients with relapsing disease and can be considered in patients with new-onset PMR at high risk for glucocorticoid-related adverse events. Methotrexate or rituximab may be alternatives. Older and frail patients should also be offered an individualized exercise program. Conclusion These updated recommendations should serve as an aid to evidence-based decisions ensuring high-quality care for all patients with PMR.

ABSTRACT Acute renal failure due to cast nephropathy (CAN) is a severe complication of multiple myeloma (MM). Here, we aimed to identify parameters associated with renal outcomes and survival in newly diagnosed MM patients with CAN‐related acute renal failure and to validate the IMWG criteria for renal response. CAN diagnosis was based on biopsy or clinical assessment. Of 787 registered patients, 354 met the inclusion criteria, requiring at least two therapy cycles with documented chemotherapy response, renal response, and eGFR. Baseline free light chain (FLC) levels (median 6825.65 mg/L) decreased below 500 mg/L in 67.8% of patients. According to IMWG classification, renal complete response, partial response, and minimal response were achieved in 33.9%, 19.5%, and 28.0% of patients, respectively. The best eGFR values > 60 mL/min/1.73 m 2 were observed in 33.9% of patients, while 33.3%, 22.3%, and 10.5% had best eGFR values of 30–59, 15–29, and < 15 mL/min/1.73 m 2 , respectively. Renal response correlated with baseline FLC levels, IgG kappa, eGFR, and ECOG status in multivariate analysis, as well as with myeloma response and FLC reduction in univariate analysis. Median overall survival was 77.6 months. Survival correlated with age, myeloma response, ECOG status, FLC kappa type, baseline eGFR, standard‐risk cytogenetics, and calcium levels, among other factors. A comparison of IMWG renal response criteria with classification based solely on best eGFR showed similar utility. Of 136 patients requiring dialysis, 80 (58.8%) were able to discontinue dialysis during therapy. Bortezomib containing myeloma therapy, along with significant FLC reduction, was associated with favorable outcome.

ABSTRACT Suicidality contributes substantially to global morbidity and mortality, yet despite its heritability, its biological etiology remains largely elusive. We conducted multi-ancestry genome-wide association study meta-analyses of suicidal ideation (259,747 cases), suicide attempt (64,993 cases), suicide death (9,197 cases), and suicidal behavior (suicide attempt/ death, 75,300 cases), across 54 cohorts (e.g., the Psychiatric Genomics Consortium, Million Veteran Program, UK Biobank). We identified 77 significant loci across meta-analyses, including 59 previously unreported for suicidality. SNP-based heritability ranged from 2.0-6.7% and there were strong, yet incomplete, genetic correlations between suicidality phenotypes (0.70-0.88). Fine-mapping prioritized putative causal SNPs and 20 credible genes. Enrichment analyses implicated synaptic pathways and neuronal populations predominantly in subcortical brain regions (e.g., amygdala excitatory, medium spiny, hippocampal CA1-3). Together, these findings establish suicidality as a polygenic set of traits with both shared and distinct genetic influences, providing a foundation for future studies of suicide biology and etiology.

Background The literature on dyslipidemia and cognitive trajectories among cognitively unimpaired (CU) persons remains inconclusive. Objective To investigate the association between baseline dyslipidemia and change in global and domain specific (i.e., memory, language, attention/executive function, and visuospatial skills) cognition in a population-based setting and whether the association differs by sex, age, or APOE ɛ4 carrier status. Methods We conducted a longitudinal study derived from the Mayo Clinic Study of Aging, involving 4236 CU persons aged ≥ 50 years. We ran linear mixed-effect models to examine baseline dyslipidemia in predicting longitudinal cognitive global and domain-specific z-scores adjusted for age, sex, education, medical comorbidity, repeated cognitive testing, and APOE ɛ4. We examined interactions among dyslipidemia, years since baseline, and separately by sex, age, and APOE ɛ4 carrier status. Results Over a median follow-up period of 6.4 years, CU individuals with dyslipidemia showed faster decline in z-scores of all domains, i.e., memory, language, attention/executive function, visuospatial and global cognition relative to CU individuals without dyslipidemia. Three-way interactions showed that dyslipidemia's effect on decline in z-scores of global cognition, attention and visuospatial skills was less pronounced in males than females. Higher age increased dyslipidemia's effect on decline in z-scores of attention but not global cognition or any other domain. APOE ɛ4 carrier status did not modify the effect of dyslipidemia on cognitive z-scores. Conclusions Dyslipidemia was associated with faster global and domain-specific cognitive decline over time in older community-dwelling individuals who were cognitively unimpaired at baseline. The effect of dyslipidemia on cognitive trajectories may be sex-influenced.

Abstract Background Photon counting detector CT (PCD‐CT) has the potential to sort detected x‐ray photons into more than two energy bins to perform multi‐material decomposition using K‐edge materials without additional mathematical constraints/assumptions. The availability of multiple energy thresholds in PCD‐CT opens the possibility for unique clinical applications such as simultaneous multi‐contrast‐agent imaging. Purpose To evaluate the technical performance of a PCD‐CT system with four energy thresholds for conducting multi‐material decomposition of iodine, gadolinium, and water after a comprehensive system calibration procedure. Methods Experiments were performed on a commercial PCD‐CT scanner (NAEOTOM Alpha, Siemens Healthineers) using a research mode with four energy thresholds. Material calibration was performed by scanning contrast materials with known concentration placed in various sizes of cylindrical water‐equivalent phantoms at various tube currents and positions. From these data, per‐voxel contrast models were derived for each material by multiple linear regressions up to second order, where the predictor variables were combinations of tube current, phantom diameter, and distance to isocenter. After calibration, small (20 cm diameter) and large (30 cm × 40 cm) uniform multi‐energy CT phantoms and an anthropomorphic thorax phantom (31 cm × 39 cm), each containing bone, soft tissue, and several quantitative inserts of iodine (0.2–5.0 mg/ml), gadolinium (0.3–5.0 mg/ml), and a mixture of both (5.0 mg/ml each) were scanned using the four‐energy threshold mode at 140 kV with energy thresholds set at 20, 52, 75, and 82 keV. Images for each energy threshold were reconstructed with a filtered back‐projection algorithm and a quantitative kernel (Qr44). Subsequent image‐based material decomposition was performed on individual voxels of the energy threshold images using the models derived from the calibration process to generate water, iodine, and gadolinium basis images. Quantitative material concentrations and image noise magnitudes, and noise power spectra (NPS) were measured. Results Iodine and gadolinium concentrations above 1.25 mg/ml were visible in the material basis images in all phantoms. Averaged quantitative accuracy for iodine and gadolinium in the small, large, and thorax phantoms were 0.39 ± 0.30 mg/ml, 0.96 ± 0.53 mg/ml, and 0.53 ± 0.35 mg/ml, respectively. In the water basis images, accuracy was within 24 HU in all phantoms. Noise magnitudes in iodine and gadolinium basis images were 2.91 and 3.52 times that of the lowest energy threshold image for the small phantom, and were 6.92 and 7.17 times that of the lowest threshold image for the large phantom. Noise texture did not change between the energy threshold and material basis images for either size phantom as measured by the NPS. Conclusions After a comprehensive system calibration, a commercial PCD‐CT with four energy thresholds performed multiple material decomposition of iodine, gadolinium, and water for concentrations above 1.25 mg/ml in human‐sized phantoms. Noise amplification and quantitative accuracy from the decomposition greatly depended on object size.

ABSTRACT Background Living kidney donation is a crucial option for addressing the global organ shortage and providing kidney transplantation for patients suffering from end‐stage kidney disease. Ensuring donor safety necessitates a comprehensive preoperative assessment of kidney anatomy and function. This study evaluates the relationship between kidney volumes derived from deep learning‐based MRI volumetry, intraoperative kidney volume measurements, split renal function measured by renal scintigraphy, and post‐donation eGFR. Deep learning‐based MRI volumetry is hypothesized to be a reliable method with good correlation. Methods This retrospective study analyzed 178 living kidney donors. Deep learning MRI volumetry‐based kidney volumes were compared with intraoperative volumes of the explanted donor kidneys obtained using the water displacement method. Additionally, MRI‐based volume ratios were compared with scintigraphy‐based split renal function ratios to determine their ability to predict the kidney with poorer renal function and post‐donation eGFR. Results Deep learning‐based MRI volumetry strongly correlated with intraoperatively measured kidney volumes (Pearson's correlation; r = 0.7671; p < 0.0001), confirming its precision in volume estimation. Although MRI‐based kidney volume ratios demonstrated only a moderate correlation with scintigraphy‐based split renal function ratios ( r = 0.4798), MRI volumetry correlated with 1‐year post‐donation eGFR. It tended to be better than renal scintigraphy ( r = 0.6829 versus r = 0.6191). Conclusion Deep learning‐based MRI volumetry is a reliable, non‐invasive tool for estimating kidney volumes in living donors, offering a radiation‐free alternative for preoperative assessment. While it differs from renal scintigraphy in evaluating split renal function ratios, its correlation with post‐donation eGFR tends to be better, supporting its potential role in living kidney donor assessment.

Abstract Purpose :Tamoxifen undergoes bioactivation to its active metabolite (Z)-endoxifen, which blocks estrogen-dependent breast tumor growth at high potency. We tested the feasibility and safety of supplementing standard tamoxifen therapy with low-dose (Z)-endoxifen in patients with breast cancer with compromised tamoxifen bioactivation. Patients and Methods :We conducted a prospective, interventional, three group randomized trial including 235 patients with hormone receptor–positive breast cancer who received standard tamoxifen therapy (20 mg/day). Patients were stratified by CYP2D6 genotype (n = 78), defining poor, intermediate, and normal metabolizers, or by baseline (Z)-endoxifen plasma concentration (n = 78), defining ≤15, 15 to 25, and ≥25 nmol/L. Co-treatment with (Z)-endoxifen 3 and 1.5 mg/day or placebo was performed, respectively. A control group (n = 79) received placebo regardless of metabolizer phenotype. The primary endpoint was the number of patients with (Z)-endoxifen levels &gt;32 nmol/L after 6 weeks of treatment. Adverse events were continuously monitored. Results: A higher proportion of patients in both intervention groups achieved target concentrations &gt;32 nmol/L compared with control (P &lt; 0.0001). At 3 mg (Z)-endoxifen supplementation, 92.3% of CYP2D6 poor metabolizer patients and all patients with baseline (Z)-endoxifen ≤15 nmol/L achieved the target concentration. At 1.5 mg (Z)-endoxifen supplementation, 88% of CYP2D6 intermediate metabolizer patients and 95% of patients with 15 to 25 nmol/L baseline (Z)-endoxifen levels achieved the target concentration. Similar proportions of patients receiving (Z)-endoxifen (6/80, 7.5%) or placebo (8/155, 5.2%) experienced grade 3 adverse events. Conclusions: Adding low-dose (Z)-endoxifen to standard tamoxifen is safe and provides a new approach to personalized antiestrogen treatment for patients with low endoxifen plasma levels.

Abstract Background: The neurokinin-1 receptor (NK1R) complex, activated by Substance P (SP), has emerged as a promising target. SP promotes cell growth, whereas its antagonist, Aprepitant (AP), used clinically for chemotherapy-induced nausea, has demonstrated anti-tumor activity. However, further insight on the anti-tumoral mechanisms after antagonistic targeting of the complex are required. Methods: We conducted bioinformatical analysis of public as well as own RNAseq data. Assays to assess cell proliferation and cell viability (MTT, scratch assays, colony formation) as well as apoptosis and autophagy were carried out. Metabolic changes were detected by SeaHorse analysis, ROS, NAD+/NADH, and MitoTracker. Results: Patient-derived organoid cultures showed reduced spheroid formation and altered morphology following AP treatment, while SP enhanced spheroid formation. SP promoted proliferation via Rho-kinase-dependent mechanisms and activated the ERK signaling pathway, with AP slightly reducing pERK levels. Further analyses revealed that AP induces apoptosis signaling without subsequent DNA fragmentation. Annexin V/PI staining indicated apoptosis induction after 24 hours, while subG1 analysis suggested a blockade in the apoptosis cascade. Prolonged AP exposure led to necrosis, which was mitigated by co-treatment with N-acetylcysteine. Western blot analysis confirmed caspase-9 and -3 activation but showed no PARP cleavage, likely due to high expression of inhibitors of apoptosis proteins (IAPs), such as XIAP. Conclusion: In conclusion, AP exhibits antiproliferative and cytotoxic effects in pancreatic tumor cells, potentially disrupting an autocrine/paracrine SP-NK1R feedback loop and altering metabolic resilience. Future studies should explore metabolic stress responses and investigate whether co-treatment could overcome incomplete apoptosis activation. Citation Format: Matthias Ilmer, Maximilian Viessmann, Bernhard Renz, Frank Braun, Jens Werner. Repurposing of the SP/NK1R-complex inhibitor aprepitant in hepatopancreatic malignancies [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research—Emerging Science Driving Transformative Solutions; Boston, MA; 2025 Sep 28-Oct 1; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2025;85(18_Suppl_3):Abstract nr B023.

ABSTRACT Bipolar disorder’s (BD) clinical heterogeneity has an unresolved genetic basis. We meta-analyzed genome-wide association studies (GWAS) of 16 BD subphenotypes in 226,032 individuals from 57 cohorts (38,022 cases); 10 advanced to multivariate and multi-trait analyses. Four factors (compulsive, psychotic, dysregulated, internalizing) explained 82.8% of shared genetic variance. BD1 and BD2 loaded on distinct factors despite a high genetic correlation; 87.0% of common-factor loci were significant in neither subtype. Unipolar mania aligned with psychosis over internalizing, and was distinguishable from BD1, and rapid cycling showed heritable cross-domain liability. We identified 356 risk loci, 158 novel, including the first univariate-GWAS associations for psychosis, unipolar mania, rapid cycling and schizoaffective disorder—and 249 credible genes (89 high-confidence), 12 with approved-drug or clinical-phase annotations. Cell-type association showed a midbrain dopaminergic–GABAergic gradient along the psychotic factor. BD’s genetic architecture appears hierarchical—a general liability resolving into dimensions of course and comorbidity beyond diagnostic subtypes.