Citations

ABSTRACT Purpose Magnetic resonance elastography (MRE) of the heart has predominantly utilized breath‐held acquisitions with limited anatomic coverage. This work investigates the feasibility of 3D, free‐breathing cardiac MRE. Methods A 3D hybrid radial and EPI acquisition is utilized and combined with retrospective binning of k ‐space via physiologic monitoring, iterative reconstruction, MRE processing and inversions, and post‐processing specialized for cardiac imaging. Results Feasibility of free‐breathing stiffness mapping of the left ventricular myocardium was demonstrated in 11 participants. Myocardial stiffness estimates were obtained throughout the left ventricle for seven temporal states of the cardiac cycle. Stiffness estimates were presented in participant‐specific images, 17‐segment bullseye plots, and stiffness plots throughout the cardiac cycle. Results indicate increased stiffness in systolic states, with localized stiffness heterogeneity observed between participants, illustrating a key benefit of 3D cardiac MRE acquisition. Mean stiffness estimates obtained through 11 subjects were 4.44 ± 0.68 kPa (begin‐systole), 5.74 ± 0.94, 5.42 ± 0.87 (end‐systole), 3.84 ± 0.71 (begin‐diastole), 3.51 ± 0.74, 3.54 ± 0.52, and 3.55 ± 0.59 kPa (end‐diastole). Statistical testing indicated significant differences in stiffness across cardiac states with one‐way, repeated‐measures ANOVA ( p < 0.001) and Friedman's test ( p < 0.001). Experiments in scanning three participants with and without applied motion indicated that stiffness changes were more robustly detected in systole than in diastole, although patterns were subject‐specific. Comparison of free‐breathing stiffness measurements against reference breath‐held measurements yielded similar systolic stiffness estimates. Conclusions This study establishes the feasibility of free‐breathing, 3D cardiac MRE in healthy volunteers. With the current framework, stiffness estimation appears more robust in systole, and the reliability of diastolic estimates is limited and subject‐specific.

Abstract Background Erdheim-Chester disease (ECD) is a very rare histiocytic/dendritic cell neoplasm driven by mutations in genes of the MAPK pathway, such as BRAFV600E. Its clinical presentation is highly heterogeneous, and data on its natural history and prognosis in large cohorts are limited. Here, we investigated the clinical features and outcomes of a very large international cohort of patients with ECD. Methods We included patients diagnosed with ECD between 1990 and 2024, followed at 13 referral centers in Europe and the Americas, who had available clinical and follow-up data (with a minimal follow-up duration of 6 months). We analyzed the clinical presentation, treatment, and outcomes, and sought to identify predictors of survival. The study was conceived and conducted within the ECD Global Alliance network. Results A total of 1044 patients with ECD were included. The median age at diagnosis was 57 years (IQR 46-66), and the male-to-female ratio was 2.2. The median age at the first ECD manifestation was 55 years (IQR 43-65). Bone pain (20%), kidney and urinary manifestations (18%), and diabetes insipidus (11%) were the most frequently reported initial features. The median number of involved sites was 4 (IQR 3-6), most frequently including the long bones (n=768, 74%), the retroperitoneum, (n=605, 58%), the periaortic space (n=449, 43%), the CNS (n=368, 35%), the facial/orbit area (n=347, 33%), and the heart (n=334, 32%). Among 955 tested patients, 572 (60%) harbored the BRAFV600E mutation, and 86 (9%) a MAP2K1 mutation. Clinical and/or pathology overlap with Langerhans cell histiocytosis and Rosai-Dorfman-Destombes disease was observed in 115 (11%) and 42 (4%) patients, respectively. Clonal hematopoiesis was identified in 217 of 556 tested patients (39%), and a history of second cancer was reported in 272 patients (26%), including both solid (14%) and hematologic (12%) neoplasms. First-line treatment mostly included interferon-alpha (n=342, 33%) and BRAFi/MEKi (n=314, 30%), while second- and third-line treatments mostly consisted of BRAFi/MEKi (55% and 63%, respectively). After a median follow-up of 51 months (IQR 20-89), 222 (21%) patients died; causes of death were related to ECD in almost half of the patients (n=101). A multivariate Cox regression model identified the following factors as significantly associated with increased mortality: older age (HR 1.058, 95%CI 1.033-1.083; p&lt;0.001), pseudo-neurodegenerative lesions (HR 2.280, 95%CI 1.337-3.891; p=0.022), elevated CRP at diagnosis (HR 2.574, 95%CI 1.024-6.467; p=0.044), and second hematologic cancer (HR 2.639, 95%CI 1.602-4.348; p&lt;0.001). Conclusions Despite advances in treatments over the last decade, ECD remains associated with substantial mortality. Age, neurodegenerative lesions, elevated CRP levels, and the presence of a second hematologic cancer are the main predictors of poor survival.

Abstract Introduction Detecting genetic abnormalities is mandatory during diagnostic workup and for potential individualization of therapy selection in multiple myeloma (MM) and its precursor conditions. At present, this requires invasive bone marrow (BM) biopsies, severely limiting early detection, patient monitoring, and the precise selection of therapy. The current standard for detecting genetic alterations in MM is fluorescence in situ hybridization (FISH), which cannot detect point mutations and other clinically relevant alterations. Consequently, the IMS-IMWG guidelines were recently updated to require next-generation sequencing for the classification of high-risk MM. Moreover, the importance of identifying alterations in therapeutic targets (e.g., BCMA, GPRC5D) for guiding immunotherapies is becoming increasingly recognized. To address this need, we recently launched GenoPredicta, a CLIA-approved Laboratory Developed Test that enables routine monitoring, informing diagnosis, and treatment selection by comprehensively and robustly characterizing MM genomes with whole genome sequencing (WGS) from a minimum of ~50 circulating tumor cells (CTCs) isolated from peripheral blood (PB) or tumor cells from BM. Here, we describe the characterization of clinical and research samples with GenoPredicta, highlighting resistance-conferring genetic alterations that can only be detected by sequencing and that are consistent with patients' clinical histories, while further demonstrating the complete concordance of GenoPredicta with prior FISH results. Methods Tumor cells were isolated from BM and/or PB samples using fluorescence-activated cell sorting (FACS) (after CD138+ enrichment for PB) and subjected to whole genome sequencing (WGS), from which we identified copy number alterations, structural variants, and single nucleotide variants and indels. For a subset of samples, the BM was also characterized by FISH, using a standard clinical panel for characterizing MM; for other samples prior FISH results were available from patients' clinical records. Results The analytical validation of GenoPredicta, conducted on a retrospective cohort of &gt;60 viably frozen samples from &gt;30 patients, showed complete concordance between BM and PB for detected genomic abnormalities, with all clinically relevant events (11 translocations and 125 CNVs) observed in BM recapitulated in PB (100% recall). All events identified by FISH in 14 samples (8 translocations and 30 CNVs) were also identified in the BM (100% recall), with 50 translocations and 30 CNVs not detected by FISH also absent in the WGS data (100% precision). The abnormalities detected in these samples also included multiple high-risk events not assayed by FISH, including biallelic TP53 loss (Del 17p coupled with a deleterious TP53 mutation, observed in 4 patients) and MYC::IGL translocations (2 patients). Moreover, for all fresh peripheral blood clinical samples with FISH results available from patients' histories, GenoPredicta recalled 100% of reported events. Among these clinical samples, we notably observed a case with both a biallelic GPRC5D deletion and a TNFRSF17 (BCMA) deletion combined with a truncating mutation on the remaining allele. This was consistent with the patient's clinical history showing progression after therapy with talquetamab (anti-GPRC5D bispecific), and previous nonresponse to teclistamab (anti-BCMA bispecific) after prior therapy with Cilta-cel (BCMA-directed CAR T). GenoPredicta also detected other mutations likely to confer resistance to immunotherapies, including loss-of-function mutations in IKZF3 and deletions of FCRL5 in frozen peripheral blood research samples. Conclusion We demonstrate that WGS-based characterization of MM from BM or CTCs is a viable replacement for FISH for clinical diagnosis and monitoring, with blood-based measurements enabling comprehensive profiling of the myeloma cancer genome. Importantly, this includes genetic alterations that confer resistance to therapy, allowing for both early detection of such alterations and more precise selection of therapy.

Abstract Anaplastic large cell lymphomas (ALCLs) are CD30+ T-cell lymphomas that share pathologic features but differ in presentation, outcome, and genetics. Current classification incorporates clinical presentation and anaplastic lymphoma kinase (ALK) status but inadequately addresses molecular heterogeneity and therapeutic vulnerabilities. We studied 689 patients with ALCL in the LLMPP (Lymphoma/Leukemia Molecular Profiling Project) and performed expert consensus review, genetic subtyping (ALK, DUSP22, TP63, and triple negative), and immunohistochemistry for phosphorylated STAT3Tyr705. RNA sequencing with unsupervised gene expression profiling in 393 patients identified 2 main molecular types of ALCL that could be predicted with 91% accuracy based on the presence (type I) or absence (type II) of phosphorylated STAT3Y705 expression. Type I ALCLs included ALK+ ALCL and a subset of triple-negative ALCLs (TN-I); type II ALCLs included tumors with DUSP22 and/or TP63 rearrangements and the remaining triple-negative ALCLs (TN-II). Type I ALCLs were enriched for JAK-STAT3, whereas type II ALCLs were enriched for non–tyrosine kinase pathways, particularly epigenetic regulators such as EZH2. Immunohistochemistry showed overexpression of EZH2 and its trimethylated substrate H3K27. Prognosis in systemic ALCL was favorable for DUSP22-rearranged ALCL (5-year overall survival, 95%) and ALK+ ALCL (88%), intermediate for triple-negative ALCL (TN-I, 52% and TN-II, 37%), and poor for TP63-rearranged ALCL (0%). We introduce an integrated molecular classification that preserves currently diagnosed ALCL entities but identifies 4 molecularly distinct ALK− ALCL subtypes (DUSP22-rearranged, TP63-rearranged, TN-I, and TN-II). This classification can be easily implemented on paraffin tissue in routine practice or clinical trials, and stratifies ALCL into diagnostically, prognostically, biologically, and potentially therapeutically relevant subtypes.

Abstract Deep brain stimulation (DBS) of the subthalamic nucleus improves motor symptoms in patients with Parkinson’s disease. Using functional MRI, optimal DBS response networks have been characterized. However, neural activity associated with Parkinsonian symptoms is magnitudes faster than what can be resolved by this method. Although both spatial and temporal domains of these networks appear crucial, no single study has yet investigated both domains simultaneously. Here, we aimed at closing this gap by analysing electrophysiological data from a total of n = 127 hemispheres. Using subthalamic local field potentials that were recorded concurrently alongside whole-brain magnetoencephalography in a multi-centre cohort of patients who underwent subthalamic DBS for the treatment of Parkinson’s disease (n = 100 hemispheres), we analysed the DBS response network in both spatial and temporal domains. In every cortical vertex, cortico-subthalamic coupling was correlated with stimulation outcomes. This network spatially resembled functional MRI-based findings (R = 0.40, P = 0.039) and explained significant amounts of variance in clinical outcomes (βstd = 0.30, P = 0.002), whereas theta–alpha and low beta coupling did not show significant associations with DBS response (theta–alpha: βstd = −0.02, P = 0.805; low beta: βstd = −0.08, P = 0.426). The ‘optimal’ high beta coupling map was robust when subjected to various cross-validation designs (10-fold cross-validation: R = 0.29, P = 0.009; split-half design: R = 0.31, P = 0.026) and was able to predict outcomes across DBS centres [R = 0.74; P(1) = 8.9 × 10−5]. We identified a DBS response network that resembles the previously defined MRI network and operates in the high beta band. Maximal connectivity to this network was associated with optimal DBS outcomes and was able to cross-predict clinical improvements across DBS surgeons and centres.

Background The association between lifestyle factors and Alzheimer's disease (AD) pathophysiology remains incompletely understood. Objective The aim of this study was to assess the association of alcohol consumption, smoking behavior, sleep quality and physical, cognitive, and social activity with cerebral amyloid pathology. Methods For this cross-sectional study, we selected participants from the Amyloid Biomarker Study data pooling initiative. We used generalized estimating equations to assess associations of dichotomized lifestyle measures with amyloid pathology. Results We included 9171 participants with normal cognition (NC) and 2555 participants with mild cognitive impairment (MCI) from the Amyloid Biomarker Study. Of participants with NC, 58% were women, 34% were APOE ε4 carrier, and 27% had amyloid pathology. Of participants with MCI, 48% were women, 47% were APOE ε4 carrier, and 57% had amyloid pathology. In NC, cognitively active participants were less likely to have amyloid pathology (OR = 0.77, 95%CI 0.66–0.89, p < 0.001). In MCI, participants who had ever smoked or had sleep problems were less likely to have amyloid pathology (OR = 0.85, 95%CI 0.73–0.99, p = 0.029; OR = 0.62, 95%CI 0.45–0.86, p = 0.004). Conclusions In NC, cognitive activity was associated with a lower frequency of amyloid pathology. In MCI, favorable lifestyle behaviors were not associated with a lower frequency of amyloid pathology. The results of the current study contribute to the broader evidence base on lifestyle and AD by further characterizing the role of lifestyle behaviors in AD pathology across different clinical stages.

Importance Treatment for cognitive dysfunction due to postacute sequelae of long COVID (ie, symptoms of fatigue, malaise, weakness, confusion that persist beyond 12 weeks after an initial COVID infection) remains a significant unmet need. Objective To test evidence-based rehabilitation strategies for improving cognitive symptoms in persons with long COVID. Design, Setting, and Participants This was a 5-arm, multicenter, randomized clinical trial of 3 remotely delivered interventions conducted between August 17, 2023, and June 10, 2024. The study took place at 22 trial sites and included the screening of individuals with cognitive long COVID. Interventions Participants were randomized to 1 of 5 arms: adaptive computerized cognitive training (BrainHQ [Posit Science]), cognitive-behavioral rehabilitation involving both group and individual counseling sessions (PASC-Cognitive Recovery [PASC-CoRE]) paired with BrainHQ, and transcranial direct current stimulation (tDCS) paired with BrainHQ. Two comparator arms were included as follows: unstructured computer puzzles and games (active comparator) and sham tDCS paired with BrainHQ. The interventions occurred 5 times per week over 10 weeks. Main Outcomes and Measures Cognitive and behavioral in-person assessments were performed at baseline, midintervention, at the end of intervention, and 3 months after the end of the intervention. The primary outcome measure was the modified Everyday Cognition Scale 2 (ECog2) completed at the end of the intervention compared to the baseline visit based on participant self-report looking back over the prior 7 days. Results A total of 378 individuals were screened, from which there were 328 participants (median [IQR] age, 48.0 [37.0-58.0] years; 241 female [73.5%]; race: 15 Asian [4.6%], 47 Black [14.3%], and 235 White [71.6%]; ethnicity: 52 Hispanic [15.9%]). None of the 3 active interventions demonstrated benefits on the modified ECog2 in the intention-to-treat population by the end of the intervention period. The adjusted differences in mean change were 0.0 (95% CI, −0.2 to 0.2) for BrainHQ vs active comparator, 0.1 (95% CI, −0.1 to 0.3) for PASC-CoRE + BrainHQ vs active comparator, 0.0 (95% CI, −0.2 to 0.2) for tDCS-active + BrainHQ vs tDCS-sham + BrainHQ, and 0.1 (95% CI, −0.1 to 0.3) for PASC-CoRE + BrainHQ vs BrainHQ alone. Secondary participant-reported outcomes and neuropsychological tests showed no differential benefits for any treatment arm. All 5 arms demonstrated some improvements over time on the modified ECog2 and on secondary outcomes. There were no serious adverse events attributable to the interventions. Conclusions and Relevance This phase 2 randomized clinical trial failed to demonstrate differential benefits for online cognitive training, a structured cognitive rehabilitation program, and tDCS for cognitive long COVID. Trial Registration ClinicalTrials.gov Identifier: NCT05965739 .

OBJECTIVE While endonasal transsphenoidal surgery (ETS) is the standard treatment for nonfunctioning pituitary adenomas (NFPAs), the postoperative recovery rates of secondary adrenal insufficiency and their predictive factors remain poorly understood. The authors investigated the relationship between the tumor resection rate and adrenal function recovery in patients with NFPAs. METHODS This retrospective study included 450 patients with NFPAs who underwent ETS between January 2013 and November 2023. The rates of preoperative hypopituitarism and postoperative recovery rates of secondary adrenal insufficiency and their associated factors were analyzed. Recovery was defined as normalization of serum cortisol levels without replacement therapy for at least 24 hours, accompanied by symptom resolution. The tumor resection rate was calculated as the percentage of the tumor volume resected. RESULTS The median follow-up period for the entire cohort was 52 months (range 1–131 months). A total of 246 (55%) patients had dysfunction in one or more pituitary axes. Fifty-three (47%) of 114 patients with preoperative adrenal insufficiency showed postoperative adrenal insufficiency recovery. The cumulative adrenal insufficiency recovery rates were 12% at 1 month, 19% at 3 months, 32% at 6 months, and 41% at 12 months. Among the 114 patients with preoperative adrenal insufficiency, the factors associated with postoperative adrenal insufficiency recovery were investigated. Patients with smaller tumor sizes of < 20 mm (log-rank test, p = 0.001) and those with tumor resection rates of more than 85% (log-rank test, p = 0.032) demonstrated better postoperative adrenal insufficiency improvement. Bivariate Cox proportional hazards analysis demonstrated that smaller tumor sizes (continuous, HR 0.97, 95% CI 0.93–0.98; p = 0.043) and higher tumor resection rates (HR 1.03, 95% CI 1.01–1.07; p = 0.001) were significantly associated with better postoperative adrenal insufficiency recovery. Multivariable analysis confirmed that only higher tumor resection rates were significantly associated with better postoperative adrenal insufficiency recovery (HR 1.03, 95% CI 1.01–1.06; p = 0.019). CONCLUSIONS Nearly half of the patients with preoperative adrenal insufficiency achieved recovery after ETS for NFPAs. The enhanced extent of tumor removal was an independent factor associated with better postoperative recovery, indicating that optimizing safe maximal resection procedures may be crucial in enhancing adrenal function.