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Importance There is a lack of long-term efficacy and safety data on hereditary transthyretin amyloidosis with polyneuropathy (hATTR-PN) and on RNA interference (RNAi) therapeutics in general. This study presents the longest-term data to date on patisiran for hATTR-PN. Objective To present the long-term efficacy and safety of patisiran in adults with hATTR-PN. Design, Setting, and Participants This global open-label extension (OLE) of the APOLLO randomized clinical trial and phase 2 OLE study enrolled patients from 43 hospitals or clinical centers across 19 countries between July 2015 and August 2017, with follow-up until November 2022. Of 212 eligible patients with hATTR who completed the phase 3 APOLLO or phase 2 OLE parent studies, 211 enrolled in and 138 completed the global OLE. Intervention Patisiran, 0.3 mg/kg, intravenously once every 3 weeks for up to 5 years. Main Outcomes and Measures Outcomes evaluated at year 5 of the global OLE included disability (polyneuropathy disability [PND] score); polyneuropathy severity (Neuropathy Impairment Score [NIS]), nutritional status (modified body mass index [mBMI]), quality of life (Norfolk Quality of Life–Diabetic Neuropathy [Norfolk QOL-DN]), and Rasch-Built Overall Disability Scale (R-ODS), with no statistical hierarchy. Safety, survival probability, and mortality were also assessed. Results At the global OLE baseline, the mean (SD) age was 61.3 (12.3) years, and 156 patients (73.9%) were male. In 138 patients completing the study, PND scores remained stable or improved in 89 patients (65.0%), NISs showed a mean (SD) change of 10.9 (14.7), and mean (SD) mBMI (calculated as weight in kilograms divided by height in meters squared times serum albumin in grams per liter) increased by 46.4 (120.7) over 5 years from baseline. Norfolk QOL-DN and R-ODS scores showed mean (SD) changes of 4.1 (16.7) and –3.7 (6.2), respectively. Adverse events (AEs) leading to study withdrawal occurred in 47 patients (22.3%). Infusion-related reactions were the most common treatment-related AE (n = 34 [16.1%]). Overall, 41 patients (19.4%) died during the study. Patisiran treatment in the parent study and low familial amyloid polyneuropathy score at parent study baseline were associated with significantly improved survival. Conclusions and Relevance In the longest study of an RNAi therapeutic for any disease, patisiran treatment resulted in modest changes for patients with hATTR-PN with an acceptable safety profile. These results highlight the importance of initiating early treatment for hATTR and the potential of RNAi therapeutics in medicine. Trial Registration ClinicalTrials.gov Identifier: NCT02510261

Background. Study of myeloid neoplasms (MN) has been rapidly transformed by genome characterization. Gene mutations have been reported to influence disease phenotype and risk of disease progression, and the evaluation of mutational status can provide valuable insights to improve the decision-making process. In this international study, we evaluated the clinical impact of mutational screening in patients with CMML, which is characterized by significant clinical and genomic heterogeneity, including a substantial proportion of patients with poor outcomes and unmet needs. Currently, only limited molecular information has been incorporated into CMML classification and prognostication. Methods. We retrospectively collected 3182 CMML patients. We used MOSAIC, an AI-based framework for multimodal analysis in rare cancers (PMID: 38875514) to develop innovative, molecular-based tools for classification and prognostication. An independent validation of the results on 516 prospectively collected patients was performed. Results. Bayesian Networs and Hierarchical Dirichlet Processes were used to identify genomic associations and define a CMML molecular classification. We identified 11 clusters with distinct clinical and genomic features, including splicing machinery, signal transduction and tyrosine kinase pathways aberrations, and high-risk molecular signatures (i.e., AML-like and TP53 mutations). Up to 15% of patients showed clear genomic overlap with other MN. Importantly, extensive multi-color flow cytometry on T lymphocytes, NK and myeloid cells (BD FACSymphony A5 Cell Analyzer) revealed specific immunologic and inflammation signatures associated with molecular subgroups. We then integrated molecular and clinical information to build an international CMML Prognostic Scoring System (iCPSS). We assessed the performance of different statistical and AI-based methods; L1-penalized Cox Model resulted as the best performing method. Selected features included hematological parameters (WBC, Hb, PLT and marrow blasts), cytogenetic abnormalities, and mutations in 10 genes (ASXL1, DNMT3A, EZH2, NRAS, RUNX1, SETBP1, STAG2, TET2, TP53, U2AF1). By Bayesian thresholds optimization, we identified 5 risk classes (i.e., very-low, low, intermediate, high and very-high) with median overall survival (OS) ranging from 99 to 9 months (P<.001), and median leukemia-free survival (LFS) ranging from 210 to 18 months (P<.001). iCPSS provided better patient discrimination across all clinical endpoints compared to currently available prognostic tools, with a Concordance Index (CI) for OS of 0.75 versus 0.62-0.64, respectively. Notably, compared to available scoring systems, up to 40% of patients were reassigned to higher or lower risk classes by the iCPSS. External validation on an independent prospective cohort confirmed that the performance of iCPSS is superior to existing prognostic models (CI for OS 0.71 vs 0.54-0.61, respectively) To demonstrate the clinical utility of iCPSS, we focused on 753 patients who underwent allogeneic stem cell transplantation (HSCT). In multivariable analysis, iCPSS stratified the probability of OS post-HSCT (P<.001) and identified groups of patients with different probabilities of disease relapse, ranging from 9% to 62% (P<.001). We employed a clinical- and genomic-based decision support system (PMID: 38723212) to determine the optimal timing of HSCT. Preliminary analyses indicated that higher-risk patients according to iCPSS (i.e., intermediate, high, and very high) benefit from an immediate HSCT strategy. Lower-risk patients (i.e., very low and low) had life expectancy maximized with delayed HSCT. Modeling decision analysis using iCPSS compared to conventional scores, resulted in a change in transplantation policy for a significant proportion of patients (up to 25%). Conclusion. Molecular information significantly improves the classification of CMML patients, providing a basis for refining diagnostic boundaries with other MN and for a more rational inclusion of patients in clinical trials. The iCPSS demonstrated superior performance over currently available scoring systems and improved HSCT decision making process.

Background: The optimal timing of pacemaker reimplantation following transvenous lead removal (TLR) of infected cardiac implantable electronic device (CIED) remains unclear. Objective: Our study aimed to assess the impact of timing to pacemaker reimplantation after TLR of infected CIED on hospital outcomes. Method: Using the Nationwide Readmissions Database, patients aged ≥18 years who underwent new pacemaker implantation with percutaneous approach following TLR of infected CIED from 2017 to 2020 were identified. The study population was stratified based on the timing of pacemaker reimplantation following TLR of infected CIED: early (<5 days) vs delayed (≥5 days). Weighted-propensity-score matched conditional multivariable logistic regressions were performed to determine the impact of the timing on various outcomes. Results: In our study, 469 (66.9%) patients received early device reimplantation, and 232 (33.1%) patients received delayed device reimplantation (≥5 days). Post-procedurally, patients in the delayed group had a higher risk of prolonged hospital stay (95% CI OR: 42.37 (6.36 – 282.11); p<0.01) and non-home discharge (95% CI OR: 2.00 (1.35 – 2.95), p<0.01). There was no significant difference between both groups in the early mortality, 30-day readmission, and procedural complications. Conclusion: Our study suggests that time-to-device reimplantation from TLR of infected CIED did not affect the overall short-term in-hospital outcomes. However, delayed device reimplantation was associated with a higher rate of prolonged hospital stay and non-home discharge.

Abstract Glioblastoma (GBM) is the most common malignant primary brain tumor in adults with a median survival of 8-14 months and 5-year survival rate of 6.9%. Its aggressive nature arises mostly from molecular heterogeneity and resistance to standard of care (SOC), including radiation and temozolomide (TMZ). Recurrence is nearly inevitable, driven by highly invasive brain tumor initiating cells (BTICs). Our previous studies revealed that exposing BTICs to cerebrospinal fluid (CSF) from GBM patients increases cell migration and proliferation compared to non-cancer CSF. Transcriptomic analysis identified the upregulation of the SERPINA3 gene, which encodes alpha-1-antichymotrypsin (ACT). Silencing of SERPINA3 reduces BTIC migration and proliferation and abolishes the promigratory response to GBM-derived CSF, highlighting SERPINA3 as a potential therapeutic target. ACT has been reported to bind to DNA, although the implications of this interaction are unknown. We have previously observed higher levels of intranuclear ACT in human GBM compared to non-cancer brain tissues. We hypothesize that the nuclear localization of SERPINA3 in GBM contributes to increased malignancy, opening the possibility of therapeutically targeting its intranuclear transport. Here, we determined the intracellular localization of ACT in BTICs and GBM and compared it to non-cancer tissues. Additionally, we evaluated whether SOC affected intranuclear localization of ACT. Patient-derived BTICs were treated with TMZ, radiation, and a combination of both, to assess changes in ACT expression via Western Blot, PCR, and ICC. A decrease in cell confluency was correlated with a significant decrease (p&lt;0.05) in SERPINA3 mRNA and overall protein expression when BTICs were treated with TMZ alone or in combination. Interestingly, confocal microscopy revealed a significant increase (p&lt;0.05) in its nuclear localization, particularly with TMZ treatment, indicating a change in its intracellular distribution. Overall, nuclear translocation of SERPINA3 increases in response to SOC with potential implications as a treatment resistance mechanism.

Abstract Background Guidelines recognize the role of exercise stress testing in evaluating functional capacity in patients with asymptomatic severe aortic stenosis (AS). The study aimed to identify the prognostic role of exercise stress echocardiography (ESE) in asymptomatic severe AS. Methods We enrolled 153 asymptomatic patients (70±13 years; 88 male, 57%) with severe AS, aortic valve area (AVA) &lt;1.0 cm2, mean aortic gradient ≥ 40 mmHg, ejection fraction (EF) ≥55%. All were referred for ESE in 7 quality-controlled centers from 5 countries. Rest and ESE assessment also included global longitudinal strain (GLS) and left atrial volume index (LAVI). B-lines were assessed by LUS with the 4-site simplified scan of the third intercostal space. A 4-point ESE score was based on 4 parameters (0 for normal, 1 for abnormal), with the following pre-determined cutoffs of abnormality: ∆-maximal aortic gradient (MAG) ≥20 mmHg; GLS at peak ≤ 19%, according to receiver operating characteristics curve analysis, stress B-lines ≥2; stress LAVI ≥ 34 mL/m2. Follow-up was completed in 142/153 patients (92%). Results At rest, AVA was 0.85±0.14 cm2, maximal aortic gradient: 79±14 mmHg, and peak aortic velocity: 4.42 ± 0.41 m/s. Mean EF at rest: 63.4±5.3% During a median follow-up of 1802 days (IQ range 651-2302), 41 events occurred in 39 patients: 15 all-cause deaths, 17 acute HF, 1 stroke, 1 myocardial infarction, and 7 coronary revascularization. Patients experiencing events displayed a greater increase in MAG during peak ESE, more B-lines with exercise, greater degree of LAVI dilation with exercise and slightly lower GLS compared to those without events (Table). Increase in ESE score was associated with a significant rise (p=0.001) in event incidence from score 0 (n=0/13, 0%) to score 1 (n=2/21, 9.5%), score 2 (n=10/42, 23.8%), and ≥3 (n=27/66, 40.9%), see figure. Conclusions In asymptomatic severe AS cases with preserved LV EF, comprehensive ESE provides early marker of potential cardiac decompensation at follow-up. The composite ESE index, including MAG, GLS, LAVI, and B-lines, holds promise as a prognostic predictor.TableFigure

Abstract Disclosure: R.J. Auchus: Consulting Fee; Self; Neurocrine Biosciences, Inc., Crinetics Pharmaceuticals, OMass Therapeutics, H Lundbeck A/S, Adrenas Therapeutics. Research Investigator; Self; Neurocrine Biosciences, Inc., Diurnal, Crinetics Pharmaceuticals, Spruce Biosciences. O. Hamidi: Advisory Board Member; Self; Corcept Therapeutics, Recordati Rare Diseases, Amryt Pharma, Neurocrine Biosciences, Inc., Xeris, Lantheus. R. Pivonello: Advisory Board Member; Self; Corcept Therapeutics, Recordati AG, Crinetics Pharmaceuticals, H. Lundbeck A/S. Research Investigator; Self; Corcept Therapeutics, Recordati AG, Strongbridge Biopharma, Neurocrine Biosciences, Inc. I. Bancos: Consulting Fee; Self; Corcept Therapeutics, Recordati Rare Diseases, HRA Pharmaceuticals, Neurocrine Biosciences, Inc., Diurnal, Spruce Biosciences, Sparrow Pharmaceuticals, Adrenas Therapeutics. Research Investigator; Self; Recordati Rare Diseases. G. Russo: Advisory Board Member; Self; Novartis Pharmaceuticals, Sandoz, Diurnal. Speaker; Self; Novartis Pharmaceuticals, Sandoz, Diurnal. S.F. Witchel: Research Investigator; Self; Neurocrine Biosciences, Inc. A.M. Isidori: Research Investigator; Self; Pfizer, Inc., Merck Serono, HRA Pharmaceuticals, Recordati AG, Corcept. P. Rodien: Consulting Fee; Self; Pfizer, Inc., Novo Nordisk, Lilly USA, LLC, Ipsen, HRA Pharmaceuticals, IBSA Pharma, Recordati Rare Diseases. U. Srirangalingam: Advisory Board Member; Self; Diurnal. Speaker; Self; Diurnal. F.W. Kiefer: Advisory Board Member; Self; AstraZeneca, Boehringer Ingelheim, Eli Lilly & Company, Novartis Pharmaceuticals, Novo Nordisk, Pfizer, Inc., Sanofi. Speaker; Self; AstraZeneca, Boehringer Ingelheim, Eli Lilly & Company, Novartis Pharmaceuticals, Novo Nordisk, Pfizer, Inc., Sanofi. H. Falhammar: Consulting Fee; Self; Diurnal, Roche Diagnostics, Neurocrine Biosciences, Inc., H Lundbeck A/S, Adrenas Therapeutics. D.P. Merke: Research Investigator; Self; Diurnal, Adrenas Therapeutics, Neurocrine Biosciences, Inc. N. Reisch: Consulting Fee; Self; Diurnal, Crinetics Pharmaceuticals, Neurocrine Biosciences, Inc., Spruce Biosciences, H Lundbeck A/S. J. Sturgeon: Employee; Self; Neurocrine Biosciences, Inc. E. Roberts: Employee; Self; Neurocrine Biosciences, Inc. V.H. Lin: Employee; Self; Neurocrine Biosciences, Inc. J.L. Chan: Employee; Self; Neurocrine Biosciences, Inc. R. Farber: Employee; Self; Neurocrine Biosciences, Inc.. Introduction: Classic congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency (21OHD), a genetic disorder characterized by cortisol deficiency and excess adrenal androgens, typically requires management with supraphysiological glucocorticoid (GC) doses. Crinecerfont is a novel oral CRF1 antagonist that reduced elevated adrenocorticotropic hormone and adrenal androgens in patients with 21OHD in 14-day open-label Phase 2 studies. This Phase 3 study (CAHtalyst: NCT04490915) evaluated whether crinecerfont can reduce daily GC dose while maintaining androgen control in adults with 21OHD. Methods: Adults (≥18 years) with 21OHD, stable GC regimens at doses &gt;13 mg/m2/d in hydrocortisone equivalents (HCe), and normal or elevated androstenedione (A4) were randomized (2:1) to crinecerfont 100 mg BID or placebo for 24 weeks. GC dosing was maintained stable for 4 weeks, followed by a planned GC down-titration over 8 weeks to achieve a GC dose of 8-10 mg/m2/d. GC doses were adjusted as needed during the last 12 weeks to maintain A4 control (≤120% of baseline or ≤upper limit of normal [ULN]) by week 24. Results: In the 182 randomized participants (51% male, mean age 31 years), demographics and baseline characteristics were similar between treatment arms (122 crinecerfont, 60 placebo). Mean GC dose at baseline was 17.6 mg/m2/d HCe (32 mg/d), with 58% on HC alone, 29% taking predniso[lo]ne, and 13% taking dexamethasone; mean pre-GC A4 (620 ng/dL) was elevated &gt;2-3-fold the ULN. Over 95% of participants completed the double-blind treatment period. At week 24, the crinecerfont arm had a significantly greater percent reduction in GC dose while maintaining A4 control vs placebo (-27% vs -10%; least squares mean difference [LSMD]: -17%; p&lt;0.0001) (primary endpoint). At week 4 (end of GC-stable period), a greater reduction in A4 prior to the morning GC dose was observed with crinecerfont vs placebo (LSMD: -345 ng/dL; p&lt;0.0001) (key secondary endpoint). At week 24, a higher percentage of participants reached a protocol-defined physiological GC dose (≤11 mg/m2/d) while maintaining A4 control with crinecerfont (63% vs 18% for placebo; p&lt;0.0001) (key secondary endpoint). The most common treatment-emergent adverse events (AEs) in the crinecerfont arm were fatigue (25% vs 15% for placebo), headache (16% vs 15%), and COVID-19 (14% vs 9%). There were few serious AEs (3% overall), with none assessed as related to the study drug. Conclusions: Crinecerfont, an oral CRF1 antagonist, represents a novel treatment option to improve androgen control for patients with 21OHD. In the largest interventional Phase 3 study conducted to date in adults with 21OHD, crinecerfont led to a significant reduction in A4 while GC dose was stable, enabling a significant percent reduction in GC dose while maintaining A4 control at 24 weeks. Crinecerfont was overall well tolerated. Presentation: 6/1/2024

Abstract Aims To assess the reproducibility of interpreting hypoattenuated thickening (HAT) and peridevice leak (PDL) using cardiac computed tomography (CT) imaging following Watchman FLX left atrial appendage closure (LAAC). Methods and results In this multicentre retrospective reproducibility study, 100 anonymized post-LAAC cardiac CT scans were evaluated within the same cardiac phase by an experienced and a novice rater blinded to prior evaluations. All scans were evaluated twice by each rater, assessing overall HAT and PDL categories as well as specific associated findings based on suggested algorithms for post-LAAC interpretation. Inter- and intra-rater agreement and reliability were evaluated using absolute agreement, Cohen’s kappa, and Kendall’s tau for categorical variables, and mean difference, Bland–Altman plots, limits of agreement (lower and upper), and intra-class correlation coefficients (ICCs) for continuous variables. Within overall categories of both HAT and PDL, substantial agreement (kappa ≥0.61) and reliability (Kendall’s tau-b ≥ 0.75) were observed. Specifically, identifying high-grade HAT (kappa ≥0.78) and distal patency (kappa ≥0.85) displayed the highest agreement within HAT and PDL interpretation. Meanwhile, measuring the height of the proximal screw hub cove represented the least reliable HAT assessment among both inter- and intra-rater comparisons (ICC &lt; 0.75), while suspected leak mechanism represented the least reproducible PDL measure. Conclusion Despite only minimal training of one rater, overall high levels of inter- and intra-rater agreement and reliability were observed across the chosen algorithms for interpretation of HAT and PDL following Watchman FLX LAAC. The prognostic implications of the included variables are to be explored in future trials and registries.