Citations

ObjectiveTo describe a 41‐year‐old woman with a history of neonatal onset multisystem inflammatory disease, on treatment with daily subcutaneous injections of 600 mg of recombinant interleukin‐1 receptor antagonist (IL‐1Ra) protein, anakinra, since the age of 28, who presented with golf‐ball size nodules at the anakinra injection sites, early satiety, new onset nephrotic syndrome in the context of normal markers of systemic inflammation.MethodsClinical history and histologic evaluation of biopsies of skin, gastric mucosa, and kidney with Congo‐red staining and proteomic evaluation of microdissected Congo red–positive amyloid deposits by liquid chromatography‐tandem mass spectrometry.ResultsThe skin, stomach, and kidney biopsies all showed the presence of Congo red–positive amyloid deposits. Mass spectrometry‐based proteomics demonstrated that the amyloid deposits in all sites were of AIL1RAP (IL‐1Ra protein)‐type. These were characterized by high spectral counts of the amyloid signature proteins (apolipoprotein AIV, apolipoprotein E, and serum amyloid P‐component) and the amyloidogenic IL‐1Ra protein, which were present in Congo red–positive areas and absent in Congo red–negative areas. The amino acid sequence identified by mass spectrometry confirmed that the amyloid precursor protein was recombinant IL‐1Ra (anakinra) and not endogenous wild‐type IL‐1Ra.ConclusionThis is the first report of iatrogenic systemic amyloidosis due to an injectable protein drug, which was caused by recombinant IL1Ra (anakinra).

Background Obstructive sleep apnea (OSA) is common in heart failure with preserved ejection fraction (HFpEF). However, current evidence is equivocal regarding the potential benefits of treating OSA with positive airway pressure (PAP) therapy in HFpEF. This study assessed the association between adherence to PAP therapy and health care resource use in patients with OSA and HFpEF. Methods and Results Administrative insurance claims data linked with objective PAP therapy usage data from patients with OSA and HFpEF were used to determine associations between PAP adherence and a composite outcome including hospitalizations and emergency room visits. One‐year PAP adherence was based on an adapted US Medicare definition. Propensity score methods were used to create groups with similar characteristics across PAP adherence levels. The study cohort included 4237 patients (54.0% female, mean age 64.1 years); 40% were considered adherent to PAP therapy (30% intermediate adherent, 30% nonadherent). In the matched cohort, PAP‐adherent patients had fewer health care resource use visits than nonadherent patients, a 57% decrease in hospitalizations, and a 36% decrease in emergency room visits versus the year before PAP initiation. Total health care costs were lower in adherent patients than nonadherent patients ($12 732 versus $15 610, P <0.001). Outcomes for intermediately adherent patients were most similar to those for nonadherent patients. Conclusions Treating OSA with PAP therapy in patients with HFpEF was associated with a reduction in health care resource use. These data highlight the importance of managing concomitant OSA in patients with HFpEF, and the need for strategies to enhance PAP adherence in this population.

Importance Lensectomy with primary intraocular lens (IOL) implantation is often used in the management of nontraumatic pediatric cataract, but long-term data evaluating the association of age and IOL location with the incidence of complications are limited. Objective To describe the incidence of complications and additional eye surgeries through 5 years following pediatric lensectomy with primary IOL implantation and association with age at surgery and IOL location. Design, Setting, and Participants This prospective cohort study used Pediatric Eye Disease Investigator Group cataract registry data from 61 institution- and community-based practices over 3 years (June 2012 to July 2015). Participants were children younger than 13 years without baseline glaucoma who had primary IOL implantation (345 bilateral and 264 unilateral) for nontraumatic cataract. Data analysis was performed between September 2021 and January 2023. Exposures Lensectomy with primary IOL implantation. Main Outcome and Measures Five-year cumulative incidence of complications by age at surgery (&amp;lt;2 years, 2 to &amp;lt;4 years, 4 to &amp;lt;7 years, and 7 to &amp;lt;13 years) and by IOL location (sulcus vs capsular bag) were estimated using Cox proportional hazards models. Results The cohort included 609 eyes from 491 children (mean [SD] age, 5.6 [3.3] years; 261 [53%] male and 230 [47%] female). Following cataract extraction with primary IOL implantation, a frequent complication was surgery for visual axis opacification (VAO) (cumulative incidence, 32%; 95% CI, 27%-36%). Cumulative incidence was lower with anterior vitrectomy at the time of IOL placement (12%; 95% CI, 8%-16%) vs without (58%; 95% CI, 50%-65%), and the risk of undergoing surgery for VAO was associated with not performing anterior vitrectomy (hazard ratio [HR], 6.19; 95% CI, 3.70-10.34; P &amp;lt; .001). After adjusting for anterior vitrectomy at lens surgery, there were no differences in incidence of surgery for VAO by age at surgery (&amp;lt;2 years, HR, 1.35 [95% CI, 0.63-2.87], 2 to &amp;lt;4 years, HR, 0.86 [95% CI, 0.44-1.68], 4 to &amp;lt;7 years, HR, 1.06 [95% CI, 0.72-1.56]; P = .74) or by capsular bag vs sulcus IOL fixation (HR, 1.22; 95% CI, 0.36-4.17; P = .75). Cumulative incidence of glaucoma plus glaucoma suspect by 5 years was 7% (95% CI, 4%-9%), which did not differ by age after controlling for IOL location and laterality. Conclusions and Relevance In this cohort study, a frequent complication following pediatric lensectomy with primary IOL was surgery for VAO, which was associated with primary anterior vitrectomy not being performed but was not associated with age at surgery or IOL location. The risk of glaucoma development across all ages at surgery suggests a need for long-term monitoring.

Background Previous studies have established that higher baseline quality of life (QOL) scores are associated with improved survival in patients with metastatic colorectal cancer (mCRC). We examined the relationship between overall survival (OS) and baseline QOL. Patients and Methods A total of 1 247 patients with mCRC participating in N9741 (comparing bolus 5-FU/LV, irinotecan [IFL] vs infusional 5-FU/leucovorin [LV]/oxaliplatin [FOLFOX] vs. irinotecan/oxaliplatin [IROX]) provided data at baseline on overall QOL using a single-item linear analogue self-assessment (LASA) 0–100 point scale. The association of OS according to clinically deficient (defined as CD-QOL, score 0–50) vs not clinically deficient (nCD-QOL, score 51–100) baseline QOL scores was tested. A multivariable analysis using Cox proportional hazards modeling was performed to adjust for the effects of multiple baseline factors. An exploratory analysis was performed evaluating OS according to baseline QOL status among patients who did or did not receive second-line therapy. Results Baseline QOL was a strong predictor of OS for the whole cohort (CD-QOL vs nCD-QOL: 11.2 months vs 18.4 months, P < .0001), and in each arm IFL 12.4 vs 15.1 months, FOLFOX 11.1 months vs 20.6 months, and IROX 8.9 months vs 18.1 months. Baseline QOL was associated with baseline performance status (PS) ( P < .0001). After adjusting for PS and treatment arm, baseline QOL was still associated with OS ( P = .017). Conclusions Baseline QOL is an independent prognostic factor for OS in patients with mCRC. The demonstration that patient-assessed QOL and PS are independent prognostic indicators suggests that these assessments provide important complementary prognostic information.

Introduction: Deep-learning artificial intelligence (AI) algorithms can identify hypertrophic cardiomyopathy (HCM) from the electrocardiogram (ECG). Preliminary data indicate that AI-ECG may also track treatment response in HCM patients (pts) receiving mavacamten (Mava). In this placebo-controlled analysis, we investigated the performance of AI-ECG in HCM detection and its changes during Mava treatment compared to placebo in the phase 3, EXPLORER-HCM trial. Methods: Pts with non-paced ECGs enrolled in EXPLORER-HCM, evaluating Mava over 30 weeks of treatment, were included. All pts had a 12-lead ECG pre-treatment, at each study visit, and 8 weeks after treatment end. Two independently developed AI-ECG convolutional neural network algorithms from the Mayo Clinic and the University of California, San Francisco (UCSF) were applied to all ECGs suitable for analysis. Serial AI-ECG-predicted scores, which correlate with HCM likelihood (range 0-1), were examined between Mava and placebo groups. Results: A total of 101 Mava and 110 placebo pts were included (mean age 58.6, female 40%). At baseline, the mean Mayo and UCSF AI-ECG scores for HCM were 0.82 and 0.65, with 94% and 88% of pts exceeding the respective diagnostic thresholds of 0.11 (Mayo) and 0.4 (UCSF). During 30 weeks of follow-up in the Mava group, the algorithms showed a mean AI-ECG score reduction of 0.32 (Mayo) and 0.17 (UCSF) in all pts between start and end of treatment. In comparison, AI-ECG scores decreased by 0.05 (Mayo) and increased by 0.02 (UCSF) in the placebo group (Mava vs placebo, t-test p-values <0.001 for both algorithms; Figure ) Conclusion: In the EXPLORER-HCM trial population, two independent deep-learning AI-ECG algorithms correctly identified most HCM pts and demonstrated significant reductions in predicted HCM scores after treatment with Mava when compared to placebo. This relative normalization of the ECG suggests disease-modifying properties of Mava, deserving further investigation.

TPS7587 Background: Covalent (c) Bruton tyrosine kinase inhibitors (BTKi) have transformed the management of MCL, but these agents are not curative. cBTKi share pharmacologic liabilities (e.g., low oral bioavailability, short half-life), which collectively may lead to suboptimal BTK target coverage especially in rapidly proliferating tumors with high BTK protein turnover such as MCL, which can manifest as acquired resistance to BTKi. Pirtobrutinib, a highly selective, non-covalent (reversible) BTKi, has favorable oral pharmacology that enables continuous BTK inhibition throughout the dosing interval regardless of intrinsic rate of BTK turnover. In the phase 1/2 BRUIN study, pirtobrutinib demonstrated promising durable overall response rates and was well tolerated in patients (pts) with MCL regardless of prior therapy (including cBTKi), number of prior lines of therapy, or reason for prior cBTKi discontinuation. Pirtobrutinib was approved by the FDA in January 2023 for R/R MCL after 2 prior lines of therapy including a BTKi. The objective of this study is to establish whether pirtobrutinib is superior to investigator’s choice of cBTKi in pts with previously treated, BTKi naïve MCL. Methods: BRUIN MCL-321 (NCT04662255) is a randomized, open-label, global phase 3 study comparing pirtobrutinib monotherapy versus investigator’s choice of cBTKi monotherapy (ibrutinib, acalabrutinib, or zanubrutinib) in pts with previously treated, BTKi naïve MCL. Approximately 500 pts will be randomized 1:1 and stratified by sMIPI risk (low/intermediate vs high), comparator BTKi (ibrutinib vs acalabrutinib/zanubrutinib), and number of prior lines of therapy (1 vs ≥ 2). Enrollment for this study is ongoing. Adults with a diagnosis of MCL who have received ≥ 1 prior line of systemic therapy for MCL and are BTKi naïve are eligible. Pts must have measurable disease by imaging per Lugano criteria and have progressed on or relapsed following the most recent line of therapy. A history of current or prior CNS involvement, significant cardiovascular disease, stroke or intracranial hemorrhage within 6 months of randomization, and autologous stem cell transplant (SCT), allogeneic SCT or chimeric antigen receptor (CAR) T-cell therapy within 60 days of randomization are key exclusion criteria. Progression-free survival (PFS) per Lugano criteria assessed by an independent review committee is the primary endpoint. Overall response rate, duration of response, investigator-assessed PFS per Lugano criteria, overall survival, event-free survival, time to treatment failure, time to next treatment, PFS2 (time from randomization to disease progression on next line of treatment or death from any cause), safety and tolerability, and pt reported outcomes are secondary endpoints. Clinical trial information: NCT04662255 .

5094 Background: In prior studies, basal vs. luminal differentiation portends differential response to a) androgen suppression (AS) duration for high-risk prostate cancer (PCa) (NRG-GU-TS006) and b) docetaxel chemotherapy (CT) and AS for metastatic hormone-sensitive disease (CHAARTED). In NRG-GU-TS006, basal tumors appeared to benefit the most from longer duration of AS while those with luminal subtype did not whereas, in CHAARTED, luminal subtype had greater benefit from addition of CT. Herein, we examined basal-luminal subtyping to predict differential response to the addition of CT in the setting of high-risk PCa treated with AS and definitive radiotherapy (AS + RT) in NRG/RTOG 0521. Methods: Per pre-specified and approved NCI analysis plan (Navigator #1061), we obtained available NRG biobank biopsy specimens from patients enrolled on the NRG/RTOG 0521 phase III trial, which randomized patients to AS + RT +/- CT. The highest-grade tumors were profiled on clinical-grade whole-transcriptome arrays (Veracyte, San Diego, CA). Basal-luminal subtypes were generated using a 215-gene PCa subtyping classifier (PSC), a second generation PAM50 basal-luminal model. Treatment effects in Luminal Proliferating (LP) and non-LP subtypes were examined with Cox (for overall survival, OS, and metastasis-free survival, MFS) and Fine & Gray (for distant metastasis, DM) multivariable (MVA) models adjusted for age and trial risk stratification, as well as with restricted mean survival times (RMST). Results: Of 183 samples available for analysis (91 from control and 92 from the CT arm), 52 (28%) were classified as LP subtype. Median follow-up for OS was 9.9 years. No significant differences in clinical or pathological variables were observed between LP and non-LP subtypes. In MVA, we did not detect any significant LP subtype-by-CT treatment interaction but observed evidence of non-proportional hazards (Grambsch-Therneau test, p<0.05). In unselected patients, 5- and 10-year RMST difference between the arms was 0.9 (95% CI [-1.5, 3.4], p=0.46) and 5.7 (95% CI [-2.5, 13.9], p=0.17) months of OS. Stratifying by tumor subtype, at 5 years the RMST difference in months was 3.8 (95% CI [0.3, 7.2], p=0.03) for LP and -0.2 ([-3.4, 2.9], p=0.89) for non-LP. The RMST difference in months at 10-years was 13.7 (95% CI [-0.2, 27.5], p=0.053) for LP and 2.5 ([-7.6, 12.5], p=0.63) for non-LP. Conclusions: In pre-treatment biopsy samples from a Phase 3 trial cohort of localized high-risk men, luminal-basal subtyping of tumors demonstrated differential response to docetaxel CT. Similar to results from the CHAARTED trial of metastatic disease, LP tumors may derive greater benefit from addition of CT. Validation of these findings may enable effective earlier use of CT in men with PCa.

Background Obstructive sleep apnea (OSA) is a common comorbidity in patients with heart failure, although current evidence is equivocal regarding the potential benefits of treating OSA with positive airway pressure (PAP) therapy in patients with heart failure. This study assessed the impact of adherence to PAP therapy on health care resource utilization in patients with OSA and heart failure with reduced ejection fraction. Methods and Results Administrative insurance claims data linked with objective PAP therapy use data from patients with OSA and heart failure with reduced ejection fraction were used to determine associations between PAP adherence and a composite outcome of hospitalizations and emergency room visits. One‐year PAP adherence was based on an adapted US Medicare definition. Propensity score methods were used to create groups with similar characteristics across PAP adherence levels. The study cohort included 3182 patients (69.9% male, mean age 59.7 years); 39% were considered adherent to PAP therapy (29% intermediate adherent, 31% nonadherent). One year after PAP initiation, adherent patients had fewer composite visits than matched nonadherent patients, driven by a 24% reduction in emergency room visits for adherent patients. Composite visit costs were lower in adherent versus nonadherent patients ($3500 versus $5879, P =0.031), although total health care costs were not statistically different ($13 028 versus $14 729, P =0.889). Conclusions PAP therapy adherence in patients with OSA with heart failure with reduced ejection fraction was associated with a reduction in health care resource utilization. This suggests that greater emphasis should be placed on diagnosing and effectively treating OSA with PAP in patients with heart failure with reduced ejection fraction.

Abstract Whether initiation of statins could increase survival free of dementia and disability in adults aged ≥75 years is unknown. PREVENTABLE, a double‐blind, placebo‐controlled randomized pragmatic clinical trial, will compare high‐intensity statin therapy (atorvastatin 40 mg) with placebo in 20,000 community‐dwelling adults aged ≥75 years without cardiovascular disease, disability, or dementia at baseline. Exclusion criteria include statin use in the prior year or for >5 years and inability to take a statin. Potential participants are identified using computable phenotypes derived from the electronic health record and local referrals from the community. Participants will undergo baseline cognitive testing, with physical testing and a blinded lipid panel if feasible. Cognitive testing and disability screening will be conducted annually. Multiple data sources will be queried for cardiovascular events, dementia, and disability; survival is site‐reported and supplemented by a National Death Index search. The primary outcome is survival free of new dementia or persisting disability. Co‐secondary outcomes are a composite of cardiovascular death, hospitalization for unstable angina or myocardial infarction, heart failure, stroke, or coronary revascularization; and a composite of mild cognitive impairment or dementia. Ancillary studies will offer mechanistic insights into the effects of statins on key outcomes. Biorepository samples are obtained and stored for future study. These results will inform the benefit of statins for increasing survival free of dementia and disability among older adults. This is a pioneering pragmatic study testing important questions with low participant burden to align with the needs of the growing population of older adults.