Citations

OBJECTIVE The Centers for Medicare & Medicaid Services (CMS) requires a low C-peptide level for insulin pump coverage unless the individual is β-cell autoantibody positive, which precludes coverage of automated insulin delivery (AID) systems for many people with type 2 diabetes. RESEARCH DESIGN AND METHODS In the Randomized Trial Evaluating the Efficacy and Safety of Control-IQ+ Technology in Adults With Type 2 Diabetes Using Basal-Bolus Insulin Therapy study evaluating the t:slim X2 insulin pump with Control-IQ+ technology, adults with insulin-treated type 2 diabetes were categorized into high C-peptide (n = 195) and low C-peptide (n = 59) groups based on CMS criteria. RESULTS In the AID group, mean HbA1c decreased from baseline by 0.8%, which was significantly greater than in the control group with both high (P < 0.001) and low (P = 0.02) C-peptide levels. Results were similar in participants ≥65 years old. CONCLUSIONS The benefit of AID is present with high and low C-peptide levels. Thus, requiring a low C-peptide level as a prerequisite for AID therapy is not warranted.

Abstract Rationale Inflammation is central to chronic obstructive pulmonary disease (COPD) pathogenesis but incompletely represented in COPD prognostic models. The neutrophil-to-lymphocyte ratio (NLR) is a readily available inflammatory biomarker. Objectives To explore the associations of NLR with smoking status, clinical features of COPD, and future adverse outcomes. Methods We analyzed NLR calculated from the complete blood count of participants who currently or formerly smoked (n = 2,624) and tobacco-naive control subjects (n = 187) in the SPIROMICS multicenter observational cohort study. We assessed the stability of NLR at 6 weeks and 1 year, the association with select blood biomarkers, and the impact of smoking on NLR and cell counts. We stratified participants by NLR quartiles to compare cross-sectional clinical features at enrollment, prospectively observed exacerbations at 1 year, and mortality during longitudinal follow up. Results Higher NLR quartiles were broadly associated with more severe clinical features of COPD. NLR values were repeatable at 6 weeks (intraclass correlation coefficient, 0.74) and 1 year (intraclass correlation coefficient, 0.62). The impact of smoking on NLR varied with the severity of airflow limitation, mediated by an interaction between smoking, forced expiratory volume in 1 second percent predicted, and neutrophil counts but not lymphocyte counts. The highest NLR quartile (>3.11) was associated with an increased risk of exacerbation over 1 year (adjusted odds ratio, 1.51; 95% confidence interval, 1.18, 1.92) and increased risk of mortality (adjusted hazard ratio, 1.41; 95% confidence interval, 1.20, 1.66) compared with quartiles 1–3. Conclusions Elevated NLR in stable COPD is a widely available biomarker associated with increased risk for exacerbation and death. The impact of cigarette smoking on NLR varies with disease severity.

Rationale Immunoglobulin A (IgA) deficiency, a rare, highly heritable trait, is associated with frequent pulmonary infections, emphysema, airway changes and low lung function; however, it is unclear if reduced IgA levels may affect lung structure and function. Methods Serum IgA, IgA1 and galactose-deficient IgA1 (Gd-IgA1) levels were measured in the population-based Multi-Ethnic Study on Atherosclerosis (MESA). The MESA Lung Study measured percent emphysema on cardiac CT and airway dimensions on chest CT, and performed spirometry. Regression models were evaluated after adjustment for demographic and CT factors. Mendelian randomisation (MR) analyses were conducted using genetic variants from the Trans-Omics for Precision Medicine (TOPMed) programme. A replication analysis was performed in the SubPopulations and InteRmediate Outcome Measures In COPD Study (SPIROMICS). Measurements and main results Among 5497 participants, lower log-normalised serum IgA levels were associated with greater percent emphysema (β=−0.084; 95% CI −0.14 to –0.026; p=0.005), which was confirmed on MR (β=−0.79; 95% CI −1.4 to –0.18; p=0.011). Greater log-normalised serum Gd-IgA1 levels were associated with airway wall thickness (β=0.0079; 95% CI 0.0017 to 0.014; p=0.012; n=2580) and decline in the forced expiratory volume in one second (FEV1) (β=−0.012; 95% CI −0.021 to –0.0036; p=0.0055; n=2778) and FEV1/forced vital capacity (FVC) ratio (β=−0.0028; 95% CI −0.0048 to –0.00084; p=0.0054; n=2778). Conclusion Lower serum IgA levels were associated with greater percent emphysema. Additionally, higher Gd-IgA1 levels were associated with airway wall thickness and lung function decline. These findings support a protective role of IgA in emphysema pathogenesis and possible deleterious role of Gd-IgA1 in airway diseases.

Background Percutaneous left atrial appendage occlusion (LAAO) is an alternative to long‐term anticoagulation for preventing ischemic stroke in patients with atrial fibrillation. There are limited long‐term outcomes data for “real‐world” patients undergoing LAAO. Methods We performed a retrospective cohort study using the National Cardiovascular Data Registry LAAO registry from January 1, 2016, through December 31, 2019. We linked LAAO data to inpatient Medicare fee‐for‐service claims data using probabilistic matching to establish a cohort of patients 65 years and older undergoing LAAO with a WATCHMAN device. The primary outcomes were any stroke and all‐cause mortality. Results A total of 34 975 patients with a mean±SD CHA 2 DS 2 ‐VASc (congestive heart failure, hypertension, age ≥75 years, diabetes, previous stroke or transient ischemic attack, vascular disease, age 65 to 74 years, and sex category) score of 4.7±1.4 were included. The median follow‐up was 2.8 years (interquartile range, 2.2–3.7 years). The cumulative incidence of any stroke was 1.57 per 100 person‐years (95% CI, 1.45–1.70), with a 1‐year and 5‐year any stroke estimate of 1.70% (95% CI, 1.57–1.84%) and 5.70% (95% CI, 5.37–6.05%), respectively. The cumulative incidence of ischemic stroke was 1.36 per 100 person‐years (95% CI, 1.25–1.48), with a 1‐year and 5‐year ischemic stroke estimate of 1.42% (95% CI, 1.30–1.54%) and 5.03% (95% CI, 4.71–5.36%), respectively. The cumulative incidence of death was 10.82 per 100 person‐years (95% CI, 10.49–11.13), with a 5‐year mortality estimate of 44.34% (95% CI, 43.35–45.23%). Conclusions Long‐term stroke rates in a large nationally representative cohort of Medicare patients following LAAO were low and durably consistent during long‐term follow‐up despite a high thromboembolic risk. High mortality rates in this elderly population underscore the importance of incorporating patient values and preferences when considering LAAO.

SummaryIn individuals with high‐count monoclonal B‐cell lymphocytosis (MBL), we investigated if lymphadenopathy or splenomegaly found by imaging was associated with shorter time to first chronic lymphocytic leukaemia (CLL) therapy (TTFT) and overall survival (OS). Individuals with MBL seen at Mayo Clinic (2002–2019) were retrospectively divided into three cohorts based on imaging studies within 1 year of diagnosis: no imaging studies (Cohort A); imaging with no evidence of lymphadenopathy/splenomegaly (Cohort B); imaging with evidence of lymphadenopathy/splenomegaly (Cohort C). We compared baseline characteristics, TTFT and OS across the MBL cohorts to a cohort of individuals with small lymphocytic lymphoma (SLL). A total of 1078 patients were included: 640 with MBL and 438 with SLL. Compared to Cohort B, individuals in Cohort C were more likely to have unmutated immunoglobulin heavy chain variable region (IGHV) (43% vs. 25% p = 0.016), high‐risk fluorescence in situ hybridization (FISH) (del17p and del11q in 15% vs. 4%, p = 0.038) and higher expression of CD38 (31% vs. 16%; p = 0.011). After adjusting for sex and CLL‐International Prognostic Index (IPI), lymphadenopathy/splenomegaly was associated with a shorter TTFT (hazard ratio [HR] = 2.04, 95% confidence interval [CI]: 1.02–4.04, p = 0.042) but not OS (HR = 1.09, 95% CI: 0.62–1.92, p = 0.775). Lymphadenopathy/splenomegaly on imaging in individuals with high‐count MBL is associated with a more unfavourable risk profile and shorter time to first CLL‐directed therapy.

Objectives: To evaluate the performance of noninvasive, elastic scattering spectroscopy, algorithm-powered device (DermaSensor) to detect melanoma and basal and squamous cell cancers in the primary care setting. Patients & Methods: DERM-SUCCESS, a blinded, prospective, multicenter pivotal study, enrolled adult patients between August 17, 2020, and December 9, 2021, with lesions that their primary care physicians (PCPs) suspected of skin cancer at clinics in the US (n = 18) and Australia (n = 4). These lesions were assessed by PCPs and scanned with the DermaSensor device. Biopsy specimens were collected, and histopathologic analysis was performed by dermatopathologists. The diagnostic performance of the device, dermatopathologist discordance, and subgroup analyses of clinical interest were calculated. Results: Of the 1579 skin lesions enrolled, dermatopathologic analysis identified 224 (14.2%) cancers. Device sensitivity was 95.5% (95% CI, 91.7%-97.6%) overall and 96.3% (92.9%-98.4%) for patients in the FDA-approved age group 40 years and older (90.2% for melanoma, 97.8% for basal cell carcinoma, and 97.7% for squamous cell carcinoma). Device specificity was 20.7%. The negative predictive value was 96.6%, and the positive predictive value was 16.6% (NNB 6). The device misclassified as “ monitor ” rather than “ investigate further ” 4 keratinocyte carcinomas and 4 melanomas in patients aged 40 years or older (n = 8, 0.5% of lesions, 3.7% of cancers biopsied). Conclusions: The DermaSensor device is an easy-to-use, point-of-care, hand-held skin cancer adjunctive diagnostic device with high sensitivity and NPV to help inform PCP decision-making about skin lesions suspicious for cancer that need further evaluation and those that may be monitored.

3011 Background: BMS-986504 selectively binds to the PRMT5-MTA complex, which represents a synthetic lethal target in MTAP -del cancer cells, while sparing MTAP– wild-type cells. In the first-in-human phase 1/2 CA240-0007 study in advanced, unresectable or metastatic solid tumors with homozygous MTAP -del, BMS-986504 was found to be well tolerated and demonstrated antitumor activity in multiple tumors. Here, we report clinical results and the first PK and PD analyses of BMS-986504 from the dose escalation and expansion phases of CA240-0007. Methods: Pts with measurable/evaluable disease and no available treatment (Tx) with curative intent were enrolled; 7 doses were evaluated (50 to 800 mg) in dose escalation. Objective response rate (ORR), disease control rate (DCR), duration of response (DOR), time to response (TTR), safety, PK, PD, including plasma SDMA were assessed. Results: As of 2 Dec 24, 152 heavily pretreated pts were enrolled across all doses: NSCLC (n = 34), PDAC (n = 41), cholangiocarcinoma (n = 12), and mesothelioma (n = 12) were the most common tumor types. With a median f/u of 9.0 mo (95% CI 7.6–9.9), continued durable antitumor activity and deepening tumor regression were seen across tumor types and doses (ORR = 23%, DCR = 70%, median DOR = 10.5 mo, TTR = 4.6 mo). No new safety signals were identified. Most Tx-related adverse events (TRAEs) were grade (Gr) 1 or 2; 13% had Gr ≥ 3 TRAEs (Gr 3 = 12%, Gr 4 = < 1%, Gr 5 = 0). Doses from 50 to 600 mg QD were assessed for PK/PD. The AUC (0-24) after multiple doses was approximately dose proportional at 200 to 600 mg, and the terminal t 1/2 after a single dose was approximately 24 h (table). There were dose-dependent reductions in predicted plasma SDMA, with the 400 and 600 mg doses approaching the plateau. Conclusions: With longer f/u, BMS-986504 continued to show increasingly durable antitumor activity. BMS-986504 demonstrated a favorable PK/PD profile, supporting QD dosing at 400 and 600 mg. These results support further investigation of BMS-986504 at 400 and 600 mg QD as a potential first-in-class synthetic lethal Tx option in pts with advanced solid tumors with MTAP -del. Clinical trial information: NCT05245500 . PK and PD. 50 mg QD 100 mg QD 200 mg QD 400 mg QD 600 mg QD PK after multiple doses t max a (min–max), h 2.0 (2.0–4.0)n = 3 2.0 (1.0–2.0)n = 3 2.0 (0.5–6.0)n = 8 2.0 (0.5–4.0)n = 10 2.0 (1.0–6.0)n = 10 C max , b ng/mL 107n = 3 377n = 3 685n = 8 1240n = 10 2110n = 10 AUC (0-24) , b h∙ng/mL 948 n = 3 3060 n = 3 7150 n = 7 11,800n = 10 26,700n = 9 AUC (0-24) , b,c h∙ng/mL/mg 19.0n = 3 30.6n = 3 35.8n = 7 29.5n = 10 44.6n = 9 Terminal t 1/2 after single dose, d h 21.7 n = 1 80.7 n = 1 21.5 n = 14 21.7 n = 14 24.1 n = 1 PD Translational exposure targets (C avgss ), X 0.08 0.21 0.5 1.1 1.7 Predicted plasma SDMA reduction, a % (90% PI) 30.0 (23.2–37.8) 38.8 (27.1–47.5) 48.3 (42.0–53.0) 55.0 (50.7–57.6) 57.4 (54.3–59.0) a Median. b Geometric mean. c Dose-normalized. d Arithmetic mean.