Dose-Blinded Myosin Inhibition in Patients With Obstructive Hypertrophic Cardiomyopathy Referred for Septal Reduction Therapy: Outcomes Through 32 Weeks.

BACKGROUND: Septal reduction therapy (SRT) in patients with intractable symptoms from obstructive hypertrophic cardiomyopathy (oHCM) is associated with variable morbidity and mortality. The VALOR-HCM trial (A Study to Evaluate Mavacamten in Adults with Symptomatic Obstructive Hypertrophic Cardiomyopathy Who Are Eligible for Septal Reduction Therapy) examined the effect of mavacamten on the need for SRT through week 32 in oHCM. METHODS: A double-blind randomized placebo-controlled multicenter trial at 19 US sites included patients with oHCM on maximal tolerated medical therapy referred for SRT with left ventricular outflow tract gradient ≥50 mm Hg at rest or provocation (enrollment, July 2020-October 2021). The group initially randomized to mavacamten continued the drug for 32 weeks, and the placebo group crossed over to dose-blinded mavacamten from week 16 to week 32. Dose titrations were based on investigator-blinded echocardiographic assessment of left ventricular outflow tract gradient and left ventricular ejection fraction. The principal end point was the proportion of patients proceeding with SRT or remaining guideline eligible at 32 weeks in both treatment groups. RESULTS: From the 112 randomized patients with oHCM, 108 (mean age, 60.3 years; 50% men; 94% in New York Heart Association class III/IV) qualified for week 32 evaluation (56 in the original mavacamten group and 52 in the placebo cross-over group). After 32 weeks, 6 of 56 patients (10.7%) in the original mavacamten group and 7 of 52 patients (13.5%) in the placebo cross-over group met SRT guideline criteria or elected to undergo SRT. After 32 weeks, a sustained reduction in resting left ventricular outflow tract gradient (-33.0 mm Hg [95% CI, -41.1 to -24.9]) and Valsalva left ventricular outflow tract gradient (-43.0 mm Hg [95% CI, -52.1 to -33.9]) was observed in the original mavacamten group. A similar reduction in resting (-33.7 mm Hg [95% CI, -42.2 to -25.2]) and Valsalva (-52.9 mm Hg [95% CI, -63.2 to -42.6]) gradients was quantified in the cross-over group after 16 weeks of mavacamten. After 32 weeks, improvement by ≥1 New York Heart Association class was observed in 48 of 53 patients (90.6%) in the original mavacamten group and 35 of 50 patients (70%) after 16 weeks in the cross-over group. CONCLUSIONS: In severely symptomatic patients with oHCM, 32 weeks of mavacamten treatment showed sustained reduction in the proportion proceeding to SRT or remaining guideline eligible, with similar effects observed in patients who crossed over from placebo after 16 weeks. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT04349072.

Plasma-based longitudinal mutation monitoring as a potential predictor of disease progression in subjects with adenocarcinoma in advanced non-small cell lung cancer.

BACKGROUND: Identifying and tracking somatic mutations in cell-free DNA (cfDNA) by next-generation sequencing (NGS) has the potential to transform the clinical management of subjects with advanced non-small cell lung cancer (NSCLC). METHODS: Baseline tumor tissue (n = 47) and longitudinal plasma (n = 445) were collected from 71 NSCLC subjects treated with chemotherapy. cfDNA was enriched using a targeted-capture NGS kit containing 197 genes. Clinical responses to treatment were determined using RECIST v1.1 and correlations between changes in plasma somatic variant allele frequencies and disease progression were assessed. RESULTS: Somatic variants were detected in 89.4% (42/47) of tissue and 91.5% (407/445) of plasma samples. The most commonly mutated genes in tissue were TP53 (42.6%), KRAS (25.5%), and KEAP1 (19.1%). In some subjects, the allele frequencies of mutations detected in plasma increased 3-5 months prior to disease progression. In other cases, the allele frequencies of detected mutations declined or decreased to undetectable levels, indicating clinical response. Subjects with circulating tumor DNA (ctDNA) levels above background had significantly shorter progression-free survival (median: 5.6 vs 8.9 months, respectively; log-rank p = 0.0183). CONCLUSION: Longitudinal monitoring of mutational changes in plasma has the potential to predict disease progression early. The presence of ctDNA mutations during first-line treatment is a risk factor for earlier disease progression in advanced NSCLC.

MYC/BCL2 protein coexpression contributes to the inferior survival of activated B-cell subtype of diffuse large B-cell lymphoma and demonstrates high-risk gene expression signatures: a report from The International DLBCL Rituximab-CHOP Consortium Program.

Diffuse large B-cell lymphoma (DLBCL) is stratified into prognostically favorable germinal center B-cell (GCB)-like and unfavorable activated B-cell (ABC)-like subtypes based on gene expression signatures. In this study, we analyzed 893 de novo DLBCL patients treated with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone). We show that MYC/BCL2 protein coexpression occurred significantly more commonly in the ABC subtype. Patients with the ABC or GCB subtype of DLBCL had similar prognoses with MYC/BCL2 coexpression and without MYC/BCL2 coexpression. Consistent with the notion that the prognostic difference between the 2 subtypes is attributable to MYC/BCL2 coexpression, there is no difference in gene expression signatures between the 2 subtypes in the absence of MYC/BCL2 coexpression. DLBCL with MYC/BCL2 coexpression demonstrated a signature of marked downregulation of genes encoding extracellular matrix proteins, those involving matrix deposition/remodeling and cell adhesion, and upregulation of proliferation-associated genes. We conclude that MYC/BCL2 coexpression in DLBCL is associated with an aggressive clinical course, is more common in the ABC subtype, and contributes to the overall inferior prognosis of patients with ABC-DLBCL. In conclusion, the data suggest that MYC/BCL2 coexpression, rather than cell-of-origin classification, is a better predictor of prognosis in patients with DLBCL treated with R-CHOP.

CD30 expression defines a novel subgroup of diffuse large B-cell lymphoma with favorable prognosis and distinct gene expression signature: a report from the International DLBCL Rituximab-CHOP Consortium Program Study.

CD30, originally identified as a cell-surface marker of Reed-Sternberg and Hodgkin cells of classical Hodgkin lymphoma, is also expressed by several types of non-Hodgkin lymphoma, including a subset of diffuse large B-cell lymphoma (DLBCL). However, the prognostic and biological importance of CD30 expression in DLBCL is unknown. Here we report that CD30 expression is a favorable prognostic factor in a cohort of 903 de novo DLBCL patients. CD30 was expressed in ∼14% of DLBCL patients. Patients with CD30(+) DLBCL had superior 5-year overall survival (CD30(+), 79% vs CD30(-), 59%; P = .001) and progression-free survival (P = .003). The favorable outcome of CD30 expression was maintained in both the germinal center B-cell and activated B-cell subtypes. Gene expression profiling revealed the upregulation of genes encoding negative regulators of nuclear factor κB activation and lymphocyte survival, and downregulation of genes encoding B-cell receptor signaling and proliferation, as well as prominent cytokine and stromal signatures in CD30(+) DLBCL patients, suggesting a distinct molecular basis for its favorable outcome. Given the superior prognostic value, unique gene expression signature, and significant value of CD30 as a therapeutic target for brentuximab vedotin in ongoing successful clinical trials, it seems appropriate to consider CD30(+) DLBCL as a distinct subgroup of DLBCL.

Patient-Level Artificial Intelligence-Enhanced Electrocardiography in Hypertrophic Cardiomyopathy: Longitudinal Treatment and Clinical Biomarker Correlations.

BACKGROUND: Artificial intelligence (AI) applied to 12-lead electrocardiographs (ECGs) can detect hypertrophic cardiomyopathy (HCM). OBJECTIVES: The purpose of this study was to determine if AI-enhanced ECG (AI-ECG) can track longitudinal therapeutic response and changes in cardiac structure, function, or hemodynamics in obstructive HCM during mavacamten treatment. METHODS: We applied 2 independently developed AI-ECG algorithms (University of California-San Francisco and Mayo Clinic) to serial ECGs (n = 216) from the phase 2 PIONEER-OLE trial of mavacamten for symptomatic obstructive HCM (n = 13 patients, mean age 57.8 years, 69.2% male). Control ECGs from 2,600 age- and sex-matched individuals without HCM were obtained. AI-ECG output was correlated longitudinally to echocardiographic and laboratory metrics of mavacamten treatment response. RESULTS: In the validation cohorts, both algorithms exhibited similar performance for HCM diagnosis, and exhibited mean HCM score decreases during mavacamten treatment: patient-level score reduction ranged from approximately 0.80 to 0.45 for Mayo and 0.70 to 0.35 for USCF algorithms; 11 of 13 patients demonstrated absolute score reduction from start to end of follow-up for both algorithms. HCM scores were significantly associated with other HCM-relevant parameters, including left ventricular outflow tract gradient at rest, postexercise, and with Valsalva, and NT-proBNP level, independent of age and sex (all P < 0.01). For both algorithms, the strongest longitudinal correlation was between AI-ECG HCM score and left ventricular outflow tract gradient postexercise (slope estimate: University of California-San Francisco 0.70 [95% CI: 0.45-0.96], P < 0.0001; Mayo 0.40 [95% CI: 0.11-0.68], P = 0.007). CONCLUSIONS: AI-ECG analysis longitudinally correlated with changes in echocardiographic and laboratory markers during mavacamten treatment in obstructive HCM. These results provide early evidence for a potential paradigm for monitoring HCM therapeutic response.

Early Assessment of Chemotherapy Response in Advanced Non-Small Cell Lung Cancer with Circulating Tumor DNA.

Monitoring treatment efficacy early during therapy could enable a change in treatment to improve patient outcomes. We report an early assessment of response to treatment in advanced NSCLC using a plasma-only strategy to measure changes in ctDNA levels after one cycle of chemotherapy. Plasma samples were collected from 92 patients with Stage IIIB-IV NSCLC treated with first-line chemo- or chemoradiation therapies in an observational, prospective study. Retrospective ctDNA analysis was performed using next-generation sequencing with a targeted 198-kb panel designed for lung cancer surveillance and monitoring. We assessed whether changes in ctDNA levels after one or two cycles of treatment were associated with clinical outcomes. Subjects with ≤50% decrease in ctDNA level after one cycle of chemotherapy had a lower 6-month progression-free survival rate (33% vs. 58%, HR 2.3, 95% CI 1.2 to 4.2, log-rank p = 0.009) and a lower 12-month overall survival rate (25% vs. 70%, HR 4.3, 95% CI 2.2 to 9.7, log-rank p < 0.001). Subjects with ≤50% decrease in ctDNA level after two cycles of chemotherapy also had shorter survival. Using non-invasive liquid biopsies to measure early changes in ctDNA levels in response to chemotherapy may help identify non-responders before standard-of-care imaging in advanced NSCLC.

Concordance of Genomic Alterations by Next-Generation Sequencing in Tumor Tissue versus Cell-Free DNA in Stage I-IV Non-Small Cell Lung Cancer.

Molecular biomarkers hold promise for personalization of cancer treatment. However, a typical tumor biopsy may be difficult to acquire and may not capture genetic variations within or across tumors. Given these limitations, tumor genotyping using next-generation sequencing of plasma-derived circulating tumor (ct)-DNA has the potential to transform non-small cell lung cancer (NSCLC) management. Importantly, mutations detected in biopsied tissue must also be detected in plasma-derived ctDNA at different disease stages. Using the AVENIO ctDNA Surveillance kit (research use only), mutations in ctDNA from NSCLC subjects were compared with those identified in matched tumor tissue samples, retrospectively. Plasma and tissue samples were collected from 141 treatment-naïve NSCLC subjects (stage I, n = 48; stage II, n = 37; stage III, n = 33; stage IV, n = 23). In plasma samples, the median numbers of variants per subject were 4, 6, 8, and 9 in those with stage I, II, III, and IV disease, respectively. The corresponding values in tissue samples were 5, 5, 6, and 4. The overall tissue-plasma concordance of stage II through IV was 62.2% by AVENIO software call. On multivariate analysis, concordance was positively and significantly associated with tumor size and cancer stage. Next-generation sequencing-based analyses with the AVENIO ctDNA Surveillance kit could be an alternative approach to detecting genetic variations in plasma-derived ctDNA isolated from NSCLC subjects.

Appropriateness of cholesterol management in primary care by sex and level of cardiovascular risk.

A study was undertaken to ascertain the appropriateness of lipid screening and management per the Third Report of the Adult Treatment Panel National Cholesterol Education Program (ATP III) guideline in a sample of North Carolina primary care practices. Demographics, cholesterol values, and comorbid conditions were abstracted from the medical records from 60 community practices participating in a randomized practice-based trial (Guideline Adherence for Heart Health). Eligible patients were aged 21 to 84 years, seen during the baseline period of June 1, 2001, through May 31, 2003, and who were not taking lipid-lowering therapy. Multivariable logistic regression was utilized to assess whether age, sex, race/ethnicity, diabetes, cardiovascular disease, ATP III risk category, or pretreatment low-density lipoprotein (LDL) influenced treatment. Among 5031 eligible patients, 1711 (34.5%) received screening lipid profiles. Screening rates were higher with older age, diabetes, and cardiovascular disease. No large differences were seen by sex. Among patients screened (mean age, 51.6 years; 57.9% female), 76.6% were appropriately managed within 4 months. In adjusted analyses, older age was associated with less appropriate treatment (odds ratio [OR] per 5 years, 0.91; P=.01), and patients with LDL cholesterol or=190 mg/dL and those at high risk. Among 375 patients eligible for drug treatment, those with LDL levels between 131 and 159 mg/dL were much less likely to be treated (OR, 0.15; P<.001) compared with those with LDL >190 mg/dL, whereas risk category did not influence treatment. The challenge facing implementation of ATP III guidelines is much greater for intermediate- and high-risk patients than for low-risk patients.

Associations of adiponectin with body fat distribution and insulin sensitivity in nondiabetic Hispanics and African-Americans.

CONTEXT: Hypoadiponectinemia has emerged as an independent risk factor for type 2 diabetes and cardiovascular disease. Although associations of adiponectin with central obesity and insulin resistance have been reported, very little data are available from studies using detailed measures of insulin sensitivity (S(I)) and/or body fat distribution in ethnic groups at high risk for metabolic disease. OBJECTIVE: The aim of the study was to identify the correlates of adiponectin in 1636 nondiabetic Hispanics and African-Americans. DESIGN: A cross-sectional analysis of participants in the Insulin Resistance Atherosclerosis Family Study was conducted. S(I) was determined from frequently sampled iv glucose tolerance tests with minimal model analysis. Subcutaneous and visceral adipose tissues (SAT, VAT, respectively) were determined with computed tomography. Triglyceride, high-density lipoprotein, C-reactive protein, and adiponectin were measured in fasting samples. Generalized estimating equation (GEE) models were used to identify factors associated with adiponectin concentration. SETTING: A multicenter study using a family-based design was conducted. PARTICIPANTS: A total of 1636 nondiabetic Hispanic and African-American subjects participated. MAIN OUTCOME MEASURES: Circulating adiponectin concentration was measured. RESULTS: Age, female gender, high-density lipoprotein, SAT, and S(I) were positive independent correlates of adiponectin, whereas glucose, CRP, and VAT were negative independent correlates (all P < 0.05). Ethnicity was not an independent correlate of adiponectin in this model (P = 0.27); however, an ethnicity by VAT interaction term was retained, indicating a stronger negative association of VAT with adiponectin in African-Americans compared with Hispanics. CONCLUSION: Directly measured S(I), VAT, and SAT were independently correlated with adiponectin in Hispanic and African-American subjects. The inverse association of VAT with adiponectin was stronger in African-Americans compared with Hispanics, a finding that suggests possible ethnic differences in the effects of visceral obesity.

Value of recruitment strategies used in a primary care practice-based trial.

PURPOSE: "Physicians-recruiting-physicians" is the preferred recruitment approach for practice-based research. However, yields are variable; and the approach can be costly and lead to biased, unrepresentative samples. We sought to explore the potential efficiency of alternative methods. METHODS: We conducted a retrospective analysis of the yield and cost of 10 recruitment strategies used to recruit primary care practices to a randomized trial to improve cardiovascular disease risk factor management. We measured response and recruitment yields and the resources used to estimate the value of each strategy. Providers at recruited practices were surveyed about motivation for participation. RESULTS: Response to 6 opt-in marketing strategies was 0.40% (53/13290), ranging from 0% to 2.86% by strategy; 33.96% (18/53) of responders were recruited to the study. Of those recruited from opt-out strategies, 8.68% joined the study, ranging from 5.35% to 41.67% per strategy. A strategy that combined both opt-in and opt-out approaches resulted in a 51.14% (90/176) response and a 10.80% (19/90) recruitment rate. Cost of recruitment was $613 per recruited practice. Recruitment approaches based on in-person meetings (41.67%), previous relationships (33.33%), and borrowing an Area Health Education Center's established networks (10.80%), yielded the most recruited practices per effort and were most cost efficient. Individual providers who chose to participate were motivated by interest in improving their clinical practice (80.5%); contributing to CVD primary prevention (54.4%); and invigorating their practice with new ideas (42.1%). CONCLUSIONS: This analysis provides suggestions for future recruitment efforts and research. Translational studies with limited funds could consider multi-modal recruitment approaches including in-person presentations to practice groups and exploitation of previous relationships, which require the providers to opt-out, and interactive opt-in approaches which rely on borrowed networks. These approaches can be supplemented with non-relationship-based opt-out strategies such as cold calls strategically targeted to underrepresented provider groups.

Quality of cholesterol screening and management with respect to the National Cholesterol Education's Third Adult Treatment Panel (ATPIII) guideline in primary care practices in North Carolina.

BACKGROUND: Adherence to previous national cholesterol guidelines has been low. We assessed whether lipid screening and management was consistent with the National Cholesterol Education's ATPIII in a sample of primary care practices participating in a quality improvement study. METHODS: Demographic and clinical data were abstracted from charts of 5071 patients aged 21 to 84 years, which were seen between June 1, 2001, and May 31, 2003, at 60 practices. Clinical sites were non-university-based primary care practices from 22 North Carolina counties. A dyslipidemia screening test was defined as a lipid profile performed on persons when not on a lipid-lowering drug. Among patients receiving a lipid profile, the proportion of patients appropriately treated, per ATPIII, was calculated. Practice level variation in screening and management was examined using the 50th (20th and 80th) percentile values across practices. RESULTS: The median practice level dyslipidemia screening rate during the 2 years was 40.1% (25.8%, 53.7%) of their age-eligible patients. The appropriate decision regarding lipid-lowering therapy was documented within 4 months of the lipid profile for 79.3% (69.0%, 86.0%) of practices' patients. Within 4 months, among the drug-ineligible patients, 100% (94%, 100%) were not prescribed drugs; 33.3% (6.3%, 50.0%) of the drug-eligible patients were prescribed lipid-lowering agents. CONCLUSIONS: The median dyslipidemia screening rate met the recommendations. There remains a need to improve the management of dyslipidemia; in particular, there was a significant underprescription of lipid-lowering drugs.

Geographic and racial/ethnic differences in HFE mutation frequencies in the Hemochromatosis and Iron Overload Screening (HEIRS) Study.

OBJECTIVE: To assess geographic differences in the frequencies of HFE C282Y and H63D genotypes in six racial/ethnic groups recruited in the Hemochromatosis and Iron Overload Screening (HEIRS) Study. DESIGN: HFE C282Y and H63D genotypes of 97,551 participants, ages > or = 25 years, who reported that they belonged to one of six racial/ethnic groups, were analyzed. HFE genotype frequencies were compared among the racial/ethnic groups and among the HEIRS Study field centers within each racial/ethnic group. RESULTS: The distribution of HFE C282Y and H63D genotypes differed among racial/ethnic groups (P<.0001) and among field centers in Hispanics, Asians, Whites, and Blacks (each P<.05). Genotype frequencies were similar among field centers in Native Americans and Pacific Islanders. Frequencies of C282Y and H63D genotypes were greatest in Whites. The lowest frequencies of C282Y genotypes were observed in Asians; Blacks had the lowest H63D genotype frequencies and the highest frequency of the wild-type genotype. Among racial/ethnic groups, Hispanics had the greatest variation in HFE genotypes across geographic regions. CONCLUSION: HFE C282Y and H63D genotype frequencies vary significantly between racial/ethnic groups and within some racial/ethnic groups across geographic regions.

Adherence to behavioral interventions for urge incontinence when combined with drug therapy: adherence rates, barriers, and predictors.

BACKGROUND: Behavioral intervention outcomes for urinary incontinence (UI) depend on active patient participation. OBJECTIVE: The purpose of this study was to describe adherence to behavioral interventions (pelvic-floor muscle [PFM] exercises, UI prevention strategies, and delayed voiding), patient-perceived exercise barriers, and predictors of exercise adherence in women with urge-predominant UI. DESIGN: This was a prospectively planned secondary data analysis from a 2-stage, multicenter, randomized clinical trial. PATIENTS AND INTERVENTION: Three hundred seven women with urge-predominant UI were randomly assigned to receive either 10 weeks of drug therapy only or 10 weeks of drug therapy combined with a behavioral intervention for UI. One hundred fifty-four participants who received the combined intervention were included in this analysis. MEASUREMENTS: Pelvic-floor muscle exercise adherence and exercise barriers were assessed during the intervention phase and 1 year afterward. Adherence to UI prevention strategies and delayed voiding were assessed during the intervention only. RESULTS: During intervention, 81% of women exercised at least 5 to 6 days per week, and 87% performed at least 30 PFM contractions per day. Ninety-two percent of the women used the urge suppression strategy successfully. At the 12-month follow-up, only 32% of the women exercised at least 5 to 6 days per week, and 56% performed 15 or more PFM contractions on the days they exercised. The most persistent PFM exercise barriers were difficulty remembering to exercise and finding time to exercise. Similarly, difficulty finding time to exercise persisted as a predictor of PFM exercise adherence over time. LIMITATIONS: Co-administration of medication for UI may have influenced adherence. CONCLUSIONS: Most women adhered to exercise during supervised intervention; however, adherence declined over the long term. Interventions to help women remember to exercise and to integrate PFM exercises and UI prevention strategies into daily life may be useful to promote long-term adherence.