A Pilot Study Comparing the Efficacy of Lactate Dehydrogenase Levels Versus Circulating Cell-Free microRNAs in Monitoring Responses to Checkpoint Inhibitor Immunotherapy in Metastatic Melanoma Patients.

Serum lactate dehydrogenase (LDH) is a standard prognostic biomarker for stage IV melanoma patients. Often, LDH levels do not provide real-time information about the metastatic melanoma patients\u27 disease status and treatment response. Therefore, there is a need to find reliable blood biomarkers for improved monitoring of metastatic melanoma patients who are undergoing checkpoint inhibitor immunotherapy (CII). The objective in this prospective pilot study was to discover circulating cell-free microRNA (cfmiR) signatures in the plasma that could assess melanoma patients\u27 responses during CII. The cfmiRs were evaluated by the next-generation sequencing (NGS) HTG EdgeSeq microRNA (miR) Whole Transcriptome Assay (WTA; 2083 miRs) in 158 plasma samples obtained before and during the course of CII from 47 AJCC stage III/IV melanoma patients\u27 and 73 normal donors\u27 plasma samples. Initially, cfmiR profiles for pre- and post-treatment plasma samples of stage IV non-responder melanoma patients were compared to normal donors\u27 plasma samples. Using machine learning, we identified a 9 cfmiR signature that was associated with stage IV melanoma patients being non-responsive to CII. These cfmiRs were compared in pre- and post-treatment plasma samples from stage IV melanoma patients that showed good responses. Circulating miR-4649-3p, miR-615-3p, and miR-1234-3p demonstrated potential prognostic utility in assessing CII responses. Compared to LDH levels during CII, circulating miR-615-3p levels were consistently more efficient in detecting melanoma patients undergoing CII who developed progressive disease. By combining stage III/IV patients, 92 and 17 differentially expressed cfmiRs were identified in pre-treatment plasma samples from responder and non-responder patients, respectively. In conclusion, this pilot study demonstrated cfmiRs that identified treatment responses and could allow for real-time monitoring of patients receiving CII

SUPPORT-AF: Piloting a Multi-Faceted, Electronic Medical Record-Based Intervention to Improve Prescription of Anticoagulation

Background: Only 50% of eligible atrial fibrillation ( AF ) patients receive anticoagulation ( AC ). Feasibility and effectiveness of electronic medical record (EMR)-based interventions to profile and raise provider AC percentage is poorly understood. The SUPPORT-AF (Supporting Use of AC Through Provider Profiling of Oral AC Therapy for AF) study aims to improve rates of adherence to AC guidelines by developing and delivering supportive tools based on the EMR to providers treating patients with AF. Methods and Results: We emailed cardiologists and community-based primary care providers affiliated with our institution reports of their AC percentage relative to peers. We also sent an electronic medical record-based message to these providers the day before an appointment with an atrial fibrillation patient who was eligible but not receiving AC . The electronic medical record message asked the provider to discuss AC with the patient if he or she deemed it appropriate. To assess feasibility, we tracked provider review of our correspondence. We also tracked the change in AC for intervention providers relative to alternate primary care providers not receiving our intervention. We identified 3786, 1054, and 566 patients cared for by 49 cardiology providers, 90 community-based primary care providers, and 88 control providers, respectively. At baseline, the percentage of AC was 71.3%, 63.5%, and 58.3% for these 3 respective groups. Intervention providers reviewed our e-mails and electronic medical record messages 45% and 96% of the time, respectively. For providers responding, patient refusal was the most common reason for patients not being on AC (21%) followed by high bleeding risk (19%). At follow-up 10 weeks later, change in AC was no different for either cardiology or community-based primary care providers relative to controls (0.2% lower and 0.01% higher, respectively). Conclusions: Our intervention profiling AC was feasible, but not sufficient to increase AC in our population

Integrated Assessment of Circulating Cell-Free MicroRNA Signatures in Plasma of Patients with Melanoma Brain Metastasis.

Primary cutaneous melanoma frequently metastasizes to distant organs including the brain. Identification of cell-free microRNAs (cfmiRs) found in the blood can be used as potential body fluid biomarkers for detecting and monitoring patients with melanoma brain metastasis (MBM). In this pilot study, we initially aimed to identify cfmiRs in the blood of MBM patients. Normal donors plasma (healthy, n = 48) and pre-operative MBM patients\u27 plasma samples (n = 36) were compared for differences in \u3e2000 microRNAs (miRs) using a next generation sequencing (NGS) probe-based assay. A 74 cfmiR signature was identified in an initial cohort of MBM plasma samples and then verified in a second cohort of MBM plasma samples (n = 24). Of these, only 58 cfmiRs were also detected in MBM tissues (n = 24). CfmiR signatures were also found in patients who have lung and breast cancer brain metastasis (n = 13) and glioblastomas (n = 36) compared to MBM plasma samples. The 74 cfmiR signature and the latter cfmiR signatures were then compared. We found a 6 cfmiR signature that was commonly upregulated in MBM plasma samples in all of the comparisons, and a 29 cfmiR signature that distinguishes MBM patients from normal donors\u27 samples. In addition, we assessed for cfmiRs in plasma (n = 20) and urine (n = 14) samples collected from metastatic melanoma patients receiving checkpoint inhibitor immunotherapy (CII). Pre- and post-treatment samples showed consistent changes in cfmiRs. Analysis of pre- and post-treatment plasma samples showed 8 differentially expressed (DE) cfmiRs that overlapped with the 35 cfmiR signature found in MBM patients. In paired pre-treatment plasma and urine samples receiving CII 8 cfmiRs overlapped. This study identified specific cfmiRs in MBM plasma samples that may potentially allow for assessment of melanoma patients developing MBM. The cfmiR signatures identified in both blood and urine may have potential utility to assess CII responses after further validation

Relation of Atrial Fibrillation in Acute Myocardial Infarction to In-Hospital Complications and Early Hospital Readmission

Atrial fibrillation (AF) is a common complication of acute myocardial infarction (AMI) and contributes to high rates of in-hospital adverse events. However, there are few contemporary studies examining rates of AF in the contemporary era of AMI or the impact of new-onset AF on key in-hospital and postdischarge outcomes. We examined trends in AF in 6,384 residents of Worcester, Massachusetts, who were hospitalized with confirmed AMI during 7 biennial periods between 1999 and 2011. Multivariate logistic regression analysis was used to examine associations between occurrence of AF and various in-hospital and postdischarge complications. The overall incidence of AF complicating AMI was 10.8%. Rates of new-onset AF increased from 1999 to 2003 (9.8% to 13.2%), and decreased thereafter. In multivariable adjusted models, patients developing new-onset AF after AMI were at a higher risk for in-hospital stroke (odds ratio [OR] 2.5, 95% confidence interval [CI] 1.6 to 4.1), heart failure (OR 2.0, 95% CI 1.7 to 2.4), cardiogenic shock (OR 3.7, 95% CI 2.8 to 4.9), and death (OR 2.3, 95% CI 1.9 to 3.0) than patients without AF. Development of AF during hospitalization for AMI was associated with higher rates of readmission within 30 days after discharge (21.7% vs 16.0%), but no significant difference was noted in early postdischarge 30-day all-cause mortality rates (8.3% vs 5.1%). In conclusion, new-onset AF after AMI is strongly related to in-hospital complications of AMI and higher short-term readmission rates

Cardiac and Obstetric Outcomes Associated With Mitral Valve Prolapse

Mitral valve prolapse (MVP) is the most common valvular heart disease in women of reproductive age. Whether MVP increases the likelihood of adverse outcomes in pregnancy is unknown. The study objective was to examine the cardiac and obstetric outcomes associated with MVP in pregnant women. This retrospective cohort study, using the Healthcare Cost and Utilization Project National Readmission Sample database between 2010 and 2017, identified all pregnant women with MVP using the International Classification of Disease, Ninth and Tenth Revisions codes. The maternal cardiac and obstetric outcomes in pregnant women diagnosed with MVP were compared with women without MVP using multivariable logistic and Cox proportional hazard regression models adjusted for baseline demographic characteristics. There were 23,000 pregnancy admissions with MVP with an overall incidence of 16.9 cases per 10,000 pregnancy admissions. Pregnant women with MVP were more likely to die during pregnancy (adjusted hazard ratio 5.13, 95% confidence interval [CI] 1.09 to 24.16), develop cardiac arrest (adjusted odds ratio [aOR] 4.44, 95% CI 1.04 to 18.89), arrhythmia (aOR 10.96, 95% CI 9.17 to 13.12), stroke (aOR 6.90, 95% CI 1.26 to 37.58), heart failure (aOR 5.81, 95% CI 3.84 to 8.79), or suffer a coronary artery dissection (aOR 25.22, 95% CI 3.42 to 186.07) compared with women without MVP. Pregnancies with MVP were also associated with increased risks of preterm delivery (aOR 1.21, 95% CI 1.02 to 1.44) and preeclampsia/hemolysis, elevated liver enzymes, and low platelets syndrome (aOR 1.22, 95% CI 1.05 to 1.41). In conclusion, MVP in pregnancy is associated with adverse maternal cardiac outcomes and higher obstetric risks

Prospective Molecular Profiling of Circulating Tumor Cells from Patients with Melanoma Receiving Combinatorial Immunotherapy.

BACKGROUND: Blood molecular profiling of circulating tumor cells (CTCs) can enable monitoring of patients with metastatic melanoma during checkpoint inhibitor immunotherapy (CII) and in combination with targeted therapies. We developed a microfluidics-based CTC platform to explore CTC profiling utility in CII-treated patients with melanoma using a melanoma messenger RNA (mRNA)/DNA biomarker panel. METHODS: Blood samples (n = 213) were collected prospectively from 75 American Joint Committee on Cancer-staged III/IV melanoma patients during CII treatment and those enriched for CTCs. CTC profiling was performed using 5 known melanoma mRNA biomarkers and BRAF V600E DNA mutation. CTC biomarker status associations with clinical outcomes were assessed. RESULTS: CTCs were detected in 88% of blood samples from patients with melanoma. CTC-derived biomarkers and clinical variables analyzed using classification and regression tree analysis revealed that a combination of lactate dehydrogenase, CTC-mRNA biomarkers, and tumor BRAF-mutation status was indicative of clinical outcomes for patients with stage IV melanoma (n = 52). The panel stratified low-risk and high-risk patients, whereby the latter had poor disease-free ( CONCLUSIONS: CTC-derived mRNA/DNA biomarkers have utility for monitoring CII, targeted, and combinatorial therapies in metastatic melanoma patients