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Mimicking Complex Receptor Actions with Small(ish) Molecules

As a therapeutic area, type 2 diabetes includes a wide range of treatment options in several mechanistic classes (although metformin has multiple classifications). One of the best therapies, however, is and has always been weight loss through diet and exercise. On the face of it, a weight-loss strategy involving diet…

Gene Expression Profiling and Melanoma Sentinel Node Status

In this issue of JAMA Surgery, Hieken et al present the first blinded, prospective trial analyzing gene expression profiling (GEP) in patients with melanoma undergoing sentinel lymph node biopsy (SLNB). The authors introduce the Merlin assay and hypothesize it can identify who can safely forgo SLNB, with a long-term objective of determining the test’s prognostic significance for patients with node-negative disease. Results focus on the former objective. The assay combines GEP with patient age and tumor depth (clinicopathological factors plus GEP, or CP-GEP) to classify a “low” or “high” risk of SLNB metastases in 1761 patients. This study had strict eligibility criteria, resulting in overall SLNB positivity of 17% and low-risk-score SLNB positivity of 7.1%. While it came very close, the low risk score did not reach the National Comprehensive Cancer Network arbitrary benchmark, which indicates SLNB can be excluded if the risk of SLN metastasis is less than 5%.

Next-Generation Sequencing in Cutaneous T-Cell Lymphoma

Early cutaneous T-cell lymphoma (CTCL) remains challenging to diagnose, as it clinically and histologically may mimic inflammatory conditions such as eczematous dermatitis, pityriasis lichenoides, or psoriasis. The consequence is delay in time from symptom onset to diagnosis, which commonly spans years (median, 36 months; interquartile range, 12-90 months). Definitive diagnosis continues to hinge on careful clinicopathologic correlation, which is sometimes supported by detection of a clonal T-cell population in skin and/or blood. Yet, the polymerase chain reaction (PCR)–based T-cell receptor (TCR) γ and β gene rearrangement assays most widely available in practice have limited sensitivity and can yield false-negative results; conversely, clonal T-cell populations are not pathognomonic and may be detected in inflammatory conditions. However, detecting clonal T-cell populations is not only important in establishing diagnosis of CTCL, but also, the overall clonal burden or tumor clone frequency (TCF) is associated with prognosis. In patients with a TCF greater than 25%, there is a reduction in progression-free survival and overall survival. Against this backdrop, technologies that provide more sensitive and granular assessment of TCR repertoires are particularly salient, as they promise to refine diagnosis, quantify clonal burden, and potentially inform prognosis and management.

Defibrillators in Private Homes

Defibrillation is a highly effective treatment for ventricular fibrillation and pulseless ventricular tachycardia when delivered promptly after the onset of cardiac arrest. As time in cardiac arrest progresses, shockable rhythms degenerate to nonshockable rhythms, global organ damage worsens, and the likelihood of successful resuscitation and neurological recovery diminishes. Reducing the time to defibrillation is therefore crucial to survival and good recovery. A key strategy to reducing time to defibrillation is harnessing the community response to deliver bystander-initiated defibrillation using an automated external defibrillator (AED). Public access defibrillator programs, where AEDs are placed in public places, have been highly effective. However, only 20% of out-of-hospital cardiac arrests occur in a public place. The majority occur in the home, where access to AEDs is limited. Strategies to enable timely community defibrillation in the home setting, such as provision of AEDs in private homes, have the potential to extend the benefits of early defibrillation and save thousands more lives.

Shot Through the Heart—Can RSV Vaccination Reduce Risk of Cardiovascular Outcomes?

Respiratory syncytial virus (RSV) causes severe disease in older adults at rates similar to seasonal influenza, particularly among those with chronic heart and lung disease, including congestive heart failure, chronic obstructive pulmonary disease (COPD), and bronchiolitis. Patients may present with signs and symptoms of viral pneumonia but commonly present with decompensated heart failure or COPD exacerbations, with RSV as the inciting event leading to worsening of their underlying disease. Recently, adults hospitalized with RSV have been shown to have a higher risk of invasive mechanical ventilation and death compared with those with influenza or COVID-19 who had received vaccination.

Digitoxin — A Reminder for Digoxin

Cardiac glycosides are among the oldest medications in cardiovascular care, prized for their actions as positive inotropic agents and modulators of atrioventricular conduction. In heart failure with reduced ejection fraction, their mechanistic rationale was so convincing that digitalis became a mainstay of treatment long before the initiation of large-scale trials...

Progress through Persistence — Turning the Page in Pulmonary Fibrosis Clinical Trials

The field of pulmonary fibrosis has come a long way in the past 25 years, with the approach to patient care evolving from a predominantly experience-based decision-making model to a more data-driven model. Along that journey, we have learned that certain practices that were considered to be standards of care…

Precision Genomic Medicine Paradigm

Precision medicine tailors clinical management strategies for treatment and prevention in light of each person’s genetic makeup, history of environmental exposures, and lifestyle. More specifically, precision medicine is about making correct, actionable diagnoses and offering appropriate, patient-specific treatment. Genomics has contributed to precision medicine, especially in the areas of rare…