2 Minute Medicine Rewind July 4, 2016

PD-1 Blockade with Pembrolizumab in Advanced Merkel-Cell Carcinoma

Merkel cell is a relatively slow-growing but aggressive skin cancer with limited treatment options with durable response. There is hope that cancer immunotherapy with programmed death 1 (PD-1) inhibitors as tumor cells express PD-L1. In this multicenter phase 2 trial, 26 patients with advanced Merkel-cell carcinoma and no prior exposure to cytotoxic chemotherapy received 2mg/kg of pembrolizumab (anti-PD-1 antibody). There was an objective response rate of 56% (95% CI: 35 to 76%) with a complete response in 4 patients and partial response in 10 patients. The response duration lasted from 2.2 months to 9.7 months, with a 6 month progression-free survival rate of 67%. Moderate to severe adverse events occurred in 15% of patients. In this first trial of pembrolizumab in patients with Merkel-cell carcinoma, there was a significant and substantial response that compares favorably with current treatment options. Further placebo controlled randomized trials will be performed to further characterize the efficacy.

Time- and Region-Specific Season of Birth Effects in Multiple Sclerosis in the United Kingdom

The etiology of multiple sclerosis (MS) is unknown, although there are regional and temporal variations in its incidence and prevalence. It is unknown whether such trends are suggestive of pathophysiology or just associated with background patterns in the general pattern. In this analysis of patients from 8 specialized multiple sclerosis clinics in the United Kingdom, population studies, and records from the UK Registrar General, the birth patterns of 21,138 patients with MS were compared with national records. In both the general population and in the cohort of patients with MS, there are seasonal and regional differences in the UK, however after adjusting for variations in the general population, there was still a significant increase in risk of disease during the peak month (April) compared to the trough month (November) with an OR of 1.24 (95% CI: 1.10 to 1.41). The reason for such variation is still unknown, however the seasonality appears to be in excess of variation in the general population.

Long-Term Risk of Atherosclerotic Cardiovascular Disease in US Adults With the Familial Hypercholesterolemia Phenotype

Familial hypercholesterolemia affects at least 0.5% of the population of the United States however long-term cardiovascular disease risk has not been well characterized. In this analysis of 6 large epidemiological cohorts totally 68,565 participants, 3,850 participants with LDL cholesterol greater than 190mg/dL (defined as the FH phenotype) were identified and evaluated for cardiovascular outcomes. Compared to the baseline population, there was significantly elevated 30-year risk of atherosclerotic cardiovascular disease (HR 4.1, 95% CI: 1.2 to 13.4) with risk consistent with baseline individuals 10 to 20 years older in the male population and 20 to 30 years older in the female population. Similar risk profiles were identified in patients with likely FH by family history, more stringent LDL cholesterol thresholds, or changes in lipid fractions. This study of epidemiological data confirms individuals with FH had increased risk of atherosclerotic disease.

Angiotensin II–Receptor Inhibition With Candesartan to Prevent Trastuzumab-Related Cardiotoxic Effects in Patients With Early Breast Cancer

Trastuzumab is associated with dose-related cardiotoxicity that can result in reduction of left ventricular ejection fraction and cause congestive heart failure. Although typical heart failure regimens are started with the development of heart failure, there are hopes to prevent such cardiotoxicity. In this multicenter, randomized trial of 206 women in the Netherlands receiving anthracycline-containing chemotherapy followed by trastuzumab, patients were randomized to either candesartan on the initiation of trastuzumab or placebo and followed for evidence of myocardial damage and congestive heart failure. There was no significant difference in LVEF cardiomyopathy endpoints, with 16 vs. 19% of patients developing cardiac events (3.8% more events, 95% CI: -7 to 15%, p = 0.58). There were no difference in NT-proBNP or troponin T changes. This trial did not show significant efficacy of candesartan to prevent cardiomyopathy in patients with early breast cancer being treated with trastuzumab.

 Seven-Year Efficacy of RTS,S/AS01 Malaria Vaccine among Young African Children

Malaria remains a public health epidemic in many parts of Africa, Asia, and South America leading to significant morbidity and mortality. Many treatment and prevention strategies have been attempted and RTS,S/AS01 is a malaria vaccine candidate that has undergone medium term validation with decreases in malaria transmission by two year follow-up. There is concern that immunity with RTS,S/AS01 wanes over time and this article was follow-up of a randomized trial in Kenya and Tanzania of 447 children between 5 and 17 months of age vaccinated by RTS,S/AS01 or placebo (rabies vaccine) and followed for rates of protection. At 7 years of follow-up, there were 1002 episodes of clinical malaria in study participants who received RTS,S/AS01 and 992 episodes of clinical malaria in study participants in the control arm. There was significant evidence of vaccine efficacy waning over time (p = 0.006 for interaction with time to vaccination) with negative efficacy during the fifth year after vaccination (vaccine efficacy -.43.5%, 95% CI: -100.3 to -2.8%, p = 0.03). Although initially showing efficacy, RTS,S/AS01 exhibited rebound in the rate of clinical malaria in later years with areas with high exposure to malaria.

Image: PD

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