In this section, we highlight the key high-impact studies, updates, and analyses published in medicine during the past week.
BRAF inhibitors have shown efficacy in the treatment of patients with previously untreated metastatic melanoma with BRAF V600E and V600K mutations. This study investigated combining dabrafenib with a MEK inhibitor trametinib as compared to vemurafenib alone in the treatment of metastatic melanoma. This open label phase 3 trial enrolled 704 patients with metastatic melanoma with a BRAF V600 mutation and randomly assigned these patients to receive either a combination of dabrafenib (150 mg BID) and trametinib (2 mg daily) or vemurafenib (960 mg BID) alone. Overall survival was studied as an endpoint. The overall survival rate at 12 months in the combination therapy group was 72% (95% CI 67 to 77%) and in the vemurafenib group 65% (95% CI 59 to 70%) (hazard ratio for death 0.69; 95% CI, 0.53 to 0.89; p=0.005). Progression free survival was 11.4 months in the combination therapy group and 7.3 months in the vemurafenib group (hazard ratio, 0.56; 95% CI, 0.46 to 0.69; p<0.001). Rates of severe adverse events were comparable between the two groups. Thus, the study concluded that combination therapy of dabrafenib and trametinib as compared to vemurafenib alone significantly improved overall survival rates in patients with untreated melanoma with BRAF V600E or V600K mutations, without significantly increasing the frequency of severe adverse events.
Leptin deficiency has been reported as a very rare cause of early onset extreme obesity. Leptin is produced by the adipocytes to signal satiety, and it exerts its functions on the hypothalamus. To date, all reported cases of congenital leptin deficiency have been associated with very low or undetectable levels of leptin. In this report, however, a case of a 2 year -old boy with early onset extreme obesity is described, and interestingly, the patient in this study is described to have high circulating levels of leptin. This patient described in the case report is characterized to have a novel form of a mutation in the gene encoding leptin, with a homozygous transversion (c.298 G->T), leading to aspartic acid to tyrosine amino acid substitution at position 100 in the leptin gene. The mutated leptin protein is then expressed and secreted, but is unable to bind to or activate the leptin receptor. This mutant protein also fails to reduce food intake and body weight in leptin deficient objob mice. Treatment of the patient in this study with metreleptin, a recombinant human leptin, which is the standard of care for patients with other forms of leptin deficiency, provided adequate normalization of eating behavior and weight loss.
On August 8, 2014, the WHO declared the Ebola epidemic in West Africa as a public health emergency of international concern. This study aimed to assess the potential for Ebola virus spread across international borders via commercial air travel and to understand the efficacy of the exit and entry traveler screenings in curbing the spread of the epidemic. The study looked at the worldwide flight schedules between September 1, 2014 and December 31, 2014 to describe the overall population movements through air travel, and it aimed to model the predicted spread of the Ebola virus out of Guinea, Liberia, and Sierra Leone, assuming that all individuals starting their travel in any one of these three countries to have possible exposure to the virus. According to the analysis of this study, Ebola epidemic contributed to the international flight restrictions to and from Guinea, Liberia and Sierra Leone with passenger seat reductions of 51% for Liberia, 66% for Guinea, and 85% for Sierra Leone. The final destinations of the travelers leaving the above three countries appeared to be mostly in the middle and lower income countries, with only 29% of the travelers from Guinea, Liberia, and Sierra Leone having their final destination in the high income country and 7% in the upper-middle income country. Overall, assuming complete unrestricted travel and lack of health screening of the passengers, the model estimated that one infected international air traveller would leave Guinea every 2.7 months, Liberia every 0.2 months, and Sierra Leone every 0.6 months. The study also found that the health screening of the travelers at risk of exposure to the Ebola virus, if performed, should be done at the site of departure versus at the point of entry, with screening at the site of exit having higher efficacy and easier modes of implementation.
Hypoxic ischemic encephalopathy is a significant cause of childhood neurodevelopmental deficits, and induced hypothermia appears to have a role in improving outcomes in this condition. This randomized, 2×2 factorial design clinical trial taking place in 18 US centers between October 2010 and November 2013 aimed to understand whether longer duration of cooling of 120 hours, deeper cooling to 32.0 degrees Celsius, or both, are superior to the standard cooling procedure at 33.5 degrees Celsius for 72 hours in full term neonates with moderate to severe hypoxic ischemic encephalopathy. The study assigned neonates to 4 groups: 33.5 degrees Celsius for 72 hours control group, 32.0 degrees Celsius for 72 hours, 33.5 degrees Celsius for 120 hours, and 32.0 degrees Celsius for 120 hours, and the primary outcome that the study aimed to measure was death or disability at 18 to 22 months. However, the trial was closed prematurely due to the emerging safety profile and futility analysis with only 364 neonates enrolled, and this report instead focused on the safety and NICU death rates following the differential cooling strategies. NICU death rates were found to be the following in the 4 groups: 7% for 33.5 degrees Celsius for 72 hours group, 14% for the 32 degrees Celsius for 72 hours group, 16% for the 33.5 degrees Celsius for 120 hours group, and 17% for the 32 degrees Celsius for 120 hours group. The adjusted risk ratio for the NICU deaths comparing 120 hour cooling vs 72 hour cooling was 1.37 (95% CI, 0.92-2.04). The adjusted risk ratio for the NICU deaths comparing 32.0 degrees Celsius group vs 33.5 degrees Celsius group was 1.24 (95% CI, 0.69-2.25). Safety outcomes were similar across all groups, except the risk of major bleeding, with major bleeding occurring in 1% of patients in 120 hour group and 3% of patients in 72 hour group (RR 0.25, 95% CI 0.07-0.91). The futility analysis also concluded that the probability of detecting a statistically significant benefit for longer or deeper cooling on NICU deaths was less than 2%. Thus, the study concluded that for full term neonates with moderate to severe hypoxic ischemic encephalopathy there does not appear to be any benefit in NICU mortality for deeper or longer cooling protocols compared to the standard 33.5 degrees Celsius for 72 hours induced hypothermia procedure.
The patient or family centered medical home practice models are now widely recommended, particularly for high risk patients. This randomized clinical trial taking place in Houston, Texas between March 2011 and February 2013 assigned 201 high risk children with chronic illnesses (defined as >/= 3 emergency department visits, >/= 2 hospitalizations, or >/= 1 pediatric ICU admissions in the past year, with >50% estimated risk for hospitalization) to either a comprehensive care (with treatment from primary care doctors and specialists in the same clinic with multiple additional features, promoting prompt and effective care) or the usual care groups. The study measured the rates of death, ICU admissions or hospital stays > 7 days as well as costs in the two study groups, and found that both the rates of children with a serious illness and total costs were lower in the comprehensive care group as compared to the usual care practice group. The rates of serious illnesses were found to be 10 per 100 child-years in the comprehensive care group as compared to 22 per 100 child-years in the usual care group (RR 0.45, 95% CI 0.28-0.73). The total hospital and clinic costs were found to be $16,523 per child-year in the comprehensive care group as compared to $26,781 per child-year in the usual care group (cost ratio 0.58, 95% CI 0.38-0.88). Thus, this study showed that at least in this single site study, comprehensive care groups for high risk children have benefits with both reducing serious illnesses and cutting the costs of care.
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