Publications

HIV departments within Kenyan health facilities are usually better staffed and equipped than departments offering non-HIV services. Integration of HIV services into primary care may address this issue of skewed resource allocation. Between 2008 and 2010, we piloted a system of integrating HIV services into primary care in rural Kenya. Before integration, we conducted a survey among returning adults ≥18-year old attending the HIV clinic. We then integrated HIV and primary care services. Three and twelve months after integration, we administered the same questionnaires to a sample of returning adults attending the integrated clinic. Changes in patient responses were assessed using truncated linear regression and logistic regression. At 12 months after integration, respondents were more likely to be satisfied with reception services (adjusted odds ratio, aOR 2.71, 95% CI 1.32-5.56), HIV education (aOR 3.28, 95% CI 1.92-6.83), and wait time (aOR 1.97 95% CI 1.03-3.76). Men's comfort with receiving care at an integrated clinic did not change (aOR = 0.46 95% CI 0.06-3.86). Women were more likely to express discomfort after integration (aOR 3.37 95% CI 1.33-8.52). Integration of HIV services into primary care services was associated with significant increases in patient satisfaction in certain domains, with no negative effect on satisfaction.

The central melanocortin system is essential for the regulation of long-term energy homeostasis in humans. Rodent experiments suggest that this system also affects glucose metabolism, in particular by modulating peripheral insulin sensitivity independently of its effect on adiposity. Rare patients with complete genetic defects in the central melanocortin system can provide insight into the role of this system in glucose homeostasis in humans. We here describe the eighth individual with complete proopiomelanocortin (POMC) deficiency and the first with coincidental concomitant type 1 diabetes, which provides a unique opportunity to determine the role of melanocortins in glucose homeostasis in human. Direct sequencing of the POMC gene in this severely obese patient with isolated adrenocorticotropic hormone deficiency identified a homozygous 5' untranslated region mutation -11C>A, which we find to abolish normal POMC protein synthesis, as assessed in vitro. The patient's insulin requirements were as expected for his age and pubertal development. This unique patient suggests that in humans the central melanocortin system does not seem to affect peripheral insulin sensitivity, independently of its effect on adiposity.

PURPOSE

Entinostat is an oral isoform selective histone deacetylase inhibitor that targets resistance to hormonal therapies in estrogen receptor-positive (ER+) breast cancer. This randomized, placebo-controlled, phase II study evaluated entinostat combined with the aromatase inhibitor exemestane versus exemestane alone.

PATIENTS AND METHODS

Postmenopausal women with ER+ advanced breast cancer progressing on a nonsteroidal aromatase inhibitor were randomly assigned to exemestane 25 mg daily plus entinostat 5 mg once per week (EE) or exemestane plus placebo (EP). The primary end point was progression-free survival (PFS). Blood was collected in a subset of patients for evaluation of protein lysine acetylation as a biomarker of entinostat activity.

RESULTS

One hundred thirty patients were randomly assigned (EE group, n = 64; EP group, n = 66). Based on intent-to-treat analysis, treatment with EE improved median PFS to 4.3 months versus 2.3 months with EP (hazard ratio [HR], 0.73; 95% CI, 0.50 to 1.07; one-sided P = .055; two-sided P = .11 [predefined significance level of .10, one-sided]). Median overall survival was an exploratory end point and improved to 28.1 months with EE versus 19.8 months with EP (HR, 0.59; 95% CI, 0.36 to 0.97; P = .036). Fatigue and neutropenia were the most frequent grade 3/4 toxicities. Treatment discontinuation because of adverse events was higher in the EE group versus the EP group (11% v 2%). Protein lysine hyperacetylation in the EE biomarker subset was associated with prolonged PFS.

CONCLUSION

Entinostat added to exemestane is generally well tolerated and demonstrated activity in patients with ER+ advanced breast cancer in this signal-finding phase II study. Acetylation changes may provide an opportunity to maximize clinical benefit with entinostat. Plans for a confirmatory study are underway.

Chronic kidney disease and atrial fibrillation (AF) commonly coexist, and data suggest that renal patients have AF rates in excess of double that encountered in the general population. These patients are at increased risk of stroke, regardless of the presence or absence of AF. Furthermore, a lower GFR causes increased thromboembolic risk in patients with AF - independent of other risk factors. The dilemma facing clinicians treating this cohort of patients is that renal insufficiency confers both a thromboembolic and a bleeding risk. Renal disease also commonly coexists with other risk factors for stroke and bleeding such as hypertension and advanced age. Furthermore, bleeding risk tracks stroke risk and many risk factors are common to both thromboembolism and haemorrhage. Patients with severe renal impairment are also actively excluded from the majority of trials for stroke prevention in AF, including those trials which informed the development of stroke risk factor scoring schemes. Therefore, patients with renal disease and AF present a unique management challenge. The available data suggests that the benefit from warfarin in terms of stroke reduction is not as clear as in the general population, and there is an increased risk of bleeding complications and even ectopic vascular calcification. Thus, it is problematic to extrapolate the benefits of warfarin in the general population to a subgroup that has been actively excluded from clinical trials. The new oral anticoagulants have relatively little data in patients with severe renal impairment, and all have an element of renal excretion. There is a need for large randomised control trials in patients with renal insufficiency and on haemodialysis to provide a bank of high-quality scientific data on which clinicians can base their management decisions. Until then, we must adopt a pragmatic approach which involves careful consideration of the relative risk of stroke and bleeding in each individual patient.