Publications

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.

BACKGROUND

Patient handling is a major risk factor for musculoskeletal injuries among nurses. Lifting equipment is a main component of safe patient handling programs that aim to prevent musculoskeletal injury. However, the actual levels of lift availability and usage are far from optimal.

OBJECTIVE

To examine the effect of patient lifting equipment on musculoskeletal pain by level of lift availability and lift use among critical-care nurses.

DESIGN AND PARTICIPANTS

A cross-sectional postal survey of a random sample of 361 critical-care nurses in the United States.

METHODS

The survey collected data on low-back, neck, and shoulder pain, lift availability, lift use, physical and psychosocial job factors, and sociodemographics. Musculoskeletal pain was assessed by three types of measures: any pain, work-related pain, and major pain. Multivariable logistic regressions were used to examine the associations between musculoskeletal pain and lift variables, controlling for demographic and job factors.

RESULTS

Less than half (46%) of respondents reported that their employer provided lifts. Of 168 nurses who had lifts in their workplace, the level of lift availability was high for 59.5%, medium for 25.0%, and low for 13.7%; the level of lift use was high for 32.1%, medium for 31.5%, and low for 31.5%. Significant associations were found between lift availability and work-related low-back and shoulder pain. Compared to nurses without lifts, nurses reporting high-level lift availability were half as likely to have work-related low-back pain (OR=0.50, 95% CI 0.26-0.96) and nurses reporting medium-level lift availability were 3.6 times less likely to have work-related shoulder pain (OR=0.28, 95% CI 0.09-0.91). With respect to lift use, work-related shoulder pain was three times less common among nurses reporting medium-level use (OR=0.33, 95% CI 0.12-0.93); any neck pain was three times more common among nurses reporting low-level use (OR=3.13, 95% CI 1.19-8.28).

CONCLUSIONS

Greater availability and use of lifts were associated with less musculoskeletal pain among critical-care nurses. These findings suggest that for lift interventions to be effective, lifts must be readily available when needed and barriers against lift use must be removed.

Abacavir is a nucleoside analogue reverse transcriptase inhibitor indicated for the treatment of human immunodeficiency virus infection as part of a multidrug, highly active antiretroviral therapy regimen. Despite its efficacy, approximately 5% of individuals who receive abacavir develop an immune-mediated hypersensitivity reaction (HSR) that warrants immediate discontinuation of abacavir and switching to an alternative antiretroviral regimen. Abacavir HSR is associated with individuals who carry the *57:01 variant in the human leukocyte antigen B (HLA-B) gene. There is a large volume of evidence to show that those who carry HLA-B*57:01 are at significantly increased risk of developing HSR and should not receive abacavir. Pharmacogenetic screening to ensure individuals who carry HLA-B*57:01 do not receive abacavir can reduce the incidence of HSR and is now considered the standard of care before prescribing abacavir. Genetic testing to prevent abacavir HSR is currently one of the best examples of integrating pharmacogenetic testing into clinical practice.