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.
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.
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.
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.
We present the combined results of two trials that compared adjuvant chemotherapy with or without concurrent trastuzumab in women with surgically removed HER2-positive breast cancer.
The National ...Surgical Adjuvant Breast and Bowel Project trial B-31 compared doxorubicin and cyclophosphamide followed by paclitaxel every 3 weeks (group 1) with the same regimen plus 52 weeks of trastuzumab beginning with the first dose of paclitaxel (group 2). The North Central Cancer Treatment Group trial N9831 compared three regimens: doxorubicin and cyclophosphamide followed by weekly paclitaxel (group A), the same regimen followed by 52 weeks of trastuzumab after paclitaxel (group B), and the same regimen plus 52 weeks of trastuzumab initiated concomitantly with paclitaxel (group C). The studies were amended to include a joint analysis comparing groups 1 and A (the control group) with groups 2 and C (the trastuzumab group). Group B was excluded because trastuzumab was not given concurrently with paclitaxel.
By March 15, 2005, 394 events (recurrent, second primary cancer, or death before recurrence) had been reported, triggering the first scheduled interim analysis. Of these, 133 were in the trastuzumab group and 261 in the control group (hazard ratio, 0.48; P<0.0001). This result crossed the early stopping boundary. The absolute difference in disease-free survival between the trastuzumab group and the control group was 12 percent at three years. Trastuzumab therapy was associated with a 33 percent reduction in the risk of death (P=0.015). The three-year cumulative incidence of class III or IV congestive heart failure or death from cardiac causes in the trastuzumab group was 4.1 percent in trial B-31 and 2.9 percent in trial N9831.
Trastuzumab combined with paclitaxel after doxorubicin and cyclophosphamide improves outcomes among women with surgically removed HER2-positive breast cancer. (ClinicalTrials.gov numbers, NCT00004067 and NCT00005970.)
Chagas disease, a neglected tropical disease that affects millions of Latin Americans, has been effectively controlled in Guatemala after multiple rounds of indoor residual insecticide spraying ...(IRS). However, a few foci remain with persistent Triatoma dimidiata infestation. One such area is the municipality of Comapa, Department of Jutiapa, in the southeastern region of Guatemala, where control interventions appear less effective. We carried out three cross sectional entomological and serological surveys in Comapa to evaluate a decade of vector control activities. Baseline serological (1999) and entomological (2001-2) surveys were followed by three rounds of insecticide applications (2003-2005) and intermittent focal spraying of infested houses, until approximately 2012. Household inspections to determine entomological indices and construction materials were conducted in 2001, 2007 and 2011. Seroprevalence surveys were conducted in school-age children in 1999, 2007 and 2015, and in women of child bearing age (15-44 years) only in 2015. After multiple rounds of indoor residual sprayings (IRS), the infestation index decreased significantly from 39% (2001-2) to 27% (2011). Household construction materials alone predicted <10% of infested houses. Chagas seroprevalence in Comapa declined in school-aged children by 10-fold, from 10% (1999) to 1% (2015). However, seroprevalence in women of child bearing age remains >10%.
After a decade of vector control activities in Comapa, there is evidence of significantly reduced transmission. However, the continued risk for vector-borne and congenital transmission pose a threat to the 2022 Chagas disease elimination goal. Systematic integrated vector control and improved Chagas disease screening and treatment programs for congenital and vector-borne disease are needed to reach the elimination goal in regions with persistent vector infestation.
Background and Objectives:
Most studies based on self-reported data indicate that female patients more often than males have a same-gender preference for their primary care physician (PCP). Because ...self-reported preferences may not reflect true preferences, we analyzed objective data to investigate patients’ preferences for PCP gender.
Methods:
Analyses were performed on 2192 new patients seen within a university-based healthcare system by 13 PCPs (2 male, 11 female) during 2017. New patients were asked about their PCP gender preference when assigned a PCP. We compared the expected prevalence (proportion of males/females in overall patient population) and observed prevalence (gender distribution of patients for each PCP) by PCP gender. A mixed model with PCP as a random effect examined the odds of male and female patients being assigned a same-gender physician.
Results:
The expected prevalence of new patients was 65% female and 35% male. The observed prevalence (95% confidence interval CI) of male patients among male and female PCPs was, respectively, 59.7% (49.0%-69.5%) and 28.0% (24.0%-32.4%), with neither CI containing the expected prevalence of male patients (35%). Similarly, the observed prevalence of female patients among male and female PCPs was, respectively, 40.3% (95% CI 30.5%-51.0%) and 72.0% (95% CI 67.6%-76.0%), with neither CI containing the expected prevalence of female patients (65%).
Conclusions:
Both male and female patients often preferred to see a same-gender PCP with this preference more pronounced in males. Future research should seek to clarify the relationships between patients’ gender preferences, patient-physician gender concordance/discordance, patient satisfaction, and health outcomes.
The overall 5-year survival for melanoma is 91%. However, if distant metastasis occurs (stage IV), cure rates are <15%. Hence, melanoma detection in earlier stages (stages I–III) maximises the ...chances of patient survival. We measured the expression of a panel of 17 microRNAs (miRNAs) (MELmiR-17) in melanoma tissues (stage III; n=76 and IV; n=10) and serum samples (collected from controls with no melanoma, n=130; and patients with melanoma (stages I/II, n=86; III, n=50; and IV, n=119)) obtained from biobanks in Australia and Germany. In melanoma tissues, members of the ‘MELmiR-17’ panel were found to be predictors of stage, recurrence, and survival. Additionally, in a minimally-invasive blood test, a seven-miRNA panel (MELmiR-7) detected the presence of melanoma (relative to controls) with high sensitivity (93%) and specificity (≥82%) when ≥4 miRNAs were expressed. Moreover, the ‘MELmiR-7’ panel characterised overall survival of melanoma patients better than both serum LDH and S100B (delta log likelihood=11, p<0.001). This panel was found to be superior to currently used serological markers for melanoma progression, recurrence, and survival; and would be ideally suited to monitor tumour progression in patients diagnosed with early metastatic disease (stages IIIa–c/IV M1a–b) to detect relapse following surgical or adjuvant treatment.
•A seven-miRNA panel (MELmiR-7) detected the presence of melanoma with high sensitivity (93%) and specificity (≥82%).•In serially collected stage IV specimens, members of the ‘MELmiR-7’ panel confirmed tumour progression in 100% of cases.•The ‘MELmiR-7’ panel is superior to currently used serological markers for melanoma progression, recurrence, and survival.
Purpose To evaluate the efficacy and safety of erlotinib in advanced breast cancer. Experimental design Multicenter, phase II study of erlotinib (150 mg orally daily). Cohort 1: progression after ...anthracyclines, taxanes, and capecitabine (n = 47). Cohort 2: progression after >1 chemotherapy for advanced-stage disease (n = 22). Primary endpoint was response rate (World Health Organization criteria). Secondary endpoints were safety, time to progression, and survival. Results One patient in each cohort (n = 2, 3.0%) had a partial response. Response duration was 17 weeks for the Cohort 1 patient and 32 weeks for the Cohort 2 patient. Median time to progression was 43 days for Cohort 1 (range 1-204) and 43 days for Cohort 2 (range 25-419). Common adverse events were diarrhea, rash, dry skin, asthenia, nausea, anorexia. Conclusion Erlotinib had minimal activity in unselected previously treated women with advanced breast cancer. Predictive factors are needed to identify breast cancer patients who may derive benefit from erlotinib treatment.
Emotion expression is a central aspect of social–emotional functioning. Theorists assert that emotion expression undergoes significant changes in the preschool period. There is, however, limited ...observational evidence of those changes, which may vary by interpersonal context and gender. The present longitudinal study examined developmental changes in emotion expressions from ages 3 to 5 years in 120 children from rural economically strained families. Children's facial, vocal, and postural sadness, anger, and happiness expressions were observed in frustrating tasks in 3 social contexts (a perfect circles task with an experimenter, a toy wait task with mother, a locked box task when alone). Findings indicted that sadness expressions decreased with age in all 3 contexts. Anger expressions increased with age in the frustrating task with the experimenter and when alone but not with the mother. From age 4 to 5 years, happiness expressions decreased in the task with experimenter but increased when alone and increased marginally with mother. In terms of gender, girls expressed greater happiness (and lower sadness) than boys but only in the task with the experimenter. Findings suggest that sadness expressions decrease over the preschool years. Developmental changes in happiness and anger expressions (and gender differences) likely depend on context.
Highlights
The study examined developmental changes and gender differences in emotion expression from age 3–5 years in three frustrating interpersonal contexts.
Sadness decreased, anger increased with the experimenter and alone (but not with mother), and happiness decreased with the experimenter.
Findings suggest declines in sadness expressions, but that anger and happiness expressions are selectively expressed to fit contextual demands.
Women with HER2-overexpressing breast cancer have an unfavorable prognosis. Trastuzumab improves survival when combined with chemotherapy in the first-line treatment of patients with ...HER2-overexpressing metastatic breast cancer and decreases the rate of disease relapse by 52% and the rate of death by 33% in women with HER2-overexpressing early-stage breast cancer. HER2 testing can be performed using immunohistochemistry (IHC) or fluorescence in situ hybridization (FISH) and can be performed at local pathology laboratories or at central/reference laboratories. Because of the significant benefit seen with trastuzumab, it is critical to accurately identify women most likely to benefit. The method and the location of HER2 testing contribute to the accuracy of test results.
HER-First, a prospective, community-based, phase IV study of first-line trastuzumab/taxane therapy, enrolled patients with HER2-overexpressing metastatic breast cancer. Retesting of all tumor specimens by HER2 IHC and FISH at a high-volume, experienced laboratory was required.
Concordance between local and central laboratory HER2 IHC testing was highest for local IHC 3+ samples (n = 377; 77%) and lowest for IHC 2+ samples (n = 184; 26%). Thirtythree percent of samples testing IHC 2+ at a local laboratory tested FISH-positive at the central laboratory. Concordance between HER2 IHC and FISH results was higher when both tests were performed at the central laboratory.
Accurate HER2 test results are critical to identify patients who are appropriate candidates for trastuzumab, a therapy with significant clinical benefits in HER2-overexpressing breast cancer. These data show that HER2 testing is most accurate when performed at a high-volume reference laboratory.
Trastuzumab, a humanized, recombinant antibody directed against HER2, can significantly improve survival in women with HER2-positive metastatic breast cancer. Treatment with trastuzumab has been ...associated with cardiac toxicity, most commonly manifested as asymptomatic decreases in left ventricular ejection fraction on multiple gated acquisition scans. These asymptomatic decreases appear to be reversible, and their clinical significance is not well understood. Fortunately, studies are beginning to show that the majority of women with decreases in left ventricular ejection fraction never develop clinical evidence of cardiac dysfunction. Although cardiotoxicity has been difficult to study, in part because of the small number of actual clinical events, preliminary evidence appears to indicate that the mechanism of trastuzumab-related cardiotoxicity is different than that induced by anthracyclines. The development of animal models may yield further understanding of the mechanism(s) of trastuzumab-associated cardiac dysfunction, and may provide a focus for clinical trials of treatment or prevention. Current investigations with rodent and primate models of cardiac dysfunction are briefly discussed in this article.
Sex hormones play a major role in determining the risk of cardiovascular disease. While several studies have shown that reduced sex hormone-binding globulin is associated with an atherogenic pattern ...of lipoproteins and increased glucose concentrations in premenopausal women, little data are available examining the association of sex hormone-binding globulin and sex hormones with cardiovascular risk factors in postmenopausal women, a group with high rates of cardiovascular disease. The investigators hypothesized that in postmenopausal women decreased sex hormone-binding globulin and increased testosterone would be associated with an atherogenic pattern of cardiovascular risk factors. The sex hormone-binding globulin, total and free testosterone, estrone, and dehydroepiandrosterone sulfate (DHEA-SO4) in 253 postmenopausal women who were not taking hormones were measured in a population-based study, the Beaver Dam Eye Study (Beaver Dam, Wisconsin, 1988-1990). Sex hormone-binding globulin was significantly inversely correlated with body mass index (r = -0.53, p 0.001), glycosylated hemoglobin (r = -0.34, p < 0.001), and diastolic blood pressure (r = -0.25, p < 0.001), and positively correlated with high density lipoprotein cholesterol (HDL cholesterol) (r = 0.31, p < 0.001), and HDL cholesterol/total cholesterol (r = 0.31, p < 0.001). Total (r = -0.20, p < 0.01) and free (r = -0.14, p < 0.05) testosterone were significantly inversely correlated with HDL cholesterol/total cholesterol ratio. Total testosterone concentrations were also significantly positively correlated with total cholesterol (r = 0.15), body mass index (r = 0.16), and systolic (r = 0.17) and diastolic (r = 0.18) blood pressures (all p < 0.01). DHEA-SO4 was not associated with any of the metabolic variables, while estrone was inversely associated only with the HDL cholesterol/total cholesterol ratio (r = 0.13, p < 0.05). The authors conclude that increased androgenization in postmenopausal women is associated with atherogenic changes in cardiovascular risk factors.
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