Randomized Phase II Study of Two Doses of Pixantrone in Patients with Metastatic Breast Cancer (NCCTG N1031, Alliance)

BackgroundAnthracycline use in metastatic breast cancer (MBC) is hindered by cumulative exposure limits and risk of cardiotoxicity. Pixantrone, a novel aza-anthracenedione with structural similarities to mitoxantrone and anthracyclines, is theorized to exhibit less cardiotoxicity, mainly due to lack of iron binding. We conducted a randomized phase II study to evaluate the efficacy and safety of 2 dosing schedules of pixantrone in patients with refractory HER2-negative MBC.MethodsIntravenous pixantrone was administered at 180 mg/m² every 3 weeks (group A) versus 85 mg/m² on days 1, 8, and 15 of a 28-day cycle (group B). Primary endpoint was objective response rate (ORR) and secondary endpoints included progression-free survival (PFS), median 6-month PFS, overall survival (OS), safety, quality of life, and serial assessment of circulating tumor cells. A 20% ORR was targeted as sufficient for further testing of pixantrone in this patient population.ResultsForty-five patients were evaluable, with 2 confirmed partial responses in group A and 1 in group B. The trial was terminated due to insufficient activity. Overall median PFS and OS were 2.8 (95% confidence interval [CI]: 2.0-4.1) and 16.8 (95% CI: 8.9-21.6) months, respectively. Notable overall grade 3-4 adverse events were the following: neutrophil count decrease (62%), fatigue (16%), and decrease in ejection fraction (EF) (4%).ConclusionPixantrone has insufficient activity in the second- and third-line MBC setting. It appears, however, to have limited cardiotoxicity. (ClinicalTrials.gov ID: {"type":"clinical-trial","attrs":{"text":"NCT01086605","term_id":"NCT01086605"}}NCT01086605).     

Dried Plum’s Polyphenolic Compounds and Carbohydrates Contribute to Its Osteoprotective Effects and Exhibit Prebiotic Activity in Estrogen Deficient C57BL/6 Mice

Evidence of dried plum’s benefits on bone continues to emerge. This study investigated the contribution of the fruit’s polyphenol (PP) and carbohydrate (CHO) components on a bone model of postmenopausal osteoporosis to explore their prebiotic activity. Osteopenic ovariectomized mice were fed diets supplemented with dried plum, a crude extract of dried plum’s polyphenolic compounds, or the PP or CHO fraction of the crude extract. The effects of treatments on the bone phenotype were assessed at 5 and 10 weeks as well as the prebiotic activity of the different components of dried plum. Both the CHO and PP fractions of the extract contributed to the effects on bone with the CHO suppressing bone formation and resorption, and the PP temporally down-regulating formation. The PP and CHO components also altered the gut microbiota and cecal short chain fatty acids. These findings demonstrate that the CHO as well as the PP components of dried plum have potential prebiotic activity, but they have differential roles in mediating the alterations in bone formation and resorption that protect bone in estrogen deficiency.     

Pharmacometabonomic association of cyclophosphamide 4‐hydroxylation in hematopoietic cell transplant recipients

The widely used alkylating agent cyclophosphamide (CY) has substantive interpatient variability in the area under the curve (AUC) of it and its metabolites. Numerous factors may influence the drug‐metabolizing enzymes that metabolize CY to 4‐hydroxycyclophosphamide (4HCY), the principal precursor to CY’s cytotoxic metabolite. We sought to identify endogenous metabolomics compounds (EMCs) associated with 4HCY formation clearance (ratio of 4HCY/CY AUC) using global metabolomics. Patients who undergo hematopoietic cell transplantation receiving post‐transplant CY (PT‐CY) were enrolled, cohort 1 (n = 26) and cohort 2 (n = 25) donating longitudinal blood samples before they started HCT (pre‐HCT), before infusion of the donor allograft (pre‐graft), before the first dose of PT‐CY (pre‐CY), and 24 h after the first dose of PT‐CY (24‐h post‐CY), which is also immediately before the second dose of CY. A total of 512 and 498 EMCs were quantitated in two cohorts, respectively. Both univariate linear regression with false discovery rate (FDR), and pathway enrichment analyses using a global association test were performed. At the pre‐CY time point, no EMCs were associated at FDR less than 0.1. At pre‐HCT, cohort 1 had one EMC (levoglucosan) survive the FDR threshold. At pre‐graft, cohort 1 and cohort 2 had 20 and 13 EMCs, respectively, exhibiting unadjusted p values less than 0.05, with the only EMCs having an FDR less than 0.1 being two unknown EMCs. At 24‐h post‐CY, there were three EMCs, two ketones, and threitol, at FDR less than 0.1 in cohort 2. These results demonstrate the potential of pharmacometabonomics, but future studies in larger samples are needed to optimize CY.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

We report the first pharmacometabonomic study of the association of plasma EMCs with cyclophosphamide pharmacokinetics, specifically the ratio of 4HCY/CY AUC.

• WHAT QUESTION DID THIS STUDY ADDRESS?

This study addresses the question regarding if EMCs in the plasma before PT‐CY administration are associated with the ratio of 4HCY/CY AUC.

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

This study adds to our knowledge that longitudinal collection of plasma EMC samples is feasible in HCT patients receiving PT‐CY. In addition, the plasma EMC changes over the ~21‐day time period that starts pre‐HCT to 24‐hr after the first PT‐CY dose.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

This study demonstrates the possibility of pharmacometabolomic research to evaluate the pharmacokinetics of a drug – in this case, cyclophosphamide – with a complex pharmacokinetic disposition.     

Balance,Muscle Strength,and Fear of Falling in Older Adults

This study examined balance ability, lower-extremity muscle strength, fear of falling and their inter-relationships in 40 community-dwelling older adults (>65 years). Subjects who self-identified either as being fearful offalling or not (no concern) were screened to exclude those with known risk factors for falling. Limits of stability, maximal isometric strength, gait speed, and fear of falling were contrasted between groups (27 control subjects, 13 fearful subjects). Those fearful of falling demonstrated smaller center of pressure (COP) excursions in anterior, left, and right directions ( p <.0001) and used a smaller percentage of their base of support during maximal weight shifting in combined anterior-posterior and right-left directions ( p <.001) compared to the control group. Strength did not differ between groups, but was associated with the ability to shift the COP in the anterior-posterior direction ( p <.05). Fear of falling also related to weight shifting ability ( p <.017). Seniors fearful of falling demonstrated limitations in balance ability and balance confidence that could not be explained by muscle weakness.     

Community-Dwelling,Older Women's Perspectives on Therapeutic Life Review: A Qualitative Analysis

The purpose of this study was to elicit the participants' perspective of a Therapeutic Life Review intervention program delivered by a home care worker. Following the intervention by the home care worker, 13 of the 14 older women receiving home care services were interviewed to examine their experiences. Qualitative data analysis revealed five themes: (1) Someone was there to listen to my story, (2) It was a special time, (3) A valued interaction with the home care worker developed, (4) Remembering was meaningful and pleasurable, and (5) Integration with one's lived experiences was healing. Three case scenarios illustrate the lives of these older women.     

Expert clinician to clinical teacher: Developing a faculty academy and mentoring initiative

The lack of sufficient numbers of qualified nursing faculty to prepare nursing students for entry into the field of nursing is of national and international concern. Recruiting expert clinicians and preparing them as clinical teachers is one approach to addressing the faculty shortage. Adequate training for the new role is paramount to promote job satisfaction and reduce attrition. Various models for orienting and preparing expert nurse clinicians as clinical educators are reported in the literature with little consensus or research to support a single approach. This paper describes a collaborative effort to prepare experienced registered nurse clinicians for new roles as part-time clinical faculty. Using a blend of learning strategies (face-to-face, online, simulation, and group mentoring sessions), this training experience was designed to cover content while promoting discussion of issues and challenges and providing much-needed mentorship. Outcomes include 12 new clinical faculty, 25% from groups underrepresented in nursing, with nine newly employed as part-time clinical teachers.     

Patterns of hepatitis C prevalence and seroconversion in hemodialysis units from three continents: the DOPPS

BACKGROUND: Hepatitis C virus (HCV) remains a problem within hemodialysis units. This study measures HCV prevalence and seroconversion rates across seven countries and investigates associations with facility-level practice patterns. METHODS: The study sample was from the Dialysis Outcomes and Practice Patterns Study (DOPPS), a prospective, observational study of adult hemodialysis patients randomly selected from 308 representative dialysis facilities in France, Germany, Italy, Japan, Spain, the United Kingdom, and the United States. Logistic regression was used to model odds of HCV prevalence, and Cox regression was used to model time from study entry to HCV seroconversion. RESULTS: Mean HCV facility prevalence was 13.5% and varied among countries from 2.6% to 22.9%. Increased HCV prevalence was associated with longer time on dialysis, male gender, black race, diabetes, hepatitis B (HBV) infection, prior renal transplant, and alcohol or substance abuse in the previous 12 months. Approximately half of the facilities (55.6%) had no seroconversions during the study period. HCV seroconversion was associated with longer time on dialysis, human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS), HBV infection, and recurrent cellulitis or gangrene. An increase in highly trained staff was associated with lower HCV prevalence (OR = 0.93 per 10% increase, P= 0.003) and risk of seroconversion (RR = 0.92, P= 0.07). Seroconversion was associated with an increase in facility HCV prevalence (RR = 1.36, P < 0.0001), but not with isolation of HCV-infected patients (RR = 1.01, P= 0.99). CONCLUSION: There are differences in HCV prevalence and rate of seroconversion at the country and the hemodialysis facility level. The observed variation suggests opportunities for improved HCV outcomes.