Aprepitant for the control of delayed nausea and vomiting associated with the use of high-dose melphalan for autologous peripheral blood stem cell transplants in patients with multiple myeloma: a phase II study

Study objective

The aim of this study is to evaluate the efficacy of aprepitant as part of the antiemetic regimen for high-dose melphalan conditioning in multiple myeloma patients.

Design

This is a prospective, single-arm study.

Setting

The study was conducted at an Academic Medical Facility.

Subjects

Twenty-six patients receiving high-dose melphalan with autologous stem cell support were included in this study.

Intervention

Eligible patients were >18 years with a diagnosis of MM undergoing high-dose melphalan followed by autologous peripheral blood stem cell transplantation (PBSCT). All patients had serum aminotransferases and total bilirubin less than 2× upper limit of normal. Treatment consisted of aprepitant 125 mg orally on day 1, followed by 80 mg orally 24 and 48 h after the initial dose; ondansetron 16 mg orally day 1; dexamethasone 12 mg orally day 1, and 8 mg orally days 2–4 with breakthrough medications as needed.

Measurements and main results

Patients were evaluated for the frequency of emetic episodes, the need for breakthrough antiemetic medication, and the mean nausea score in 24-h increments beginning 24 h after chemotherapy and continuing until 120 h. Nausea score was determined using a linear analog scale (0–10). Complete response (CR) was defined as no more than one (1) emetic episode during the evaluation period. A total of 26 patients (17 male, 9 female) were enrolled in the study. Of these, 25 (96 %) were complete responders and 24 (92 %) had no documented emetic episodes during the study period. One patient (4 %) had 1 emetic episode and one patient (4 %) had 2 emetic episodes. Some degree of nausea was reported by 23/26 patients, and the mean nausea score for the entire group over the study period was 0.7 (range 0–10).

Conclusions

Addition of aprepitant to standard antiemetics resulted in low rates of delayed nausea/vomiting associated with high-dose melphalan and PBSCT, and has now become standard practice in this patient population at our institution.     

High prevalence of cardiovascular and respiratory abnormalities in advanced,intensively treated (transplanted) myeloma: The case for ‘late effects’ screening and preventive strategies

Objectives: Modern management of myeloma has significantly improved survival, with increasing numbers of patients living beyond a decade. However, little is known about the long-term cardiovascular and respiratory status of intensively treated and multiply relapsed survivors.

Methods: We performed detailed cardiovascular and respiratory evaluations in patients with intensively treated, advanced but stable myeloma. All patients had received at least two lines of treatment, including at least one haematopoietic stem cell transplantation procedure, but had stable, controlled disease and were off active treatment at the time of evaluation.

Results: Thirty-two patients with a median duration of 6 years (range 2–12) from original diagnosis of myeloma and three lines (range 2–6) of treatment were evaluated. Despite normal physical examination in the majority, there was a high prevalence of sub-clinical cardiac and respiratory dysfunction, reflected by abnormalities of electrocardiography (45%), echocardiography (50%), serum N-terminal pro-B-type natriuretic peptide level (NT-pro-BNP, 50%), and pulmonary function testing (45%). NT-pro-BNP level correlated negatively with quality of life (P?=?0.012) and positively with serum ferritin (P?=?0.027). Dyspnoea score correlated with BMI (P?=?0.001). Risk factors for cardiovascular disease (obesity, hypertension, hyperlipidaemia, and hyperinsulinaemia) were common.

Discussion: Even in the absence of overt clinical features, the majority of intensively treated long-term survivors of myeloma have established cardiovascular and/or respiratory dysfunction, above levels expected in the general population of a similar age.

Conclusion: This study supports routine screening and lifestyle modification combined with primary and secondary preventive strategies to reduce cardiovascular and respiratory disease and to preserve quality of life in transplanted myeloma patients.     

Associations between socioeconomic status,atrial fibrillation,and outcomes: a systematic review

ABSTRACT

Background: Atrial fibrillation (AF) is a growing epidemic and evidence of a relationship to socioeconomic status (SES) is inconsistent. We aimed to summarize the literature about SES and AF and defined two objectives: (1) To examine the association between SES and the risk of AF; (2) To examine the association between SES and AF-related outcomes in an AF-population.

Methods: We performed a separate search for each objective in Ovid-MEDLINE and Ovid-Embase. For objective 1, the population included was healthy participants and outcome of interest was AF. For objective 2, the population included were patients with AF and outcome of interest was mortality, treatment, ablation for AF, knowledge about AF, and morbidity.

Results: For objective 1, 12 studies were included. No consistent pattern for an association between SES and the risk of AF was discovered. For objective 2, 39 studies comprising 42 outcomes were included. The majority of studies showed an association between low SES and increased mortality and morbidity.

Conclusion: Low SES was associated with poorer outcomes when AF was present. These findings may imply that health-care professionals and policy interventions should focus on the promotion of AF-education and management among patients with AF and low SES.     

Cyclic AMP Effectors in African Trypanosomes Revealed by Genome-Scale RNA Interference Library Screening for Resistance to the Phosphodiesterase Inhibitor CpdA

One of the most promising new targets for trypanocidal drugs to emerge in recent years is the cyclic AMP (cAMP) phosphodiesterase (PDE) activity encoded by TbrPDEB1 and TbrPDEB2. These genes were genetically confirmed as essential, and a high-affinity inhibitor, CpdA, displays potent antitrypanosomal activity. To identify effectors of the elevated cAMP levels resulting from CpdA action and, consequently, potential sites for adaptations giving resistance to PDE inhibitors, resistance to the drug was induced. Selection of mutagenized trypanosomes resulted in resistance to CpdA as well as cross-resistance to membrane-permeable cAMP analogues but not to currently used trypanocidal drugs. Resistance was not due to changes in cAMP levels or in PDEB genes. A second approach, a genome-wide RNA interference (RNAi) library screen, returned four genes giving resistance to CpdA upon knockdown. Validation by independent RNAi strategies confirmed resistance to CpdA and suggested a role for the identified cAMP Response Proteins (CARPs) in cAMP action. CARP1 is unique to kinetoplastid parasites and has predicted cyclic nucleotide binding-like domains, and RNAi repression resulted in >100-fold resistance. CARP2 and CARP4 are hypothetical conserved proteins associated with the eukaryotic flagellar proteome or with flagellar function, with an orthologue of CARP4 implicated in human disease. CARP3 is a hypothetical protein, unique to Trypanosoma. CARP1 to CARP4 likely represent components of a novel cAMP signaling pathway in the parasite. As cAMP metabolism is validated as a drug target in Trypanosoma brucei, cAMP effectors highly divergent from the mammalian host, such as CARP1, lend themselves to further pharmacological development.     

The attitudes of Korean cancer patients, family caregivers, oncologists, and members of the general public toward advance directives

Purpose

The purpose of this study was to investigate Korean attitudes toward advance directives (ADs) among cancer patients, family caregivers, oncologists, and the general public.

Methods

A multicenter survey study explored the attitudes of participants to ADs, and hospice–palliative care (HPC) was conducted. A total of 1,242 cancer patients, 1,289 family caregivers, 303 oncologists, and 1,006 members of the general public participated in the survey.

Results

The majority of patients, family caregivers, oncologists, and general public agreed with the necessity of ADs. However, oncologists regard “when became terminal status” as an optimal timing for completion of ADs (52.2 %), while other groups regard earlier periods as it. More than 95 % oncologist answered that cardiopulmonary resuscitation and mechanical ventilator are necessity items for ADs form, while around 70 % of other groups answered so. Multivariate analysis revealed that several factors including agreement with terminal disclosures and a positive attitude toward HPC were independently associated with necessity of ADs.

Conclusions

We found that attitudes toward ADs among cancer patients, family caregivers, oncologists, and the general public were significantly different. Our study also suggests that favorable attitudes toward comfort end-of-life care and HPC are keys that influence the perceived need for ADs.