Safety evaluation of olaparib for treating ovarian cancer

Introduction: Olaparib (Lynparza®) is an oral, small molecule, poly (ADP-ribose) polymerase inhibitor that has become the first ‘personalized’ therapy available for patients with BRCA mutation-positive ovarian cancer (OC). A capsule formulation of the drug has recently received approval for use in this population for platinum-sensitive recurrent disease for maintenance therapy following platinum-based chemotherapy in Europe and as third- or fourth-line platinum-sensitive therapy in the USA.

Areas covered: This article reviews the development of olaparib in OC with a focus on safety evaluation. Data are based on published literature and reports available from the olaparib development program database.

Expert opinion: Oral olaparib 400 mg twice daily has acceptable tolerability when administered as maintenance monochemotherapy in women with relapsed OC. The common toxicities – nausea/vomiting, fatigue and anemia – are mild or moderate in severity and appear consistent across subgroups (BRCA carriers/wild-type). Though the risk is low, long-term monitoring of patients is warranted to determine the potential risk for hematological complications such as anemia, myelodysplastic syndrome or acute myeloid leukemia.     

HLA-A amino acid polymorphism and delayed kidney allograft function

Delayed allograft function (DGF) is a common adverse event in postrenal transplantation. The etiology of DGF is thought to include both nonimmunologic (donor age, cold ischemia time, and recipient race) and immunologic factors. We examined the association of DGF with amino acid mismatches at 66 variable sites of the HLA-A molecule in a prospective cohort study of 697 renal transplant recipients of deceased donors. Using a multivariate logistic regression model adjusted for nonimmunologic risk factors, we show that combinations of a few amino acid mismatches at crucial sites of HLA-A molecules were associated with DGF. In Caucasian recipients, a mismatch at position 62, 95, or 163, all known to be functionally important within the antigen recognition site, was associated with an increased risk for DGF. Furthermore, a decreased risk for DGF was associated with a mismatch at HLA-A family-specific sites (149, 184, 193, or 246), indicating that evolutionary features of HLA-A polymorphism separating HLA-A families and lineages among donor-recipient pairs may correlate with the magnitude of alloreactivity influencing the development of DGF. These findings suggest that amino acid polymorphisms at functionally important positions at the antigen recognition site of the HLA-A molecule have a significant influence on DGF.     

Improving residents’ confidence in using psychosocial skills

OBJECTIVE: To evaluate an intensive training program’s effects on residents’ confidence in their ability in, anticipation of positive outcomes from, and personal commitment to psychosocial behaviors. DESIGN: Controlled randomized study. SETTING: A university- and community-based primary care residency training program. PARTICIPANTS: 26 first-year residents in internal medicine and family practice. INTERVENTION: The residents were randomly assigned to a control group or to one-month intensive training centered on psychosocial skills needed in primary care. MEASUREMENTS: Questionnaires measuring knowledge of psychosocial medicine, and self-confidence in, anticipation of positive outcomes from, and personal commitment to five skill areas: psychological sensitivity, emotional sensitivity, management of somatization, and directive and nondirective facilitation of patient communication. RESULTS: The trained residents expressed higher self-confidence in all five areas of psychosocial skill (p<0.03 for all tests), anticipated more positive outcomes for emotional sensitivity (p=0.05), managing somatization (p=0.03), and nondirectively facilitating patient communication (p=0.02), and were more strongly committed to being emotionally sensitive (p=0.055) and managing somatization (p=0.056), compared with the untrained residents. The trained residents also evidenced more knowledge of psychosocial medicine than did the untrained residents (p<0.001). CONCLUSIONS: Intensive psychosocial training improves residents’ self-confidence in their ability regarding key psychosocial behaviors and increases their knowledge of psychosocial medicine. Training also increases anticipation of positive outcomes from and personal commitment to some, but not all, psychosocial skills. Presented at the annual meeting of the Society of General Internal Medicine, Washington, DC, April 27–29, 1994. Supported by the Fetzer Institute in Kalamazoo, MI.