Buparlisib,an oral pan-PI3K inhibitor for the treatment of breast cancer

Introduction: Deregulation of the phosphatidylinositol-3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) intracellular signaling pathway is common in breast cancer (BC) and has been found to be potentially implicated in resistance to endocrine and anti-HER2 therapies. Targeting the PI3K/Akt/mTOR pathway may remove this inhibition and restore sensitivity to these compounds. Buparlisib (BKM120) is a potent oral pan-class I PI3K inhibitor that is being extensively evaluated in multiple tumor types.

Areas covered: This review briefly summarizes the pharmacodynamics and pharmacokinetics of buparlisib, focusing on preclinical and clinical data in BC and on ongoing randomized trials.

Expert opinion: Overall, buparlisib is a safe and tolerable drug and, despite its peculiar toxicity profile, it is suitable for studies in combination with other anticancer agents in BC. Early-phase clinical trials in BC have provided evidence of antitumor activity. Several trials are being conducted in all the biological subsets of BC, including combinations with endocrine therapy, anti-HER2 agents, PARP-inhibitors and chemotherapy. While clinical results are eagerly awaited, biological material suitable for both genomic and non-genomic analyses is being collected. The authors expect an intense investigation of the potential biomarkers that explain response or resistance to buparlisib and inspire strategies to rationally explore the therapeutic potential of this drug.     

Treatment of hepatitis C-related kidney disease

Introduction: Hepatitis C virus (HCV) infection has been associated with a large spectrum of glomerular lesions in both native and transplanted kidneys. The most common HCV-associated renal disease is type I membranoproliferative glomerulonephritis usually, but not invariably, in the context of type II mixed cryoglobulinemia (MC). HCV infection is also the major cause of MC, a systemic vasculitis characterized by involvement of small and, less frequently, medium-sized vessels. Conflicting data exist on the treatment of HCV-associated glomerular disease.

Areas covered: This review examines the drugs used for management of HCV-related kidney disease and discusses current and new strategies. All literature concerning treatment of HCV-associated kidney disease has been retrieved by electronic (Medline) and manual searches.

Expert opinion: Various approaches have been recommended for the treatment of HCV-related glomerular disease, including immunosuppressive therapy (corticosteroids, cytotoxic agents and mAbs) and antiviral therapy. These regimens should be considered according to the level or proteinuria and kidney failure. Immunosuppressive agents are recommended in patients with nephrotic syndrome and/or rapidly progressive kidney failure. Antiviral treatment based on IFN and/or ribavirin or triple antiviral therapy (PEGylated-IFN/ribavirin/telaprevir or boceprevir) has been adopted in patients with moderate proteinuria and slow loss of kidney failure; however, the number of patients enrolled was small. Some patients with HCV-related cryoglobulinemic glomerulonephritis have been treated with rituximab but some issues about its role remain to be clarified. The antiviral treatment of HCV-related glomerular disease is expected to improve in the near future with new agents provided with greater efficacy and safety. However, the affordability of these drugs remains a pivotal issue, particularly in low-income countries.     

p.Arg1809Cys substitution in neurofibromin is associated with a distinctive NF1 phenotype without neurofibromas

Analysis of 786 NF1 mutation-positive subjects with clinical diagnosis of neurofibromatosis type 1 (NF1) allowed to identify the heterozygous c.5425C>T missense variant (p.Arg1809Cys) in six (0.7%) unrelated probands (three familial and three sporadic cases), all exhibiting a mild form of disease. Detailed clinical characterization of these subjects and other eight affected relatives showed that all individuals had multiple cafè-au-lait spots, frequently associated with skinfold freckling, but absence of discrete cutaneous or plexiform neurofibromas, Lisch nodules, typical NF1 osseous lesions or symptomatic optic gliomas. Facial features in half of the individuals were suggestive of Noonan syndrome. Our finding and revision of the literature consistently indicate that the c.5425C>T change is associated with a distinctive, mild form of NF1, providing new data with direct impact on genetic counseling and patient management.     

Correlates of major complications and mortality in patients presenting to the emergency department with chest pain and more than bibasilar rales

Objective: To identify correlates of major complications and mortality in patients presenting to the emergency department with chest pain and more than bibasilar rales. Design: Prospective cohort study. Setting: The emergency departments of three university and four community hospitals. Patients: Five hundred patients more than 30 years of age presenting to the emergency departments between 1984 and 1985 with a chief complaint of chest pain not explained by obvious trauma or chest x-ray abnormalities, and more than bibasilar rales on physical examination. Measurements and main results: A standard data form was used to collect the history, physical examination, vital sign, and electrocardiographic findings. Chart review was carried out to record complications and mortality. One hundred eleven (22%) of the patients had a major complication (ventricular fibrillation, Mobitz II heart block, complete heart block, atrioventricular dissociation, cardiogenic shock, cardiac arrest, endotracheal intubation, intra-aortic balloon pump) or died, 160 (32%) were diagnosed as having myocardial infarction, and 58 (12%) died. Of those patients who had major complications or who died, the first complication occurred within six hours of hospital admission for 32% of the patients and within 24 hours for 47% of the patients. Univariate correlates (p<0.10) of a major complication or death were entered into a stepwise logistic regression model. In the multivariate model, ST elevation or Q waves not known to be old [adjusted odds ratio (OR) 5.8, 95% confidence interval (CI) 3.0–11.1], ST-T changes of ischemia not known to be old (OR 2.6, 95% CI 1.5–4.6), systolic blood pressure ≤ 120 mm Hg (OR 3.2, 95% CI 1.9–5.6), and age >70 years (OR 1.8, 95% CI 1.1–3.0) were correlates of a major complication or death. Conclusion: For patients presenting to the emergency department with chest pain and more than bibasilar rales, major electrocardiographic changes, systolic blood pressure ≤ 120 mm Hg, and age >70 years were correlated with a higher risk of a major complication or death. Supported by a grant (83102-2H) from the John A. Hartford Foundation, New York. Dr. Lee is the recipient of an Established Investigator Award (900119) from the American Heart Association.