A phase 1 study of OSI-930 in combination with erlotinib in patients with advanced solid tumours.

AIM: To determine the maximum tolerated dose (MTD) of OSI-930 that can be combined with erlotinib, and establish recommended phase 2 doses when both agents are administered daily in patients with advanced solid tumours. PATIENTS AND METHODS: Eligible patients with advanced solid tumours were enrolled into this standard "three+three" dose escalation study. Study treatment commenced on day 1 with OSI-930, and erlotinib was introduced on day 8. PK profiles of OSI-930, erlotinib and its active metabolite, OSI-420, were determined. Changes in sVEGFR2 as a pharmacodynamic biomarker of OSI-930 activity were assessed. RESULTS: Twenty one patients were enrolled to 1 of 3 cohorts: 200 mg OSI-930 BID+100 mg erlotinib QD; 200 mg OSI-930 BID+150 mg erlotinib QD; 300 mg OSI-930 BID+150 mg erlotinib QD. The most common adverse events were anorexia (85%), diarrhoea (75%), rash (70%) and lethargy (65%). The MTD was not reached but the onset of cumulative toxicity necessitating dose modification after the 28-d DLT assessment period was common at the highest dose level. A PK interaction was identified with co-administration of both agents resulting in a two-fold increase in OSI-930 exposure. Pharmacodynamic activity was observed with a decline in sVEGFR levels detected in all patients. Ten patients had disease stabilization (median duration 119 d). CONCLUSIONS: 200 mg OSI-930 BID+150 mg erlotinib QD were the recommended doses for further evaluation of this combination.

Sevoflurane induction for emergency caesarean section: two case reports in women with needle phobia.

Needle phobia is an unusual but well-recognised clinical entity. It is claimed that it may affect up to 10% of the general population and may prevent potential patients from seeking medical care, thereby reducing its apparent incidence in the hospital population. Its occurrence in a parturient requiring urgent caesarean section presents special challenges to the anaesthetist. This report discusses the clinical, ethical and medico-legal dilemmas presented by two such cases that were successfully managed by inhalational induction of general anaesthesia using sevoflurane.

Depletion of CD34+ CD4+ cells in bone marrow from HIV-1-infected individuals.

Pancytopenia as a consequence of bone marrow abnormalities is commonly seen in HIV-infected individuals. To examine the effect that HIV-1 has on hematopoietic cells, we compared hematopoietic properties of bone marrow samples from HTV+ patients at various stages of disease with bone marrow samples from uninfected donors. While the absolute number of recovered CD34+ cells and the cloning efficiency of these cells did not differ significantly in HIV+ donors, the percentage of CD34+ CD4+ cells was significantly depleted in late-stage HIV+ patients. We observed a direct correlation between the numbers of CD34+ CD4+ cells in the bone marrow and the peripheral CD4 count. Further characterization of the CD34+ CD4+ subpopulation demonstrated that these cells expressed lower levels of HLA-DR on their surface compared with CD34+ CD4- cells, suggesting an immature phenotype. We also found evidence for expression of HIV-1 coreceptors CXCR-4 and CKR-5 message and protein in CD34+ bone marrow cells. While this finding suggested that hematopoietic cells might be susceptible to HIV infection at an early stage of maturation, thus affecting different cell lineages as they matured, we did not find any evidence for infection of HIV in these cells. These data suggest that HIV affects early hematopoietic progenitor cells either directly or indirectly, and in particular CD34+ CD4+ cells. This finding has important implications for disease pathogenesis and for application of gene therapy approaches that use CD34+ hematopoietic cells.