Safety of vemurafenib in patients with BRAF V600 mutated metastatic melanoma: the Spanish experience.

OBJECTIVES: Vemurafenib tolerability was assessed in a large, open-label, multicentre study in patients with BRAF V600 mutated advanced melanoma. We investigated safety, tolerability and efficacy of vemurafenib in Spanish patients participating in that study. METHODS: Patients with previously treated or treatment-naive, unresectable stage IIIC or stage IV, BRAF V600 mutation-positive melanoma received vemurafenib 960 mg twice daily until disease progression, unacceptable toxicity, withdrawal of consent or death. The primary endpoint was safety; secondary endpoints included overall response rate (ORR), progression-free survival (PFS) and overall survival (OS). RESULTS: 301 Spanish patients were included, 70 % with M1c disease, 22 % with brain metastases and 51 % with prior systemic therapy for metastatic disease. Most frequent adverse events included fatigue (48 %), arthralgia (45 %), rash (41 %), photosensitivity (34 %) and skin neoplasms (21 %). Grade 3/4 adverse events occurred in 156 patients (52 %), including cutaneous squamous cell carcinoma (including keratoacanthoma; 16 %), fatigue (6 %) and arthralgia (5 %). The ORR was 28 % (95 % CI 23-34 %). Responses occurred in patients with brain metastases (18 %), elevated baseline lactate dehydrogenase (19 %) and poor performance status (15 %), and elderly patients (22 %). Median PFS was 5.8 (95 % CI 5.0-6.4) months; median OS was 10.5 (95 % CI 9.5-13.5) months. CONCLUSION: Our results for Spanish patients in the vemurafenib safety study indicate similar efficacy and a comparable safety profile in Spanish patients with no new safety signals compared with the overall population. Clinical benefit was demonstrated in poor-prognosis patients and in those with favourable baseline characteristics, suggesting that poor-prognosis patients may also benefit from vemurafenib treatment.

A phase II study of feasibility and toxicity of bevacizumab in combination with temozolomide in patients with recurrent glioblastoma.

PURPOSE: The aim of this prospective and multicentric phase II study was to evaluate the efficacy and safety of temozolomide (TMZ) and bevacizumab (BV) in patients (pts) with recurrent glioblastoma (GB), previously treated with chemoradiotherapy and at least three cycles of adjuvant TMZ. PATIENTS AND METHODS: Patients with GB at first relapse received BV 10 mg/kg day every 2 weeks and TMZ 150 mg/m(2) days 1-7 and 15-21, every 28 days. Patients underwent brain magnetic resonance imaging every 8 weeks. RESULTS: Thirty-two evaluable pts were recruited in 8 sites. Fourteen pts (44%) had gross total resection. O(6)-methylguanine-DNA methyltransferase (MGMT) promoter was methylated in 12 pts, unmethylated in 6 pts, and missing in 14 pts. The estimated 6-month progression free survival (PFS) rate was 21.9% (95% CI 9.3-40.0%). The median PFS and overall survival (OS) were 4.2 months (95% CI 3.6-5.4 months) and 7.3 months (95% CI 5.8-8.8 months), respectively. No significant association with MGMT status was found in terms of OS or PFS. Six of 32 pts (19%; 95% CI 7.2-36.4) were long-term survivors, with a median PFS and OS (50% events) of 9.5 months (95% CI 7.9-23.6) and 15.4 (95% CI 8.9-NA), respectively: no differences in baseline characteristics were identified in comparison with total population. No unexpected toxicities or treatment-related deaths were observed. CONCLUSIONS: This regimen showed to be feasible and well tolerated in pts with recurrent GB pretreated with TMZ. Further investigation is warranted to identify subpopulations that are more likely to benefit from addition of BV to GB therapy.

Skeletal maturation in intrauterine growth-retarded rats treated with growth hormone.

The objective of this study was to analyse the effects of intrauterine growth retardation (IUGR) and growth hormone (Gh) therapy on skeletal maturation in growth retarded rats. One-hundred and thirty-five rats constituted the groups: Control (C), Sham-operated (SH), IUGR and IUGR+Gh: injected with Genotropin 3.0 mg/kg/day) from 21 to 60 days of age. SH was injected only with saline solution. The thickness of tibial cartilage was assessed on X-ray at the ages 1, 21, 42, 63 and 84 days and categorised according to three levels. L1: maximal thickness, L2: reduction of 50% and L3: absence. The percentual differences between frequencies for each level were compared and clustered by simple ligation in Euclidean distance. The results lead to us to conclude that skeletal maturation does not appear to be modified by IUGR, while it is accelerated by growth hormone in growth-retarded rats.

Sexual responses to intrauterine stress: body and brain growth.

The aims of this work were to analyse body and brain growth as produced by deficiencies in the uteroplacental blood supply, and to evaluate sexual responses to intrauterine stress. Intrauterine growth retardation (IUGR) was experimentally induced in pregnant rats by partial obstruction in both uterine vessels at 1,7 and 14 gestational days. The dysfunctions in the placental circulation retarded both somatic and cerebral growth, depending on the period of gestational stress and the sex. Brain weight had a relatively greater resistance than body weight, which is called a "brain sparing" mechanism. The body and brain sexual dimorphism in control pups was inhibited in IUGR pups. This study shows that prenatal stress exposition might modify growth and sexual dimorphism at birth.

Effects of bilateral uterine vessel ligation on skeletal growth in rats.

The aim of the present study was to assess the catch-up growth in the postcranial skeleton of intrauterine growth retarded (IUGR) rats. Male and female Wistar rats were assigned to one of the following groups: controls, sham-operated, IUGR. The IUGR was produced by uterine vessels bending (day 14th of pregnancy). Trunk, pelvis, femur and humerus were measured on Rx of each animal, from I to 84 days of age. Data were processed by repeated analysis of variance and LSD post hoc test. The reduced placental blood flow disturbed the skeletal growth in pups, with the axial skeleton relatively more affected than the bones of the extremities. The catch up only took place in femur length of both sexes. The widths of long bones remained significantly retarded. We concluded that nutritional rehabilitation during the postnatal period might not be enough to allow a complete growth recovery.