High prevalence of BRCA1 founder mutations in Greek breast/ovarian families.

We have screened 473 breast/ovarian cancer patients with family history, aiming to define the prevalence and enrich the spectrum of BRCA1/2 pathogenic mutations occurring in the Greek population. An overall mutation prevalence of 32% was observed. Six BRCA1 recurrent/founder mutations dominate the observed spectrum (58.5% of all mutations found). These include three mutations in exon 20 and three large genomic deletions. Of the 44 different deleterious mutations found in both genes, 16 are novel and reported here for the first time. Correlation with available histopathology data showed that 80% of BRCA1 carriers presented a triple-negative breast cancer phenotype while 82% of BRCA2 carriers had oestrogen receptor positive tumours. This study provides a comprehensive view of the frequency, type and distribution of BRCA1/2 mutations in the Greek population as well as an insight of the screening strategy of choice for patients of Greek origin. We conclude that the Greek population has a diverse mutation spectrum influenced by strong founder effects.

Avascular necrosis of bone: the hidden risk of glucocorticoids used as antiemetics in cancer chemotherapy.

The role of antiemetics is invaluable in allowing cancer patients to complete otherwise potentially intolerable chemotherapy. Corticosteroids have an established place in the prevention and treatment of nausea and vomiting due to emetogenic cytotoxic agents. Avascular necrosis of bone is a recognised complication of glucocorticoid treatment--the risk of this increasing with higher doses and longer duration of use. This report details a case of bilateral avascular necrosis of the femoral heads in a patient receiving 'standard' doses of dexamethasone as part of the antiemetic regimen used in cisplatin-based combination chemotherapy.

Multiple ways of silencing E-cadherin gene expression in lobular carcinoma of the breast.

The cell-cell adhesion receptor gene E-cadherin (CDH1) is expressed by epithelial cells, in which it mediates adhesion and morphogenesis. Invasive lobular carcinoma (ILC) characteristically infiltrates diffusely as single cells; by immunohistochemistry, many of these tumours lack E-cadherin expression. In the present study we investigated various ways in which loss of function of the E-cadherin gene could occur in ILCs, namely, promoter methylation, mutation and allelic loss. We analysed 22 ILCs and found 12 (55%) E-cadherin-negative samples by immunohistochemical analysis. Methylation-specific polymerase chain reaction (PCR) showed that 17/22 (77%) of these tumours had methylation of the CDH1 promoter, including 11/12 (91%) of the E-cadherin-negative tumours. All 16 exons of E-cadherin (including intron-exon boundaries) were amplified from chromosomal DNA and screened for mutations by conformation-sensitive gel electrophoresis (CSGE). Bands with altered mobility were analysed by direct sequencing. We identified five frameshift mutations, which resulted in downstream stop codons and one splice site mutation in six different tumours (29%). Loss of heterozygosity (LOH) was assessed using microsatellite markers, and 9/18 (50%) informative tumours showed LOH. We conclude that most ILCs show genetic or epigenetic changes affecting the E-cadherin gene and that many of these tumours lack E-cadherin expression. In all cases in which there was loss of expression, this was consistent with biallelic inactivation of CDH1 by promoter methylation, mutation or allelic loss in any combination.

Antiemetic efficacy of high-dose metoclopramide and dexamethasone in patients receiving cisplatin chemotherapy: a randomized trial.

In a prospective randomized trial we compared the antiemetic efficacy of metoclopramide (MCP) and dexamethasone (DXM). A total of 172 patients receiving chemotherapy based on cisplatin 100 mg/m2/day were randomly allocated to four groups. CP was administered in 5 doses of 1.5 mg/kg (group A), 2 mg/kg (group C), or combined with 4 doses of DXM 4 mg/6 h (MCP: 1.5 mg/kg in group B; 2 mg/kg in group D). Vomiting was decreased in the DXM groups compared to groups A and C (p < 0.002), and the duration of nausea was greater in group A than in group D (P < 0.004). A greater disturbance in appetite was observed in group A compared to groups B (p < 0.028), D(p < 0.001) and C (p < 0.045). Activity problems were greater in group A than in C (p < 0.003) and D(p < 0.005). We noticed that a small increase in MCP (0.5 mg/kg) did not influence the antiemetic effect. The addition of DXM did not significantly alter the antiemetic results at the lower MCP dose, but improved them when MCP was slightly increased. We conclude that DXM slightly improves the antiemetic effect of MCP and the effects are related to the MCP dose.