Purpose: The cytochromes P450 are a multigene family of enzymes with a central role in the oxidative metabolism of a wide range of xenobiotics, including anticancer drugs and biologically active endogenous compounds. The purpose of this study was to define the cytochrome P450 profile of ovarian cancer and identify novel therapeutic targets and establish the prognostic significance of expression of individual cytochrome P450s in this type of cancer. Experimental Design: Immunohistochemistry for a panel of 23 cytochrome P450s and cytochrome P450 reductase was done on an ovarian cancer tissue microarray consisting of 99 primary epithelial ovarian cancers, 22 peritoneal metastasis, and 13 normal ovarian samples. The intensity of immunoreactivity in each sample was established by light microscopy. Results: In primary ovarian cancer, several P450s (CYP1B1, CYP2A/2B, CYP2F1, CYP2R1, CYP2U1, CYP3A5, CYP3A7, CYP3A43, CYP4Z1, CYP26A1, and CYP51) were present at a significantly higher level of intensity compared with normal ovary. P450 expression was also detected in ovarian cancer metastasis and CYP2S1 and P450 reductase both showed significantly increased expression in metastasis compared with primary ovarian cancer. The presence of low/ negative CYP2A/2B (log rank = 7.06, P = 0.008) or positive CYP4Z1 (log rank = 6.19, P = 0.01) immunoreactivity in primary ovarian cancer were each associated with poor prognosis. Both CYP2A/2B and CYP4Z1were also independent markers of prognosis. Conclusions: The expression profile of individual P450s has been established in ovarian cancer. Several P450s show increased expression in ovarian cancer and this provides the basis for developing P450-based therapeutics in ovarian cancer. Expression of CYP2A/2B or CYP4Z1in primary ovarian cancer were independent markers of prognosis.Ovarian cancer is the most common gynecological malignancy worldwide; yet, the 5-year survival rate for this disease has remained low at f30% for the last 20 years and with relatively little recent improvement (1, 2). Poor prognosis is generally considered to be the result of late presentation when ovarian cancer is of advanced stage and the unpredictable and generally very limited response of this type of cancer to current cancer therapies (3, 4). Improved survival in ovarian cancer is, therefore, dependent on the development of new paradigms in treatment.The cytochrome P450 (P450) enzymes are a large family of constitutive and inducible mono-oxygenase enzymes that metabolize many lipophilic, biologically active endogenous and xenobiotic substrates, including a large number of therapeutic drugs and toxic environmental chemicals (5 -8). Currently, the human P450 superfamily is classified into 18 distinct families based on nucleic acid homology (5). Some P450s, especially the major xenobiotic metabolizing forms of P450, have been very well characterized, whereas very little is known about the biology of some of the more recently identified P450s. Individual P450s show characteristic cell type -and tissue-spe...

Globally, an increasing number of test of cure algorithms now incorporate HPV testing although there is heterogeneity of practice with respect to assay, number of post treatment tests, testing intervals, follow up time. While type specific persistence identified through genotyping may identify those at greater risk of disease there is no consensus as to how this may be applied, clinically. Data on HPV testing in women treated for glandular lesions would be welcome as would the performance of different HPV assays and associated biomarkers in this context.

Epithelial carcinoma of the ovary is one of the most common gynaecologic malignancies, and the fourth most frequent cause of cancer death in women (Yancik, 1993). The asymptomatic early stages of ovarian cancer mean that most patients have widespread disease at the time of diagnosis. Patients with FIGO stage III and IV disease and significant residual tumour masses after primary surgery can expect a 5-year survival rate of less than 10%, despite multiple courses of platinum-based chemotherapy (Omura et al, 1991).Until the mid-1990s, the combination of a platinum compound and an alkylating agent was considered best therapy for these patients, but a new standard of care emerged after the publication of trial GOG-111 in 1996 which was followed by the first reports of the INTERGROUP trial, OV10, in 1998(Piccart et al, 2000. Both these large, prospective randomized studies demonstrated that patients treated with cisplatin-paclitaxel in combination had significantly higher response rates, progression-free survival and overall survival compared with the previous standard treatment of cisplatin and cyclophosphamide. However, this higher efficacy was at the expense of greater toxicity. In GOG-111, 135 mg/m 2 paclitaxel was administered with 75 mg/m 2 cisplatin as an inconvenient 24-hour infusion, and neurotoxicity in particular was more frequently observed (28% vs 21%, P ≤ 0.05). Reducing the paclitaxel infusion time to 3 hours (with a concomitant increase in dose to 175 mg/m 2 ) in OV.10 produced a further increase in neurotoxicity, with 19.6% patients experiencing CTC grade III or IV sensory neurotoxicity, compared with 1% of patients receiving cisplatin-cyclophosphamide. Meta-analyses incorporating data on nearly 10 000 patients from 45 randomized trials suggested that the substitution of carboplatin for cisplatin was equally effective either as a single agent or in combination (Aabo et al, 1998). The addition of carboplatin to paclitaxel was expected to produce less emesis and neurotoxicity, but greater myelosuppression compared with cisplatin-paclitaxel. Seven phase I-II trials of carboplatin-paclitaxel combinations have been reported, involving 260 chemo-naïve ovarian cancer patients (Bookman et al, 1996;Lhomme et al, 1996;Bolis et al, 1997;duBois et al, 1997;Huizing et al, 1997;ten Bokkel Huinink et al, 1997;Siddiqui et al, 1997). Doses of carboplatin ranged from AUC 5-10, and paclitaxel from 120-250 mg/m 2 and almost all the trials used a 3-hour paclitaxel administration schedule. As expected the major toxicities in all studies were myelosuppression and neurotoxicity, however, an apparent reduction in the expected level of thrombocytopenia was observed in many of these trials, and an interaction at the megakaryocyte level rather than a pharmacokinetic interaction is thought to be responsible (Calvert et al, 1995). Antitumour activity was substantial, with response rates ranging from 70-100%.The direct comparison of carboplatin-paclitaxel with cisplatinpaclitaxel in a prospective, randomized trial as first-line t...

Objective To determine the pattern of abnormal cervical cytology in women aged 50 to 60 years and to determine whether the development of cervical neoplasia in this age group is confined to women who have been inadequately screened.Design Retrospective case analysis study.Population An 11-year birth cohort of women in Grampian Region born between 2110133 and 1/10/44, and those who had significant cytological abnormalities in the 5 year period 1/10189 to 3019194.Main outcome measures Cytological and histological outcome for women with significant cytological abnormalities between 50 to 60 years of age and the interval between three consecutive smears taken up to 50 years of age for those women.Results Of 23,440 women aged 50 to 60 years ever screened in Grampian Region, 229 (1%) had significant cytological abnormalities. Seventy had CIN 3 and 15 had invasive disease of the cervix. Among approximately 9000 women with adequate smear histories prior to age 50, one case of CIN 3 and one case of invasion were detected. The prevalence of invasive disease in the whole cohort during this five year period was 59/100,000. Among the previously well screened women the prevalence was 11/100,000.Conclusion The incidence of preinvasive disease of the cervix is low over the age of 50 and is seen almost exclusively in inadequately screened women. There would appear to be little benefit in continuing cervical screening over the age of 50 in women who have had regular negative smears. The release of this low risk group from the cervical screening programme could alleviate anxiety and could enable reallocation of resources to target better high risk women who default from regular screening and to reduce screening intervals where necessary to three years.