Primary umbilical adenocarcinoma.

Primary umbilical tumours are extremely rare. We report primary serous adenocarcinoma arising from the coelomic mesothelium of the hernial sac. A 60-year-old woman presented with an umbilical swelling of six months duration that became painful in the last three days. Examination revealed a tender umbilical swelling diagnosed as obstructive hernia that needed surgery. When dissecting the sac during surgery, a small subcutaneous abscess was encountered. The sac contained an omentum with a hard nodule at the surface which was excised. Umbilical hernia repair was performed. Histology of the omental nodule revealed serous papillary adenocarcinoma. Chest and abdomen computed tomography, pelvic magnetic resonance imaging, gastroscopy, colonoscopy and laparotomy did not reveal the primary site of the tumour.

Factors influencing the quality of life of infertile women in United Arab Emirates.

OBJECTIVES: To measure the quality of life in a representative sample of infertile women and evaluate their sociocultural attitude to this condition. METHODS: Two hundred sixty-nine infertile women attending the Assisted Reproduction clinic, Tawam Hospital were consecutively selected. They were interviewed about the effect of infertility on their quality of life using a structured, measurement-specific and pre-tested questionnaire. RESULTS: Parameters mostly affected were mood-related mainly in women above 30 years, with primary and female factor infertility and those in polygamous marriages. Quality of life did not affect sexual performance and was not affected by duration of infertility or cost of treatment. CONCLUSION: The results highlight the importance of bearing children and the stresses exerted on infertile women in Eastern societies. Thorough counseling and continuing support of infertile women is therefore indicated to improve their quality of life.

Knowledge and practice of contraception in United Arab Emirates women.

OBJECTIVE: To determine the knowledge and practice of contraception among United Arab Emirates (UAE) women. METHOD: Four hundred and fifty UAE women at risk of pregnancy were randomly selected from the community and primary health care centres and interviewed about knowledge and practice of contraception using a structured questionnaire. RESULTS: Four hundred women (89%) gave consent to participate in the study. One hundred and sixty-six participants (41.5%) were using contraception. All used natural methods backed with other methods. There were significant associations between using contraception and each of age, high level of education and low family income (p < 0.0001 for the three variables). Religious beliefs and low expectation of success of birth control were the reasons given for non-use. Eighty-five percent of subjects did not accept sterilisation without medical indications, nor using contraception before the first pregnancy. Of the women, 42.5% believed that contraceptive methods should not be used after the age of 40, and 78% were unaware that they could be used for treatment of gynaecological diseases. Disturbed bleeding patterns occurred in 48.7% of users, and these were most bothered by the inability to pray (100%) and to have sexual intercourse (97.5%). CONCLUSION: Contraception is not commonly used by UAE women because of sociocultural traditions, religious beliefs and poor knowledge.

Pharmacokinetically guided dose escalation of carboplatin in epithelial ovarian cancer: effect on drug-plasma AUC and peripheral blood drug-DNA adduct levels.

BACKGROUND: Platinum based drugs are active agents in epithelial ovarian cancer and increased platinum drug dose intensity is thought to lead to improved survival, because of the largely untested assumption that increased dose intensity results in an increased interaction of the platinum drug with its target, DNA. In a previously reported phase I trial (Lind et al., J Clin Oncol 1996; 14: 800-5), carboplatin dose intensity was increased by the use of G-CSF to support the bone marrow and using pharmacokinetically-guided carboplatin dosing. The objectives of this study were to validate the carboplatin dosing formula during high dose intensity therapy and evaluate the relationship between systemic carboplatin exposure and Pt-DNA adduct levels in peripheral blood leucocytes. PATIENTS AND METHODS: A total of 17 patients were studied over four levels of dose intensification. The carboplatin dose was calculated using the 'Calvert formula'. Levels of drug-target interaction in peripheral blood leukocytes were measured using an immunoassay based on a monoclonal antibody that recognises DNA-platinum adducts. Pharmacokinetic measurements were carried out using a previously validated single sample method. RESULTS: The area under the curve of concentration of unbound carboplatin in plasma versus time (AUC) for target AUC values of 5, 7 and 9 mg/ml x min were: 5.6 +/- 1.0, 7.3 +/- 0.7 and 9.8 +/- 0.5 mg/ml x min (mean +/- S.D.). There was a good correlation between target and achieved dose intensities (r2 = 0.899) and the slope of the linear regression line was 0.95 (+/- 0.09 SD) not significantly different to 1.0 (P > 0.6). The levels of immunoreactive DNA adducts were not detectable at a target AUC of 5 mg/ml x min but increased progressively at the higher AUC levels. Accumulation of adducts between courses was not detected. CONCLUSIONS: Pharmacokinetically-based carboplatin dosing during high intensity therapy accurately predicted the dose required to achieve a target AUC and resulted in consistent patient exposure to active drug. During the dose escalation study, peripheral blood leucocyte DNA platinum-DNA adduct levels were positively related to drug dose and drug AUC.

The relationship between tumour glutathione concentration, glutathione S-transferase isoenzyme expression and response to single agent carboplatin in epithelial ovarian cancer patients.

There is evidence to suggest that glutathione (GSH) and glutathione-S-transferases (GST) are important factors in determining sensitivity to cytotoxic drugs in vitro and in preclinical in vivo model systems. To define the relationship between tumour GSH concentration, GST isoenzyme expression and response to carboplatin in epithelial ovarian cancer (EOC), tumour samples from 39 patients with assessable disease after primary surgery were analyzed for GSH content and GST expression. Response was assessed after completing six courses of single agent carboplatin therapy. GSH was measured by high performance liquid chromatography (HPLC) in fresh tumour samples taken at primary laparatomy. GST isoenzyme expression was assessed by immunohistochemistry of fixed tumour material using antibodies specific for pi, alpha and mu classes. GST isoenzyme expression was defined as positive if the staining intensity was strong and more than 10% of tumour cells were involved. The mean GSH concentrations were: 8351 +/- 4496, 7211 +/- 5026, 6559 +/- 4573 and 3758 +/- 1885 (nmol g-1 tissue dry weight mean +/- s.d.) for tumours from patients who subsequently achieved a complete response (CR, n = 18), partial response (PR, n = 10) or who had static disease (SD, n = 7) or progressive disease (PD, n = 4) respectively. There was no relationship between GSH concentration and response (ANOVA, P = 0.32). There were also no relationship between GST isoenzyme expression and response (P Fisher's exact test 0.51-0.55 and chi-squared test 0.98-0.99). In conclusion, there was no association between the concentration of GSH or expression of GST isoenzymes and response to single agent carboplatin in primary previously untreated EOC.

Phase I study of pharmacologically based dosing of carboplatin with filgrastim support in women with epithelial ovarian cancer.

PURPOSE: The aim of this study was to increase the dose intensity of carboplatin in women with International Federation of Gynecology and Obstetrics (FIGO) Stage Ic-IV epithelial ovarian cancer with the use of granulocyte colony-stimulating factor (G-CSF; filgrastim; Amgen, Thousand Oaks, CA). PATIENTS AND METHODS: A phase I study of escalating target area under the curves (AUCs) of carboplatin with G-CSF (filgrastim) ws undertaken. The target AUCs were 5 mg/mL.min every 21 days for four cycles, 5 mg/mL.min every 14 days for four cycles, 7 mg/mL.min every 14 days for four cycles, 9 mg/mL.min every 14 days for four cycles, and 11 mg/mL.min every 14 days for four cycles. G-CSF was given at a dose of 5 microg/kg/d starting 24 hours after carboplatin administration and lasting until 24 hours before the next cycle and until day 14 after the last cycle. RESULTS: We were able to escalate to an AUC level of 9 mg/mL.min every 14 days for four cycles. At this dose, severe thrombocytopenia, that necessitated dosage delays, and failure to give subsequent cycles of carboplatin were observed. We then reduced the AUC level to 8 mg/mL.min every 14 days for four cycles. However, severe thrombocytopenia was also observed at this level. CONCLUSION: An AUC of 7 mg/mL.min every 14 days for four cycles is the maximum tolerated AUC level that can be achieved with G-CSF. Further escalations may be possible using either combinations of cytokines or peripheral stem-cell collections.

A single-sample assay for the estimation of the area under the free carboplatin plasma concentration versus time curve.

The aim of this study was to develop and validate a simple and rapid method for the estimation of the area under the free carboplatin plasma concentration versus time curve (AUC). The relationship between the carboplatin AUC and the total plasma platinum (Pt) concentration 24 h after treatment was studied using data from 49 patients treated with 20-1600 mg/m2 carboplatin as a 60-100 min infusion (median 60 min). The relationship was confirmed by the in vitro incubation of carboplatin in human plasma and prospectively validated in 13 ovarian cancer patients. Free carboplatin was separated by ultrafiltration (MW cut off 30,000), and free and total Pt measured by atomic absorption spectrophotometry. There was a linear relationship in vivo between the 24 h (median 24.4; range 16.3-27.3 h) total plasma Pt concentration (microM) and free carboplatin AUC (mg/ml.min): AUC=(24 h Pt+0.3)/0.82 (r2=0.93, AUC median 5.8 (0.13-28)mg/ml.min, 24h Pt median 4.4 (0.1-23) microM). A similar relationship was observed in vitro [AUC =(24h Pt +0.1)/0.93 (r2=0.98, AUC median 7.9 (2.0-17) mg/ml.min, 24 h Pt median 7.1 (1.8-15) microM)]. The relationship derived from the in vivo data gave an unbiased and reasonably accurate estimate of the measured carboplatin AUC in 13 patients (AUC =5.1-8.7 mg/ml.min, GFR=59-129 ml/min, infusion time 30-45 min, 24 h sampling time 22.9-24.5 h), giving a percentage mean error of -4.2% and root mean squared percentage error of 11.5%. These results show that the analysis of a single blood sample taken 24 h after carboplatin administration can be used to produce an unbiased and reasonably accurate measure of the free carboplatin AUC. Unlike published limited sampling strategies, this method is not complicated by the need to accurately control the duration of the carboplatin infusion or the time at which the sample is taken.

Carboplatin and granulocyte colony-stimulating factor as first-line treatment for epithelial ovarian cancer: a phase I dose-intensity escalation study.

A phase I study of frequently administered carboplatin with recombinant human granulocyte colony-stimulating factor (filgrastim) has been performed in patients with newly diagnosed epithelial ovarian cancer. Recombinant human granulocyte colony-stimulating factor was administered at a dose of 5 micrograms/kg/d for days 1 through 12 after carboplatin treatment. Carboplatin doses were calculated using a pharmacokinetic formula on an area under the curve (AUC) basis. Four doses of carboplatin were planned for each patient. The first cohort of patients received an AUC of 5 mg/mL x min every 3 weeks. Subsequently four additional cohorts received AUCs of 5, 7, 9, and 8 every 2 weeks. Non-hematologic toxicities were mild and not significant. The dose-limiting toxicity was thrombocytopenia and occurred at an AUC of 9. Most patients could complete treatment at an AUC of 7. Results for AUC 8 are awaited. Complete and partial responses were seen in most patients at all dose levels.