Insulin-sensitizing agents: use in pregnancy and as therapy in polycystic ovary syndrome.

Treatment with insulin-sensitizing agents is a relatively recent therapeutic strategy in women with polycystic ovary syndrome (PCOS) and insulin resistance. The key areas addressed in this review include PCOS and the development of type 2 diabetes mellitus and gestational diabetes, as well as the use of insulin-sensitizing agents, particularly metformin, in the management of infertility in obese and non-obese PCOS women. Treatment with metformin in PCOS women undergoing IVF and the use of metformin during gestation will be discussed. The challenge for the health care professional should be the appropriate utilization of pharmacotherapies to improve insulin sensitivity and lower circulating insulin levels resulting in beneficial changes in PCOS phenotype. Further research into the potential role of other insulin-sensitizing agents, such as pioglitazone and rosiglitazone, in the treatment of infertile women with PCOS is needed.

Antigenic differences between metastatic cells in bone marrow and primary tumours and the anti-MUC1 humoral immune response induced in breast cancer patients.

The dissemination of a malignant neoplasia is a complex process, which requires a set of molecules that remains unknown. It has been suggested that mucins and their carbohydrate-associated antigens may be implicated in tumour spreading which may be also influenced by an anti-MUC1 immune response. In this pilot study, we report the pattern of carbohydrate and peptidic MUC1-associated epitopes on carcinoma cells isolated from bone marrow (BM), taking into account primary tumour histopathologic features. We also bring information about the anti-MUC1 humoral response in these patients. Seventeen patients with invasive breast carcinoma were included. A sample of the primary tumour, a serum sample and a BM aspirate were obtained from each patient. Clinical features studied were tumour size, number of metastatic nodes, histological type and disease stage. Standard immunohistochemistry was performed with antigenic retrieval using different monoclonal antibodies (MAbs): anti carbohydrate antigens: Lewis x (KM380), sLewis x (KM93), Lewis y (C14) and Tn, anti-MUC1 peptide core MAbs: C595, HMFG2 and SM3, anti-cytokeratins, anti-protoncogenes ErbB2 and ErbB3 (IgG) MAbs and also anti-CD34 and anti-CD45 MAbs. ELISA techniques were employed to study circulating MUC1 as well as free and complexed anti-MUC1 antibodies. Immunohistochemical results showed that carbohydrate antigenic expression increases in BM neoplastic cells compared to the original tumours. However, we were not able to demonstrate that a humoral immune response to MUC1 has been induced in these patients. Finally, the employed procedures allow the selective immortalisation of micrometastatic carcinoma cells since short-term cell lines were established.

[S100 protein in tumours of the central nervous system]. / Proteína S100 en tumores del sistema nervioso central.

OBJECTIVE: S100 protein has been detected in glials cells. The subject of this study is to evaluate the usefulness of serum levels of S100 as tumor marker for the screening diagnosis and follow up in patients with CNS tumors. PATIENTS AND METHODS: 57 patients were studied with tumors of the CNS: 24 multiform glioblastomas (GM), 11 anaplastic astrocytomas (AA), 3 oligodedrogliomas, 1 pinealoblastoma, 3 neurinomas, 1 low grade glioma and 13 brain metastasis of other extraneural primary tumors. 25 healthy people have been taken as control group. The S100 was analyzed by an immunoradiometric assay (IRMA) with 125 Iode. The cut off value was 0.2 g/L. RESULTS: The presurgical mean serum values of S100 didn t differ of the mean values of the control group (0.08 and 0.07 g/L, respectively). In the surgical treated patients with residual tumoral or recurrent tumors, the values of S100 increases to 38.9% in GM, 57.11% in AA and 76.9% in brain metastasis. In GM the serum values are significantly higher in patients with active tumor before receiving treatment with chemotherapy, radiotherapy or radiosurgery (p < 0.05). The values decreses to normal levels after response to oncological therapies. During the follow up (mean 551 days), the global sensitivity of S100 for progression of the disease was 47.5% and specificity was 90% with a correspondence between S100 and disease s evolution of 56%. CONCLUSIONS: S100 protein is not useful in the initial diagnosis of tumoral disease but it could be of help in the follow up of the disease because it decreases with successful treatments and increases at the time when the tumor progress.

Risk factors for high-order multiple implantation after ovarian stimulation with gonadotrophins: evidence from a large series of 1878 consecutive pregnancies in a single centre.

BACKGROUND: High-order multiple pregnancies (triplets or more) have a large adverse impact on perinatal morbidity and mortality as well as important economic consequences. Most triplets and higher births are due to ovulation induction alone or in combination with intrauterine insemination (IUI) rather than to in-vitro fertilization (IVF). The present investigation was undertaken to determine whether there were specific variables that related to patient clinical characteristics (age of the woman, duration of infertility, type of infertility, body mass index, basal FSH and LH concentrations), treatment characteristics (initial dose of gonadotrophins, total dose of gonadotrophins administered, number of days of ovarian stimulation, insemination procedure, number of spermatozoa inseminated in patients undergoing IUI, type of luteal support), and ovarian response (oestradiol serum concentrations, number and size of follicles) that might be associated with the occurrence of high-order multiple implantation in order to develop a prediction model. METHODS: This study employed univariate, multivariate and receiver-operating characteristic (ROC) analysis of a large series of 1878 consecutive pregnancies obtained in cycles stimulated with gonadotrophins. Of them, 1771 (94.3%) were low-order pregnancies (1477 singletons and 294 pairs of twins) and 107 (5.7%) were high-order pregnancies. RESULTS: Predictive variables in the multivariate analysis were age of the woman, serum oestradiol concentrations and number of follicles >10 mm on the day of HCG injection. Stratification of the number of follicles into three categories (1 to 3, 4 to 5, and >5 follicles respectively), peak serum oestradiol and woman's age according to the ROC curves, showed that the risk of high-order multiple implantation correlated significantly with increasing total number of follicles and was significantly increased in women with a serum oestradiol >862 pg/ml and aged < or =32 years. CONCLUSIONS: This three-variable model can help to identify patients at high-risk for high-order multiple pregnancy in ovulation induction cycles.

Multicenter phase II trial of temozolomide in patients with anaplastic astrocytoma or anaplastic oligoastrocytoma at first relapse. Temodal Brain Tumor Group.

PURPOSE: To determine the antitumor efficacy and safety profile of temozolomide in patients with malignant astrocytoma at first relapse. PATIENTS AND METHODS: This open-label, multicenter, phase II trial enrolled 162 patients (intent-to-treat [ITT] population). After central histologic review, 111 patients were confirmed to have had an anaplastic astrocytoma (AA) or anaplastic mixed oligoastrocytoma. Chemotherapy-naive patients were treated with temozolomide 200 mg/m(2)/d. Patients previously treated with chemotherapy received temozolomide 150 mg/m(2)/d; the dose could be increased to 200 mg/m(2)/d in the absence of grade 3/4 toxicity. Therapy was administered orally on the first 5 days of a 28-day cycle. RESULTS: Progression-free survival (PFS) at 6 months, the primary protocol end point, was 46% (95% confidence interval, 38% to 54%). The median PFS was 5.4 months, and PFS at 12 months was 24%. The median overall survival was 13.6 months, and the 6- and 12-month survival rates were 75% and 56%, respectively. The objective response rate determined by independent central review of gadolinium-enhanced magnetic resonance imaging scans of the ITT population was 35% (8% complete response [CR], 27% partial response [PR]), with an additional 26% of patients with stable disease (SD). The median PFS for patients with SD was 4.4 months, with 33% progression-free at 6 months. Maintenance of progression-free status and objectively assessed response (CR/PR/SD) were both associated with health-related quality-of-life (HQL) benefits. Adverse events were mild to moderate, with hematologic side effects occurring in less than 10% of patients. CONCLUSION: Temozolomide demonstrated good single-agent activity, an acceptable safety profile, and documented HQL benefits in patients with recurrent AA.

Trilineage phenotypic compromise in acute leukemia.

The expression of three lineage specific antigens in the leukemic blasts is extremely infrequent. We here report a case of triphenotypic acute leukemia with involvement of the myeloid and B and T lineages. The morphology of the blasts showed promyelocytic features with agranular cytoplasm, suggesting a M3-variant of AML. The blasts were positive for myeloperoxidase PAS and Sudan Black. Immunophenotype and cytogenetics did not confirm M3-AML diagnosis, showing a trilineage compromise (myeloid and T and B lymphoid markers) and the cytogenetic alterations +8 and +11, respectively. This report highlights the importance of correlating the results of multiple diagnostic methods in order to establish a correct diagnosis of mixed lineage acute leukemias, and allows evaluation of the prognostic importance of this subgroup of patients.

Further characterization of the luteal phase inadequacy after gonadotrophin-releasing hormone agonist-induced ovulation in gonadotrophin-stimulated cycles.

To characterize further the luteal phase ensuing gonadotrophin-releasing hormone agonist (GnRHa)-induced ovulation in exogenous gonadotrophin-stimulated cycles, plasma progesterone concentrations on luteal days +2 and +8 were determined in 20 patients (group 1) receiving one s.c. 0.5 mg injection of the GnRHa leuprolide acetate and in 10 patients (group 2) receiving two doses 12 h apart in multifollicular cycles stimulated with highly purified follicle-stimulating hormone (FSH). The patients received luteal support with micronized vaginal progesterone from day +2 (after sampling for plasma progesterone determination) until the onset of menses. The duration of the luteal phase was also assessed. As a control group, we included five fertile women who underwent plasma progesterone determinations on days +2 and +8 according to the luteinizing hormone peak in their spontaneous ovulatory cycles. On day +2, plasma progesterone concentrations were significantly higher in groups 1 and 2 than in the controls. However, on day +8, the mean plasma progesterone concentration and the average progesterone concentration per pre-ovulatory follicle were significantly higher in the control women than in groups 1 and 2. Furthermore, 13 patients (65%) in group 1 and seven patients (70%) in group 2 had plasma progesterone concentrations < 2 SD below the mean value obtained in the controls on that post-ovulatory day. Percentage increments in the plasma progesterone concentration from day +2 to day +8 were significantly lower in groups 1 and 2 than in the control group of spontaneous ovulatory cycles.(ABSTRACT TRUNCATED AT 250 WORDS)

Triggering of ovulation by a gonadotropin releasing hormone agonist in gonadotropin-stimulated cycles for prevention of ovarian hyperstimulation syndrome and multiple pregnancy.

Ovarian hyperstimulation syndrome (OHSS) and multiple pregnancies are the two main complications of ovulation induction using gonadotropins. Withholding an ovulatory dose of human chorionic gonadotropin (hCG) remains the safest option for prevention of both complications. However, this policy frustrates both patient and physician, wastes time and money due to cancelled treatment, and results in cancellation of a high proportion of cycles that would not have progressed to clinical OHSS. As gonadotropin releasing hormone analogs (GnRH-a) may elicit surges of endogenous luteinizing hormone and follicle stimulating hormone, we investigated the usefullness of a single s.c. injection of leuprolide acetate (0.5 mg) to trigger ovulation, without inducing OHSS or multiple pregnancy, in 23 consecutive gonadotropin-stimulated cycles which would otherwise have been cancelled. All patients had at least 4 mature follicles (> or = 14 mm in diameter) and plasma estradiol levels > 1000 pg/ml on the day of GnRH-a injection. No luteal support was given. Seventeen of the 23 (74%) cycles were ovulatory and four singleton pregnancies resulted, giving a pregnancy rate of 17.4% per cycle. The remaining six patients (26%) clearly had defective or short luteal phases. No patient developed OHSS. It is concluded that GnRH-a may be an acceptable substitute for hCG to salvage treatment cycles in patients thought to be at risk for OHSS or multiple pregnancy. However, further studies are necessary for optimization of this approach in order to improve ovulatory and conceptional results.

Ovarian function during hormonal replacement therapy in perimenopausal women.

To determine the need for contraception during Hormonal Replacement Therapy (HRT) in perimenopausal women, ultrasound monitoring of ovarian function was performed on 10 perimenopausal women in the second month of treatment. All patients were not at risk of unwanted pregnancy during the study period and had last regular menses at least three months before starting HRT. All of them received transdermal implants of 50 mg of estrogen, twice per week, and 10 mg of oral dydrogesterone on the fourth week. Ultrasound performed at treatment days 7, 14 and 21 of the second month revealed follicular development and rupture in 5 out of the 10 patients. Contraceptive implications are discussed.