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.

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.

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.

Mechanism of vascular relaxation by thaligrisine: functional and binding assays.

In the present study we examine the mechanism by which thaligrisine, a bisbenzyltetrahydroisoquinoline alkaloid, inhibits the contractile response of vascular smooth muscle. The work includes functional studies on rat isolated aorta and tail artery precontracted with noradrenaline or KCl. In other experiments rat aorta was precontracted by caffeine in the presence or absence of extracellular Ca2+. In order to assess whether thaligrisine interacts directly with calcium channel binding sites or with alpha-adrenoceptors we examined the effect of the alkaloid on [3H]-(+)-cis diltiazem, [3H]-nitrendipine and [3H]-prazosin binding to cerebral cortical membranes. The functional studies showed that the alkaloid inhibited in a concentration-dependent manner the contractile response induced by depolarization in rat aorta (IC50 = 8.9+/-2.9 microM, n=5) and in tail artery (IC50 = 3.04+/-0.3 microM, n=6) or noradrenaline induced contraction in rat aorta (IC50 = 23.0+/-0.39 microM, n=9) and in tail artery (IC50 = 3.8+/-0.9 microM, n=7). In rat aorta, thaligrisine concentration-dependently inhibited noradrenaline-induced contraction in Ca2+-free solution (IC50 = 13.3 microM, n=18). The alkaloid also relaxed the spontaneous contractile response elicited by extracellular calcium after depletion of noradrenaline-sensitive intracellular stores (IC50 = 7.7 microM, n=4). The radioligand receptor-binding study showed that thaligrisine has higher affinity for [3H]-prazosin than for [3H]-(+)-cis-diltiazem binding sites, with Ki values of 0.048+/-0.007 microM and 1.5+/-1.1 microM respectively. [3H]-nitrendipine binding was not affected by thaligrisine. The present work provides evidence that thaligrisine shows higher affinity for [3H]-prazosin binding site than [3H]-(+)-cis-diltiazem binding sites, in contrast with tetrandrine and isotetrandrine that present similar affinity for both receptors. In functional studies thaligrisine, acted as an alpha1-adrenoceptor antagonist and as a Ca2+ channel blocker, relaxing noradrenaline or KCl-induced contractions in vascular smooth muscle. This compound specifically inhibits the refilling of internal Ca2+-stores sensitive to noradrenaline, by blocking Ca2+-entry through voltage-dependent Ca2+-channels.

Alpha-adrenoceptor interaction of tetrandrine and isotetrandrine in the rat: functional and binding assays.

The action of 1S,1'S-tetrandrine, a bisbenzyltetrahydroisoquinoline alkaloid, on alpha1-adrenoceptors has been compared with that of its isomer 1R,1'S-isotetrandrine. The work includes binding assays to analyse the affinity of these products for the [3H]prazosin binding site of rat cerebral cortical membranes and functional studies on rat isolated aorta to examine the effects of both alkaloids on intracellular calcium processes related or not to alpha-adrenoceptor activation. A radioligand receptor-binding study showed that both compounds interacted with the alpha1-adrenoceptors displacing [3H]prazosin from the specific binding site. The Ki values (inhibition constants) were 0.69+/-0.12 and 1.6+/-0.4 microM for tetrandrine and isotetrandrine, respectively. The functional studies showed that both alkaloids concentration-dependently inhibited noradrenaline-induced contraction in Ca2+-free solution (IC50 values, i.e. the concentrations needed to induce 50% inhibition, were 252.8 and 174.9 microM for tetrandrine and isotetrandrine, respectively), the spontaneous contractile response elicited by extracellular calcium after depletion of noradrenaline-sensitive intracellular stores (increase in resting tone; IC50 values 11.6 and 19.6 microM for tetrandrine and isotetrandrine, respectively) and the refilling of intracellular Ca2+ stores sensitive to noradrenaline (IC50 values 7.4 and 14.9 microM for tetrandrine and isotetrandrine, respectively). The results show that tetrandrine and isotetrandrine interact with alpha1-adrenoceptors by displacing the [3H]prazosin binding site and that both compounds inhibit mainly the Ca2+-dependent process and have less action on alpha1-adrenoceptors. Tetrandrine is more potent than isotetrandrine.

[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.

Acute rheumatic fever in a grown up with repaired tetralogy of Fallot: the role of acquired diseases in patients with congenital heart diseases.

We report a 20 year old patient with repaired Tetralogy of Fallot who presented with acute right side heart failure. The echocardiogram showed severe mitral regurgitation which was not present one year before. Because of mitral insufficiency, pulmonary pressure increased and it was nearby 70% systemic pressure. Pulmonary regurgitation got worse, and the patient came to the hospital in a state of anasarca. After valve replacement, histopathological study of the mitral valve and the aortic valve revealed Aschoff nodules and rheumatic fever was confirmed.

Prevention of multiple pregnancy following IVF in Spain.

Since the development of assisted reproduction techniques most countries have witnessed increased rates of multiple pregnancy. Despite the guidelines proposed by various scientific societies these rates continue to be abnormally high. In Spain, as in other Mediterranean countries, a greater number of embryos are transferred than in northern and central European countries and the incidence of multiple pregnancies is greater in comparison. Effective strategies must be established to prevent multiple pregnancy without reducing overall pregnancy rates. In the authors' institute, taking into account the authors' experience, the relevant literature, and despite the limitation of retrospective studies, it is recommended that a maximum of two embryos are transferred in young women with good quality embryos at the time of transfer. The transfer of three embryos is only recommended in women >or=38 years who have one or no good quality embryos available at the time of transfer. The responsibility for preventing multiple pregnancy lies with health professionals, who must be aware of the risks involved in twin and triplet pregnancy. Couples must be provided with objective information before starting an IVF cycle. Professional societies should highlight the problem and make suitable recommendations.

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.

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.

Comparison of the role of cervical and intrauterine insemination techniques on the incidence of multiple pregnancy after artificial insemination with donor sperm.

PURPOSE: Our purpose was to investigate the role of the insemination technique used in an artificial insemination program with donor sperm (AID) in multiple pregnancy rates. METHODS: We carried out a retrospective nonrandom analysis of 300 pregnancies corresponding to 300 cycles in women from our Artificial Insemination Donor Sperm Program. All cycles were stimulated with gonadotropins. Single and multiple pregnancy cycles and intracervical and intrauterine pregnant cycles were compared. RESULTS: Intracervical insemination was performed in 173 cycles (58%), and intrauterine insemination in 127 (42%). Two hundred twenty-three pregnancies were single (74%), and 77 multiple (26%). In multiple pregnancy cycles, initial dose and mean total daily dose of gonadotropins, plasma estradiol levels, and number of follicles > or = 14 mm were significantly higher compared to those in single pregnancy cycles. Multiple pregnancy rte was significantly higher among pregnancies after intrauterine insemination (32%) than after intracervical insemination (21%). CONCLUSIONS: The intrauterine technique of insemination in AID-stimulated cycles with gonadotropins is related to multiple pregnancy risk.

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.

Cervical ectopic twin pregnancy: diagnosis and conservative treatment: case report.

A case of cervical ectopic twin pregnancy with cardiac activity in both embryos is presented. It was diagnosed in the eighth week of gestation by ultrasonography, and treated conservatively with intra-amniotic administration of methotrexate under ultrasonographic guidance followed by curettage. This procedure allows subsequent gestations.

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.

Women with poor response to IVF have lowered circulating gonadotrophin surge-attenuating factor (GnSAF) bioactivity during spontaneous and stimulated cycles.

BACKGROUND: Up to 13% of IVF cancellations are due to poor responses during down-regulated cycles. Because premature luteinization occurs more frequently in older or "poor responder" patients, defective production of gonadotrophin surge-attenuating factor (GnSAF) may be involved. METHODS: Nine women with normal previous IVF response (NORM) and 9 with previous poor IVF response (POOR) were monitored in a spontaneous cycle (blood samples: days 2, 7, 11, 15 and 20) and then stimulated with recombinant human FSH (rFSH) under GnRH agonist (blood samples: treatment days GnRH agonist + 2, GnRH agonist + 7, day of HCG administration and days HCG + 1 and HCG + 8). LH, FSH, estradiol, progesterone and inhibin-A and -B were assayed in individual samples while GnSAF bioactivity was determined in samples pooled according to day, cycle and IVF response. RESULTS: During spontaneous cycles LH, steroids and inhibins were similar between NORM and POOR women, FSH was elevated in POOR women (4.9 +/- 0.3 versus 6.7 +/- 0.6 mIU/l, P < 0.01) and GnSAF bioactivity was detectable on days 2, 7 and 11 in NORM women only. During IVF cycles inhibin-A and -B rose more markedly in NORM than POOR women. Similarly GnSAF production peaked on day GnRH agonist + 7 in NORM women, but on the day of HCG administration in POOR women. CONCLUSIONS: Defects in ovarian responsiveness to FSH include reduced GnSAF production. This suggests that GnSAF should be investigated as a marker of ovarian reserve once an immunoassay becomes available.

The safety and effectiveness of stepwise and low-dose administration of follicle stimulating hormone in WHO group II anovulatory infertile women: evidence from a large multicenter study in Spain.

PURPOSE: Our goal was to investigate the safety, effectiveness, and feasibility for the practicing physician of stepwise and low-dose administration of FSH in WHO group II anovulatory infertile women. METHODS: Infertile female patients (n = 234) suffering from WHO group II anovulation, and who failed to became pregnant with clomiphene citrate, were included in a multicenter, prospective, clinical study of treatment with a protocol of chronic low-dose and small incremental rises with urinary purified or highly purified FSH. Follicular development was monitored with ultrasonographic scans. RESULTS: The 234 patients received a total of 534 cycles of treatment, for a mean number of 2.3 treated cycles per patient. hCG was withheld in 65 (12.2%) cyles because of no response and in 28 (5.2%) cycles because of hyperresponse. Of the remaining 441 cycles, 419 (95%) were ovulatory, and in 198 (47.3%) of these cycles a single dominant follicle developed. There were 93 pregnancies (39.7% per patient), for a cycle fecundity rate of 17.4%. Cumulative conception rate after two treated cycles was 33.5%. There were 14 (15%) pairs of twins and 10 (10.8%) spontaneous miscarriages. The prevalence of complications was low with no cases of severe OHSS. Basal LH/FSH ratio was significantly higher in the pregnant group of patients than in nonpregnant women. CONCLUSIONS: Stepwise and chronic low-dose administration of FSH is a safe and effective method for treatment of WHO group II anovulatory infertility, mainly in those patients having high LH/FSH ratios.