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Unlabelled: Concurrent chemoradiotherapy has become a standard therapy for locoregionally advanced inoperable nonsmall cell lung cancer (NSCLC). The purpose of this phase II trial was to evaluate the efficacy and toxicity of concurrent chemoradiotherapy following induction with non-platinum chemotherapy in patients with inoperable locally advanced NSCLC., Patients and Methods: All patients with locally advanced inoperable NSCLC ECOG performance status (PS): 0-1 following staging received paclitaxel 200 mg/m2 in a 3-h infusion on day 1 and gemcitabine 1000 mg/m2 on days 1 and 8 every 21 days for two cycles. The patients with a response or stable disease (SD) continued to receive paclitaxel 60 mg/m2 weekly and radiotherapy 63 Gy given at 1.8 Gy once a day for 7 weeks., Results: Forty-three eligible patients entered the study. The median age was 63 years (range 42-76), male 93%, IIIB 63% and IIIA 37%. Following induction 15 (36.5%) of the patients responded: complete response (CR), 2%; partial response (PR), 33%; and 19 (46.5%) SD. From those with SD, 7 (37%) improved to a PR following concurrent chemoradiotherapy. With a median follow-up of 44 months (95% CI: range 36-53) the median survival was 20.8 months (95% CI: range 15.4-26.3) and time-to-progression 8.4 months (95% CI: range 6.2-10.6). The median survival of those who had improved response from SD to PR was 31.4 months (95% CI: range 18.7-44.1) versus 20.8 months (95% CI: range 5.5-11.3) for those who had no improvement (p=0.20). The commonest grade 3/4 toxicity in induction was neutropenia 12% with 2 febrile neutropenic patients whereas in the concurrent chemoradiotherapy neutropenia, neurotoxicity and oesophagitis were observed in 6% of the patients., Conclusion: Concurrent chemoradiotherapy following induction chemotherapy in patients with stage III NSCLC is feasible with reasonable efficacy and acceptable toxicity.

Aim: To prospectively investigate blood visfatin concentrations during the perinatal period in normal pregnancies., Methods: Visfatin concentrations were determined in maternal, umbilical cord (representing the foetal state) and neonatal blood on day 1 (N1) and 4 (N4)., Results: Maternal and foetal visfatin concentrations were similar (18.83+/-4.27 and 19.35+/-4.90 ng/mL, respectively). There were significant correlations between maternal and foetal (r=0.742, p<0.001), as well as between N1 and N4 (r=0.487, p=0.029) visfatin concentrations. Foetal concentrations were significantly elevated compared to N1 (p=0.032). There was no difference between N1 and N4 concentrations. However, there was a correlation between birth weight and neonatal visfatin concentrations: there was a mean increase in N1 and N4 visfatin concentrations by 0.221 ng/mL and 0.292 ng/mL, respectively, for every unit increase in customized centile (adjusted birth weight) (p=0.021 and p=0.005, respectively). No association was found between serum visfatin concentrations and gender, parity or mode of delivery., Conclusions: Expression in foetal membranes and placental transfer could be responsible for higher blood visfatin concentrations during intrauterine life. Customized centiles seem to be independent predictor variables for postnatal visfatin concentrations. This finding could be attributed to the production of visfatin in adipose tissue, a main contributor to birth weight and consequently to customized centiles.

The development of intracytoplasmic sperm injection (ICSI) for treatment of infertility as a result of severe male factor has improved the chances of achieving pregnancy in many infertile couples. However, concerns have been raised regarding the safety of this technique, because natural sperm selection is bypassed. In the present study, 25 oligoasthenozoospermic patients who were divided into two groups according to age: group A, 20-34 (n = 10) and group B, 35-50 (n = 15), were included. Pooling the data of the three semen parameters that were tested (volume, concentration and progressive motility) no statistically significant difference between the two age groups was found. A total of 50 883 decondensed spermatozoa was analysed using the dual and triple colour fluorescence in situ hybridization to estimate the rates of aneuploidy for chromosomes 13, 18, 21, X and Y in the two age groups. There was a significantly higher incidence of disomy for chromosome 21 compared to the other autosomes (chromosomes 13 and 18) in both age groups. The disomy rate of XY was significantly higher in the younger subject group (0.1%) compared to the older group (0.05%, p < 0.05). Statistically significant differences in the mean number of clinical pregnancies and abortions were not observed between the two age groups. The aneuploidy rates for all the analysed chromosomes did not differ significantly, both between and within the two age groups, and as a result there seems to be no effect of male age on chromosome numbers in the spermatozoa and on the ICSI outcome.

The objective of this study was to investigate circulating levels of cystatin C (an important endogenous marker of renal function) in mothers, fetuses, and neonates from intrauterine growth-restricted (IUGR; characterized by impaired nephrogenesis) and appropriate-for-gestational-age (AGA) pregnancies. Serum cystatin C levels were measured by enzyme immunoassay in 40 parturients and their 20 IUGR (or= 0.376 and P

Insulin-like growth factor (IGF)-I and insulin are essential for fetal growth. We investigated perinatal changes of both factors in 40 mothers and their 20 appropriate-for-gestational-age (AGA) and 20 intrauterine-growth-restricted (IUGR) fetuses and neonates on day 1 (N1) and day 4 (N4) postpartum. Fetal and N1, but not N4, IGF-I levels were increased in AGA (P < .001 and P = .037, resp.). N1 insulin levels were lower in IUGR (P = .048). Maternal, fetal, and N1 IGF-I, and fetal insulin levels positively correlated with customized centiles (r = .374, P = .035, r = .608, P < .001, r = .485, P = .006, and r = .654, P = .021, resp.). Female infants presented elevated fetal and N4 IGF-I levels (P = .023 and P = .016, resp.). Positive correlations of maternal, fetal, and neonatal IGF-I levels, and fetal insulin levels with customized centiles underline implication of both hormones in fetal growth. IUGR infants present gradually increasing IGF-I levels. Higher IGF-I levels are documented in females.

In this article, we review best standard practice for the management of small-cell lung cancer (SCLC) and indicate the likely areas of development over the next 5-10 years. A number of prognostic scores have been developed and these allow more rational decisions on treatment. Treatment with cisplatin plus etoposide with early, concurrent radiotherapy is the standard of care for patients with limited-stage disease (LD) suitable for this approach. A 5-year survival rate of 25% has been reported for concurrent hyperfractionated radiotherapy; however, the applicability of this in most busy hospitals is uncertain and this treatment is currently being compared with a high-dose, once-daily regimen. Patients unsuitable for concurrent chemo-radiotherapy are treated with a sequential approach. Patients with LD responding to treatment should be offered prophylactic cranial irradiation (PCI). A variety of strategies for improving survival have been investigated. Intensification of chemotherapy has not shown any clear survival advantage, but maintenance of dose intensity in patients with good prognosis is important. The evidence around maintenance therapy is conflicting and this is not routinely used. Patients with extensive-stage disease but few other adverse prognostic factors should be treated with a platinum compound plus etoposide, and carboplatin is a reasonable choice. Responding patients should be offered PCI as this is associated with a survival benefit. The initial positive results for irinotecan have not been repeated in a larger study. Age is not a prognostic factor, but caution needs to be exercised as prognostic scores do not reflect co-morbidity. Patients with relapsed disease have a poor prognosis, but there is evidence of a survival benefit for salvage chemotherapy in those fit for treatment. The choice of treatment will depend on a number of factors, including the disease-free interval. Topotecan is the only drug licensed in this indication, but myelosuppression is considerable. A number of new drugs are under evaluation and showing promise in SCLC. One of the most promising of these is amrubicin. A large randomised study has failed to show any benefit from the addition of thalidomide to chemotherapy with carboplatin and etoposide in extensive-stage disease patients responding to chemotherapy. Studies of a number of targeted treatments are also ongoing. The challenge for the future is to identify new targets, overcome drug-resistance mechanisms and redundancy in biological systems, and incorporate these new treatments into concurrent chemo-radiotherapy schedules.

Monocyte-chemotactic-protein-1 (MCP-1) plays vital roles in immune response, angiogenesis, and pregnancy outcome. We investigated plasma MCP-1 concentrations in 40 mothers and their 20 intrauterine-growth-restricted (IUGR) and 20 appropriate-for-gestational-age (AGA) fetuses and neonates on postnatal days 1 (N1) and 4 (N4). Maternal and fetal MCP-1 concentrations were decreased (P<001 and P = .018, resp.), whereas N1 MCP-1 concentrations were elevated in IUGR group (P = .012). In both groups, fetal MCP-1 concentrations were lower compared to N1 and N4 ones (P = .045, P = .012, resp., for AGA, P< .001 in each case for IUGR). Reduced maternal and fetal MCP-1 concentrations in IUGR may reflect failure of trophoblast invasion, suggesting that down-regulation of MCP-1 may be involved in the pathogenesis of IUGR. Increased MCP-1 concentrations in IUGR neonates and higher postnatal ones in all infants may be attributed to gradual initiation of ex utero angiogenesis, which is possibly enhanced in IUGR.

Intrauterine growth restriction (IUGR) implies fetal hypoxia, resulting in blood flow redistribution and sparing of vital organs (brain, heart). Serum cardiac Troponin-I (cTnI), a well-established marker of myocardial ischaemia, was measured in 40 mothers prior to delivery, the doubly clamped umbilical cords (representing fetal state), and their 20 IUGR and 20 appropriate-for-gestational-age (AGA) neonates on day 1 and 4 postpartum. At all time points, no differences in cTnI levels were observed between the AGA and IUGR groups. Strong positive correlations were documented between maternal and fetal/neonatal values (r > or = .498, P < or = .025 in all cases in the AGA and r > or = .615, P < or = .009 in all cases in the IUGR group). These results may indicate (a) normal heart function, due to heart sparing, in the IUGR group (b) potential crossing of the placental barrier by cTnI in both groups.

Background: N-terminal parathyroid hormone-related protein has a vital role in regulating cell growth and differentiation, uteroplacental vasodilatation, uterine muscle relaxation, and placental transport. These functions are compromised in intrauterine growth restriction. We aimed to investigate N-terminal parathyroid hormone-related protein concentrations in maternal, fetal, and neonatal plasma of intrauterine-growth-restricted and appropriate for gestational age pregnancies., Methods: Plasma N-terminal parathyroid hormone-related protein levels were determined in 40 mothers and their 20 intrauterine-growth-restricted and 20 appropriate for gestational age singleton full-term fetuses and neonates on postnatal days 1 and 4., Results: Fetal N-terminal parathyroid hormone-related protein levels were significantly lower in the intrauterine growth restriction group (b=1.166, 95%CI: 0.430-1.902, p=0.003) and correlated with the customized centiles of the infants (r=0.407, p=0.009). In the appropriate for gestational age group, neonatal day 1 N-terminal parathyroid hormone-related protein levels were significantly lower compared to maternal (p<0.001) and fetal (p=0.022) ones. Fetal and neonatal day 1 levels were significantly lower in males (b=-1.303, 95%CI: -2.508 to -0.097, p=0.036, and b=-0.802, 95%CI: -1.5 to -0.105, p=0.027, respectively). In the intrauterine growth restriction group, maternal N-terminal parathyroid hormone-related protein levels were significantly increased compared to fetal (p<0.001) and neonatal day 1 (p=0.001) levels., Conclusions: The reduced fetal N-terminal parathyroid hormone-related protein concentrations in intrauterine growth restriction may reflect compromised placental function and impaired fetal growth, suggesting that N-terminal parathyroid hormone-related protein may be involved in the pathogenesis of intrauterine growth restriction.

Objective: To investigate changes in NT-proBNP in intrauterine-growth-restricted (IUGR) and appropriate-for-gestational-age (AGA) pregnancies., Methods: NT-proBNP levels were measured in 40 mothers (MS), umbilical cords (UC), and their 20 IUGR/ 20 AGA neonates on day 1 (N1) and day 4 (N4)., Results: UC, N1, and N4 NT-proBNP was lower in IUGR pregnancies (p

Neurotrophins (NTs), nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), NT-3, and NT-4 are of major importance in prenatal and postnatal brain development, due to their neuroprotective action. Developmental changes alter the neuronal responsiveness to certain NTs, which subsequently are variously expressed, to properly balance their action. The following study aimed at examining the pattern of perinatal changes of the four NTs--NGF, BDNF, NT-3, and NT-4 in 30 appropriate for gestational age (AGA) full-term fetuses and neonates by determining their circulating levels at characteristic time points. This study show a gradual decrease of circulating levels of the NTs, NT-3 and NT-4 from umbilical cord (UC) to neonates day 4 (N4), while circulating levels of NGF and BDNF present the opposite pattern: an increase from UC to N4. These patterns of perinatal changes differ according to their impact on the process of neuronal development and their reaction to perinatal stress. NT3 and NT4 have been documented to act at early stages of neuronal development and to decrease after hypoxia-ischemia, while NGF and BDNF to increase. Further studies should investigate these patterns in premature or full-term infants, presenting various pathological conditions in the perinatal period.

Angiogenesis plays an important role in the formation of new blood vessels and is crucial for tumour development and progression. Imbalance between pro- and antiangiogenesis factors regulates the biological process of angiogenesis. The best characterised of the proangiogenic factors and the most potent is vascular endothelial growth factor (VEGF). The binding of VEGF to one of its transmembrane tyrosine kinase receptors, which are predominantly found on endothelial cells, results in receptor dimerisation, activation and autophosphorylation of the tyrosine kinase domain. This triggers a cascade of complex downstream signalling pathways. Several strategies targeting the VEGF signalling pathway have been developed. These include neutralising antibodies to VEGF (bevacizumab) or VEGF receptors (VEGFRs) (DC101), soluble VEGFR/VEGFR hybrids (VEGF-Trap), and tyrosine kinase inhibitors of VEGFRs (BAY43-9006, SU11248, ZD6474, AZD2171, PTK/ZK and others). Several of these agents are now being investigated in clinical trials.

Interferon-gamma-inducible T cell-alpha chemoattractant (ITAC) is a chemokine, directing activated T lymphocytes toward sites of inflammation. ADAM-8 (A disintegrin and metalloprotease-8) is a glycoprotein expressed in cells promoting inflammation. Elastase, a protease targeting at the degradation of intra- or extracellular proteins, is inhibited by secretory leukocyte proteinase inhibitor (SLPI), which protects against microbial invasion. Adhesion molecules (soluble intercellular adhesion molecule--sICAM-1 and soluble vascular cell adhesion molecule-sVCAM--1) serve as markers of inflammation or tissue damage. We hypothesized that elevated midtrimester amniotic fluid concentrations of above substances, and decreased levels of SLPI could possibly be useful predictors of asymptomatic intra-amniotic inflammation and/or infection, eventually resulting in preterm labor and delivery. The study involved 312 women undergoing midtrimester amniocentesis. Thirteen cases, progressing to preterm delivery (<37 weeks), were matched with 21 controls (delivering >37 weeks) for age, parity, and gestational age at amniocentesis. Amniotic fluid levels of the above substances were measured by enzyme-linked immunosorbent assay (ELISA). Only amniotic fluid ITAC and ADAM-8 levels were significantly higher (P=0.005 and P < 0.02, respectively) in women delivering at <37 weeks than at >37 weeks. SLPI concentrations significantly increased in women going into labor without ruptured membranes irrespective of pre- or term delivery (P < 0.007, P < 0.001, respectively) and correlated with elastase (r=0.508, P < 0.002). In conclusion, elevated midtrimester amniotic fluid levels of ITAC and ADAM-8 could predict occult infections/inflammations, possibly resulting in preterm birth.

Management of women with a poor response to controlled ovarian hyperstimulation during IVF remains a frustrating challenge. The present study included 96 cycles from an equal number of women with a poor ovarian response and successful oocyte retrieval. Poor response was defined by the presence of at least one of the following characteristics: three or fewer oocytes on retrieval, serum estradiol level less than 500 pg/mL on the day of hCG administration, and serum FSH levels less than 20 IU/L. The same patients had a previous cycle cancelled because of a poor ovarian response whereas in the second cycle they preferred to continue the treatment despite the poor prognosis. We obtained 241 oocytes in the 96 IVF cycles. The fertilization rate was 60.2%. Three oocytes per cycle were retrieved in 56 cycles (58.3%), two oocytes per cycle in 33 cycles (34.4%), and one oocyte per cycle in 7 cycles (7.3%). In 19 cycles (19.8%) no fertilization was achieved. An embryo transfer was finally performed in 74 out of 96 cycles. Pregnancy rate was 12.5% per cycle and 16.2% per transfer. Among the 12 pregnancies achieved, 7 were in the 3-oocyte cycles and 5 in the 2-oocyte cycles. No pregnancies were achieved in the 1-oocyte cycles. Our data demonstrate that continuation of therapy in poor responders undergoing IVF can be an option despite the low pregnancy rates. The prognosis of these patients is not affected by a poor response in the first cycle and for some of them the outcome can be favorable.

Unlabelled: This is a dose-finding study of fixed dose gemcitabine and escalating doses of ifosfamide, in chemo naïve patients with advanced non-small cell lung cancer. The purpose of the study was to determine the optimal dosage and the maximal tolerated dose (MTD) of a specified schedule of gemcitabine and ifosfamide. Patients received gemcitabine 1250 mg/m2 and ifosfamide between 1.6 and 2.2 g/m2, intravenously, on days 1 and 8, repeated every 3 weeks for a maximum of four cycles., Results: Sixteen patients entered the study. Three patients were entered at the first dose level of ifosfamide (1.6 g/m2) and none experienced any dose limiting (DLT) toxicity. In dose level 2 (1.8 g/m2), two patients had grade IV haematological toxicities, but they reached 21 days without any other dose limiting toxicity (DLT). Three further patients entered at this level but they were withdrawn due to disease progression. The sixth patient entered without any DLT. Three patients entered dose level 3 (2.0 g/m2), without any grade IV toxicity. The first patient entered into dose level 4 (2.2 g/m2), had progressive disease within 21 days and was withdrawn and another three were entered and had no DLT during the first 21 days. Four (33%) of the patients had stable disease and 67% had progressive disease., Conclusion: The MTD of the ifosfamide gemcitabine combination was not reached in the present study, as no DLT was observed. This combination at the dose levels of this protocol has little or no activity in patients with advanced NSCLC.

Background: Phase III studies suggest that non-small-cell lung cancer (NSCLC) patients treated with cisplatin-docetaxel may have higher response rates and better survival compared with other platinum-based regimens. We report the final results of a randomised phase III study of docetaxel and carboplatin versus MIC or MVP in patients with advanced NSCLC., Patients and Methods: Patients with biopsy proven stage III-IV NSCLC not suitable for curative surgery or radiotherapy were randomised to receive four cycles of either DCb (docetaxel 75 mg/m(2), carboplatin AUC 6), or MIC/MVP (mitomycin 6 mg/m(2), ifosfamide 3 g/m(2) and cisplatin 50 mg/m(2) or mitomycin 6 mg/m(2), vinblastine 6 mg/m(2) and cisplatin 50 mg/m(2), respectively), 3 weekly. The primary end point was survival, secondary end points included response rates, toxicity and quality of life., Results: The median follow-up was 17.4 months. Overall response rate was 32% for both arms (partial response = 31%, complete response = 1%); 32% of MIC/MVP and 26% of DCb patients had stable disease. One-year survival was 39% and 35% for DCb and MIC/MVP, respectively. Two-year survival was 13% with both arms. Grade 3/4 neutropenia (74% versus 43%, P < 0.005), infection (18% versus 9%, P = 0.01) and mucositis (5% versus 1%, P = 0.02) were more common with DCb than MIC/MVP. The MIC/MVP arm had significant worsening in overall EORTC score and global health status whereas the DCb arm showed no significant change., Conclusions: The combination of DCb had similar efficacy to MIC/MVP but quality of life was better maintained.

Objective: The aim of this study was to evaluate the prevalence of symptomatic vaginal candidiasis and probable predisposing factors in a university-based hospital., Study Design: A total of 576 cases of clinical vaginal candidiasis were enrolled in this survey and wet mount preparations, Gram-stained smears and vaginal cultures were assessed. Possible risk factors, such as pregnancy, diabetes mellitus, contraceptive and antibiotic use were evaluated., Results: Clinical vaginal candidiasis was detected in 12.1% of the cases. Candida albicans was isolated in 80.2% of patients and non-albicans species in 19.8%. Pruritus was the most common symptom (85.9%), followed by vaginal discharge (66.1%), soreness (31.1%) and dyspareunia (5.0%). Reproductive age, pregnancy, diabetes, contraception as well as recent antibiotic use correlated positively with both C. albicans and non-albicans isolates. Soreness and dyspareunia were significantly related to non-albicans species. The overall recurrence rate was 8.5%. Recurrences correlated positively to non-albicans infections., Conclusions: C. albicans was, by far, the predominant yeast isolate. Non-albicans isolates caused significantly more frequent soreness, dyspareunia and recurrences than C. albicans. Clinical and laboratory findings, together with possible predisposing factors must be taken into consideration in order to achieve appropriate treatment.

The aim of IVF centres today is to obtain high quality, developmentally competent embryos, and thus increase live birth rates. Apoptosis in the patient's follicles in among the factors that will determine IVF outcome. Follicular fluid constitutes an important microenvironment, containing apoptotic factors and others, which influence oocyte growth. The sFas-sFas ligand system is present in the follicular fluid and may play a role in preventing oocyte aresia during folliculogenesis. Levels of the anti-apoptotic molecule sFas may be related positively to oocyte maturation and negatively to fertilization and embryo quality. Reactive oxygen species exert a toxic effect when found in high concentrations in the follicular fluid, whereas in low concentrations they might be indispensable for pregnancy and therefore serve as a potential marker for successful IVF outcome. Nitric oxide plays a dual role; in some cells promoting and in others inhibiting apoptosis. Nitric oxide production is stimulated by TNF-alpha, so the latter is also implicated in the apoptotic process. Hyaluronan, a disaccharide, whose functions have not been fully elucidated, is a valuable predictor of oocyte fertilization. Gelatinases are responsible for remodelling during follicular atresia. In conclusion, a number of factors found in the follicular fluid, some involved in apoptosis, can infulence assisted reproduction.

Objective: To determine during mid-trimester amniocentesis if elevated concentrations of ADAM-8 (A Disintegrin And Metalloprotease 8) and/or cortisol can recognize women at risk for spontaneous preterm delivery., Methods: The study involved 312 women who underwent mid-trimester amniocentesis. Thirteen patients, who progressed to preterm delivery, were matched with 21 controls for age, parity, gestational age at amniocentesis, and year of amniocentesis. ADAM-8 and cortisol levels were measured by enzyme-linked immunosorbent assay and radioimmunoassay, respectively., Results: ADAM-8 mean amniotic fluid concentrations were significantly higher in women with preterm delivery than in women delivering at term (mean 1213.9 [SE 96.7] pg/mL [range, 780 to 1854 pg/mL] vs mean 937.2 [SE 50.3] pg/mL [range, 486 to 1508 pg/mL], P < .02). Amniotic fluid ADAM-8 concentrations higher than 1149 pg/mL had the highest specificity and odds ratio (OR) in the identification of the women with increased risk for preterm delivery (sensitivity 61.5%; specificity 81.7%; OR, 9.6 [95% confidence interval (CI), 1.8 to 50.3]). Women with preterm delivery had suggestively higher amniotic fluid concentrations of cortisol (mean 1.3 [SE 0.2] microg/dL [range, 0.4 to 2.2 microg/dL]) than women delivering at term (mean 1.0 [SE 0.09] microg/dL [range, 0.6 to 1.7 microg/dL], P < .07). Furthermore, cortisol levels were positively correlated with ADAM-8 levels (Spearman's r = .418, P < .014)., Conclusions: Elevated mid-trimester amniotic fluid ADAM-8 concentrations possibly are a risk factor for preterm delivery, particularly if ADAM-8 levels are greater than 1149 pg/mL. Potential intrauterine inflammation is also associated with suggestively increased amniotic fluid cortisol levels.

Aims: Our aim is to investigate, in 13 cases (delivering preterm) and 21 matched (for age, parity, and gestational age) controls (delivering at term), whether midtrimester amniotic fluid concentrations of elastase, secretory leukocyte proteinase inhibitor (SLPI), soluble intercellular adhesion molecule-1, and soluble vascular cell adhesion molecule predict asymptomatic intra-amniotic inflammation/infection and preterm labor., Results: Concentrations of all substances were not statistically different among mothers, delivering preterm or at term. SLPI concentrations significantly increased in women, going into labor without ruptured membranes, irrespective of pre- or term delivery (P < .007, P < .001, resp) and correlated with elastase (r = 0.508, P < .002)., Conclusions: Midtrimester amniotic fluid SLPI concentrations significantly decrease when membrane rupture precedes pre- or full-term labor. However, none of the investigated substances predict preterm delivery.

Objective: To determine and correlate midtrimester amniotic fluid concentrations of interferon gamma-inducible T-cell alpha chemoattractant (ITAC, a chemokine directing the migration of activated T lymphocytes toward inflammation sites) and C-reactive protein (CRP) in women undergoing amniocentesis and subsequently delivering pre-or full-term infants., Methods: Among 312 women undergoing midtrimester transabdominal amniocentesis, 13 progressed to spontaneous delivery at less than 37 gestational weeks (GW). Subjects were matched for maternal age, parity, and GW at amniocentesis with 21 controls who delivered at greater than 37 GW. Amniotic fluid ITAC and CRP levels were determined by enzyme-linked immunosorbent assay (ELISA) and by nephelometry, respectively., Results: Both ITAC and CRP values were significantly higher (P = .005 and P = .04, respectively) in the amniotic fluid of women delivering at less than 37 GW. A statistically significant correlation between amniotic fluid ITAC and CRP concentrations was also found (r = .366, P < .05). The receiver operator curve (ROC) analysis of delivery at less than 37 GW gave the best cutoff point for ITAC at a concentration of 44 pg/mL and for CRP at a concentration of 0.16 mg/dL. Positive and negative predictive values for ITAC were 82% and 85%, respectively, and for CRP, 55% and 76%, respectively., Conclusions: Present data indicate that from the second trimester of pregnancy elevated amniotic fluid concentrations of ITAC are found in women delivering at less than 37 GW, as compared to women delivering at term. Therefore, ITAC in combination with other cytokines or CRP could possibly serve as predictor of preterm delivery.

Rubitecan (RFS2000, 9 nitrocamptothecin,) is a new oral topoisomerase I inhibitor. We report a phase II, single-arm, open-label study of RFS2000 as first line treatment for non-small cell lung cancer (NSCLC). Seventeen treatment-naïve patients with stage IIIB (9/17) and IV (8/17) NSCLC (11 male and 6 female) were treated, the median age was 62 years (range 52-86), and the majority of patients (14/17) were of performance status 1. RFS2000 was given orally, daily for 5 days, repeated every week. The starting dose was 1.5 mg/m(2)/day, and dose adjustment was permitted based upon toxicity. Fifteen patients had a dose escalation to 1.75 mg/m(2)/day and 7 had a second dose escalation to the protocol maximum level of 2.0 mg/m(2)/day. RFS2000 was tolerated well. Almost all adverse events were grade 1 and 2. The most frequently encountered adverse events were diarrhoea, nausea, anorexia, and lethargy. Neutropenia and thrombocytopenia were not observed in any patient. There were no responders to RFS2000 treatment, 10 patients had stable disease as their best response, whilst five had tumour progression. Two patients were not assessable for tumour response. The median survival time was 257 days (95% CI = 222-352). RFS2000 appears to be inactive at dose levels of 1.5-2.0 mg/m(2)/day in advanced NSCLC patients. Since only mild toxicity and no myelosuppression were encountered, these dose level are too low for this treatment-naïve patient population with NSCLC. Further studies at an increased dose would be required to identify whether this agent has merit in the treatment of NSCLC.

Purpose: This randomized phase II study compared two treatment schedules of gemcitabine in patients with non-small-cell lung cancer (NSCLC) and impaired Karnofsky performance status (KP). Primary objectives were to record changes from baseline KP and to assess symptom palliation. Secondary objectives were overall survival, tumor response, and toxicity., Patients and Methods: Patients with stage IIIb and IV NSCLC and KP

Objective: To evaluate the effect of sperm treatment with exogenous platelet-activating factor (PAF) on IUI clinical pregnancy rate., Design: Prospective randomized study., Setting: Assisted Reproduction Unit, 2nd Department of Obstetrics and Gynecology, University of Athens, Aretaieion Hospital, Athens, Greece., Subject(s): Fifty-two couples with unexplained infertility, candidates for IUI., Intervention(s): Sperm treatment with an exogenous mixture of PAF (final concentration, 10(-7) mol/L) in sperm-washing medium, direct swim-up technique of sperm preparation, a maximum of six IUI cycles per couple with or without PAF treatment., Main Outcome Measure(s): Clinical pregnancy rate (pregnancies confirmed by ultrasonography per hundred cycles)., Result(s): The overall clinical pregnancy rate after a maximum of six IUI cycles was significantly higher when sperm was treated with PAF compared with the rate after the direct swim-up technique (23.07% vs. 7.92%)., Conclusion(s): Treatment of sperm with exogenous PAF might improve the clinical outcome of IUI in cases of unexplained infertility.

Aim: The aim of the study was to investigate the type of pregnancy loss (PL) in women with recurrent miscarriages., Materials and Methods: The study population included 411 women with a history of recurrent pregnancy loss (RPL) attending the Recurrent Miscarriage Clinic of the 2nd Department of Obstetrics and Gynecology, University of Athens (tertiary referral center). Subjects were divided in groups according to their underlying pathology and in some of them appropriate treatment was applied., Results: The study of the 323 pregnancies achieved after referral, revealed that the PL after ultrasonographic detection of fetal heart (FH) is overall increased, is more common in women with anatomical uterine anomalies and unexplained RPL, and treatment reduces its rate in women with anatomical uterine anomalies and an inadequate luteal phase. The PL before the detection of FH is reduced after treatment in women with thrombotic tendency and an inadequate luteal phase.

Objective: Because soluble Fas (sFas) inhibits Fas-mediated apoptosis by preventing death signal transduction, we determined sFas concentrations in the follicular fluid (FF) and oocyte-cumulus complex culture medium (CM) from women undergoing in vitro fertilization (IVF) in order to associate its concentrations with oocyte maturity, fertilization, and embryo quality., Methods: We studied 82 follicles from 11 healthy women (mean age, 35.4 +/- 3.8 years) using a long protocol for IVF treatment. Individual FF and matched CM samples were immediately centrifuged at 4C and sFas concentrations were determined by sandwich enzyme-linked immunosorbent assays., Results: sFas concentrations were significantly higher in FF than in CM (P <.0001) and when oocytes were mature rather than immature (P <.002). Of 70 mature and 12 immature oocytes, 56 (80%) and two (16.6%), respectively, were fertilized. sFas concentrations in CM were significantly lower when mature oocytes were fertilized versus nonfertilized (P <.005). sFas concentrations in FF and CM were significantly related in an inverse manner to embryo quality (P = .004 and P = .0002, respectively)., Conclusion: FF and CM from women undergoing IVF contain sFas. The latter has anti-apoptotic properties and levels are higher: in FF when oocytes are mature and in CM when oocytes are nonfertilized. Furthermore, FF and CM sFas concentrations are negatively correlated with embryo quality.

The studies reported investigated the concentrations of angiogenic, proliferative, and apoptotic factors in the follicular fluid (FF) of individual follicles, aspirated from women undergoing controlled ovarian hyperstimulation using a long protocol for IVF treatment. Furthermore, the association of the concentrations of the preceding factors with oocyte maturity was studied. Vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), angiogenin, tissue polypeptide specific antigen (TPS), and soluble Fas (sFas) were all found in the FF of all follicles examined. Moreover, from the angiogenic factors only angiogenin concentrations, and from the apoptotic factors sFas concentrations (the soluble form expressing rather an antiapoptotic function), were positively associated with oocyte maturity, possibly indicating angiogenin's biological role beyond neovascularization and a lower apoptotic rate allowing oocytes to mature. Last, the abundant expression of TPS in FF may be indicative of intense cell proliferation, in cases of ovarian stimulation.

Objective: To determine the concentration of angiogenic factors (vascular endothelial growth factor [VEGF], basic fibroblast growth factor [bFGF], and angiogenin) in the follicular fluid (FF) and oocyte-cumulus complex culture medium (CM) of women undergoing IVF and to investigate the association of the concentrations with the maturity and fertilization of the oocyte., Design: Prospective study., Setting: Academic tertiary-care institution., Patient(s): IVF patients with unexplained or tubal factor infertility., Intervention(s): Analysis of VEGF, bFGF, and angiogenin FF and CM concentrations., Main Outcome Measure(s): Oocyte maturity and fertilization and FF and CM angiogenic factor concentrations., Result(s): VEGF, bFGF, and angiogenin were determined in FF and CM. FF angiogenin concentrations were significantly higher when the oocyte was mature versus immature. CM VEGF concentrations were significantly higher when the oocyte was nonfertilized versus fertilized. Positive correlations were observed between angiogenic factors in CM., Conclusion(s): VEGF, bFGF, and angiogenin (determined for the first time) are secreted in the FF and CM. Elevated CM VEGF concentrations, probably implying oocyte-cumulus complex hypoxia, are negatively associated with oocyte fertilization. Elevated FF angiogenin concentrations are positively associated with oocyte maturity, possibly indicating angiogenin's biological role beyond neovascularization.

Objective: To determine whether intracytoplasmic sperm injection has an adverse effect on the meiotic spindle of oocytes after injection of a sperm into the ooplasm., Design: Hamster oocytes were injected with human sperm (Test group) and evaluated for meiotic spindle and chromosome morphology using immunofluorescent staining. Results were compared with control uninjected oocytes exposed to the microscope environment (CS group) and untreated oocytes remaining in the incubator (CI group)., Setting: Basic research center at a medical school., Results: No significant differences were noted in spindle appearance and chromosome alignment between Test (13 abnormal/68 normal) and both control groups (CS 9/73 and CI 12/71; P = 0.602)., Conclusion: Our results demonstrate that injection of human sperm into the cytoplasm of hamster oocytes may not result in a significant increase in damage to the meiotic spindle provided care is taken to orient the polar body away from the site of injection.

The present study was conducted to determine if the cryopreservation of immature human oocytes has a deleterious effect on the meiotic spindle following maturation in vitro. Oocytes were obtained in excess from in-vitro fertilization patients and divided into four groups. Groups 1 (n = 98) and 2 (n = 80) consisted of immature oocytes cryopreserved before or after maturation in vitro respectively. Groups 3 (n = 37) and 4 (n = 9) served as non-frozen controls and included oocytes matured in vitro and in vivo respectively. The meiotic spindle was identified after incubation in anti-tubulin monoclonal antibody (1 h, 37 degrees C) and fluorescein-conjugated goat anti-mouse immunoglobulin G (IgG) (1 h, RT). Chromosomes were counterstained with 4',6'-diamidino-2-phenylindole. Following cryopreservation, group 1 oocytes demonstrated a 63% survival rate and 68% maturation rate in vitro. In all, 58% of the oocytes in group 2 survived the thaw. The number of oocytes with normal spindles in group 1 (81.0%) was not significantly different from control groups 3 (83.8%) and 4 (88.9%), while the number of group 2 oocytes with normal structures (43.5%) was significantly lower than groups 1 (P = 0.0004), 3 (P = 0.0002), and 4 (P = 0.025). These results suggest that cryopreservation of the prophase I human oocyte does not significantly increase abnormalities in the resulting meiotic spindle.

Little is known about the molecular mechanisms governing the development of human oocyte and pre-embryo. We characterized the expression pattern of c-mos, cyclin B1 and beta-actin mRNA in oocytes and granulosa cells from human and monkey, and in human early embryos, using both qualitative and semi-quantitative reverse transcriptase polymerase chain reaction. The proto-oncogene c-mos was expressed in an oocyte-specific manner and no mRNA for c-mos could be detected in the granulosa cells. Similarly, strong expression of cyclin-B1 was seen in the oocytes. In human pre-embryos, the expression of cyclin-B1 and beta-actin increased from the 6-cell stage onwards, indicating active transcription and thus activation of embryonic genome either at or before the 6-cell stage. The expression of c-mos was transient and very little c-mos mRNA could be detected in the human embryos beyond the 6-cell stage. Thus, both its time-specific and site-specific expression suggest meiosis-specific functions for the proto-oncogene c-mos in human oocytes. As judged by the disappearance of c-mos, the maternal pool of mRNA seems to be degraded towards the 6- to 8-cell stage. The transient expression of c-mos and high levels of cyclin-B1 mRNA suggest that mechanisms similar to those found in lower organisms govern the growth and development of the human oocyte and preimplantation embryo.

Objective: To determine the potential for in vitro maturation, fertilization, and cleavage after cryopreservation of immature, prophase I human oocytes., Design: Immature oocytes obtained in excess of the number required by the patient were randomized and cryopreserved at the prophase I stage or cultured as control. After thawing and maturation in vitro, test and control oocytes were inseminated with husband's sperm and evaluated for fertilization and cleavage in vitro., Setting: In vitro fertilization program., Patients: Consenting patients undergoing controlled ovarian hyperstimulation for the purposes of IVF., Main Outcome Measures: Rates of maturation to metaphase II, fertilization, and cleavage were compared between control and cryopreserved oocytes., Results: Upon thaw, 58.5% (72/123) of prophase I oocytes were viable. Control oocytes demonstrated a 74.8% (98/131) maturation rate to metaphase II, a 56.5% (52/92) fertilization rate, and an 11.5% (6/52) blastocyst rate. Cryopreserved oocytes showed a 83.3% (60/72) rate of maturation, a 57.7% (30/52) fertilization rate, and a 3.3% (1/30) blastocyst rate. No significant differences were noted between any of these parameters., Conclusions: These results demonstrate that prophase I oocytes from stimulated IVF cycles are able to survive cryopreservation and resume meiosis to achieve full nuclear maturation post-thaw. In addition, cryopreserved oocytes retain the same capacity for fertilization and development as control oocytes.