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Objectives Safe implementation and thorough evaluation of new treatments require prospective data monitoring and standardization of treatments. Pressurized intraperitoneal aerosol chemotherapy (PIPAC) is a promising alternative for the treatment of patients with peritoneal disease with an increasing number of suggested drug regimens. The aim was to reach expert consensus on current PIPAC treatment protocols and to define the most important research topics. Methods The expert panel included the most active PIPAC centers, organizers of PIPAC courses and principal investigators of prospective studies on PIPAC. A comprehensive literature review served as base for a two-day hybrid consensus meeting which was accompanied by a modified three-round Delphi process. Consensus bar was set at 70% for combined (strong and weak) positive or negative votes according to GRADE. Research questions were prioritized from 0 to 10 (highest importance). Results Twenty-two out of 26 invited experts completed the entire consensus process. Consensus was reached for 10/10 final questions. The combination of doxorubicin (2.1 mg/m2) and cisplatin (10.5 mg/m2) was endorsed by 20/22 experts (90.9%). 16/22 (72.7%) supported oxaliplatin at 120 with potential reduction to 90 mg/m2 (frail patients), and 77.2% suggested PIPAC-Ox in combination with 5-FU. Mitomycin-C and Nab-paclitaxel were favoured as alternative regimens. The most important research questions concerned PIPAC conditions (n=3), standard (n=4) and alternative regimens (n=5) and efficacy of PIPAC treatment (n=2); 8/14 were given a priority of ≥8/10. Conclusions The current consensus should help to limit heterogeneity of treatment protocols but underlines the utmost importance of further research.

Background: Fertility preservation by ovarian cryopreservation and heterotopic ovarian transplant is hampered by ischemic damage of the transplanted graft and poor oocyte viability. Design: Two longitudinal experiments were done - phase A: to evaluate if the administration of gonadotrophins (hMG) or vascular endothelial growth factor (VEGF) increases follicular survival after heterotopic autologous ovarian transplantation, and phase B: to determine if the administration of hMG enhanced neovascularization by increase in microvessel density in the heterotopic xenologous ovarian transplant. Methods: A: In three sheep, ovaries were removed and immediately transplanted into the abdominal wall. In one sheep, VEGF was administered at the transplantation site during surgery, the second was treated with hMG after transplantation for 2 weeks, and the third sheep served as control. B: The ovaries from two other sheep were removed, prepared in tissue pieces, and immediately grafted into the subcutaneous space of several combined immunodeficient (SCID-)mice (n=20). Following the transplantation, 10 of these mice (group 1) were treated with hMG until they were sacrificed, the other 10 untreated mice (group 2) served as controls. In each group, two mice were sacrificed at intervals of 2,4,6,10, and 14 days after grafting to permit histologic examination of the grafted tissue. Results: A: Whereas VEGF had no effect on follicular survival after transplantation (12.0% vs. 7.4%.),the administration of hMG increased follicular survival (12.0% vs. 29.0%). B: The use of hMG resulted in significantly higher numbers of microvessels per mm 2 (mean) at all of the time points studied - at 2 days 22 vs. 13 (p < 0.001), 4 days 22 vs. 13 (p < 0.001), 6 days 17 vs. 13 (p = 0.006), 10 days 28 vs. 12 (p < 0.001), and 14 days 35 vs. 16 (p

Objective To evaluate the association between the presence of uterine leiomyomas and three functional single nucleotide polymorphisms (SNPs) of the estrogen receptor alpha (ESR1), catechol-O-methyltransferase (COMT), and cytochrom P450 17 (CYP17A) genes, which have been described to modify the estrogen metabolism. Design Prospective case control study. Setting Academic research institution. Patient(s) One hundred thirty women with clinically and surgically diagnosed uterine leiomyomas and 139 population controls. Intervention(s) Peripheral venous puncture. Main Outcome Measure(s) Polymerase chain reaction and pyrosequencing were performed to genotype women with respect to the ESR1 IVS1-397 T/C (PvuII), COMT G158A, and the CYP17A 34T→C SNPs. Result(s) Comparing women with uterine leiomyomas and controls, no statistically significant differences with respect to allele frequency and genotype distribution were ascertained for ESR1 IVS 1-397 T/C (PvuII) ( P =0.9 and P =0.6, respectively), COMT G158A ( P =0.3 and P =0.6, respectively), and CYP17A 34T→C ( P =0.1 and P =0.5, respectively). When all two-way interactions of investigated SNPs were ascertained, no significant interactions were observed. In a multivariate model, no SNP was significantly associated with leiomyomas. Conclusion(s) Carriage of the ESR1 IVS1-397 T/C (PvuII), COMT G158A, and the CYP17A 34T→C SNPs is not associated with the susceptibility to uterine leiomyoma in a Caucasian population.

Genetic thrombophilia has been established as a risk factor for pregnancy-associated disorders, such as thrombosis, early and late miscarriage, and pre-eclampsia. Associations between the factor V (F5) Leiden G1691A and the prothrombin/factor II (F2) G20210A SNPs and pre-eclampsia have been evaluated in over 50 association studies. A pooled analysis of 23 and 11 studies demonstrates that carriage of the F5 Leiden G1691A (p < 0.001; odds ratio [OR] 2.0; 95% confidence interval [CI] 1.6–2.5) and the F2 G20210A (p < 0.001; OR 1.8; 95% CI 1.1–2.9) SNPs is significantly associated with pre-eclampsia. Besides pre-eclampsia, genotyping for the F5 Leiden G1691A and the F2 G20210A SNPs is also useful for individual risk assessment regarding pregnancy-associated thrombosis. Carriers of the F5 Leiden G1691A SNP will develop this condition in 6.4% of heterozygotes and in 8.9–16.7% of homozygotes. A total of 6.2% of women with the F2 G20210A SNP and 17.8% of women with simultaneous carriage of the F5 Leiden G1691A and F2 G20210A SNPs will develop pregnancy-associated thrombosis. Both the F5 Leiden G1691A and F2 G20210A SNPs are also risk factors of early recurrent, late recurrent and late spontaneous miscarriage based on a published meta-analysis of 31 studies. These women may benefit from prophylactic heparinization. Six case–control and cohort studies of 687 women with genetic thrombophilia document live birth rates of 82% (181/221) using low-molecular-weight heparin or fractionated heparin compared with 20% (95/466) without therapy (p < 0.001, OR 17.7; 95% CI 12.2–25.5). Based on the data in the literature, including association studies and meta-analyses of these association studies, it can be concluded that genetic thrombophilia due to carriage of the F5 Leiden G1691A and F2 G20210A SNPs is a significant and clinically relevant risk factor for pre-eclampsia, pregnancy-associated thrombosis, and early and late miscarriages.

Objective: Deficiency of the gene encoding endothelial nitric oxide synthase, i.e. Nos3 , has been reported to be associated with late menarche, reduced ovulation rates, fewer deliveries, and earlier onset of menopause in a mouse model. Methods: We assessed the Glu298Asp and the T-786C polymorphisms of Nos3 in 87 consecutive healthy postmenopausal women by pyro- and capillary-sequencing, respectively. Results were correlated with age at menarche and natural menopause, number of miscarriages and live births, as well as body mass index (BMI) and smoking habits. Results: Allelic frequencies of the Glu298Asp polymorphism of Nos3 were 121 (69.5%) and 53 (30.5%) for the wild-type G allele and the mutant T allele, respectively. Forty-one women (47.1%) were homozygote wild-type (G/G), 39 (44.9%) were heterozygote (G/T), and 7 (8.0%) were homozygote mutant (T/T). Allelic frequencies of the T-786C polymorphism of Nos3 were 105 (60.6%) and 69 (39.4%) for the wild-type T allele and the mutant C allele, respectively. Thirty-three women (38.0%) were homozygote wild-type (T/T), 39 (45.1%) were heterozygote (T/C), and 15 (16.9%) were homozygote mutant (C/C). Presence of at least one mutant allele of the Glu298Asp or the T-786C polymorphisms of Nos3 were not associated with age at menarche, natural menopause, and number of miscarriages and deliveries. BMI above 27 kg/m 2 and smoking were associated with earlier onset of natural menopause (47.8 years versus 50.2 years ( P =0.01) and 46.8 years versus 49.8 years ( P =0.02)). Conclusions: Our data show that smoking and increased BMI, but not Glu298Asp or the T-786C polymorphisms of Nos3 , are associated with an early onset of natural menopause.

Polymorphisms are a potentially useful tool for assessing the individual physiology and risk profile of pregnancy-associated disorders. Associations between selected polymorphisms and preeclampsia and thrombosis have been evaluated in over 60 studies. We performed a meta-analysis of 22,11, and 10 association studies and demonstrated that presence of the F-V-Leiden G1691A (OR 1.9; 95% CI 1.6-2.5), the FII G20210A (OR 1.8; 95% CI 1.1-2.9), and the ACT Met235Thr polymorphism (OR 1.6; 95% CI 1.4-1.8), respectively, is significantly associated with preeclampsia. Presence of the MTHFR C677T polymorphism, however, is not associated with preeclampsia in a meta-analysis of 24 association studies (OR 1.1; 95% CI 0.9-1.3). Besides preeclampsia, genotyping for the F-V-Leiden G1691A and the FII G20210A polymorphisms is useful for individual risk assessment regarding pregnancy-associated thrombosis. Heterozygous and homozygous carriers of the F-V-Leiden G1691A polymorphism will develop this condition in 6.4% and 8.9% to 16.7% of cases, respectively. 6.2 % of women with the F II G20210A polymorphism and 17.8% of women with simultaneous carriage of the F-V-Leiden G1691A and FII G20210A polymorphisms will develop pregnancy-associated thrombosis. The thrombophilic polymorphisms F-V-Leiden G1691A and FII G20210A are also risk factors of early recurrent, late recurrent, and late spontaneous miscarriage based on a published meta-analysis of 31 studies. Six case-control and cohort studies of 687 women with thrombophilic polymorphisms demonstrate live birth rates of 82% (181/221) using low molecular weight heparin or fractionated heparin compared to 20% (95/466) without therapy (p < 0.001, OR 17.7; 95%-KI 12.2-25.5). Based on the data in the literature and a meta-analysis of 67 association studies, we conclude that the F-V-Leiden G1691A, FII G20210A, and ACT Met235Thr polymorphisms are significant risk factors for preeclampsia, pregnancy-associated thrombosis, and early and late miscarriages.

We present the case of an 84-year-old man with concomitant breast and prostate cancer. The patient presented with the clinical clinical picture of a T4-breast cancer. During preoperative staging prostate cancer was diagnosed. The patient received neo-adjuvant endocrine therapy followed by breast surgery and systemic endocrine therapy for breast and prostate cancer, respectively. We discuss treatment options in male breast cancer and the implications of concomitant prostate cancer.

Objective To determine what percentage of women can be given individualized counseling based on genetic information, as single nucleotide polymorphisms (SNPs) are associated with risks and benefits of estrogen therapy and hormone therapy such as thrombosis, myocardial infarction, breast cancer, and bone protection. Design Cross-sectional study. Setting Academic research institution. Patient(s) A consecutive series of 2,507 perimenopausal and postmenopausal women. Intervention(s) Peripheral venous puncture and multiplex polymerase chain reaction on a microarray system. Main outcome measure(s) Analysis of 22 SNPs of 17 genes: AGTMet235Thr, APOECys112Arg, APOEArg158Cys, COMTVal158Met, CYP17–34T>C, CYP191558C>T, CYP19Arg264Cys, CYP1A16235T>C, CYP1A1Ile462Val, CYP1B1Leu432Val, CYP1B1Asn453Ser, HSD17B1–27A>C, ER-αIVS-401T>C, prothrombin20210G>A, factor V Leiden, eNOS–786T>C, eNOSGlu298Asp, MRSer810Leu, MTHFR677C>T, PAI 15G>4G, SRD5A2Val89Leu, and VDRb>B. Result(s) Among the women in the study, 66% had at least two homozygous mutant SNPs of interest. A thrombophilic disposition was found in 9.9% of women, and 23% of women had at least two SNPs associated with an increased risk of breast cancer (COMT, CYP17, CYP19, CYP1A1, and CYP1B1). The SNPs predisposing women to cardiovascular pathologies (e.g., APOE, AGT, eNOS, and PAI 1) were found in 12.3% of women. Carriage of SNPs predisposing to early postmenopausal bone loss and osteoporosis (ER-α and VDR) were found in 26.7% of women. Conclusion(s) These data suggest that the assessment of SNPs associated with risks and benefits of estrogen/hormone therapy may be a new means to individualize counseling about and prescription of estrogen/hormone therapy in up to 66% of women.

The tumor necrosis factor alpha (TNFalpha) gene plays an important role in immunology and inflammation. Variant alleles of TNFalpha are associated with altered RNA and serum protein levels in humans. Conflicting results have been obtained regarding the role of TNFalpha during pregnancy and recurrent pregnancy loss (RPL). This study investigated the relationship between RPL and two polymorphisms in the promoter of the TNFalpha gene (TNFalpha -308 and -863). Genotyping was performed in 168 RPL women and 212 ethnically matched healthy individuals. In addition, we performed analysis of TNFalpha serum protein levels. We demonstrate that neither the polymorphism -308 nor the polymorphism -863 of the TNFalpha gene is associated with RPL in Caucasian women. In addition, we did not find any association between TNFalpha serum levels and the occurrence of RPL in a subset of 36 RPL women and 36 healthy individuals. We conclude that TNFalpha polymorphisms and resting blood TNFalpha levels do not correlate with the propensity to recurrent pregnancy loss in Caucasian women.

The ovarian corpus luteum plays a critical role in reproduction being the primary source of circulating progesterone. After ovulation the corpus luteum is build by avascular granulosa lutein cells through rapid vascularization regulated by gonadotropic hormones. The present study was performed to investigate whether this process might be influenced by the human chorionic gonadotropin (hCG)-dependent expression of different tumor suppressor genes and hypoxia dependent transcription factors. RNA was isolated from cultured granulosa lutein cells, transcribed into cDNA, and the transcript level of following genes were determined: RB-1, VHL, NF-1, NF-2, Wt-1, p53, APC, and hypoxia inducible factor-1 (HIF-1), -2, and -3α. Additionally, the influence of hCG on the expression of VHL, p53, and HIf2α were investigated. We demonstrate that in human granulosa lutein cells the tumor suppressor genes RB-1, VHL, NF-1, NF-2, Wt-1, p53, and APC and the hypoxia dependent transcription factors HIF-1α, -2α, and -3α are expressed. In addition, we showed that hCG regulates the expression of p53, VHL, and HIF-2α. Our results indicate that hCG may determine the growth and development of the corpus luteum by mediating hypoxic and apoptotic pathways in human granulosa lutein cells. Mol. Reprod. Dev. 69: 397–401, 2004. © 2004 Wiley-Liss, Inc.

Experimental data indicate that interleukin (IL)-1 plays a role in the pathogenesis of endometriosis. We determined the genotype and the allele frequencies of the IL1B exon 5 polymorphism and the corresponding IL-1beta serum levels in women with endometriosis.We genotyped 92 women with surgically and histologically confirmed endometriosis and 69 controls without history of endometriosis. Both groups were of middle European genetic background for the IL1B exon 5 polymorphism (at position +3954). Genotyping was performed by pyrosequencing. IL-1beta serum levels were analyzed by a commercially available enzyme-linked immunosorbent assay.Allele frequencies in women with endometriosis and controls were 76.6% and 76.8%, respectively, for the E1 allele (wild type) and 23.4% and 23.2%, respectively, for the E2 allele (polymorphic) (odds ratio 1.01; P.99). The investigated polymorphism of the IL-1beta gene was not correlated with IL-1beta serum levels.We did not find an association between the IL1B exon 5 polymorphism, endometriosis, or increased serum IL-1beta levels.

Interleukin (IL)-6 has been implicated in the etiology of endometriosis. A single nucleotide polymorphism (SNP) at position - 174 in the IL-6 gene promoter appears to influence IL-6 transcription rates in vitro and basal IL-6 levels in vivo. We determined the genotype and the allele frequencies of the -174 IL-6 promoter polymorphism and the corresponding IL-6 serum levels in women with endometriosis. The pyrosequencing technique was used to assess the IL-6 genotypes in 94 women with histologically confirmed endometriosis (study group). A series of 70 healthy women without history of uterine disease served as clinical controls (control group). Allele frequencies for the G allele among women with and without endometriosis were 59.6% and 55.0%, respectively (P =.430; odds ratio [OR] 0.83, 95% confidence interval [CI] 0.53, 1.29). Homozygotes for the protective allele C were present in 17.0% of women with endometriosis and in 18.6% of controls were homozygous for the protective allele C (P =.797; OR 0.90, 95% CI 0.40, 2.02). When patients with various disease manifestations were compared, we found an association between the -174 G allele and chocolate cysts (P =.037). Serum levels of IL-6 were significantly higher in women with endometriosis than in controls (P

Malignant melanoma derives from pigmented cells of neuroectodermal origin. Melanoma cells express estrogen receptors. An influence of steroid hormones on the proliferation rate of melanoma cells was demonstrated in some animal experiments. Thus it is of concern whether or not women with malignant melanoma are candidates for hormone replacement therapy (HRT). Until today, no prospective randomized trial on the association between HRT and malignant melanoma has been published. However, from the data available from in vitro-studies, in vivo-studies, and epidemiological reports, we can draw the following conclusions: there is no convincing evidence that the intake of sexual steroids increases the risk for the development of malignant melanoma and there is no evidence that HRT, taken after a diagnosis of malignant melanoma, negatively influences the outcome of the disease.

To explore whether having the mutant tumor necrosis factor (TNF)2 (G-308*A) and TNFA-A (G-238*A) alleles in the TNF-alpha gene promotor region is higher in women with endometriosis, we determined the respective genotype and allele frequencies in a retrospective case-control study. Polymerase chain reaction was performed to identify the G-308A and G-238A promotor polymorphisms in 92 women with surgically and histologically confirmed endometriosis. A series of 69 healthy women without a history of endometriosis served as clinical controls. The allele frequencies of the TNF2 polymorphism were 0.13 and 0.16 in women with endometriosis and in the control group, respectively, and the frequencies of the TNFA-A polymorphisms in women with endometriosis and in the control group were 0.04 and 0.05, respectively, with no significant difference between the study and control groups. The TNF2 polymorphism was present in the homozygous form (TNF(2/2)) in 4.3% of women with endometriosis and in 2.9% of controls (P=.7). No TNFA-A homozygotes (TNFA(A/A)) were detected. We studied TNF-alpha promotor gene variants among women with endometriosis and found that having the G-308A TNF-alpha and the G-238A TNF-alpha polymorphism was not associated with endometriosis in a white population.

Human papillomavirus (HPV) infection is the most important singular factor in the etiology of cervical cancer. Among young women, infection with HPV is a common and transient occurrence with prevalence rates between 20% and 46% and a mean duration of 8 months. Indications for HPV typing in current clinical practice include (1) triage to colposcopy and colposcopically directed biopsy, (2) triage to conization, (3) detection of HPV persistence after conization and (4) use of HPV within primary screening programmes of cervical cancer. Available data demonstrate that HPV typing increases the sensitivity of detecting severe dysplastic lesions among women with a diagnosis of atypical cells of undetermined significance (ASCUS), but not among women with a diagnosis of low grade squamous intraepithelial lesion (LSIL). This increased sensitivity, however, seems to be equivalent to that provided by repeat cervical cytology. Infection with HPV high risk types is strongly associated with disease progression of cervical dysplasia. Cases of severe dysplasia should be treated exclusively by surgical intervention. HPV typing might aid in the selection of women with established mild or moderate dysplasia, who should also undergo surgery. Whether an HPV-based approach in this clinical setting is safe as well as cost-effective, remains unclear. There is concern, that triaging women with mild or moderate dysplasia based on their HPV status might significantly increase treatment related morbidity due to the high prevalence of HPV infections among these women Persistence of high-risk HPV infection after surgical therapy of cervical dysplasia is significantly associated with residual disease and the risk of recurrence of dysplasia. Whether routine HPV typing before and after surgical therapy of cervical dysplasia is a superior strategy compared to cytologic follow-up examinations, has not been proven. Persistent HPV infection is the most important etiologic factor of cervical cancer. Many authors have therefore proposed to incorporate HPV typing into cervical cancer screening programmes. Up to date, however, there are no clinical studies available demonstrating the safety and efficacy of HPV typing, either alone or in combination with cervical cytology, in population-based screening programmes. In summary, there is not enough evidence today to support the routine use of HPV typing in common clinical practice.

OBJECTIVE: To investigate the association between the C677T polymorphism of the 5,10-methylenetetrahydrofolate reductase gene (MTHFR), serum homocysteine levels, and idiopathic recurrent miscarriage in a Middle-European white population. METHODS: In a case control study, we investigated 133 women with a history of three or more consecutive pregnancy losses before 20 weeks’ gestation and 74 healthy controls with at least two live births and no history of pregnancy loss. A DNA extraction and polymerase chain reaction followed by restriction fragment length polymorphism analysis were used to genotype women for the presence of the MTHFR C677T polymorphism. Serum homocysteine levels were assessed by a fluorescence polarization immunoassay. RESULTS: The MTHFR allele frequencies in women with idiopathic recurrent miscarriage and controls were 34.6% and 21.6%, respectively, for the T allele (mutant) and 65.4% and 78.4%, respectively, for the C allele (wild type) (P = .007, odds ratio 1.9, 95% confidence interval 1.2, 3.1). The MTHFR genotype frequencies in women with idiopathic recurrent miscarriage and controls were: 17.3% (T/T), 34.6% (C/T), 48.1% (C/C) and 5.4% (T/T), 32.4% (C/T), 62.2% (C/C), respectively (P = .03, odds ratio 3.7, 95% confidence interval 1.2, 11.8 [T/T versus C/T and C/C]). Serum concentrations of homocysteine were significantly higher in carriers of a MTHFR mutant allele compared with women with no mutant allele (mean 7.4 ± 2.4 μmol/L [T/T + C/T] versus 6.5 ± 2.6 μmol/L [C/C], P = .05). CONCLUSION: Carriage of the mutant allele of the MTHFR C677T polymorphism is associated with elevated serum levels of homocysteine and idiopathic recurrent miscarriage.

Acta Obstet Gynecol Scand 2002; 81: 168-171. © Acta Obstet Gynecol Scand 2002 Background. Isoforms of transforming growth factor-beta (TGF-β1) are thought to be involved in the pathogenesis of pre-eclampsia. Data with respect to TGF-β1 are controversial. We examined the correlation between TGF-β1 serum levels and the occurrence and severity of pre-eclampsia. Methods. Transforming growth factor-beta 1 serum levels were measured using a commercially available enzyme-linked immunosorbent assay in 44 women with pre-eclampsia and 44 healthy pregnant women. Results were correlated with clinical data. Results. No difference in TGF-β1 serum levels was assessed between women with pre-eclampsia and healthy pregnant women. Transforming growth factor-beta 1 serum levels were not associated with the severity of the disease and were not correlated with clinical maternal (blood pressure, proteinuria) and fetal (5-min APGAR score, umbilical cord pH values, birth weight) parameters. Conclusions. Our data support the assum...

Purpose: Catechol-O-methyltransferase (COMT) inactivates the estradiol metabolites, 2-hydroxy and 4-hydroxy catechols, which have been implicated in the pathogenesis of endometriosis. A COMT valine to methionine polymorphism (G-to-A) in exon 4 of the COMT gene is polymorphic in the human population, with 25% of Caucasians being homozygous for the low-activity allele (COMT-L) of the enzyme. In a case-control study we investigated whether this COMT polymorphism is associated with endometriosis.

Progesterone inhibits lymphocyte cytotoxicity, natural killer cell degraulation, and release of proinflammatory cytokines and has been shown to protect against spontaneous miscarriage. We investigated the association between idiopathic recurrent miscarriage (IRM) and the PROGINS 306 base pair insertion polymorphism in intron G of the progesterone receptor gene, which is known to segregate with progesterone-dependent neoplasms. In a case-control study we investigated 125 women with a history of three or more consecutive pregnancy losses before 20 weeks’ gestation and 79 healthy controls with at least two live births and no history of pregnancy loss. Peripheral venous puncture, DNA extraction, and polymerase chain reaction were used to genotype women for the presence of the PROGINS polymorphism. Allele frequencies among women with IRM and controls were 85.2% and 89.2%, respectively, for allele T1 (wild type) and 14.8% and 10.8%, respectively, for allele T2 (mutant). No association between allele T2 and the occurrence of IRM was found (P = .3; odds ratio [OR] 0.69; confidence interval [CI] 0.34, 1.40). Genotype frequencies were not significantly different between the study group (T1/T1 73.6%, T1/T2 23.2%, T2/T2 3.2%) and the control group (T1/T1 79.7%, T1/T2 19%, T2/T2 1.3%) (P = .4). Between women with primary and secondary IRM, there were no statistically significant differences with respect to allele frequencies (82% versus 87%, P = .4 for allele T1 and 12% versus 13%, P = .6 for allele T2). We found that the PROGINS polymorphism in the progesterone receptor gene was not associated with IRM in white women.

OBJECTIVE: To evaluate placental expression and serum cytokeratin-18 in women with preeclampsia. METHODS: Serum cytokeratin-18 was evaluated in 44 women with preeclampsia and 44 healthy pregnant women using an immunoradiometric assay. Placental expression of cytokeratin-18 was investigated in specimens from 23 women with preeclampsia and 20 healthy pregnant women by immunohistochemistry. RESULTS: Median serum cytokeratin-18 in women with preeclampsia and healthy pregnant women was 106.7 and 76. 0 U/L, respectively (P = .02). Among women with preeclampsia, serum cytokeratin-18 was significantly associated with severity of disease (P = .001) and showed a sensitivity (standard error) and specificity (standard error) of 85% (7%) and 65% (12%), respectively. In placental specimens, the cytoplasm of the syncytiotrophoblast stained positive for cytokeratin-18 with strong and widespread staining in 83% and 45% of placental specimens of women with preeclampsia and healthy pregnant women, respectively (P = .01). CONCLUSION: Elevated serum cytokeratin-18 values are associated with disease severity in women with preeclampsia. Our data provide additional evidence that the placenta might be the source of the elevated serum cytokeratin-18 values in women with preeclampsia.

Objective: To identify associations between polymorphisms within the interleukin-1β gene cluster, all of which increase protein expression, and preeclampsia. Methods: We genotyped a Hispanic population (69 women with preeclampsia and 47 controls) for two polymorphisms of the interleukin-1β gene (promoter region and exon 5) and one polymorphism of the interleukin-1 receptor antagonist gene in intron 2. Clinical data were collected from medical records. Values are given as means or medians. Statistical power to identify a difference in occurrence of interleukin-1β promoter, interleukin-1β exon 5, and interleukin-1 receptor antagonist gene polymorphisms in women with preeclampsia compared with controls was 21%, 15.9%, and 30.9%, respectively. Results: We found no association between any single polymorphism and occurrence of preeclampsia. Among women with preeclampsia, those with polymorphism of interleukin-1 receptor antagonist gene had higher mean systolic blood pressure (BP) at admission (178 ± 33.4 versus 159 ± 19.5 mmHg, P = .039). When all three polymorphisms combined were evaluated, women with preeclampsia and at least three mutant alleles (n = 8) had higher mean systolic BP at admission (182 ± 30 versus 160 ± 20.5 mmHg, P = .009) and increased alanine aminotransferase (67 [10–1024] versus 20 [3–407] IU/L, P = .04) and aspartate aminotransferase (119 [25–2239] versus 24 [4–489] IU/L, P = .002). At admission, BP in controls was independent of any polymorphism identified. Conclusion: Although the power of this study was limited, our data do not support a role for polymorphisms of the interleukin-1β and interleukin-1 receptor antagonist genes in the pathogenesis of preeclampsia among Hispanic women. Our findings do suggest that polymorphisms within the gene cluster might influence severity of preeclampsia.

Objective: To determine the value of serum soluble Fas levels as a prognostic marker for survival of women with ovarian cancer and as a discriminator between benign and malignant adnexal masses. Methods: Serum soluble Fas levels were measured with an enzyme-linked immunosorbent assay in 52 women with ovarian cancer, 30 women with benign ovarian cysts, and 35 healthy women. Results: Median serum soluble Fas levels in women with ovarian cancer, women with benign ovarian cysts, and healthy women were 3.7 (range 1.6–14.5), 2.3 (range 1.3–4.1), and 1.5 ng/mL (range 0.1–5.6), respectively (P < .001). A univariate logistic regression model showed a significant influence of serum soluble Fas and CA 125 levels on the odds of presenting with ovarian cancer versus benign cysts (P < .001 and P = .001, respectively). In a multivariable logistic regression model for soluble Fas and CA 125, both markers showed a statistically significant influence on the odds of presenting with ovarian cancer versus benign cysts (P = .01 and P = .01, respectively). Increased pretreatment serum soluble Fas levels were associated with shortened disease-free and overall survival (P = .002 and P = .001, respectively). A multivariable Cox regression model identified serum soluble Fas levels as a significant prognostic factor for disease-free and overall survival, independent of tumor stage (P = .04 and P = .03, respectively). Conclusion: Soluble Fas levels might be useful as a discriminator between benign ovarian cysts and ovarian cancer, adding to the information obtained with the use of the established tumor marker CA 125. Pretreatment serum soluble Fas levels also might be an independent prognostic factor for disease-free and overall survival.

To evaluate cytokeratin 19 as a serum marker of preeclampsia.Serum cytokeratin 19 levels were measured in 46 women with preeclampsia and 46 controls matched for gestational age and parity, using an immunoradiometric assay. Cytokeratin 19 was evaluated immunohistochemically in placental specimens from 28 healthy pregnant women and 24 women with preeclampsia.Cytokeratin 19 was identified in the syncytiotrophoblast in 13 (46. 4%) of 28 and 23 (95.8%) of 24 placental specimens from controls and women with preeclampsia, respectively (P =.03). Median serum levels of cytokeratin 19 in controls and women with preeclampsia were 1.7 (range 0.3-4.7) microg/mL and 2.7 (range 0.8-8.2) microg/mL, respectively (P.001). Cytokeratin 19 significantly influenced the odds of presenting with preeclampsia (P.001) and the odds of developing severe disease (P.001). Serum cytokeratin 19 correlated inversely with fetal birth weight (Kendall tau-b correlation coefficient = -0.2, P =.007). Compared with healthy pregnant women, women with severe preeclampsia had significantly higher and more rapidly increasing cytokeratin 19 serum levels throughout the third trimester (P.001).Placental stimulation of cytokeratin 19, and release of it into maternal circulation, seem to be a feature of preeclampsia. Correlations with clinical characteristics suggest that cytokeratin 19 is a marker of disease severity.

The chemokine monocyte chemoattractant protein (MCP)-1 is an important mediator of monocyte infiltration in various solid tumours of epithelial origin. The aim of the present study was to evaluate the role of MCP-1 in the natural history of ovarian cancer and to determine its value as differentiation marker and prognostic marker regarding disease free and overall survival. This retrospective study comprises 86 patients with ovarian cancer, 48 with primary ovarian cancer and 38 with recurrent ovarian cancer, 67 patients with benign ovarian cysts and 42 healthy women. Median serum levels in patients with primary ovarian cancer, recurrent ovarian cancer, benign ovarian cysts and in healthy women were 535.6 (range 129.6–1200) pg ml–1, 427.3 (range 193.4–1101) pg ml–1, 371.2 (range 222–986.8) pg ml–1 and 318.7 (range 241.3–681.4) pg ml–1 respectively (Mann–Whitney U-test, P < 0.001). Univariate logistic regression models revealed a significant influence of MCP-1 serum levels on the odds of presenting with primary ovarian cancer versus benign cysts and versus healthy women respectively (univariate logistic regression, P < 0.001 and P < 0.001 respectively). In a multivariate logistic regression model considering MCP-1 and CA 125 serum levels simultaneously, both MCP-1 and CA 125 revealed statistical significance on the odds of presenting with primary ovarian cancer versus benign cysts (multivariate logistic regression, P = 0.05 and P < 0.001 respectively). In ovarian cancer patients, MCP-1 serum levels showed a statistically significant correlation with histological grade (Mann–Whitney U-test, P = 0.02) and age at the time of diagnosis (Mann–Whitney U-test, P = 0.03). Elevated MCP-1 serum levels prior to therapy were not associated with disease-free and overall survival (log-rank test, P = 0.2 and P = 0.7 respectively). In summary these data indicate that MCP-1 might play a functional role in the natural history of ovarian cancer and might serve as differentiation marker between benign ovarian cysts and ovarian cancer, providing additional information to the established tumour marker CA 125. © 1999 Cancer Research Campaign

Our aim was to evaluate the clinical usefulness of serum concentrations of squamous-cell carcinoma antigen (SCC-Ag) and tissue polypeptide antigen (TPA) in the follow-up of patients with vulvar cancer. We measured SCC-Ag and TPA in 480 serum samples of 82 patients with squamous-cell vulvar cancer. Results were correlated with clinical data. SCC-Ag, TPA and the combination of SCC-Ag and TPA reached a sensitivity and specificity of 27%/97%, 28%/75% and 40%/73%, respectively. The sensitivity and specificity of the marker combination SCC-Ag and TPA was not significantly higher compared with SCC-Ag alone (McNemar's test, p = 0.6 and p = 0.09, respectively). Of the 35 patients with recurrent disease during follow-up, 19, 6 and 10 developed local, regional and distant recurrent disease, respectively. SCC-Ag showed lead-time effects in 26%, 75% and 50% and TPA in 25%, 0% and 33% of patients with local, regional and distant recurrent disease, respectively. The combination of SCC-Ag and TPA showed lead-time effects in 50%, 75% and 50% of patients with local, regional and distant recurrent disease, respectively. The difference between median lead-times of the combination of SCC-Ag and TPA and SCC-Ag alone was not statistically significant (Mann-Whitney U-test, p = 0.4). Our data show that serum SCC-Ag displays good sensitivity/specificity characteristics in the follow-up of vulvar cancer patients, with lead-time effects seen in 75% and 50% of patients with regional and distant recurrent disease, respectively. Furthermore, our data indicate that combining SCC-Ag with TPA is not a successful strategy to improve the sensitivity or the duration of lead-time effects in the follow-up of patients with vulvar cancer. Int. J. Cancer 83:167–170, 1999. © 1999 Wiley-Liss, Inc.

BACKGROUND: Adhesion molecules have been demonstrated to be involved in placental growth and development in normal pregnancy. Experimental evidence indicates that adhesion molecules are key factors of endothelial activation in preeclampsia. The aim of our study was to evaluate serum levels of the adhesion molecule Leukocyte Functional Antigen (LFA)-3 in healthy, non pregnant, female controls, healthy pregnant women, and preeclamptic women. METHODS: In our study we included 45 healthy, non pregnant, female controls, 45 healthy pregnant women, and 45 preeclamptic women. An enzyme-linked immunosorbent assay was used to determine serum levels of LFA-3. Results were correlated to clinical data. RESULTS: The median LFA-3 serum level in healthy, non pregnant, female controls was 0.2 (range 0 to 8.6) ng/mL. LFA-3 serum levels in healthy pregnant women were 4.8 (range 0 to 18) ng/mL and were significantly elevated compared to healthy, non pregnant, female controls (Mann-Whitney U-test, p=0.004). A cut-off level of 4.8 ng/mL was selected according to the 75th quantile of serum levels measured in the panel of healthy, non pregnant, female controls. In preeclamptic women, whose pregnancies had to be terminated due to exacerbation of preeclamptic symptoms, LFA-3 serum levels above the cut-off level were seen in 14/27 (52%) cases. In contrast, preeclamptic women, who went into spontaneous labor showed elevated LFA-3 serum levels in 17/18 (95%) cases (chi-square test, p=0.002). LFA-3 serum levels revealed a statistically significant influence on the odds of termination of pregnancy due to exacerbation of preeclamptic symptoms (unconditional logistic regression, p=0.02) with an odds ratio of 0.1 (95% CI, 0.006 to 0.7) by every doubling of LFA-3 values. CONCLUSIONS: Our results suggest that LFA-3 expression is upregulated in healthy pregnant women compared to healthy, non pregnant, female controls. Failure of LFA-3 upregulation in preeclampsia is associated with an increased risk for termination of pregnancy due to exacerbation of preeclamptic symptoms.

Our aim was to evaluate whether serum concentrations of squamous cell carcinoma antigen (SCC-Ag) are an independent prognostic factor in patients with vulvar cancer. We measured SCC-Ag in pretreatment serum samples of 55 patients with squamous cell vulvar cancer, 30 patients with vulvar intraepithelial neoplasia (VIN) grade III and 50 healthy female controls. The results were compared with clinical data. Median serum concentrations of SCC-Ag in healthy female controls, patients with VIN III, and patients with invasive vulvar cancer were 0.5 (range 0.1 to 3.8) ng/mL, 0.5 (range 0 to 4.1) ng/mL and 1.6 (range 0.3 to 65) ng/mL, respectively (Mann-Whitney U test, p

Preeclampsia is a severe complication in pregnancy, causing considerable maternal and fetal morbidity and mortality. Experimental evidence indicates that adhesion molecules are key factors of endothelial activation in preeclampsia. The aim of our study was to evaluate if serum levels of adhesion molecules CD44 and ELAM-1 provide clinically useful information as prognostic markers for preeclampsia.A matched-pair study including 43 women with preeclampsia and 43 women with uncomplicated pregnancies was performed. Enzyme-linked immunosorbent assay (ELISA) was used to determine serum levels of CD44 and ELAM-1. Results were correlated with clinical data.Median serum levels of ELAM-1 in controls and in women with preeclampsia were 8.9 ng/mL (minimum 0, maximum 20.0) and 12.0 ng/mL (minimum 4.0, maximum 27.0), respectively (Kruskal-Wallis test, p = 0.01). In a univariate logistic regression model, ELAM-1 did reveal a significant influence on the odds of presenting with preeclampsia as well as on the odds of premature termination of the pregnancy due to preeclampsia (univariate logistic regression, p = 0.03 and p = 0.01, respectively). The risk of premature termination of the pregnancy was 0.5%, 15.3%, and 80.5% at ELAM-1 serum levels of 0 ng/mL, 10 ng/mL, and 20 ng/mL, respectively. No significant correlation between CD44 serum levels and clinicopathological parameters due to preeclampsia was observed.If these results are confirmed in a larger series, ELAM-1 could be used as a prognostic factor in preeclamptic women, allowing early identification and appropriate management of high-risk patients with preeclampsia. It is unlikely that measurement of ELAM-1 will be of value as a screening test.

The aim of the present study was to evaluate the clinical usefulness of the cytokeratin marker CYFRA 21-1 as a screening marker for ovarian cancer, as a predictive marker in patients with adnexal masses and as a prognostic marker in women suffering from ovarian cancer. In order to determine the specificity of the CYFRA 21-1 test, we have investigated CYFRA 21-1 serum levels in several benign conditions. This retrospective study comprises 37 patients suffering from ovarian cancer FIGO stages Ia-III. Sera from patients with benign ovarian cysts, endometriosis, pelvic inflammatory disease, inflammatory bowel disease and liver cirrhosis were evaluated in 90, 10, 38, 10 and 20 cases respectively. With a sensitivity of 41% and a specificity of 95%, CYFRA 21-1 was not suitable as a screening marker for ovarian cancer. Although CYFRA 21-1 was able to discriminate between ovarian cancer and benign adnexal tumours (univariate regression model, P = 0.0001), CYFRA 21-1 did not reveal additional information to CA 125 in a multivariate regression analysis (P = 0.06). CYFRA 21-1 serum levels were elevated in benign conditions such as liver cirrhosis, but not in endometriosis and inflammatory diseases. In ovarian cancer patients, elevated CYFRA 21-1 serum levels before therapy were associated with a poor overall and disease-free survival (log-rank test, P = 0.02 and log-rank test, P = 0.005 respectively). CYFRA 21-1, while obviously not suitable for screening or differential diagnosis of adnexal masses, could be useful as an additional prognostic factor in ovarian cancer patients.

The aim of the present study was to evaluate the clinical usefulness of the cytokeratin tumor marker M3/M21 as a screening marker for ovarian cancer, as a predictive marker in patients with adnexal masses and as a prognostic factor in women with ovarian cancer. To determine the specificity of the M3/M21 test, we investigated M3/M21 serum levels in several benign conditions. This retrospective study comprises 37 patients with ovarian cancer FIGO stages Ia to III. Sera of patients with benign cysts, endometriosis, pelvic inflammatory disease, inflammatory bowel disease and liver cirrhosis were evaluated in 90, 10, 38, 10 and 20 cases, respectively. With a sensitivity of 57% and a specificity of 95%, M3/M21 is not suitable as a screening marker for ovarian cancer. Although M3/M21 is able to discriminate between ovarian cancer and benign adnexal tumors (univariate logistic regression, p = 0.0003), M3/M21 does not provide information additional to CA 125. M3/M21 serum levels are elevated in several benign conditions such as liver cirrhosis and inflammatory bowel disease. In ovarian cancer patients, elevated M3/M21 serum levels prior to therapy were associated with poor overall and disease-free survival (log-rank test, p = 0.03; log-rank test, p = 0.01, respectively). M3/M21, while obviously not suitable for screening or differential diagnosis of adnexal masses, could be useful as an additional prognostic factor in ovarian cancer patients.

Objective: To measure the serum levels of interleukin (IL)-8, prostaglandin (PG) F2α, and β-endorphin in parturients with acupuncture treatment and in controls to clarify the effect of acupuncture and duration of labor on the serum levels of substances active in cervical ripening and dilatation. Methods: A matched pair study was performed involving 80 women with and without prenatal acupuncture treatment, matched for age and parity. Serum levels of IL-8, PGF2α, and β-endorphin were measured in serum samples taken after delivery by use of enzyme-linked immunosorbent assay, enzyme immunoassay, and immunoradiometric assay, respectively. Results: The mean difference in total duration of labor between matched pairs with and without acupuncture was −136.5 minutes (95% confidence interval [CI] 191.1 minutes, −81.9 minutes; paired t test, P < .001). The mean difference of the duration of the first and second stages of labor between matched pairs with and without acupuncture was −138.8 minutes (95% CI 188.6, −89.0 minutes; paired t test, P < .001) and 2.3 minutes (95% CI 15.5, 20.1 minutes; paired t test, P = .8), respectively. The geometric means of ratios of IL-8, PGF2α, and β-endorphin between matched pairs in women with and without acupuncture showed no statistically significant differences. Serum levels of IL-8, PGF2α, and β-endorphin were not significantly correlated with the duration of the first and second stages of labor. Conclusion: Prenatal acupuncture treatment significantly reduces the duration of labor and may be a valuable tool in prenatal preparation. Serum levels of IL-8, PGF2α, and β-endorphin are not significantly influenced by acupuncture and are therefore not likely to mediate acupuncture-related effects during labor.

This retrospective study includes 425 serological examinations of 40 patients with epithelial ovarian cancer and 356 serological examinations of 33 patients with squamous cell cervical cancer. The serum levels of the tumor markers tissue polypeptide specific antigen (TPS), carbohydrate antigen 125 (CA 125) and squamous cell carcinoma antigen (SCC) were determined. Cutoff values of 93 U/l for TPS, 3 μg/l for SCC and 37 U/ml for CA 125 were selected according to the 95th percentile of serum concentrations measured in healthy control patients. For ovarian cancer sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of TPS were 67%, 84%, 59% and 90%, respectively. In 27 patients with recurrent ovarian cancer, CA 125 and TPS showed lead time effects in 8 and 11 cases, respectively. The combination of CA 125 and TPS provided lead time in 14 cases of recurrent disease with a time range from 1 to 23 months (median 3.9 months). In cervical cancer, TPS showed a sensitivity, specificity, PPV and NPV of 64%, 90%, 85% and 68%, respectively. In 16 patients with recurrent cervical cancer, SCC and TPS showed lead time effects in 7 and 8 cases, respectively. The combination of SCC and TPS provided lead time effects in 12 cases with a time range from 0.5 to 6 months (median 3.5 months). Our data indicate that TPS is a valuable tool in the follow-up of patients with ovarian or cervical cancer. However, TPS does not appear to be adequate to replace tumor markers CA 125 and SCC. Int. J. Cancer (Pred. Oncol.) 79:241–244, 1998.© 1998 Wiley-Liss, Inc.

Background. Cytokines are intercellular hormones, believed to play a functional role in the natural history of various malignant diseases. In vitro and in vivo studies have indicated that interleukin 6 (IL-6) may provide autocrine and paracrine growth stimulation in ovarian cancer cells. Methods. In the present study we measured IL-6 in the serum of 73 patients with FIGO stage I to IV ovarian cancer. Enzyme-linked immunosorbent assay (ELISA) was used to determine IL-6 serum levels. Results were correlated to clinical data. Serum levels of IL-6 were additionally evaluated in a panel of 50 normal controls. Results. Median serum levels of IL-6 in patients with ovarian cancer and normal controls were 55.6 (minimum 0, maximum 2869.0) pg/ml and 0.5 (minimum 0, maximum 2.14) pg/ml, respectively (Mann–Whitney U test, P = 0.0001). When serum levels of IL-6, taken prior to therapy, were grouped by FIGO stage, lymph node involvement, and grading of tumor cells, we found a statistically significant correlation with FIGO stage (Mann–Whitney U test, P = 0.04). Lymph node involvement and grading of tumor cells were not correlated with IL-6 levels. Elevated IL-6 serum levels prior to therapy were significantly correlated with poorer disease-free (log-rank test, P = 0.003) and overall survival (log-rank test, P = 0.01). Conclusion. Elevated IL-6 serum levels prior to therapy are correlated with a poor relapse-free and overall survival in ovarian cancer patients.

We determined whether gene polymorphisms associated with thrombophilia and vascular disease as etiologic factors were involved in the pathogenesis of pregnancy-associated complications.We conducted a multicenter case-control study in which we studied 94 women with late unexplained intrauterine fetal death (IUFD) and 94 healthy women with at least one uncomplicated full-term pregnancy and no history of IUFD. We obtained blood samples from all subjects and analyzed their DNA for 12 common polymorphisms of thrombophilic and vascular genes (factor V Leiden, factor V H1299R, prothrombin G20210A, factor XIII V34L, MTHFR C677T, MTHFR A1298C, beta-fibrinogen-455 G to A, PAI-1 4G/5G, GPIIIa L33P, HFE C282Y, apolipoprotein B R3500Q, and apolipoprotein E2/E3/E4).We found no significant association between any of the polymorphisms investigated and IUFD. Subgroup analyses involving various combinations of polymorphisms and in which gestational age and fetal weight were corrected for also showed no significant results.Our data represent the largest study to date with respect to thrombophilic and vascular gene polymorphisms in IUFD. In accordance with others, we challenge the importance of thrombophilic and vascular gene polymorphisms in the pathogenesis of this condition.

We present the data of 105 serum samples from 20 patients suffering from cervical cancer. Mean serum levels of basic fibroblast growth factor (bFGF) in patients with or without tumor present were 31.3 +/- 32.1 (minimum 0, maximum 156.7) pg/ml and 4.8 +/- 6.8 (minimum 0, maximum 29.6) pg/ml, respectively (P = 0.0001). bFGF reached a sensitivity of 65.7% at a specificity of 91.5% when applying a cut-off level of 15 pg/ml. Four patients relapsed after complete remission. A continuous increase of bFGF serum levels before the clinical detection of relapse (lead time) was seen in two cases with a mean lead time of 4 months. Preoperative serum levels were not of prognostic value and showed no correlation with pelvic lymph node metastasis. These preliminary results indicate that in cervical cancer patients soluble bFGF may be useful in early detection of primary tumors, recurrences and monitoring of therapy.

Interleukin (IL)-1 has been shown to induce peritoneal adhesions. We determined the IL-1 receptor antagonist (IL-1RN) genotype with respect to the two most common variant alleles IL-1RN*2 and IL-1RN*3 in Caucasian women with peritoneal adhesions. One hundred seven women with surgically verified peritoneal adhesions and 79 controls without peritoneal adhesions served as controls. Univariate analysis showed an increased risk for peritoneal adhesions for Caucasian women carrying the mutant IL-1RN*2 allele (OR: 2.1; 95% CI: 1.3-3.4; P = 0.004). Multiple logistic regression analysis demonstrated an increased risk for peritoneal adhesions, which is independent of previous abdominal surgery and endometriosis. Our data suggest that IL-1RN*2 allele carriers have an increased risk for adhesion formation.

Objective: Proinflammatory cytokines have been described to be involved in the pathogenesis of idiopathic recurrent miscarriage (IRM). We investigated the association between IRM and a polymorphism in exon 5 of the interleukin-1β gene (IL1B) and interleukin-1β (IL-1β) serum levels. Design: Case control study. Setting: Academic research institution. Subjects: One hundred thirty-one women with a history of three or more consecutive pregnancy losses before 20 weeks' gestation and 68 healthy controls with at least two live births and no history of pregnancy loss. Interventions: Peripheral venous puncture. Main Outcome Measures: An IL1B exon 5 (position +3953) gene polymorphism was analyzed by PCR amplification followed by restriction fragment length polymorphism analysis. IL-1β serum levels were analyzed by a commercially available ELISA. Results: Allele frequencies in women with IRM and controls were 77.9% and 80.8%, respectively, for the E1 allele (wild type), and 22.1% and 19.2%, respectively, for the E2 allele (mutant). No association between the E2 allele and the occurrence of IRM was found ( P =.57, odds ratio=.83). Genotype frequencies and IL-1β serum levels were not significantly different between the study group and the control group. Conclusions: This is the first report on an IL1B polymorphism in IRM. Although known to alter IL-1β expression, the investigated IL1B polymorphism is not associated with IRM and increased serum levels in a large Caucasian population.

TO test the hypothesis that serum levels of basic fibroblast growth f actor (bFGF) are altered among women with pregnancy-induced hypertension (PIH) and are associated with disease severity. We evaluated serum levels of bFGF in 46 women with PIH, 46 age- and parity-matched healthy pregnant women, and 46 healthy nonpregnant controls. Enzyme-linked immunosorbent assays were used to determine serum levels of bFGF. Results were correlated to clinical data. The overall mean serum levels of bFGF were 3.2 (standard deviation [SD] 9.3) μmol/L. Mean serum levels of bFGF in normal controls, healthy pregnant women, and women with PIH were 0 (SD 0) μmol/L, 2.6 (SD 6.3) μmol/L, and 6.8 (SD 13.8) μmol/L, respectively (P = .003) for normal controls compared with healthy pregnant women and P < .001 for healthy pregnant women compared with women with PIH). In a univariate logistic regression model bFGF showed a significant influence on the odds of presenting with PIH compared with healthy pregnant women (P = .002). The mean serum levels of bFGF in women with severe PIH and in women with mild PIH were 4.4 (SD 10.6) μmol/L and 9.5 (SD 17.3) μmol/L, respectively (P = .1). In a univariate logistic regression model bFGF did not reveal a significant influence on the odds of developing severe PIH (P = .3). Elevated serum levels of bFGF are associated with PIH, but bFGF does not seem to be a useful prognostic parameter for severe PIH.

A unique feature of steroids is their capacity for metamorphosis. Steroid hormones can be transformed into various metabolites exerting diverse effects. Converted steroids can be inactive, result in excretion of the steroid, occupy different receptors, and sometimes even show antagonistic effects to the precursor. This phenomenon is well documented for progesterone, androgens, and estrogen.

Interleukin-1 (IL-1) is a multifunctional cytokine playing a central role in the immune response and displaying direct cytotoxic activity in vitro. Serum IL-1 alpha and beta levels were measured by enzyme linked immunosorbent assay (ELISA) in 75 ovarian cancer patients, 30 patients with benign ovarian cysts and 50 healthy controls. Both serum IL-1 alpha and IL-1 beta levels were more often elevated in ovarian cancer patients compared with healthy controls (chi-square test, P < 0.001 and P < 0.001, respectively). Mean serum IL-1 alpha and beta levels decreased significantly after surgical intervention (paired t-test, P = 0.0001 and P = 0.0002, respectively). No correlation with histopathological parameters and overall and disease-free survival was found. These preliminary results indicate that serum levels of IL-1 alpha and beta represent a host defence reaction rather than an autonomous tumour cell production.

Cytokeratins are polypeptides which constitute a subclass of intermediate filaments in epithelial cells. The serum tumour marker M 3 M 21 is based on monoclonal antibodies against the epitopes M3 and M21 of cytokeratin 18. In the present study, we measured M 3 M 21 serum levels in 50 patients with FIGO stage IB–IIB cervical cancer and in 50 control subjects using a two-site radiometric immunoassay directed against soluble fragments of cytokeratin 18. Median serum levels of M 3 M 21 in patients with cervical cancer and in normal controls were 70.6 U/ml (range 0–397.7) and 6.5 U/ml (range 0–205.2), respectively (Mann-Whitney U-test, P = 0.0001). Median serum levels of M 3 M 21 prior to therapy and 4 weeks after therapy were 104.2 U/ml (range 24.6–397.7) and 39.3 U/ml (range 0–234.7), respectively (Mann-Whitney U-test, P = 0.004). We found a significant correlation between elevated M 3 M 21 serum levels and metastatic disease in pelvic lymph nodes (Mann-Whitney U-test, P = 0.002). 24 patients relapsed after complete remission. In these patients, elevated M 3 M 21 serum levels before the detection of relapse by computed tomography was observed in 13 cases. Considering these preliminary results, further studies with an increased number of patients are justified to clarify the prognostic value and the monitoring abilities of M 3 M 21 in cervical cancer patients.

Objective: Genetic factors have been proposed as modulators of the timing of natural menopause. Single nucleotide polymorphisms (SNPs) of genes associated with thrombophilia and vascular homeostasis may interfere with ovarian function and thus are candidate genes for early menopause. We attempted to assess the association of SNPs and the timing of menarche and natural and surgical menopause in an ethnically homogenous cohort of Middle European white women. Design: In the present cross-sectional study, eight SNPs of six genes involved in vascular function and homeostasis were analyzed by sequencing-on-chip using solid-phase polymerase chain reaction on oligonucleotide microarrays in 728 white women: factor V (F5) Leiden G1691A, factor II (F2) prothrombin G20210A, plasminogen activator inhibitor1 (PAI-1) 4G/5G, angiotensinogen (AGT) Met235Thr, endothelial nitric oxide synthase (NOS3) T768C and NOS3 Glu298Asp, apolipoprotein E-1 (APOE-1) Cys112Arg, and APOE-2 Arg158Cys. The women's reproductive and medical histories were correlated to genotypes. Results: In a univariate analysis, current smoking (P = 0.01) and the presence of at least one mutant allele of F5 Leiden (P = 0.03) and APOE-2 (P = 0.03) were significantly associated with a reduced age at natural menopause. The presence of at least one mutant allele of F5 Leiden (P = 0.02) and a body mass index above 25 kg/m2 (P = 0.009) were significantly associated with an increased risk for surgical menopause by premenopausal hysterectomy (odds ratio = 2.6, 95% CI, 1.2-5.6; odds ratio = 1.9, 95% CI, 1.2-3.0, respectively). Age at menarche was not affected by the carriage of any of the investigated SNPs. Applying stepwise linear regression models considering all two-way interactions, no interactions were found among different SNPs or between SNPs and environmental and lifestyle parameters. Conclusion: We identified various genetic and personal history parameters influencing age at natural menopause and the risk of undergoing premenopausal hysterectomy. To the best of our knowledge, we present the largest study to date determining SNPs as contributors to the genetic control of the timing of natural and surgical menopause.

BACKGROUND: Lifestyle parameters, personal history and genetic factors are thought to affect the timing of natural menopause in humans. Based on their biological function, estrogen-metabolizing gene polymorphisms have been regarded as candidate genes for early menopause. METHODS: In the present cross-sectional, multi-centre study, we analysed nine single nucleotide polymorphisms of six estrogen-metabolizing genes [three estrogen-synthesizing genes, i.e. 17-b-hydroxysteroid dehydrogenase type 1 (17-b HSD), cytochrome P-450 (CYP) 17 and CYP19; and three estrogen-inactivating genes, i.e. catechol-O-methyltransferase (COMT), CYP1A1 and CYP1B1 ]b y sequencing-on-chip-technology in 1360 Caucasian women with natural menopause. Women’s lifestyle parameters, reproductive and personal histories were ascertained. RESULTS: Carriage of at least one mutant allele of the CYP1B1-4 Asn453Ser A ! G polymorphism (P 5 0.004) and the number of full-term pregnancies ( P< 0.001) were found to be independently associated with age at natural menopause. Women with at least one polymorphic allele of CYP1B1-4 experienced natural menopause earlier than non-carriers of the polymorphism [mean (SD) 48.6 (5.0) versus 49.4 (4.3) years]. Women with no, one, two and three or more full-term pregnancies experienced natural menopause at 48.5 (5.0), 48.8 (4.8), 49.5 (4.2) and 49.6 (4.6) years, respectively. CONCLUSION: We present the most comprehensive data on estrogen-metabolizing gene polymorphisms and timing of natural menopause to date. The number of full-term pregnancies and the CYP1B1-4 polymorphism are significant predictors of timing of natural menopause in Caucasian women.

Objective To evaluate the association between the presence of uterine leiomyoma and two single nuclear polymorphisms of the p53 tumor suppressor and the angiopoietin-2 (ANGPT2) genes. Design Prospective case control study. Setting Academic research institution. Patient(s) One hundred thirty-two women with clinically and surgically diagnosed uterine leiomyomas and 280 controls. Intervention(s) Peripheral venous puncture. Main Outcome Measure(s) Genotyping was performed by polymerase chain reaction-based amplification of the Arg and Pro variants at codon 72 of the p53 gene and by restriction fragment length polymorphismanalysis of the G/G and G/A alleles in exon 4 of the ANGPT2 gene. Result(s) Comparing women with uterine leiomyomas and controls, no statistically significant difference with respect to allele frequency and genotype distribution were ascertained for the ANGPT2 polymorphism ( P =.2 and P =.5, respectively). However, for the p53 tumor suppressor gene polymorphism, statistically significant differences in terms of a higher Pro allele frequency and a higher prevalence of the Pro/Pro genotype among women with uterine leiomyoma (32.0% vs. 16.0%, respectively, and 21.3% vs. 4.7%, respectively) were ascertained ( P =.001, OR 1.74; 95% CI 1.24–2.45, P =.001; OR 3.84, 95% CI 1.81–8.14; respectively). Conclusion(s) Carriage of the p53 polymorphism at codon 72 predicts the susceptibility to leiomyoma in a Caucasian population and may contribute to the pathogenesis of uterine leiomyoma.

Objective To investigate the possible influence of a polymorphism of the Nos3 gene on menarche and onset of menopause in humans. Design Cohort study. Setting Academic research institution. Patient(s) Ninety-one consecutive Caucasian postmenopausal women. Intervention(s) Peripheral venous puncture and a patient questionnaire were administered. Main outcome measure(s) A tandem repeat polymorphism in intron 4 of Nos3 was analyzed by polymerase chain reaction amplification. Result(s) The common B allele was identified on 143 of 182 chromosomes (frequency 0.79). The polymorphic A allele was present on 39 chromosomes (frequency 0.21). The genotype frequencies were as follows: 58.2% (B/B), 40.7% (A/B), and 1.1% (A/A). Age at menarche, number of deliveries, number of miscarriages, and onset of menopause did not differ between genotypes. Smoking and increased body mass index were associated with an earlier onset of natural menopause. Conclusion(s) In contrast to mouse models, in humans Nos3 does not seem to modulate onset and cessation of menses.

OBJECTIVE: To review the efficacy of drug therapy for urinary urge incontinence by examining the published literature. METHODS OF STUDY SELECTION: In October 1999, we searched the medical databases MEDLINE, EMBASE, and Cochrane Controlled Trials Register to identify prospective randomized, double-blind, placebo-controlled clinical trials in the English literature evaluating drug therapy (except hormonal therapy) of urinary urge incontinence. Trials were categorized by type of drug and outcome variables. TABULATION, INTEGRATION, AND RESULTS: Forty-seven trials were identified. Twenty-four, 12, and 11 trials evaluated anticholinergic drugs, drugs with anticholinergic and calcium antagonistic properties, and alternative regimens, respectively. Data regarding treatment effects of anticholinergic drugs are consistent with a high therapeutic efficacy and characteristic side effects. Therapeutic efficacy and side effect patterns of terodiline, an agent with anticholinergic and calcium antagonistic properties, were comparable to those of anticholinergic agents. Terodiline, however, has been withdrawn from the market because of its association with cardiac arrhythmia. Of the investigated alternative drug regimens, the papaverine-like smooth muscle relaxant flavoxate was reported to be ineffective. Studies investigating the dopamine agonist bromocryptine, the α-adrenoceptor blocker prazosin, or the γ-aminobutyric acid receptor agonist baclofen showed subjective and/or objective improvement of symptoms without reaching statistical significance, whereas the tricyclic antidepressant doxepin, the neurotoxin capsaicin, and the prostaglandin synthase inhibitor flurbiprofen led to statistically significant subjective and/or objective improvement of symptoms. No data for subjective and/or objective improvement of symptoms could be extracted from the studies using the anticholinergic and calcium antagonistic agent propiverine and the calcium antagonist thiphenamil. CONCLUSION: Published trials support anticholinergic drugs as efficacious therapy for urinary urge incontinence, with predictable side effects. At present, these agents represent the pharmacological treatment of choice for this condition. The potential value of selected alternative drugs is underscored by the available data.

Estradiol is a pleiotropic hormone, involved in the etiology of a wide variety of diseases. Over the last decade individual genetic variability of the estradiol metabolism has been described as a significant contributor to disease susceptibility with variations depending on ethnic background. Among others, genetic variations of genes encoding cytochrome P450 (CYP) enzymes play an important role in this regard. Mutant alleles of the CYP 1A1 gene are major modulators of lung cancer risk among smokers, mediate gender differences in lung cancer susceptibility, and have been associated with an elevated risk for breast, prostate, colorectal, and oral squamous cell cancer. Variants of the CYP 1B1 gene modulate the risk for prostate, ovarian, lung, and breast cancer. Also, mutations in the CYP 1B1 gene are the major genetic determinant of congenital glaucoma. Mutant CYP 17 alleles are associated with serum and plasma levels of steroid hormones, use of hormone replacement therapy, and endometrial, prostate, and breast cancer. Available data indicate that the protective effect of a later age at menarche is limited to mutant CYP 17 allele carriers. Among women with the Polycystic Ovary (PCO) syndrome, mutant CYP 17 alleles are sufficient to aggravate the clinical presentation of the disease. Molecular variants of the CYP 19 gene are associated with an increased risk for breast cancer, advanced disease stage, and tumor aromatase production. Carriage of a mutant catechol-O-methyltransferase (COMT) allele is associated with breast cancer, neurologic disorders such as Parkinson's disease, and modulates behavior among patients with schizophrenia, alcoholics and the general population. In summary, the available evidence points to estrogen metabolising genes as strong hereditary determinants of the susceptibility to benign and malignant conditions.

Objective. Serum levels of vascular endothelial growth factor (VEGF) can be seen as surrogate markers of angiogenesis. Recently, leptin, which is involved in the control of satiety and energy expenditure, was also shown to modulate angiogenesis. As angiogenesis plays an abundant role in cervical carcinogenesis, we evaluated serum VEGF and leptin in patients with cervical intraepithelial neoplasia (CIN) and cervical cancer. Methods. Serum VEGF and leptin were measured in 84 patients with cervical cancer, in 28 patients with CIN I–III, and in 35 healthy women, using a commercially available enzyme-linked immunosorbent assay and radioimmunoassay, respectively. Results. Serum VEGF was significantly elevated in patients with cervical cancer and in patients with CIN I–III compared to healthy women. In patients with cervical cancer serum VEGF was significantly correlated with tumor stage, but not with lymph node involvement and histological grade. Univariate and multivariate analyses showed that elevated pretreatment serum VEGF was not associated with the duration of disease-free and overall survival. Serum leptin did not differ among patients with cervical cancer, patients with CIN I–III, and healthy women. Serum leptin was significantly correlated with body mass index (BMI). All further analyses were performed with absolute and serum leptin corrected by BMI. No differences in serum leptin could be ascertained between patients with cervical cancer and patients with CIN I–III. Serum leptin was not associated with any clinicopathological parameter and patients' survival. No correlation between serum VEGF and leptin was found. Conclusions. It can be speculated that serum VEGF might be used as a surrogate marker of angiogenesis in patients with cervical cancer. Our data support the concept that VEGF plays a role in malignant transformation and tumor growth, but not in the lymphatic spread of cervical cancer. This is the first report on leptin in a gynecological malignancy. Our results show that serum leptin falls short of being a useful marker in patients with cervical cancer.

OBJECTIVE: To investigate the frequency of a polymorphism in intron 7 of the tryptophan hydroxylase gene among women with idiopathic recurrent miscarriage and healthy controls. METHODS: In a case control study, we studied 125 women with a history of three or more consecutive pregnancy losses before 20 weeks’ gestation and 137 healthy controls with at least two live births and no history of pregnancy loss. Peripheral venous puncture, DNA extraction, and polymerase chain reaction followed by restriction fragment length polymorphism analysis were used to genotype women for the presence of the A218C polymorphism in intron 7 of the tryptophan hydroxylase gene. RESULTS: Allele frequencies among women with idiopathic recurrent miscarriage and controls were 32.4% and 38.7%, respectively, for allele A (wild type) and 67.6% and 61.3%, respectively, for allele C (mutant). No association between the presence of allele C and idiopathic recurrent miscarriage was found (P = .3; odds ratio 1.31; 95% confidence interval 0.93, 1.87). Genotype frequencies also were not significantly different between the study group (C/C: 44.8%; A/C: 45.6%; A/A: 9.6%) and the control group (C/C: 37.2%; A/C: 48.2%; A/A: 14.6%; P = .2). Between women with primary and women with secondary idiopathic recurrent miscarriage, no statistically significant differences with respect to allele frequencies were observed (63% vs 62% for allele C and 31% vs 38% for allele A; P = .3). CONCLUSION: The A218C polymorphism in intron 7 of the tryptophan hydroxylase gene is not associated with idiopathic recurrent miscarriage.