The influence of pregnancy on the development of autoimmunity in chronic lymphocytic leukemia.

To examine whether pregnancy influences the development of autoimmunity in chronic lymphocytic leukemia (CLL), we studied 591 consecutive CLL patients (202 post-menopausal women and 389 men). The mean observation time for all patients was 3.8 years, corresponding to approximately 2200 person-years of follow-up. Autoimmune manifestations were analyzed in 194 women with known obstetric history and known number of long-term sexual partners, and in the 389 male CLL patients for comparison. One hundred and fifty-nine of the CLL patients exhibited autoimmune manifestations, 38% in females and 21% in men. In female CLL patients, the frequency of autoimmunity and the number of pregnancies and the number of partners were strongly correlated. Each of the major autoimmune types approximately doubled in frequency for each additional pregnancy. The impact of pregnancy on expressed autoimmunity increased with each additional sexual partner (the odds of autoimmunity increased 11 times with each long-term sexual partner). The average numbers of pregnancies in female CLL patients with and without autoimmunity were 4.92 and 2.24, respectively (P < 0.001). Coombs' positive autoimmune anemia, a gastric ulcer with parietal cell autoantibodies and idiopathic thrombocytopenic purpura were equally common in women and men, whereas autoimmune thyroiditis, Sjögren's syndrome, rheumatoid arthritis and systemic lupus erythematosus were seen in higher rates in women than in men. The spectrum of autoimmunity suggests that pregnancy-related alloimmunization may be involved in the development of autoimmunity in CLL.

Hormone therapy and the impact of estrogen intake on the risk of ovarian cancer.

BACKGROUND: The association between menopausal hormone therapy (HT) and risk of ovarian cancer is as yet equivocal, and the effect of estrogen and estrogen-progestogen therapy, specifically the effect of the cumulative hormone intake, is unclear. METHODS: We conducted a nationwide population-based case-control study in Denmark. Cases were women aged 35 to 79 years with incident ovarian cancer diagnosed between January 1, 1995, and May 30, 1999. Controls were frequency age-matched women from the Danish Central Population Register. The analyses included data on 376 cases who have not undergone hysterectomy and 1111 controls. RESULTS: The risk of ovarian cancer in relation to oral HT increased with the cumulative intake of the estrogen component of HT but not with the duration or the cumulative intake of the progestogen component when the 3 variables were mutually adjusted. A simple trend was found such that each additional gram of estrogen was associated with the same relative increase. The odds ratio was constant throughout the range of cumulative intake. After adjustment for established risk factors, the estimated odds ratio per each additional gram of cumulative estrogen was 1.056 (95% confidence interval, 1.003-1.112), corresponding to an odds ratio of 1.31 (95% confidence interval, 1.01-1.70) per 5 g of estrogen. CONCLUSIONS: Oral HT is associated with risk of ovarian cancer in women who have not undergone hysterectomy. Our results imply that the risk increases with cumulative oral estrogen intake but not with duration of HT, indicating that the increased ovarian cancer risk associated with oral HT may be diminished substantially by minimizing the daily dose of estrogen from oral HT.

The prognostic value of plasma soluble urokinase plasminogen activator receptor (suPAR) levels in stage III ovarian cancer patients.

The level of the urokinase plasminogen activator receptor (uPAR) is elevated in tumor tissue from several forms of cancer. uPAR is shed from the cell surface and the soluble form, soluble urokinase plasminogen activator receptor (suPAR), has been detected in several body fluids. High plasma levels of suPAR in patients with colorectal cancer and high serum levels of suPAR in patients with recurrent metastatic breast cancer have been associated with poor prognosis. In patients with ovarian cancer (OC) it has been shown that the level of suPAR is very high in ascites and cystic fluid and that high serum levels of suPAR were associated with shorter survival of the patients. We evaluated suPAR preoperatively in plasma from primary OC stage III patients and tested for association with prognosis. The prognostic significance of suPAR was also compared to two biochemical markers; cancer antigen 125 (CA125) and tetranectin (TN). No significant differences were found between patients who died of OC compared to patients still alive regarding median plasma suPAR levels (p=0.62) and median serum CA125 levels (p=0.26). In contrast, a significant difference was found between dead and alive OC patients for the median serum TN level (p<0.0001). Dividing the patients into two groups, corresponding to preoperative plasma suPAR levels below or equal to 2.0 ng/ml and higher than 2.0 ng/ml, no significant difference in survival was found between the two groups (p=0.49). When different cut-off levels of plasma suPAR were considered (2.74 ng/ml, 3.25 ng/ml and 4.18 ng/ml), no significant differences in survival could be detected (p=0.58, p=0.68 and p=0.05). Multivariate Cox regression analysis showed that the only independent prognostic factors were radicality after primary surgery (RH=5.34; 95% CI, 2.34-12.20; p<0.0001) and preoperative serum TN (RH=0.69, 95% CI, 0.57-0.82; p<0.0001), whereas plasma suPAR (4.18 ng/ml), age, histological type of tumour and serum CA 125 had no independent prognostic value. In conclusion, preoperative plasma suPAR level was of no prognostic value in this cohort of Danish stage III OC patients.

Loss of heterozygosity on the X chromosome is an independent prognostic factor in ovarian carcinoma: from the Danish "MALOVA" Ovarian Carcinoma Study.

BACKGROUND: Ovarian carcinoma (OC) is the fifth most frequent female cancer type and the fourth most frequent cause of death from cancer among women in Denmark. At the time they are diagnosed with OC, approximately 70% of patients have advanced disease. It is believed that loss of tumor suppressor gene activity plays an important role in the origin and progression of OC and other malignancies. Loss of heterozygosity (LOH) may be detected in individuals heterozygous for an allele and is associated with loss of function of tumor suppressor genes. METHODS: The polymorphic marker regions (TP53, CACNLB1, D18S58, DXS538, and DXS454) were amplified by polymerase chain reaction followed by separation using gel electrophoresis before LOH was identified. In total, 160 women with primary epithelial OC were included in the study. RESULTS: Univariate analyses showed significant differences in survival between patients who had advanced OC with LOH or with retention using the microsatellite markers DXS454 (P = 0.04) and DXS538 (P = 0.01). Multivariate Cox regression analysis that included all patients showed that DXS454 (relative hazard [RH] = 3.5; P = 0.002; 95% confidence interval [95% CI], 1.6-7.8), radicality of primary surgery (RH = 5.5; P < 0.0001; 95% CI, 2.7-11.1), and serum tetranectin level (RH = 0.8; P = 0.009; 95% CI, 0.7-0.9) were independent prognostic factors for survival. Multivariate Cox regression analysis restricted to patients with International Federation of Obstetrics and Gynecology Stage III-IV disease showed that DXS454 (RH = 3.4; P = 0.007; 95% CI, 1.4-8.1), radicality of primary surgery (RH = 5.4; P < 0.0001; 95% CI, 2.2-12.9), and serum tetranectin level (RH = 0.8; P = 0.042; 95% CI, 0.7-1.0) were independent prognostic factors. CONCLUSIONS: LOH at DXS454 (Xq21-q23) appeared to be correlated with reduced survival in patients with OC.

Childhood tumor risk after treatment with ovulation-stimulating drugs.

OBJECTIVE: To assess childhood cancer risk among children conceived following the use of ovulation-stimulating drugs. DESIGN: Record linkage study. SETTING: Infertility patients and their offspring as identified through medical records. PATIENT(S): Cohort of 30,364 Danish women evaluated for infertility beginning in the early 1960s. MAIN OUTCOME MEASURE(S): Standardized incidence ratios (SIRs) compared cancer incidence in the children to the Danish population. Case-cohort techniques calculated rate ratios (RRs) according to prior maternal drug exposures. RESULT(S): A total of 51 cancers were identified among the study children, resulting in an SIR of 1.14 (95% confidence interval [CI] 0.8-1.5). Usage of any fertility drug was associated with an RR of 0.82 (95% CI 0.4-1.6) and clomiphene citrate with an RR of 0.77 (95% CI 0.4-1.6). Tumors occurring early in life and nonhematopoietic malignancies (including neuroblastomas) were not associated with drug usage. Nonsignificant elevations in the risk of cancers occurring later in life, especially childhood hematopoietic malignancies (RR for use of any ovulation-stimulating drugs of 2.30, 95% CI 0.8-6.6), may have been related to underlying reasons for medication usage. CONCLUSION(S): Although the findings of this study are reassuring, additional adequately powered studies should continue monitoring the effects of ovulation-stimulating drugs on specific tumors, including hematopoietic malignancies.

Evaluation of a polymorphism in intron 2 of the p53 gene in ovarian cancer patients. From the Danish "Malova" Ovarian Cancer Study.

BACKGROUND: The p53 gene is frequently mutated in various human tumours. In addition, single nucleotide polymorphisms are often observed in exons and introns of the p53 gene in normal tissues and tumours. MATERIALS AND METHODS: A total of 210 blood and tissue samples from 182 ovarian cancers (OC) and 28 ovarian borderline tumours, in addition to blood samples from 72 healthy women, were analysed. The used analyses were PCR and SSCP. The distinguishable SSCP patterns were confirmed by DNA sequencing. RESULTS: A polymorphism located at position 38 in intron 2 of the p53 gene was studied in blood and tumour tissues from Danish ovarian tumour patients and in blood from controls. Significant differences were found between the distributions of the genotypes in blood samples compared to the corresponding tissue samples (p = 0.0002). A tendency towards a significant difference in survival was observed between OC stage II patients with a shift from one genotype in the blood to another genotype in the tissue and patients with no shift (p = 0.05). In multivariate COX regression analysis restricted to stage III OC patients, the only independent factors found were shift, serum-tetranectin and age. CONCLUSION: A shift from one p53 intron 2 genotype in the blood to another genotype in the tissue may be a prognostic factor in ovarian cancer patients.

High plasma YKL-40 level in patients with ovarian cancer stage III is related to shorter survival.

YKL-40 (human cartilage glycoprotein-39) is a member of family 18 glycosyl hydrolases. YKL-40 is a growth factor and is secreted by cancer cells. High serum levels of YKL-40 in patients with colorectal cancer and recurrent metastatic breast cancer have been associated with a poor prognosis. We evaluated the prognostic value of plasma YKL-40 in patients with primary ovarian cancer (OC). YKL-40 was determined by ELISA in plasma obtained preoperatively from 47 women with stage III OC and in plasma from 79 healthy females. The results showed that plasma YKL-40 was elevated compared to healthy females in 57% of the OC patients and was highest in the patients who died during the follow-up compared to the patients still alive (186 vs. 78 micro g/l, p=0.002). Patients with high plasma YKL-40 (>130 micro g/l) had significantly (p=0.0003) shorter survival than patients with normal plasma YKL-40. Multivariate Cox regression analysis showed that plasma YKL-40 (RH=3.95; 95% CI, 1.52-10.27; p=0.005) and radicality after primary surgery (RH=4.03; 95% CI, 1.81-8.97; p=0.001) were independent prognostic factors of survival, whereas age, histological type of tumour and serum CA125 had no independent prognostic value. In conclusion, plasma levels of YKL-40 proved of prognostic value in stage III OC patients.

Distribution of HER-2 overexpression in ovarian carcinoma tissue and its prognostic value in patients with ovarian carcinoma: from the Danish MALOVA Ovarian Cancer Study.

BACKGROUND: The HER-2 (Human Epidermal Growth factor receptor-2, also known as c-erb-2/neu) protooncogene encodes a transmembrane receptor protein, M(r) 185,000. Studies have shown that the HER-2 oncogene is overexpressed in approximately 25-30% of ovarian carcinoma (OC) cases, but to the authors' knowledge, to date no consensus regarding overexpression and prognosis has been possible. The objective of the current study was first to analyze the presence of HER-2 overexpression in tissue from Danish OC patients and correlate the distribution of HER-2 overexpression with clinical and biochemical data and second to investigate the value of HER-2 overexpression as a prognostic marker in OC and to compare this value with the prognostic value of other biochemical markers. METHODS: The study population was comprised of the first 181 patients diagnosed with epithelial OC who were included in the MALOVA study. The staining procedure for HER-2 overexpression was performed using the p185 antibody. RESULTS: HER-2 overexpression was found in 95 of the 181 investigated cases (52.5%), in which 71 carcinomas (39.2%) were weakly positive (1+) and 24 carcinomas (13.3%) were moderately (2+) to intensely positive (3+). Increased HER-2 expression was found to be correlated with reduced survival. Significant differences in survival between patients with (1+, 2+, and 3+) and those without HER-2 overexpression were found for patients with International Federation of Gynecology and Obstetrics (FIGO) Stage I, Stage III, and Stage III/IV OC (Stage I: P = 0.021; Stage III: P = 0.0078; and Stage III/IV: P = 0.0054). Multivariate survival analyses including all 181 OC patients demonstrated that HER-2 overexpression is a prognostic marker (P = 0.003) together with disease stage, serum tetranectin level, and patient age. For patients with Stage III OC, the only independent prognostic factors detected were HER-2 overexpression (P = 0.009) and serum tetranectin level (P

K-ras alterations in Danish ovarian tumour patients. From the Danish "Malova" Ovarian Cancer study.

OBJECTIVE: Activation of ras oncogenes has been demonstrated in ovarian tumours. All the reported studies are based on a relatively small number of patients and the results therefore remain a subject of debate. METHODS: In this study, we analyzed the presence of mutations at codons 12 and 13 of the K-ras gene in 165 Danish women with ovarian tumours, including 138 invasive ovarian cancers and 27 borderline ovarian tumours, using a restriction fragment length polymorphism-polymerase chain reaction technique and evaluated whether such alterations were associated with the clinicopathological parameters of the patients and survival. RESULTS: K-ras codon 12 gene mutations were found in 8.7% of ovarian cancer patients and in 14.8% of the borderline ovarian tumour patients. A K-ras codon 13 gene mutation was found in 1.5% of ovarian cancer patients. K-ras mutations were found with a significantly higher frequency in mucinous tumours compared to serous tumours (P = 0.011). CONCLUSIONS: Mutation frequency was correlated with the histological type of tumour, but not with stage, radicality of operation, and age. Furthermore, no significant difference in survival was demonstrated between patients with or without K-ras mutation, neither in the univariate nor in the multivariate survival analyses.

[Who are the users of emergency contraception?]. / Hvem anvender nødpraevention?

INTRODUCTION: A user profile is necessary in order to direct future campaigns for emergency contraception (EC). MATERIAL AND METHODS: Over a three-month period, 423 women with prescriptions for EC were consecutively entered in the study, which was carried out in four inner-city pharmacies in Copenhagen, Denmark. RESULTS: The median age was 24 years (range 13-50 years). Most women (73%) were first-time users of EC. The reason for the current need for EC was most often condom failure (54%) or non-use of any contraceptive method (41%). Only six women (1.4%) reported non-use of contraception because of their knowledge of EC and only four women (0.9%) reported EC as the usual method of contraception. Knowledge about EC more often came from family or friends (51%) and advertising (47%), than from general practitioners (26%) or through sex education in schools (3%). Altogether 282 women (69%) received EC from a doctor in the medical emergency service or a casualty ward. DISCUSSION: Overall, EC is used as recommended. Its availability does not seem to reduce the use of safer contraceptive methods. The mandatory sex education in school should include information on EC.

Determinants for non-use of contraception at first intercourse; a study of 10841 young Danish women from the general population.

Based on interview data from 10841 Danish women aged 20 to 29 years, determinants for non-use of contraception at first intercourse (NU) were studied. One-fourth of the women (n = 2704) reported NU, whereas condoms and oral contraceptives were used by, respectively, 59% and 15%. NU decreased with the birth year of the first male partner (OR = 3.6; 95% CI: 2.8-4.8 for or=17 years) at the expense of both oral contraception and condom use. Finally, NU was found to predict high-risk sexual behavior in terms of subsequent multiple sex partners, non-use of condoms, and induced abortion.

P53 autoantibodies in sera from Danish ovarian cancer patients and their correlation with clinical data and prognosis.

The p53 gene, a tumour suppressor gene located on the short arm of chromosome 17 (17p13), is frequently mutated in various human tumours. Accumulation of p53 protein in neoplastic cells and its release following tumour necrosis can lead to development of circulating autoantibodies (AAb) against p53. Earlier studies of ovarian cancer (OC) patients reported different frequencies of p53 AAb and conclusions regarding the clinical and prognostic value of these AAb have not been in agreement. We therefore analysed for the presence of p53 AAb in a total of 227 preoperative serum samples from 193 OC patients and 34 patients with ovarian borderline tumours, and, in addition, serum samples from 86 healthy controls. An enzyme-linked immunosorbent assay (ELISA) was used to measure serum IgG antibodies against p53. The p53 protein used in the assay was produced as a hexahistidine-tagged fusion protein by baculovirus-infected Spodoptera frugiperda cells. Cut-off values for p53 AAb were evaluated, and correlations of p53 AAb with clinical-, biochemical data and survival were examined. We found a low sensitivity for p53 AAb alone, and no major additional effect of the detection rate of CA125 was found. No significant associations were found between p53 AAb and clinical stage, age, histological subtype and radicality after primary surgery. In contrast, we found significantly elevated CA125 levels in p53 AAb-positive patients compared to lower CA125 levels in p53 AAb-negative patients (p=0.003). No significant differences were found between p53 AAb-positive and p53 AAb-negative patients in the univariate and multivariate survival analyses. In conclusion, in a screening study for OC serum p53 AAb levels are of no diagnostic value, even if combined with the tumour marker CA125. The presence of increased serum p53 AAb in patients with diagnosed OC could not be correlated with any clinical data and preoperative serum p53 AAb status had no evident value.

Type specific persistence of high risk human papillomavirus (HPV) as indicator of high grade cervical squamous intraepithelial lesions in young women: population based prospective follow up study.

OBJECTIVES: To investigate the role of human papillomavirus (HPV) in the development of cervical neoplasia in women with no previous cervical cytological abnormalities; whether the presence of virus DNA predicts development of squamous intraepithelial lesion; and whether the risk of incident squamous intraepithelial lesions differs with repeated detection of the same HPV type versus repeated detection of different types. DESIGN: Population based prospective cohort study. SETTING: General population in Copenhagen, Denmark. PARTICIPANTS: 10 758 women aged 20-29 years followed up for development of cervical cytological abnormalities; 370 incident cases were detected (40 with atypical squamous cells of undetermined significance, 165 with low grade squamous intraepithelial lesions, 165 with high grade squamous intraepithelial lesions). MAIN OUTCOME MEASURES: RESULTS of cervical smear tests and cervical swabs at enrollment and at the second examination about two years later. RESULTS: Compared with women who were negative for human papillomavirus at enrollment, those with positive results had a significantly increased risk at follow up of having atypical cells (odds ratio 3.2, 95% confidence interval 1.3 to 7.9), low grade lesions (7.5, 4.8 to 11.7), or high grade lesions (25.8, 15.3 to 43.6). Similarly, women who were positive for HPV at the second examination had a strongly increased risk of low (34.3, 17.6 to 67.0) and high grade lesions (60.7, 25.5 to 144.0). For high grade lesions the risk was strongly increased if the same virus type was present at both examinations (813.0, 168.2 to 3229.2). CONCLUSIONS: Infection with human papillomavirus precedes the development of low and high grade squamous intraepithelial lesions. For high grade lesions the risk is greatest in women positive for the same type of HPV on repeated testing.

[Pregnancy-related thrombocytosis]. / Svangerskabsrelateret trombocytose.

Pregnancy-related thrombocythaemia comprises myeloproliferative and inflammatory reactive subsets. In pregnant women treated for myeloproliferative disorders, especially polycythaemia vera and primary thrombocytosis, only 50-70 per cent are delivered successfully of a normal healthy baby. The maternal complications are cerebral, cardiac, and abdominal arterial thrombosis, and with deep venous thrombosis of the legs, whereas bleedings are mainly seen in the case of extreme thrombocythaemia, owing to absorption of factors by the platelets. The foetal complication are dominated by abruptio placentae, pre-eclampsia, placental insufficiency, and death. Reactive thrombocythaemia includes the physiological rise in platelets postpartum, believed to be part of the normal maternal haemostasis, which almost never causes thromboembolic complications, as far as is known today. In contrast, the inflammatory reactive thrombocythaemia, related to severe foetal and/or maternal necrosis, is generally related only to a moderate rise in the platelet count. As the blood-platelet count does not appear to be routine at general pregnancy check-ups, it is necessary to be aware of risk groups, consisting of women with otherwise unexplained abortions or stillbirths, unexplained foetal and placental malformations, and pre-eclampsia, even if the woman has never had any thromboembolic complications.

[Forty four pregnancies with idiopathic thrombocytopenic purpura]. / Fireogfyrre svangerskaber med idiopatisk trombocytopenisk purpura.

INTRODUCTION: The aim of this project was to describe the course of pregnancy with idiopathic thrombocytopenic purpura (ITP) and to estimate risk factors and indications for treatment. MATERIAL AND METHODS: Birth, haematological, and neonatal files were examined retrospectively. RESULTS: Forty-eight ITP women with 55 pregnancies gave birth to 61 children, 59 live-born. The first singleton pregnancy in the observation period (the index pregnancy) was used for statistics, namely 44 index pregnancies. A maternal platelet fall from the first trimester to delivery was seen, as was a platelet rise three days after delivery (p < 0.0001), even in splenectomised women. Thirty-six per cent of the women had bleeding manifestations, none of which were fatal; 33% of the newborn infants had thrombocytopenia in cord blood. The following risk factors for perinatal thrombocytopenia were found: a sibling with thrombocytopenia, severe maternal thrombocytopenia, male gender. The nadir platelet count in the newborn infants was seen up to seven days after delivery. The presence of an older sibling with neonatal ITP is a risk factor for neonatal ITP in subsequent pregnancies. A significant association was found between the maternal platelet count in the second trimester and the platelet count in cord blood. DISCUSSION: The diagnosis and treatment of ITP in pregnancy are controversial. Vaginal delivery is generally recommended. The platelet kinetics in pregnancy with ITP is comparable with the platelet kinetics of the spleen.

Distribution of p53 codon 72 polymorphisms in ovarian tumour patients and their prognostic significance in ovarian cancer patients.

BACKGROUND: The p53 gene is frequently mutated in various human tumours. In addition, single nucleotide polymorphisms are often observed in exons and introns of the p53 gene in normal tissues and tumours. MATERIALS AND METHODS: The prevalence of a polymorphism involving codon 72 of exon 4 in the p53 gene was studied in peripheral white blood cells and tumour tissues from Danish ovarian tumour patients and in peripheral white blood cells from controls. The analyses were performed by Polymerase Chain Reaction (PCR), Restriction Fragment Length Polymorphism (RFLP) and DNA sequencing. The amino acid residue at this position is either arginine (p53-Arg) or proline (p53-Pro). RESULTS: There was no correlation between the frequency of the three genotypes (Pro/Pro, Arg/Arg and Arg/Pro) and age, stage or histological type of the tumour. A significant difference in survival was observed between ovarian cancer stage III patients with a shift from one genotype in the blood to another genotype in the tissue and patients with no shift (p=0.0216). CONCLUSION: Kaplan-Meier survival analyses and multivariate Cox regression analysis stratified to stage III ovarian cancer patients showed that a shift from one genotype in the blood to another genotype in the tissue is a prognostic factor in Danish ovarian cancer patients.