Safety profile of the 9-valent human papillomavirus vaccine: assessment in prior quadrivalent HPV vaccine recipients and in men 16 to 26 years of age.

A 9-valent HPV (9vHPV) vaccine has been developed to protect against HPV type 6/11/16/18/31/33/45/52/58-related infection and disease. Previous safety analyses from 7 clinical trials conducted in 9vHPV vaccine recipients 9-26 years of age, including comparisons of 9vHPV and quadrivalent HPV (qHPV) vaccines in girls and women 16-26 years of age, showed that the 9vHPV vaccine was generally well tolerated. Additional safety analyses were conducted to include the results of new clinical studies. The safety profile of the 9vHPV vaccine in prior qHPV vaccine recipients (n = 3756 from 1 randomized controlled trial and 2 open-label extension studies) and young men (n = 248 9vHPV and n = 248 qHPV vaccine recipients from 1 randomized controlled trial) was evaluated. Vaccine was administered as a 3-dose regimen (at Day 1 and Months 2 and 6), and adverse events (AEs) were monitored. The most common AEs were injection-site events (91.1% and 79.0% in prior qHPV vaccine recipients and young men, respectively), the majority of which were mild. Discontinuations due to an AE were rare (0.2% and 0.0% among prior qHPV vaccine recipients and young men, respectively). In young men, the AE profile of the 9vHPV vaccine was generally similar to that of the qHPV vaccine. Overall, the 9vHPV vaccine was generally well tolerated in prior qHPV vaccine recipients and in young men, with an AE profile generally consistent with that previously reported with the broader clinical program.

Medical abortion at 63 to 90 days of gestation.

OBJECTIVE: To evaluate medical abortion as a treatment alternative for late first-trimester abortions and to evaluate the decrease in beta-hCG after abortion at 63-90 days of gestation. METHODS: All women received mifepristone 200 mg orally, followed by 800 micrograms misoprostol vaginally 48 hours later. Misoprostol was repeated every 3 hours orally, to a maximum of five doses if needed. A clinical examination including ultrasonography was performed 8-14 days after treatment. beta-hCG level was determined before treatment and at follow-up. RESULTS: A total of 254 pregnant women with gestational age 63 to 90 days were included. The successful termination rate was 91.7%. Surgical evacuation was carried out in 21 (8.3%) women. Most women (91.0%) found the method of treatment highly acceptable. The beta-hCG levels of women with successful termination had decreased more than 97.5% at follow-up. CONCLUSION: Medical abortion is an effective and acceptable method for termination of pregnancy in late first trimester.

The impact of a quadrivalent human papillomavirus (types 6, 11, 16, 18) virus-like particle vaccine in European women aged 16 to 24.

BACKGROUND: Quadrivalent human papillomavirus (HPV types 6/11/16/18) L1 VLP vaccine is highly effective in preventing HPV 6/11/16/18-related cervical and external genital disease. Herein, we evaluated the impact of the quadrivalent HPV 6/11/16/18 L1 VLP vaccine on prevention of HPV-associated cervico-genital lesions in a broad population of sexually active European women. METHODS: Female subjects (N = 9265) aged 16-24 with four or fewer lifetime sexual partners were enrolled and randomized to quadrivalent HPV vaccine or placebo. Subjects underwent cervicovaginal sampling for HPV DNA detection. Papanicolaou testing and anti-HPV 6/11/16/18 serology testing was also performed. RESULTS: Vaccine efficacy against lesions representing immediate cervical cancer precursors (cervical intraepithelial neoplasia grade 2/3 or adenocarcinoma in situ) related to HPV 6/11/16/18 in the per-protocol population was 100.0%[95% confidence interval (95% CI), 89.8-100.0]. Efficacy against external genital lesions (vulvar or vaginal intraepithelial neoplasia, condyloma, vulvar or vaginal cancer) related to vaccine HPV types in the per-protocol European population was 99.0% (95% CI, 94.4-100.0). CONCLUSION: These data demonstrate that quadrivalent HPV 6/11/16/18 vaccination programs in 16- to 24-year-old European women can be beneficial. NCT0009252, NCT00092534, NCT00092495.

High sustained efficacy of a prophylactic quadrivalent human papillomavirus types 6/11/16/18 L1 virus-like particle vaccine through 5 years of follow-up.

Human papillomavirus (HPV) causes cervical, vulvar, and vaginal cancers, precancerous dysplasia, and genital warts. We report data for the longest efficacy evaluation to date of a prophylactic HPV vaccine. In total, 552 women (16-23 years) were enrolled in a randomised, placebo-controlled study of a quadrivalent HPV 6/11/16/18 L1 virus-like-particle vaccine with vaccination at months 0, 2, and 6. At regular intervals through 3 years, subjects underwent gynaecologic examination, cervicovaginal sampling for HPV DNA, serum anti-HPV testing, and Pap testing, with follow-up biopsy as indicated. A subset of 241 subjects underwent two further years of follow-up. At 5 years post enrollment, the combined incidence of HPV 6/11/16/18-related persistent infection or disease was reduced in vaccine-recipients by 96% (two cases vaccine versus 46 placebo). There were no cases of HPV 6/11/16/18-related precancerous cervical dysplasia or genital warts in vaccine recipients, and six cases in placebo recipients (efficacy = 100%; 95% CI:12-100%). Through 5 years, vaccine-induced anti-HPV geometric mean titres remained at or above those following natural infection. In conclusion, a prophylactic quadrivalent HPV vaccine was effective through 5 years for prevention of persistent infection and disease caused by HPV 6/11/16/18. This duration supports vaccination of adolescents and young adults, which is expected to greatly reduce the burden of cervical and genital cancers, precancerous dysplasia, and genital warts.

Ascitic complement system in ovarian cancer.

Ovarian cancer spreads intraperitoneally and forms fluid, whereby the diagnosis and therapy often become delayed. As the complement (C) system may provide a cytotoxic effector arm for both immunological surveillance and mAb-therapy, we have characterised the C system in the intraperitoneal ascitic fluid (AF) from ovarian cancer patients. Most of the AF samples showed alternative and classical pathway haemolytic activity. The levels of C3 and C4 were similar to or in the lower normal range when compared to values in normal sera, respectively. However, elevated levels of C3a and soluble C5b-9 suggested C activation in vivo. Malignant cells isolated from the AF samples had surface deposits of C1q and C3 activation products, but not of C5b-9 (the membrane attack complex; MAC). Activation could have become initiated by anti-tumour cell antibodies that were detected in the AFs and/or by changes on tumour cell surfaces. The lack of MAC was probably due to the expression of C membrane regulators CD46, CD55 and CD59 on the tumour cells. Soluble forms of C1 inhibitor, CD59 and CD46, and the alternative pathway inhibitors factor H and FHL-1 were present in the AF at concentrations higher than in serum samples. Despite the presence of soluble C inhibitors it was possible to use AF as a C source in antibody-initiated killing of ovarian carcinoma cells. These results demonstrate that although the ovarian ascitic C system fails as an effective immunological surveillance mechanism, it could be utilised as an effector mechanism in therapy with intraperitoneally administrated mAbs, especially if the intrinsic C regulators are neutralised.

Molecular differences between RER+ and RER- sporadic endometrial carcinomas in a large population-based series.

Studies, to date, have suggested that there are distinct molecular differences between microsatellite stable (RER(-)) and unstable (RER(+)) solid tumors, such as colorectal carcinoma. We investigated a range of molecular events including mutation frequency of K-ras, microsatellite instability within the coding region of TGF-beta RII, BAX, and IGF-IIR, loss of expression of p53, hMLH1, hMSH2, hMSH6, and PTEN, and methylation of hMLH1, hMSH2, and PTEN within a large population-based series of sporadic endometrial carcinomas to establish whether there are distinct differences between replication error repair (RER(+)) and RER(-) cases. RER(+) endometrial carcinomas tended to be diploid with normal p53 expression, compared with RER(-) cases. Mutations in TGF-beta RII, IGF-IIR, and BAX were rare, but there was a strong association between mutation and RER(+) status. Methylation and loss of hMLH1 expression were significantly more common in RER(+) cases, as was methylation of PTEN. K-ras mutations were equally frequent in RER(+) and RER(-) cases. Despite the absence of distinct clinicopathological differences between RER(+) and RER(-) cases in this series of sporadic endometrial carcinomas, our results confirm that there are molecular differences between RER(+) and RER(-) cases, but the molecular events occurring in RER(+) endometrial carcinomas differ from those seen in RER(+) colorectal carcinomas.

The impact of increasing the use of regional anaesthesia for emergency caesarean section.

BACKGROUND AND OBJECTIVE: In 1991 general anaesthesia was used extensively for emergency Caesarean section at Haukeland University Hospital even in patients with an ongoing epidural infusion. With increased knowledge of the potential safety benefits of regional anaesthesia and increased experience with the technique, we decided to use indwelling epidural catheters for emergency Caesarean section. METHODS: We conducted a retrospective analysis of a full annual data set on emergency Caesarean section in parturients with ongoing epidural analgesia in 1997 and compared it with a similar data set from 1991. RESULTS: Epidural anaesthesia was used significantly more often in 1997 with 115 (78%) cases than in 1991 with five (12%) cases (P < 0.001). Elapsed time before adequate anaesthesia and the start of surgery was significantly shorter in 1991 (mean 8.3 min) compared to 1997 (mean 13 min) (P < 0.001). No deaths or major complications were observed in either group. Intraoperative minor complications were observed more frequently in 1997 with 70 cases (47%) than in 1991 with two cases (6%) (P < 0.001). The principal complications were hypotension and nausea. Postoperative complications in mother and neonate were similar in both groups. There was a significantly shorter mean hospital stay in 1997 (6 days), compared with 1991 (8 days) (P < 0.001). CONCLUSION: The increase in the use of indwelling epidural catheters for emergency Caesarean section has resulted in a significant increase in the use of regional anaesthesia. A modest increase in time elapsed before start of surgery was observed although there were no significant differences in the number of neonates with low Apgar scores. No major complications were observed, but there was an increased frequency of minor complications in 1997.

Early pregnancy termination with mifepristone and misoprostol in Norway.

OBJECTIVES: Medical abortion was first introduced in Norway in April 1998. The aims of this study were to assess the efficacy, side effects, and acceptability of medical abortion using mifepristone orally and misoprostol vaginally in a Norwegian population. DESIGN: The study included the first 226 pregnant women with gestational age of <63 days who requested nonsurgical abortion during the first year in the first Norwegian hospital using this regimen. METHODS: All women received a single dose of mifepristone 600 mg orally, followed at 48 hours by 800 microg misoprostol vaginally. Treatment outcome and complications were the principal outcome measures. We also measured the rates of side effects such as abdominal pain and bleeding and the women's acceptability of treatment. RESULTS: Abortion was successful in 95%, surgical evacuation became necessary in 4%, and the pregnancy continued in one woman. During the study period the method was chosen by 23% of those requesting abortion before 63 days amenorrhea; 80% would use the method again; 81% would recommend it to a friend; in retrospect, 69% would not have been willing to be randomly allocated to either a medical or a surgical method. CONCLUSIONS: The combination of orally administrated mifepristone and vaginally administrated misoprostol is an abortion method that is both effective and safe, has few side effects and is well accepted by Norwegian women.

Knowledge, attitudes and management strategies in Scandinavia concerning hormone replacement therapy: a comparison between gynecologists in Denmark, Norway and Sweden.

OBJECTIVES: To describe and compare attitudes, knowledge and management strategies concerning the prescription of hormone replacement therapy (HRT) between gynecologists from three Scandinavian countries. DESIGN AND METHODS: In a cross-sectional study gynecologists in Denmark (n=386), Norway (n=475) and Sweden (n=1323) were invited by letter to complete and return an enclosed questionnaire. Then 1653 of the 2184 (76%) contacted gynecologists completed and returned the questionnaire. RESULTS: of the 1653 Scandinavian gynecologists, 42% offered HRT to all women provided there was no contraindication, while 58% recommended HRT to selected women after considering the advantages and disadvantages of HRT. In Norway and Sweden, the proportion of gynecologists routinely prescribing HRT for women without contraindications increased with age and in the oldest age group of gynecologists (>55 years) 49 and 56%, respectively, recommended HRT to all women. The gynecologists were unanimous in their choice of the type of HRT for perimenopausal women as 94% preferred cyclical or sequential combined (estrogen/progestogen) treatment or estrogen monotherapy (orally or transdermally) for hysterectomized women (95%). For postmenopausal women, 75% of the gynecologists offered continuous combined HRT while cyclical combined therapy was chosen by 15% of the gynecologists. No significant differences were found between physicians in the three countries regarding indications and contraindications to HRT. CONCLUSIONS: Scandinavian gynecologists are generally well informed concerning HRT and liberally recommend HRT for women without contraindications.

Peripartum hysterectomy-incidence and maternal morbidity.

BACKGROUND: The aim of the study was to find the incidence and clinical implications of peripartum hysterectomy in our department and to identify women at risk to improve treatment before resorting to hysterectomy. MATERIAL AND METHODS: In the period 1981-1996, cases with peripartum hysterectomy among a total of 70,546 deliveries in our department were identified from three different sources. The clinical variables were obtained by review of the maternal records. RESULTS: In the study period, 11 cases, representing an incidence of 0.2 peripartum hysterectomies per 1000 deliveries was found. Eight women had a cesarean section and three women had a spontaneous vaginal delivery. Six of the patients had previous operation on the uterus. The indication for hysterectomy was atony in seven, suspected rupture in two, placenta accreta in one and DIC in one woman. The maternal morbidity was substantial as the mean number of transfusions given was 15 units (range 7-24), and the mean hospitalization time was 15 days (range 11-29). There was no maternal mortality, but one infant died due to asphyxia caused by placental abruption. CONCLUSIONS: The incidence of peripartum hysterectomy was low, but the condition is serious with significant maternal morbidity.

The development of high venous velocity at the fetal umbilical ring during gestational weeks 11-19.

OBJECTIVE: To determine the occurrence of high venous velocities at the umbilical ring in the normal early second trimester, based on the assumption that a narrow umbilical ring may cause obstruction and increased venous blood velocity at the abdominal wall. DESIGN: Cross-sectional study. SETTING: Hospital antenatal clinic. POPULATION: One hundred and one low risk singleton pregnancies specifically recruited for the study. METHODS: Ultrasound was used at 11-19 weeks to determine the diameter and velocity in the umbilical vein at the fetal end of the cord and at the inlet through the abdominal wall. Outcome measures 10th, 50th and 90th centiles were estimated for the time-averaged maximum velocity in the cord and at the abdominal inlet. The increase of velocity as the blood entered the abdominal wall was calculated in percent of the velocity in the cord. RESULTS: During weeks 11-12 there was hardly any difference between blood velocity in the umbilical vein at the umbilical ring and that in the cord. From week 13 onwards it was increasingly common to find blood acceleration at the umbilical ring of 50-500%. Velocity increment >50% was found in 0/12 fetuses (0%) at 11-12 weeks, 5/20 (25%) at 13-14 weeks, and in 21/28 (75%) at 17-19 weeks. CONCLUSIONS: Blood velocity is higher in the umbilical vein at the abdominal wall than the cord, particularly after 13 weeks of gestation. If acceleration of blood velocity at the umbilical ring is a sign of a narrow inlet, it seems that a progressive tightening occurs during the second trimester.

[Mifepristone--a controversial drug with great potential]. / Mifepriston--et kontroversielt legemiddel med stort potensial.

BACKGROUND: Antiprogestins, agents that inhibit the action of progesterone, are among the most controversial and yet the more interesting therapeutic compounds developed over the past 20 years. MATERIAL AND METHODS: We present a review of the literature identified through limited searches on Medline, Cochrane and the Internet, with a discussion of the biological, clinical, political and ethical aspects of this important drug. RESULTS: The first effective antiprogestin in clinical use was mifepristone (also known as RU 486). This agent provides the most effective and safest means of medical abortion. It may also be used as a contraceptive and delivery-inducing agent and in the treatment of spontaneous abortion, ectopic pregnancies, leiomyoma, endometriosis, intrauterine fetal death, Cushing's syndrome and progesterone-dependent malignancies. INTERPRETATION: The introduction of mifepristone as an abortion-inducing agent has created intense political, ethical and moral controversies which have delayed clinical investigations and evaluations for potential expanded use.

[Rehabilitation of women with breast cancer]. / Rehabilitering av kvinner med brystkreft.

BACKGROUND: Previous studies on effects of rehabilitation programmes for women with breast cancer are rare, but promising. This study aimed to examine the physical and psychological conditions for these patients before and after a rehabilitation programme at Red Cross Haugland Rehabilitation Centre in Norway. MATERIAL AND METHODS: Included in the study were a total of 50 women, aged 31-66 (mean 49) years, who had undergone surgical treatment, chemotherapy and radiation therapy for cancer mammae stage 1 and 2 (limited to the breast only or spread to the axillary lymph nodes, respectively). They received a three-week rehabilitation programme, followed by a three-month period at home and a one-week follow-up at the rehabilitation centre. Examinations of physical and psychological status were performed before and after the three-week stay and at follow-up. RESULTS: Maximum oxygen uptake increased from 67% to 77% of predicted value, the mental status and subjective rating of life quality improved, the physical activity level increased, and 36 out of 46 subjects returned to their jobs during the three-month follow-up. The women themselves reported subjective positive effects of participating in the programme. INTERPRETATION: Although the present study was non-controlled, the positive results were so promising that further controlled studies should be encouraged, as well as rehabilitation programmes for women with breast cancer.

Loss of estrogen receptor (ER) expression in endometrial tumors is not associated with de novo methylation of the 5' end of the ER gene.

Normal endometrium, an estrogen-responsive tissue, expresses the estrogen receptor (ER) alpha gene. Loss of ER expression, the basis for which is currently unknown, is often seen in advanced stage, poor prognosis endometrial tumors. The ER gene undergoes de novo methylation with high frequency in a wide variety of human tumors, including ER-negative breast cancers. In this study, we used several bisulfite-based detection methods to assess whether loss of ER positivity in endometrial tumors is associated with aberrant methylation of the ER gene. Although extensive methylation of a 600-bp region at the 5' end of the gene was seen in two endometrial carcinoma cell lines, none of the 55 CpGs in this region was methylated in 25 of 26 ER-deficient endometrial carcinomas.

Methylation of hMLH1 in a population-based series of endometrial carcinomas.

Microsatellite instability (MSI) is a characteristic feature of hereditary nonpolyposis colorectal cancer and is also observed in sporadic colorectal and endometrial cancers. Alterations in the mismatch repair genes hMLH1 and hMSH2 are important for the development of MSI. It has recently been demonstrated that hypermethylation of the hMLH1 promoter region is associated with MSI and appears to be a common mechanism for gene inactivation. For endometrial carcinoma, however, previous studies have been relatively small and have not been population based. We therefore wanted to assess the frequency and prognostic significance of hypermethylation of the hMLH1 and hMSH2 genes in conjunction with hMLH1 protein expression in a prospective and population-based series of endometrial carcinoma patients with known MSI status and complete follow-up. A total of 138 patients were studied, and methylation of hMLH1 was found in 23% of tumors with conclusive results, whereas methylation of hMSH2 was seen in only 1% of tumors. Methylation of hMLH1 was significantly correlated with MSI (P < 0.001). Loss of nuclear staining of hMLH1 protein was seen in 14% of the cases and was significantly correlated with hMLH1 methylation and MSI (P < 0.001). Normal expression of hMLH1 was seen in all of the unmethylated tumors (100%). Of the 14 MSI-positive tumors that were also methylated, all but 1 (93%) showed a loss of nuclear expression of hMLH1. None of the tumors with loss of hMLH1 expression or hMLH1 methylation were aneuploid (P for both < or = 0.05), and loss of hMLH1 expression and hMLH1 methylation was significantly correlated with lack of p53 overexpression (P for both < or = 0.05). Nuclear hMLH1 staining and hMLH1 methylation did not significantly influence survival. In conclusion, hMLH1 methylation was common and was significantly correlated with loss of hMLH1 protein expression, MSI, diploid tumors, and lack of p53 overexpression. In contrast, hMSH2 methylation was infrequent in this prospective and population-based series of endometrial carcinomas.

Frequency and prognostic impact of microsatellite instability in a large population-based study of endometrial carcinomas.

The replication error repair (RER) phenotype has been reported in 9-43% of sporadic endometrial carcinomas, but there are conflicting data about its effect on prognosis in this disease. This study was performed to establish the frequency of the RER phenotype and to determine its effect on prognosis in a population-based series of 259 endometrial carcinomas with long-term follow-up. Five mononucleotide and dinucleotide microsatellite markers on different chromosomes were analyzed, and tumors exhibiting microsatellite instability at two or more loci were classified as RER+. A total of 116 of 259 tumors (45%) were RER+. The 5-year survival rate for the RER- group was 76.2% compared with 79.6% for RER+ cases (P = 0.6). The 5-year recurrence-free survival rate among the 228 patients surgically treated for cure was 80.6% in the RER- group compared with 83.6% in the RER+ group (P = 0.6). The analysis indicates that the RER phenotype is common in endometrial carcinomas, but there is no association with prognosis in this large population-based series of endometrial carcinomas.

Prognostic significance of angiogenesis and Ki-67, p53, and p21 expression: a population-based endometrial carcinoma study.

PURPOSE: For endometrial carcinoma patients, there is a need for improved identification of high-risk groups that may benefit from postoperative adjuvant therapy. We therefore studied the prognostic impact of markers for cell proliferation, cell-cycle regulation, and angiogenesis among endometrial carcinoma patients in a population-based setting. PATIENTS AND METHODS: All patients diagnosed with endometrial carcinoma between 1981 and 1985 in Hordaland County, Norway, were studied. The median follow-up for the survivors was 11.5 years (range, 8 to 15 years), with no patient lost because of insufficient follow-up information. Paraffin-embedded tumor tissue, available in 96% of the cases (n = 142), was studied immunohistochemically for microvessel density (MVD) and expression of Ki-67, p53, and p21 proteins. We used the hot spot method for calculation of MVD, and expression of Ki-67 and p21 protein, because this approach may increase the probability of detecting small aggressive clones of possible prognostic relevance. The importance of these tumor markers was investigated in univariate survival analyses and Cox regression analysis. RESULTS: The majority of traditional clinicopathologic variables was significantly associated with the tumor biomarkers. Age, International Federation of Gynecology and Obstetrics (FIGO) stage, histologic type, histologic grade, MVD, as well as Ki-67, p53, and p21 protein expression, all significantly influenced survival in univariate analyses (P < or = .05). In the Cox regression analysis, age, FIGO stage, MVD, Ki-67 expression, and p53 expression were the only variables with independent prognostic impact (P < or = .05), whereas histologic type, histologic grade, and p21 expression had no independent influence. A group of high-risk patients with more than one unfavorable marker was identified. CONCLUSION: In addition to age and FIGO stage, MVD, Ki-67, and p53 protein expression showed an independent prognostic impact. Thus, information derived from routine histologic specimens identified a subgroup of high-risk endometrial carcinoma patients in this population-based study.