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Unlabelled: The aim of this study was to assess the clinical value of preoperative blood levels of HE4 as a predictor of overall survival in patients with ovarian cancer and to validate previous data of HE4 and the ROMA algorithm including HE4 and CA125 in discriminating benign and malignant ovarian tumors., Experimental Design: The preoperative plasma levels of HE4 and CA125 were analyzed with ELISA in 312 patients with adnexal lesions. Tumors were classified as benign (n= 206), borderline (i.e. low malignant potential tumors) (n= 25), and well (n= 14), moderately (n= 15), and poorly (n= 51) differentiated malignant., Results: In univariate Cox regression analyses high levels (dichotomized at the median) of HE4, CA125, increased age (continuous variable), advanced-stage of disease 2-4, histological grade 3 and non-optimal tumor debulking at primary surgery were all significantly associated with shorter overall survival. A multivariate Cox regression model including pre-operative available covariates HE4 and CA125 both dichotomized at median in addition to age as continuous variable showed that high levels of HE4 was an independent prognostic marker for worse prognosis HR 2.02 (95% CI 1.1-3.8). In postmenopausal women the ROMA algorithm gave the highest AUC of 0.94 (95% CI, 0.90-0.97) which was higher than the separate markers HE4 AUC 0.91 (95% CI 0.86-0.95) and CA125 AUC 0.91(95% CI 0.87-0.96)., Conclusions: High concentration of plasma HE4 is an independent preoperative marker of poor prognosis in patients with ovarian cancer. The algorithm ROMA discriminates in postmenopausal women between malignant and benign tumors with an AUC of 0.94.

Following a robot-assisted radical hysterectomy and pelvic lymphadenectomy for early-stage cervical cancer, a 53-year-old woman was diagnosed with a 50-mm right-sided pelvic lymphocyst by the use of vaginal ultrasonography. She gradually developed intermittent increasingly severe neuralgic pain mimicking a meralgia paresthetica. A neurolysis was proposed by the neurosurgeons. Awaiting this intervention, a pelvic MRI revealed a partial atrophy of the ipsilateral adductor muscles and a probable entrapment of the obturator nerve by the lymphocyst as an alternative cause of the pain. Using a four-arm da Vinci-S-HD robot the lymphocyst, located deep in the right obturator fossa and surrounding the obturator nerve, was completely removed, sparing the partially atrophic obturator nerve. No bleeding occurred. The surgery time was 95 min. At 10 months' follow-up the patient was relieved of her pain with no signs of a new lymphocyst.

Objective: The aim of the study was to evaluate the sentinel node (SLN) concept for lymphatic mapping in early stage cervical cancer., Methods: 105 women with early stage (1a1-2a) cervical cancer were scheduled for the sentinel node procedure in conjunction with a complete pelvic lymphadenectomy. The day before surgery, 1-1.5 mL 120MBq Tc(99) albumin nanocolloid was injected submucosally at four points around the tumor followed by a lymphoscintigram (LSG) to achieve an overview of the radiotracer uptake., Results: During surgery, the overall detection rate (gamma probe) of at least one SLN was 90% (94/105 women) whereas at least one SLN was identified in 94% (61/65 women) with a tumor 2 cm) node without radiotracer uptake. The negative predictive value for patients with cervical cancers

Objective: To evaluate feasibility and morbidity of robot assisted laparoscopic radical hysterectomy., Methods: From December 2005 to September 2008 robot assisted laparoscopic radical hysterectomy and pelvic lymphadenectomy was performed on 80 women. Using a prospective protocol, and an active investigation policy for defined adverse events, perioperative, short and long term data were obtained., Results: Time for surgery (skin to skin) reached 176 and 132 min after 9 and 34 procedures respectively. All tumours were radically removed. Median number of retrieved lymph nodes was 26 (range 15-55). All women had an early follow up (1-3 months) and 43 of eligible 46 women (93%) had a long term follow up (> or =12 months). In 33 of 80 women (41%) the peri/postoperative period was uneventful. The remainder had one or more mainly mild adverse events, most commonly from the vaginal cuff (n=17, 21%) or the lymphatic system (n=16, 20%). The proportion of uneventful cases increased significantly over time. Five women were resutured for dehiscence of the vaginal cuff, two women were reoperated for trocar site hernias and one woman had a ureter stricture that resolved following stent treatment. Eight women (14%) needed 60 days or more to resume spontaneous voiding. One 72-year old woman with disseminated endometrial cancer on autopsy died of pulmonary embolism 31 days after surgery., Conclusions: Robot assisted laparoscopic radical hysterectomy is a feasible alternative to conventional laparoscopy and open surgery. Effort should be made to ensure proper closure of the vaginal cuff, trocar sites and to develop nerve sparing techniques.

Purpose: To evaluate the plasma level of different forms of soluble urokinase plasminogen activator receptor (suPAR) as discriminators between malignant, borderline, and benign ovarian tumors and as prognostic markers in patients with ovarian cancer., Experimental Design: The different suPAR forms were measured in preoperative plasma samples obtained from 335 patients with adnexal lesions using three different time-resolved fluoresence assays (TR-FIA): TR-FIA 1 measuring intact suPAR, suPAR(I-III), TR-FIA 2 measuring the total amount of suPAR(I-III) and the cleaved form, suPAR(II-III), and TR-FIA 3 measuring the liberated uPAR(I). Tumors were classified as benign (n = 211), borderline (possibly malignant; n = 30), and well (n = 19), moderately (n = 15), and poorly (n = 60) differentiated malignant., Results: All uPAR forms as well as CA125 were statistically significant in univariate analysis discriminating between benign, borderline, and invasive tumors. Restricting the analysis of invasive tumors to early stage (I and II) showed similar results. A combination of CA125 and suPAR(I-III) + suPAR(II-III) discriminated between malignant (all stages) and benign tumors [AUC, 0.94; 95% confidence interval (95% CI), 0.90-0.98] as well as borderline and benign tumors (AUC, 0.78; 95% CI, 0.67-0.89). All suPAR forms were markers for poor prognosis in univariate analyses, and high preoperative plasma level of uPAR(I) is an independent predictor of poor prognosis (hazard ratio, 1.84; 95% CI, 1.15-2.95; P = 0.011) in multivariate analyses including age and CA125., Conclusions: High concentration of plasma uPAR(I) is an independent preoperative marker of poor prognosis in patients with ovarian cancer. The combination of plasma suPAR(I-III) + suPAR(II-III) and CA125 discriminates between malignant and benign tumors with an AUC of 0.94.

Objective: The aim was to evaluate the outcome of fertility-sparing treatment in ovarian borderline tumors and early invasive ovarian cancer., Materials and Methods: All women diagnosed with an ovarian borderline tumor or early invasive ovarian cancer who were treated with fertility-sparing surgery at the University Hospital in Lund between 1988 and 2002 were identified and included in the study (n=23)., Results: During the follow-up period of a median 92 months, range 11-185 months, no relapse was found in the patients with Stage 1a tumors, including both borderline tumors (n=12) and invasive well-differentiated (n=9) and moderately differentiated (n=1) ovarian cancers. One patient with poorly differentiated ovarian cancer Stage 1c was 13 weeks' pregnant at the time of the primary operation. Although, unilateral oophorectomy was performed she insisted on continuing the pregnancy. At 37 weeks she had a cesarean section and the ovarian cancer was disseminated. Chemotherapy was given but she died less than a year later. None of the other patients received chemotherapy. In total, 30 children were born to 15 patients. Prophylactic removal of the remaining ovary+/-hysterectomy was accepted in only in six of the women after fulfilling their desire to have more children., Conclusions: Young women with Stage 1a epithelial ovarian cancer and borderline tumors do not have to give up their fertility in order to receive successful and safe treatment of their disease. However, several of these patients do not accept the recommendation of prophylactic oophorectomy of the contralateral ovary and hysterectomy after completion of childbearing.

Objective: To analyse the influence of socio-demographic characteristics and environmental factors on self-reported somatic and psychological symptoms among middle-aged Swedish women., Methods: A total of 6917 women living in the Lund area of southern Sweden were participates of this study. They completed a generic questionnaire pertaining to socio-demographic characteristics, lifestyle factors and current health related problems. According to hormonal status, the participants were subdivided into three groups, i.e. premenopause, postmenopause and peri- or postmenopausal women with hormone replacement therapy (HRT)., Results: By using multiple logistic regression models, a high risk for somatic symptoms was independently associated with unemployment, no exercise, unmarried, high body weight and diseases affecting the cardiovascular system as well as a history of cancer. Psychological symptoms were independently associated with higher educational level, unemployment, no exercise, unmarried, heavy smoking habits (> or =15 cig/day), weight gain and a history of cancer. In addition, the background factors seemed to have less impact on symptoms among women who used HRT., Conclusion: Socio-demographic characteristics, lifestyle factors and concurrent health problems appear to have influences on the frequency and the number of somatic and psychological symptoms in middle-age women. Hormone replacement therapy seems to be able to counteract negative impacts caused by un-healthy lifestyle and other health problems.

Background: The aim was to evaluate whether patients with benign ovarian cysts, functional ovarian cysts, or endometriosis have an increased risk of developing gynecologic cancer., Methods: The Swedish Hospital Discharge Register was used to identify a cohort of women discharged from hospital with the diagnoses of ovarian cyst (n = 42217), functional ovarian cyst (n = 17998), or endometriosis (n = 28163). To each case, three controls were matched. The National Swedish Cancer Register matched all incident cancers diagnosed among cases and controls. From the Fertility Register, the date of birth of children born to the cases and controls were obtained., Results: Women with endometriosis had an increased risk for ovarian cancer (OR 1.34; 95% CI 1.03-1.75), but no association was found between ovarian cysts or functional cysts and ovarian malignancy, including all ages. Young women (15-29 years old) discharged from hospital for ovarian cysts and functional cysts showed an increased risk of developing ovarian cancer later in life (OR 2.2; 95% CI 1.3-3.9 and OR 1.8; 95% CI 1.5-2.0), as well as women with ovarian cysts who had undergone ovarian cyst resection or unilateral oophorectomy (OR 8.8; 95% CI 5.2-15). The risk of developing ovarian cancer was inversely related to parity. Mean age at diagnosis was significantly lower in all three study groups., Conclusion: In this study women with endometriosis and young women who had undergone surgery with removal of an ovarian cyst had an increased risk of developing ovarian cancer.

The urokinase plasminogen activator (uPA) system is involved in tumor growth and metastasis. We assayed the components of the uPA system in homogenates of 64 primary epithelial ovarian tumors and 5 metastases and evaluated the association of these parameters to prognosis in the 51 malignant cases. The levels of uPA, PAI-2 and the uPA:PAI-1 complex increased with progressive loss of histological differentiation (p(trend) <0.001, <0.05 and <0.001). The level of PAI-1 was higher in poorly than in well/moderately differentiated tumors (p = 0.03). The content of uPAR was lower in benign tumors as compared to borderline malignancies (p = 0.002), invasive primary tumors (p < 0.001), and metastases (p = 0.002). Surprisingly, the level of uPAR was lower in poorly differentiated as compared to both borderline (p = 0.01) and well differentiated malignant tumors (p = 0.005). Also, the level of uPAR was lower in advanced as compared to early stages of the disease (p(trend) = 0.002). The median follow-up time for patients was 5.8 years. High tumor tissue levels of uPAR were associated with longer postoperative survival (HR = 0.4, 95% CI = 0.2-0.8, p = 0.01). In contrast, shorter survival was evident in patients with high tumor levels of uPA from 2 years on after operation (HR = 4.6, 95% CI = 1.2-17, p = 0.02). High tPA levels tended to be associated with shorter overall survival after 2 years (HR = 2.9, 95% 95% CI = 0.9-9.8, p = 0.08). Although high tumor tissue content of uPAR was associated with a less aggressive phenotype characterized by well differentiated histology and longer survival, low content of uPAR in the poorly differentiated tumors and metastases presumably results from increased elimination of uPAR., (Copyright 2003 Wiley-Liss, Inc.)

Objective: The objective was to evaluate the preoperative blood concentration of tissue plasminogen activator (tPA) as a discriminator between malignant and benign ovarian tumors, and as a potential marker of postoperative prognosis in patients with ovarian cancer., Methods and Material: The concentration of tPA was assayed with ELISA (Imulyse Biopool) in preoperative plasma samples obtained from 111 patients with adnexal lesions. Tumors were classified as benign (n = 25), borderline malignant (n = 11), well-differentiated (G1, n = 22), moderately differentiated (G2, n = 11), and poorly differentiated malignant (G3, n = 42). The median follow-up time of patients with malignant tumors was 5.6 years (range 2.1-13.2 years) and 37 patients died during the follow-up period., Results: Patients with moderately and poorly differentiated tumors had higher levels of plasma tPA compared to those with well-differentiated tumors (P = 0.004 and P = 0.005). No significant differences in the plasma tPA levels were observed between patients with benign, borderline, and well-differentiated tumors. The tPA levels were not different between stages nor within stage Ia-c. In a multivariate Cox proportional hazards model including stage, grade, age, and plasma tPA dichotomized at the median (> or =9 vs <9 ng/mL), high levels of tPA were significantly associated with shorter survival: HR = 4.4 (95% CI 2.0-9.8, P = 0.0003). In the univariate analyze high levels of tPA showed HR = 4.5 (95% CI 2.1-9.6, P = 0.0003)., Conclusions: High concentration of plasma tPA was an independent marker for poor prognosis in patients with ovarian cancer in our study. Plasma tPA did, however, not discriminate between benign and malignant adnexal lesions.

Objective: To evaluate the influence by two low doses of oral continuous-combined formulations of 17 beta-estradiol (E(2)) and norethisterone acetate (NETA) on carbohydrate metabolism in healthy postmenopausal women., Design: A double-blind, randomized, placebo-controlled trial., Setting: Volunteers at a university hospital., Subject: One hundred twenty healthy postmenopausal women., Intervention(s): One hundred twenty women were randomized to three treatment arms: (1) E(2) 1 mg/NETA 0.25 mg group (n = 40); (2) E(2) 1 mg/NETA 0.5 mg group (n = 40); (3) placebo group (n = 40). A total of 102 women completed 12 months of treatment. An oral glucose tolerance test (OGTT) was performed at baseline and at 3, 6, and 12 months., Main Outcome Measure(s): Fasting glucose, fasting insulin, total area under the curve (AUC) and insulin/glucose index during OGTT., Result(s): Fasting levels of glucose and insulin declined significantly in the E(2)/NETA 0.5 mg group. At OGTT, the total AUC for insulin declined in both active arms. The curve for glucose increased significantly in the E(2)/NETA 0.25 mg group. A lower insulin/glucose index was observed during OGTT in both active regimens when compared with placebo. In the active treatment groups, a significant reduction of fasting glucose and/or fasting insulin was encountered in women with higher basal fasting levels (fasting glucose >4.2 mmol/L or log-fasting insulin >0.87)., Conclusion(s): Oral low-dose E(2) 1 mg/NETA 0.5 mg regimen did not impair carbohydrate metabolism, but seemed to improve insulin sensitivity in healthy postmenopausal women.

The plasminogen activating system is involved in tumor growth and metastasis by degradation of extracellular matrix, and modulation of cell adhesion and migration. Benign and well-differentiated malignant ovarian tumors present as cystic lesions with preserved glandular morphology, whereas poorly differentiated tumors and metastases are solid with characteristic absence of glandular morphology. We analyzed the mRNAs for urokinase plasminogen activator (uPA), its receptor (uPAR), and inhibitor (PAI-1) in serous ovarian tumors by in situ hybridization and by densitometric scanning of Northern blots prepared from tissue extracts. The mRNA expressing cells in the in situ hybridization sections were evaluated and counted by two different observers. The number of mRNA expressing cells for uPA, uPAR and PAI-1 were all significantly increased in solid as compared with cystic malignant tumors. The increased expression of all three mRNA species was mainly located in the stroma of poorly differentiated tumors and metastases. Apart from being expressed in the stroma of these tumors, uPAR mRNA was also expressed by tumor cells located along the stromal/epithelial boarder. In addition, the tumor tissue content of uPA, uPAR and PAI-1 mRNAs as measured by Northern blots were higher in the solid as compared with the cystic tumors. Increased expression of uPA, uPAR and PAI-1 genes in the solid tumors suggest a correlation with a more aggressive phenotype.

Urokinase plasminogen activator (u-PA) plays a pivotal role in tissue degradation during tumor spread and metastasis. We have quantitated u-PA in tissue homogenates of 31 serous ovarian tumors and localized u-PA and its mRNA in tissue sections of 26 serous ovarian tumors. The content of u-PA was higher in malignant than in benign tumors, with the highest levels being found in poorly differentiated cancers. In tissue sections, the u-PA mRNA was hybridized with a radiolabeled RNA probe. Signals were almost exclusively found in the epithelium in benign and borderline tumors and in well-differentiated cancers. Poorly differentiated tumors and metastases exhibited prominent stromal expression of u-PA mRNA, whereas epithelial expression was weak or absent. Immuno-histochemical staining co-localized u-PA antigen with its mRNA in the epithelium of benign and borderline tumors and in well-differentiated cancers. Poorly differentiated malignant tumors showed extensive immunostaining in the epithelium in addition to stromal staining. The u-PA mRNA-expressing and u-PA-immunostained cells in the stroma were not tumor cells since no cells in the stroma were positive for cytokeratin. Poorly differentiated tumors had increased numbers of stromal macrophages (CD68), and they co-localized with some of the u-PA-positive cells. The presence of u-PA antigen and the absence of u-PA mRNA in tumor epithelium of poorly differentiated tumors and metastases together with the presence of u-PA mRNA in the stroma suggests production in stromal cells and subsequent binding to receptor sites in tumor cells.