Human epididymal protein 4 (HE4) is a novel biomarker and a promising prognostic factor in ovarian cancer patients.

PURPOSE OF INVESTIGATION: The aim of this work was to compare serum concentrations of HE4 in patients with benign and malignant epithelial tumors and to determine the association of preoperative concentrations of HE4 with some clinicopathologic factors. METHODS: We enrolled 94 patients, including 39 females with freshly diagnosed ovarian cancer. HE4 concentrations were measured with ELISA HE4 EIA assay from Fujirebio Diagnostics. RESULTS: Serum concentrations of HE4 differed significantly in patients with ovarian cancer (324.1 pM) compared with benign epithelial tumors (26.1 pM; p < 000.1). There was also a significant difference between HE4 concentrations at diagnosis of ovarian cancer (324.1 pM) and in patients with complete clinical remission (23.3 pM; p < 0.0001). Patients with poorly differentiated tumors had significantly higher concentrations of HE4. Preoperative HE4 levels were higher in patients in whom relapse was noted and who died before the end of the two-year follow-up period. CONCLUSION: On the basis of these findings and reports in the literature it appears likely that HE4 can complement CA125 in the monitoring of therapy in ovarian cancer and may also serve for prognostication.

Favorable effects of long-term therapy with gonadoliberin analogues in three patients with advanced and recurrent ovarian cancer.

BACKGROUND: Numerous scientific reports indicate a high possibility of gonadotrophin involvement in ovarian cancer neoplasia. CASE PRESENTATION: In a 49-year-old patient with recurrent ovarian cancer, a present survival of ten years has been achieved. She has been using GnRH analogues for nine years. A 32-year-old patient with a primary highly advanced ovarian cancer received standard therapy and additional implants with GnRH analogues as consolidation therapy for 20 months. Overall survival is 14 years. In a 56-year-old patient with advanced ovarian cancer GnRH analogues were used as consolidation therapy for seven years, achieving seven years of a complete clinical remission and nine and a half years of survival up to now. CONCLUSION: It seems that gonadoliberin analogues should find their place in ovarian cancer therapy.

Serum YKL-40 levels in patients with ovarian cancer and women with BRCA1 gene mutation--comparison to CA 125 antigen.

PURPOSE OF INVESTIGATION: Our work was undertaken to determine the usefulness ofYKL-40 as a tumor marker in patients with ovarian cancer and women with BRCA 1 gene mutations. METHODS: Our study population consisted of 111 patients. They were divided into five study groups: I--newly diagnosed ovarian caner, II--recurrence of ovarian cancer, III--complete remission, IV--benign epithelial tumors and V--patients with BRCA 1 gene mutations. YKL-40 and CA 125 were determined in patient sera. RESULTS: YKL-40 in newly diagnosed ovarian cancer patients was significantly higher (181.17 n/ml) than in patients with BRCA 1 gene mutation (97.74 ng/ml, p < 0.01), women with benign epithelial cancer (57.19 ng/ml, p < 0.005) and patients with ovarian cancer at the time of complete remission (58.12 ng/ml, p < 0.005). Taking 124 ng/ml as a cut-off value for YKL-40 (95th percentile for healthly women) we observed higher levels in 50% of patients from group I and in 38% from group II. CONCLUSIONS: YKL-40 appears to demonstrate no advantage over CA 125 as a biomarker of ovarian cancer, particularly in women with early-stage tumors. More research is needed on carriers of the BRCA 1 gene muation in view of the elevated YKL-40 concentrations in this group.

Concentrations of follicle stimulating hormone are increased in ovarian tumor fluid: implications for the management of ovarian cancer.

PURPOSE OF INVESTIGATION: Significant progress has been made in recent years in the understanding of the mechanisms postulated by the gonadotropin theory of ovarian carcinogenesis. In the present study we compare FSH concentrations between serum and fluid from cysts or the rectouterine pouch of patients with epithelial tumors and non-neoplastic lesions. METHODS: We enrolled 277 patients. They were divided into five groups: I (n = 44)--ovarian cancer patients, II (n = 16)--borderline tumors, III (n = 40)--benign epithelial cystadenomas, IV (n = 137)--non-neoplastic lesions and V (n = 22)--admitted for "second-look" laparoscopy. RESULTS: There were any significant differences between FSH concentrations in serum and tumor fluid in patients with ovarian cancer (36.46 vs 28.11 mIU/ml) and borderline epithelial tumors (31.5 vs 22.7 mIU/ml). For benign cystadenomas the respective concentrations were 28.96 mIU/ml in serum and 6.93 mIU/ml in tumor fluid in these groups p < 0.0000001. The same highly significant differences were found in non-neoplastic lesions (24.97 vs 4.77 mIU/ml), p < 0.0000001. Patients who underwent "second-look" laparoscopy demonstrated significant differences (p < 0.05) as FSH concentration in serum and peritoneal fluid when neoplastic cells were not disclosed, but the difference was not significant (p = 0.752) when fluid from the rectouterine pouch was positive for carcinoma cells. CONCLUSIONS: The results of our study can reflect an ineffective tumor: blood barrier and easy diffusion of gonadotropins into the tumor tissue. Local reduction of FSH levels through administration of GnRH analogs may in some clinical situations produce clear therapeutic benefits for the management of ovarian malignancies.

Serum adiponectin in relation to endometrial cancer and endometrial hyperplasia with atypia in obese women.

OBJECTIVES: The aim of this work was to compare concentrations of adiponectin in the serum of obese women with endometrial cancer, endometrial hyperplasia with atypia, and normal endometrium. METHODS: We enrolled 105 obese women treated at the Department of Gynecological Surgery and Oncology of Adults and Adolescents. The patients were allocated to groups depending on the histological diagnosis (R - endometrial cancer, P - polyps, K - normal endometrium). We subdivided group R depending on the stage and grade of cancer. RESULTS: Significantly lower concentrations of adiponectin were found in patients with endometrial cancer (mean 15.28 microg/ml) as compared with polyps (29.94 microg/ml, p < 0.001) or normal endometrium (22.7 microg/ml, p < 0.05). Stage of cancer had no significant effect on the adiponectin level. When cancer grade was compared, lower levels of adiponectin were observed in patients with G3 (12.86 microg/ml) than G1 (19.04 microg/ml, p < 0.05). CONCLUSION: Reduced levels of adiponectin may represent an independent risk factor for endometrial cancer.

Hysteroscopy with directed biopsy versus dilatation and curettage for the diagnosis of endometrial hyperplasia and cancer in perimenopausal women.

BACKGROUND: The present study was undertaken to compare the effectiveness of dilatation and curretage (D&C) with hysteroscopy and guided biopsy (H+B) for the collection of endometrial samples adequate for histological examination in perimenopausal women at risk of endometrial hyperplasia or cancer. METHODS: We performed hysteroscopy and biopsy followed by dilatation and curettage in 734 patients with abnormal perimenopausal bleeding or sonographically revealed endometrial pathology. Two hundred and ninety-two patients in whom lesions were totally removed during hysteroscopy were excluded from further study. RESULTS: Using both methods we disclosed 64 cases of endometrial polyps, 60 cases of endometrial hyperplasia, and 49 cases of endometrial cancer. Hysteroscopy left just four cases of endometrial pathology undiagnosed as opposed to 21 cases using dilatation and curettage. Histology could not be performed on material obtained with hysteroscopy in four cases and with curettage in 23 cases. CONCLUSIONS: 1) Hysteroscopy with directed biopsy is more sensitive in disclosing all types of uterine lesions than dilatation and curettage. 2) Curettage done after hysteroscopy and directed biopsy does not improve the detection of endometrial cancer.

BRCA1 mutation, leptin and estrogen levels in breast cancer patients.

Pre- and postmenopausal patients with breast cancer were screened for mutation of the BRCAI gene and estrogens and leptin levels were measured. In postmenopausal BRCA1 mutation carriers, leptin levels were significantly lower and correlated with the body mass index (BMI). No significant difference in leptin levels was revealed between pre- and postmenopausal patients. Our findings suggest the existence of an alternative mechanism responsible for carcinogenesis in breast cancer patients with a genetic background.

Vascular endothelial growth factor (VEGF) levels and mutation of the BRCA1 gene in breast cancer patients.

The aim of the study was to compare VEGF serum levels in breast cancer patients with and without BRCA1 gene mutation. We enrolled 80 patients, 22 premenopausal and 58 postmenopausal. We found statistically significant lower levels of VEGF in patients with BRCA1 gene mutation as compared with breast cancer patients without this mutation.

Effects of a surgical treatment of congenital cervicovaginal agenesia.

OBJECTIVE: Congenital agenesis of the uterine cervix and vagina is one of the rarest congenital defects. The objective of this manuscript is to present our experience and effects of a surgical treatment in five girls with inborn agenesis of the uterine cervix and vagina, who were operated in our clinic. METHOD: The vagina is reconstructed in four stages: (1) formation of vaginal recess; (2) phantomization of vagina; (3) joining of the reconstructed vagina with the uterus; (4) revision and correction of the junction. GnRH analogs were administered to avoid menstrual blood flow into the peritoneal cavity during phantomization. RESULTS: Patency of the uterovaginal junction was maintained with a #6 intubation tube. Normal menstruation was restored in all patients. Atresion of the canal at the uterovaginal junction was disclosed after 3-8 months in three of the patients. Patency was restored with surgical hysteroscope and the canal was mechanically distended. Clinical and ultrasonographic followup in the patients will continue.

TP53 status determines clinical significance of ERBB2 expression in ovarian cancer.

ERBB2 expression has been found in 19 to 44% of ovarian carcinomas; however, its predictive value has not been demonstrated, and trastuzumab has not found clinical application in ovarian cancer patients. We evaluated clinical significance of ERBB2 expression in relation to TP53 accumulation in ovarian carcinoma patients treated with platinum-based regimens. Immunohistochemical analysis with CB11 and a novel NCL-CBE356 antibody (against the internal and external domains of ERBB2, respectively) was performed on 233 tumours (FIGO stage IIB-IV); the US Food and Drug Administration-approved grading system with 0 to 3+ scale was used for evaluation, and the results were analysed by the Cox and logistic regression models. In all, 42% of the tumours expressed (category 1+, 2+ or 3+) either CB11 or CBE356 or both (CB11/CBE356 parameter). Associations between ERBB2 expression and clinical factors were observed only if tumours with staining category 1+ were grouped together with tumours showing staining categories 2+ and 3+. CB11/CBE356 parameter had a better predictive value than CB11 alone. CB11/CBE356 expression was negatively associated with platinum sensitivity (PS) in the TP53(-) group (P=0.022) and with disease-free survival (DFS) in the TP53(+) group (P=0.009). Our results may suggest that trastuzumab should be given postoperatively to patients with TP53(-)/ERBB2(+) ovarian carcinomas to enhance PS, and after completion of chemotherapy to patients with complete remission and TP53(+)/ERBB2(+) carcinomas to extend DFS time (in total to 30.4% of all patients analysed). Thus, novel criteria for ovarian cancer patient inclusion for clinical trials with trastuzumab should be considered and tested.

FSH and LH serum/tumor fluid ratios and malignant tumors of the ovary.

The aim of this work was to compare mean concentrations of gonadotropins in serum and fluid from malignant and benign ovarian tumors. We enrolled 126 patients diagnosed with malignant epithelial tumors (n=40), borderline epithelial tumors (n=14), benign cystadenomas (n=28) and simple cysts (n=44) of the ovary. Premenopausal and postmenopausal subgroups were formed in each group. The concentration of FSH and LH was measured in serum and tumor fluid and the serum/tumor fluid ratio was calculated. The results in each group were compared and the sensitivity, specificity, positive and negative predictive values were determined. Mean concentrations of both gonadotropins in ovarian cancer fluid were significantly higher than in the remaining groups (P ranged from <0.005 to <0.0001). Mean serum/fluid ratios were lowest in ovarian cancer (FSH=2.91, LH=4.19). Our findings support the hypothesis that gonadotropins are involved in ovarian carcinogenesis and suggest that gonadotropin serum/tumor fluid ratios could be of value in the differential diagnosis of functional and organic cysts of the ovary.

Attitudes toward preventive oophorectomy among BRCA1 mutation carriers in Poland.

Currently genetic testing for BRCA1 and BRCA2 susceptibility genes is performed throughout Europe and North America. In Poland three founder mutations in BRCA1 account for 14% of all invasive ovarian cancers and oophorectomy is frequently recommended to mutation carriers as a preventive measure. The purpose of the present study was to evaluate patient acceptance of the recommendation for prophylactic oophorectomy in a hereditary cancer clinic. Seventy-two women over the age of 40 and who carried a BRCA1 mutation were advised to undergo prophylactic oophorectomy. After a mean follow-up period of 19 months, 43 of the women (60%) had undergone the procedure. Of the 29 women who had not had an oophorectomy, five indicated that they did not intend to do so, 19 indicated that they intended to have the operation in the near future and five were undecided. In conclusion, preventive oophorectomy is acceptable to most Polish women at high risk of hereditary ovarian cancer and should be among the range of services offered in cancer genetics clinics.

Clinical features of familial ovarian cancer lacking mutations in BRCA1 or BRCA2.

PURPOSE OF INVESTIGATION: The purpose of the present study was to identify the clinical and pathologic features of ovarian cancers in patients who have a family history of breast or ovarian cancer but who do not have a mutation in the BRCA1 or BRCA2 gene. METHODS: 303 patients with ovarian cancer were reviewed for clinical features and for cancer family histories. After the exclusion of 51 patients known to carry BRCA1 or BRCA2 mutations, 24 patients with familial cancer were compared with 228 patients with non-familial cancer. RESULTS: Patients with familial cancer were more likely to have grade 2 tumors, Stage II disease and to present between ages 51 and 60 than were non-familial controls. Ten of 24 patients in the familial group presented between ages 51 and 60 with a grade 2 tumor compared to 3.0 expected (p = 0.001). CONCLUSIONS: Families of women who present with grade 2 ovarian cancer between the ages of 51 and 60 may have an unidentified ovarian cancer susceptibility gene.

Is neuropeptide Y responsible for constitutional delay of puberty in girls? A preliminary report.

Constitutional delay of puberty (CDP). in otherwise healthy girls is defined as failure to develop secondary sexual features past the age of 13 years (two standard deviations above the mean age at which secondary sexual features appear in the population of girls). The inhibitory action of neuropeptide Y (NPY) on the gonadotropic and somatotropic systems in experimental animals and stimulation by NPY of the hypothalamic-pituitary-adrenal axis have been reported, prompting us to study the levels of NPY, insulin-like growth factor-I (IGF-I) and cortisol in eight girls with CDP and normal weight (body mass index (BMI) 21.7+/-4.5 kg/mn2). The results were compared with those from a group of 40 girls (BMI = 20.0+/-3.1 kg/m2) who demonstrated a normal course of puberty (NP). All girls were studied at menarche (mean age at menarche, study vs. control: 16.4+/-0. 7 vs. 12.6+/-0.9 years). To measure NPY and IGF-1 we used a radioimmunoassay method, whereas cortisol was measured with an enzyme immunoassay. Blood was collected between 08.00 and 09.00 following an overnight fast. NPY was higher in girls with CDP (181.6+/-106.4 pg/ml) than in girls with NP (55.5+/-26.3 pg/ ml; p < 0.001). In the former group, cortisol was higher (397.3+/-241.6 nmol/l) than in NP girls (142.7+/-98.0 nmol/l; p < 0.01). Levels of IGF-I in CDP girls were lower than in NP girls (558.0+/-122.6 vs. 756.5+/- 226.8 ng/ml; p < 0.01). The results corroborate the involvement of NPY in sexual maturation and its role in delayed puberty.

P21WAF1, P27KIP1, TP53 and C-MYC analysis in 204 ovarian carcinomas treated with platinum-based regimens.

BACKGROUND: The prognostic and predictive value of cell cycle regulatory proteins in ovarian cancer has not been established. We evaluated the clinical and biological significance of P21(WAF1), P27(KIP1), C-MYC, TP53 and Ki67 expressions in ovarian cancer patients. MATERIALS AND METHODS: Immunohistochemical analysis was performed on 204 ovarian carcinomas of International Federation of Gynecology and Obstetrics (FIGO) stage IIB to IV treated with platinum-based chemotherapy. Multivariate analysis with Cox and logistic regression models was performed in the whole group, and in the TP53-negative and TP53-positive subgroups. RESULTS: High P21(WAF1) labeling index (LI) was an independent positive predictor of platinum-sensitive response (P = 0.02). Overall survival was positively influenced by P21(WAF1) LI (P = 0.02) or by P21(WAF1) plus P27(KIP1) LI (P = 0.004) in the TP53-negative group only. Ki67 LI showed borderline association with disease-free survival (P = 0.05). Growth fraction was negatively associated with P21(WAF1) and P27(KIP1) indices in the TP53-negative group (P = 0.023 and 0.008, respectively), and these associations were borderline or lost in the TP53-positive group. Endometrioid and clear cell carcinomas differed from other carcinomas by having a low incidence of TP53 accumulation, a high incidence of C-MYC overexpression (70%) and a low median Ki67 LI (all with P <0.001). CONCLUSIONS: We have shown an independent predictive value of P21(WAF1) LI in ovarian carcinoma patients. The prognostic value of P21(WAF1) and P21(WAF1) plus P27(KIP1) LI was determined by TP53 status. A high frequency of C-MYC overexpression in endometrioid and clear cell carcinomas may suggest its role in the development of these tumor types.

Leptin, neuropeptide Y, beta-endorphin, gonadotropin, and estradiol levels in girls before menarche.

More than two decades of clinical studies have provided us with the opportunity to develop and implement criteria that distinguish three phases during pre-menarche, paralleling rising levels of estrogens, namely 'pre-estrogenization', 'onset of estrogenization' and 'full estrogenization'. The aim of this study was to examine the relationships between somatic features and levels of leptin, neuropeptide Y (NPY), beta-endorphin, gonadotropin and estradiol in pubertal girls before menarche. Weight, height, body mass index (BMI), tertiary sex features, estrogen-related changes in hymen, fat and lean body mass were studied on a quarterly basis in 45 girls. At the same time, ovarian and uterine dimensions were established sonographically and serum was obtained for the determination of leptin, NPY, beta-endorphin, gonadotropin, and estradiol levels. Onset of estrogenization in girls was marked by weight loss, followed by an increase in total, fat and lean body mass, and pubertal acceleration of growth. At the time of full estrogenization, lower NPY and beta-endorphin levels were observed, accompanied by an increase in gonadotropin secretion. Changes in leptin levels are consistent with a role of this hormone in metabolic signaling.

GnRH analogues as an adjuvant therapy for ovarian cancer patients.

OBJECTIVES: Lowering gonadotropin levels with gonadotropin-releasing hormone (GnRH) analogues in patients with ovarian cancer remains open to debate. The aim of this study was to assess the results of treatment in stage III and stage IV ovarian cancer patients who had surgery supplemented with chemotherapy, radiotherapy, and GnRH analogues. Gonadotropin levels were monitored during treatment. METHODS: The study group comprised 69 patients aged 27-70 years, stratified according to the type of treatment. The overall disease-free, 5-year survival rates and the frequency of remissions were analyzed. Hormonal tests [follicle-stimulating hormone (FSH) and luteinizing hormone (LH)] were performed in 58 patients. Associations were checked between gonadotropin levels, clinical findings, and survival. The results were statistically compared. RESULTS: Statistically significant differences were noted when chemotherapy was supplemented with GnRH analogues and/or radiotherapy. Administration of GnRH analogues resulted in significantly lower levels of LH than of FSH. Levels of FSH were significantly lower in patients surviving at least 5 years or in complete remission at the time of this study. CONCLUSIONS: Combined therapy can produce favorable results in late-stage ovarian cancer, and GnRH analogues have an important role in treatment strategy.

Evaluation of clinical significance of TP53, BCL-2, BAX and MEK1 expression in 229 ovarian carcinomas treated with platinum-based regimen.

In cell line studies, BCL-2, BAX, as well as novel MEK1 protein levels have strong influence on ovarian cancer response to cisplatin-based chemotherapy. However, such associations have not been demonstrated clinically. We evaluated prognostic/predictive significance of these proteins with regard to TP53 status. Immunohistochemical analysis was performed on 229 ovarian carcinomas FIGO stage IIB-IV treated with platinum-based chemotherapy; the results were analysed by the Cox and logistic regression models. Clinical parameters (residual tumour size, patient age, FIGO stage) were the only indicators of overall survival (OS) and the strongest predictors of complete remission (CR). On the other hand, BAX expression was the strongest (P=0.005) or the only (in FIGO IIIC, P=0.02) prognostic indicator of disease-free survival (DFS) in the TP53(+) group. TP53(+) and TP53(-) ovarian carcinomas differed in clinical and molecular prognostic and predictive factors. Another novel finding is that CR was negatively influenced by high BAX expression in all patients group (P=0.047) and by BCL2 expression in the TP53(-) group (P=0.05). High MEK1 expression was associated with endometrioid and clear cell carcinomas (P=0.049); its loss was found with advancing FIGO stage (P=0.002). Our results suggest that binomial TP53 status divides ovarian carcinomas into two biologically distinct groups. BAX expression is an important factor of DFS in the TP53(+) group. BCL-2 and BAX, but not MEK1 expressions have predictive value in ovarian cancer patients treated with platinum-based chemotherapy.