Vulvar lichen sclerosus in women is associated with lower urinary tract symptoms.

INTRODUCTION AND HYPOTHESIS: Lichen sclerosus (LS) is thought to be primarily a disease of postmenopausal women. Little is reported about lower urinary tract symptoms (LUTS) in association with LS. The aims of this study were to evaluate the odds of having LS-associated LUTS and to identify the predominant type of LS-associated bladder dysfunction. METHODS: This was a cross-sectional study with two cohorts investigating the association between LS and LUTS and the predominant type of LS-associated bladder dysfunction. RESULTS: The odds of LUTS in women with LS were more than four times higher than in women without LS (OR 4.5, 95% CI 2.6-8.0; p < 0.0001). There was no significant difference in the occurrence of LUTS between women who experienced the first LS symptoms before and after the age of 50 years (36% and 53%, respectively, p = 0.14), or in the occurrence of the different types of LUTS between women with and without LS (p = 0.3). The most common type of LUTS was overactive bladder (OAB) in both women with LS (67.3%) and without LS (60%). The most prevalent type of LS-associated LUTS was OAB. CONCLUSIONS: The odds of developing LUTS (self-reported) are four times higher in women with LS than in those without. The predominant type of LUTS in women with and without LS is OAB.

Bone in the breast? Long term toxicity 21 years after interstitial brachytherapy as a boost.

An 81-year-old patient developed an exulcerous tumor in her left breast 21 years after breast cancer treatment with lumpectomy and adjuvant radiotherapy. At the time of the initial treatment 21 years ago, whole breast irradiation was performed with a prescribed dose of 48 Gy and a maximal dose of 69 Gy. In addition, the patient received a 14.7 Gy boost with multicatheter brachytherapy as partial breast irradiation. In general, fat necrosis after radiotherapy, surgery or trauma is a minor problem for patients, but can lead to diagnostic difficulties. The incidence varies: the literature indicates that it occurs in up to 34% of cases. The direct pathogenesis is not clear; it can be due to high radiation dose to the breast, dosimetric inhomogeneities or surgical complications (seromas and inflammation). The tumor in the case described here, occurring more than two decades after the primary treatment, is a rarity in this extent and is an unusual clinical, radiological, and histological finding. It provides a good example of the need for an individualized approach to treatment.

Should Groin Recurrence Still Be Considered as a Palliative Situation in Vulvar Cancer Patients?: A Brief Report.

OBJECTIVE: To assess survival after groin recurrence in patients with vulvar cancer in the transition period of the implementation of the sentinel lymph node biopsy procedure. Recurrence of groin metastases in vulvar cancer patients is assumed to be lethal. It is unknown if early detection of relapse and multimodal treatment strategies improve the outcome of patients with groin recurrence. METHODS: Multicenter retrospective cohort study of patients with recurrent vulvar cancer who presented with groin and/or pelvic lymph node metastases between 2000 and 2014 at 3 tertiary referral hospitals. Our primary outcome was to assess survival after groin recurrence of vulvar cancer and the influence of multimodal treatment. All analyses were done using Stata 12 (Stata Corporation, College Station, Tex). Hazard ratios (HRs) and their corresponding 95% confidence intervals were calculated using a Cox proportional hazards model. RESULTS: We identified 30 patients with a median time from diagnosis to groin recurrence of 10 months. The median follow-up of patients who were alive at the time of analysis was 22 months (range, 9-123 months). A Kaplan-Meier estimate showed an overall survival rate of 50% after 7 years. Patients with multimodal groin relapse treatment performed better than those with single-mode treatment (HR, 0.25; P = 0.037). Lymph node metastases at diagnosis were also associated with lower survival (HR, 6.11; P = 0.020). We observed a trend toward lower survival with a tumor size greater than T1 (HR, 2.55; P = 0.111). The time from diagnosis to groin recurrence had no influence on survival (HR, 0.99; P = 0.561). CONCLUSIONS: Close follow-up visits for at least 2 years are important to detect recurrent disease in groin and pelvic lymph nodes. Treatment of recurrent groin metastases should no longer be considered as a palliative situation--given that one half of the patients will have long-term survival after multimodal treatment strategies.

Predictive factors for preterm delivery under rural conditions in post-tsunami Banda Aceh.

OBJECTIVE: To assess the risk for preterm deliveries <37 week of gestation and associated prevalence of vaginal infection in a rural setting after the tsunami in Banda Aceh, Indonesia. METHODS: Wet mount microscopy, vaginal pH and vaginal swabs for microbiological culture were collected in pregnant women during the 2nd trimester from February to June of 2005 in four temporary outpatient clinics and the patients were followed up until delivery. RESULTS: One hundred and fifty-nine pregnant patients were screened. Sixty-two could be followed up until delivery. Thirty-nine (62.9%) delivered at term and 23 (37.1%) delivered prematurely. Significant risk factors for preterm delivery were a history of preterm delivery and group B streptococcus infection. Increased vaginal pH alone had no significant influence on preterm delivery, although there was a trend. CONCLUSION: The rate of preterm delivery was high in this cohort. We suggest risk stratification for preterm delivery in rural conditions by performing a vaginal pH and wet mount microscopy. If either is suspect we suggest collecting a vaginal swab for microbiological culture for targeted treatment. Patients with a history of preterm delivery are at increased risk and should be monitored closely.

Safe vaginal uterine morcellation following total laparoscopic hysterectomy.

The minimally invasive approach for hysterectomy with proven benefits and lower morbidity has become the gold standard, even in women with large uterine masses. Most women with a malignant condition present with abnormal vaginal bleeding and/or suspicious imaging such that few are diagnosed by final histopathology after surgery. However, if a malignancy is not diagnosed preoperatively, intraabdominal morcellation for uterus extraction has an increased risk for potential tumor spread and peritoneal metastases, especially in cases of unexpected leiomyosarcoma. We describe a simple method to wrap the uterus in a contained environment with a plastic bag through the posterior vaginal fornix prior to conventional coring morcellation for vaginal extraction in total laparoscopic hysterectomy. We further describe our experience with a risk stratification and treatment algorithm to implement this procedure in daily routine. A video and an illustrating sketch demonstrate the simplicity and safety of the procedure.

Clinical scoring system for vulvar lichen sclerosus.

INTRODUCTION: Vulvar lichen sclerosus (LS) is a chronic inflammatory and mutilating disease, which goes often undetected for years. Advanced disease severely affects quality of life like sexual disorders and is also associated with an increased risk of vulvar cancer. AIM: To develop and validate a patient-administered symptom score and a physician-administered clinical score for the diagnosis and evaluation of vulvar LS. METHODS: We included 24 patients with established LS diagnosis and 49 with other vulvar disease. The physician-administered score was based on six clinical features and the patient-administered score was a symptom-based four-item composite score. We determined inter-item correlations and internal consistency of both scores, and estimated sensitivities, specificities, likelihood ratios, and posttest probabilities for different cutoffs of the physician-administered score. MAIN OUTCOME MEASURES: Characteristics of patients with and without LS were compared using χ(2) and unpaired t-test as required. We then determined Cronbach's alpha as a measure of the overall consistency of scores and calculated positive and negative likelihoods. RESULTS: Lack of redundancy of items (correlation coefficients < 0.90) and internal consistency (Cronbach's α ≥ 0.70) suggested that final composite scores were valid and yielded excellent power to rule in LS. CONCLUSION: Scores may be useful for assessing symptoms of vulvar disorders, to ease diagnosis of LS and to evaluate treatment response over time.

Efficacy of topical progesterone versus topical clobetasol propionate in patients with vulvar Lichen sclerosus - A double-blind randomized phase II pilot study.

BACKGROUND: Lichen sclerosus (LS) is a chronic inflammatory skin disease that mostly affects the anogenital region of women and lowers patients' quality of life. Current standard treatment of LS is topical steroids. OBJECTIVE: To evaluate the efficacy of topical progesterone 8% ointment and compare to standard therapy with topical clobetasol propionate 0.05% in premenopausal women presenting with previously untreated early onset LS. STUDY DESIGN: Randomized, double-blind, 2-arm, single center superiority trial in premenopausal women with histologically confirmed vulvar LS who were randomized in a 1:1 ratio to receive clobetasol propionate 0.05% ointment or progesterone 8% ointment. The primary outcome was the clinical severity LS score after 12 weeks, which consists of six clinical features assessed by the physician. Secondary outcomes were the symptom severity LS score, which consists of three symptoms rated by the patient, the Short Form SF-12 physical and mental health scores, and adverse events. Response to medication was assessed by biopsy at the end of the treatment to evaluate inflammatory parameters. RESULTS: Overall, 105 women were screened, 102 underwent vulvar biopsy and 37 received a histologically confirmed diagnosis of LS and were randomized: 17 to progesterone and 20 to clobetasol propionate. At 12 weeks, the mean clinical LS scores improved from 4.6 (SD 2.0) to 4.5 (SD 1.7) in the progesterone arm, and from 4.6 (SD 2.8) to 2.9 (SD 2.2) in the clobetasol propionate arm (difference in favor of clobetasol 1.61; 95% CI 0.44 to 2.77, p = 0.009), and the mean symptom severity LS scores improved from 4.5 (SD 3.8) to 3.1 (SD 3.0) in the progesterone arm, and from 4.7 (SD 2.8) to 1.9 (SD 1.8) in the clobetasol propionate arm (difference in favor of clobetasol 1.32; 95% CI -0.25 to 2.89, p = 0.095). LS was in complete remission in 6 out of 10 patients (60%) with available biopsy in the progesterone arm, and in 13 out of 16 patients (81.3%) in the clobetasol propionate arm (odds ratio in favor of clobetasol 0.35; 95% CI 0.06 to 2.06, p = 0.234). No drug-related serious adverse event occurred during the trial. CONCLUSIONS: Topical progesterone 8% ointment is inferior to standard therapy with topical clobetasol propionate 0.05% in previously untreated premenopausal women with vulvar LS after 12 weeks treatment.

Dose-response effect of interleukin (IL)-1ß, tumour necrosis factor (TNF)-α, and interferon-γ on the in vitro production of epithelial neutrophil activating peptide-78 (ENA-78), IL-8, and IL-6 by human endometrial stromal cells.

PURPOSE: The production of epithelial neutrophil activating peptide-78 (NA-78) and the interleukins IL-8 and IL-6 by endometrial stromal cells is stimulated by pro-inflammatory interleukin-1 (IL-1) and tumour necrosis factor-α (TNF-α). IL-8 is suggested to play a role in the pathogenesis of endometriosis, and in these women the peritoneal fluid concentrations of ENA-78 and IL-8 are increased. TNF-α has been tested together with interferon-γ because of their cooperative stimulation of IL-6. The release of IL-8, however, is inhibited with increasing interferon levels. The aim of the study was the analysis of the production of ENA-78, IL-6 and IL-8 by cultured human endometrial stromal cells in the presence of varying concentrations of IL-1ß, TNF-α, and interferon-γ. METHODS: Eutopic endometrial tissue was obtained from seven cycling, endometriosis-free women undergoing laparoscopy for reasons of infertility or pain. The release of ENA-78, IL-8 and IL-6 by the isolated and monolayer cultured stromal cell fraction in the presence of IL-1ß (0.08 to 50 ng/mL), TNF-α, and interferon-γ (both 20 to 500 ng/mL) was determined. RESULTS: IL-1ß stimulated the production of IL-8, IL-6, and ENA-78 dose dependently from 0.08 to 2.0 ng/mL (ENA-78) or to 10 ng/mL (IL-8, IL-6); at 50 ng/mL a decrease in release was observed for IL-8 and IL-6. TNF-α stimulation yielded a plateau between 20 and 100 ng/mL. Interferon-γ stimulated IL-6 and inhibited IL-8 production above 20 ng/mL. ENA-78 release was largely unaffected by interferon-γ. CONCLUSIONS: IL-1ß and TNF-α stimulate stromal cytokine production cumulatively with different dose-response curves. The presence of interferon-γ has opposite effects on IL-8 and IL-6. TNF-α and interferon-γ should be investigated separately in future in vitro studies with endometrial cells and explants.

[Sarcomas and mixed mesodermal tumors of the uterus]. / Mesenchymale Tumoren des Uterus.

Malignant mesodermal tumors of the uterus are an inhomogenous group of uterine malignancies with different pathogenesis, clinical presentation and prognosis. These rare tumors represent approximately 1 % of all uterine malignancies. The aggressive carcinosarcomas or mixed muellerian tumors are defined by mixed malignant epithelial and malignant mesodermal histopathology and are of the same precursor cell origin like endometrial cancer. Thus, carcinosarcomas were reclassified by the FIGO as an aggressive type of endometrial cancer and treated like type II endometrial cancer. Adenosarcomas are also mixed tumors with benign epithelial proliferation and malignant mesodermal cell growth, have a good prognosis and represent less than 5 % of all mesodermal uterine malignancies. Besides carcinosarcomas, the pure mesodermal leiomyosarcomas are the most common mesodermal malignancies. Patients with leiomyosarcamos are usually perimenopausal, and although more than half of the patients present with symptoms, diagnosis occurs incidentally in most cases in final histopathologic workup of an excised putative myoma or uterus. Adequate anamnesis, gynecologic examination and careful imaging by transvaginal ultrasound in the preoperative setting might hint to correct differential diagnosis in many cases. Overall the prognosis of uterine leiomyomas is poor. Malignancies of the endometrial stroma are very rare and divided in two subgroups, the mostly estrogen receptor positive endometrial stromal sarcoma, which occur preferably in premenopausal women and show a favorable prognosis, and the very aggressive undifferentiated endometrial sarcomas. The more rare undifferentiated endometrial sarcomas occur in postmenopausal women and most patients die in the first two years after diagnosis. Risk stratification of preoperative differential diagnosis requires improvements and the correct histopathologic workup of mesodermal uterine malignancies is still a challenge for pathologists.

Outcome of perineoplasty and de-adhesion in patients with vulvar Lichen sclerosus and sexual disorders.

OBJECTIVE: Vulvar Lichen sclerosus (LS) is a chronic inflammatory disease in which architectural changes and symptoms like itching, soreness, pain and dyspareunia can affect quality of life and sexual activity. Perineoplasty has been shown to be effective as a supportive surgical treatment in women with refractory dyspareunia in addition to the standard topical immunosuppressive treatment. The aim of this study was to evaluate retrospectively general complaints, patient satisfaction concerning sexual activity, reduction of dyspareunia/apareunia, orgasm ability and recurrence of LS after perineoplasty. STUDY DESIGN: This study is a retrospective monocentric observational study, in which patients with vulvar LS who had undergone perineoplasty were invited to fill out a standardized questionnaire during the follow-up time. The main outcome measure is the overall patient satisfaction after surgical therapy of vulvar LS. RESULTS: Forty-one of the 70 invited patients with a median age at surgery of 58 years (18-74 years) and a median 60 years (19-76 years) at the last follow-up were evaluated. The median follow-up time was 2.3 years (1-5 years). There was a significant (p < 0.001) reduction in general complaints after surgery. Twenty-two patients were very satisfied, 15 were satisfied and 3 were not satisfied with the outcome of the surgery. Only 2 patients would not recommend the surgery. Although, there was a significant (p = 0.02) reduction in dyspareunia after surgery, 10 patients still felt pain during sexual intercourse. CONCLUSION: This is one of the largest studies reporting on long-term results of perineoplasty. It showed that perineoplasty is a safe surgical treatment option with a high satisfaction rate in patients with dyspareunia due to LS and a desire to regain sexual activity. Perineoplasty can improve sexual activity and achieve overall satisfaction in selected patients even though the recurrence rate of LS in sexually active patients remains high.

Gonadotropin-releasing hormone type II antagonist induces apoptosis in MCF-7 and triple-negative MDA-MB-231 human breast cancer cells in vitro and in vivo.

INTRODUCTION: Triple-negative breast cancer does not express estrogen and progesterone receptors, and no overexpression/amplification of the HER2-neu gene occurs. Therefore, this subtype of breast cancer lacks the benefits of specific therapies that target these receptors. Today chemotherapy is the only systematic therapy for patients with triple-negative breast cancer. About 50% to 64% of human breast cancers express receptors for gonadotropin-releasing hormone (GnRH), which might be used as a target. New targeted therapies are warranted. Recently, we showed that antagonists of gonadotropin-releasing hormone type II (GnRH-II) induce apoptosis in human endometrial and ovarian cancer cells in vitro and in vivo. This was mediated through activation of stress-induced mitogen-activated protein kinases (MAPKs) p38 and c-Jun N-terminal kinase (JNK), followed by activation of proapoptotic protein Bax, loss of mitochondrial membrane potential, and activation of caspase-3. In the present study, we analyzed whether GnRH-II antagonists induce apoptosis in MCF-7 and triple-negative MDA-MB-231 human breast cancer cells that express GnRH receptors. In addition, we ascertained whether knockdown of GnRH-I receptor expression affects GnRH-II antagonist-induced apoptosis and apoptotic signaling. METHODS: Induction of apoptosis was analyzed by measurement of the loss of mitochondrial membrane potential. Apoptotic signaling was measured with quantification of activated MAPK p38 and caspase-3 by using the Western blot technique. GnRH-I receptor protein expression was inhibited by using the antisense knockdown technique. In vivo experiments were performed by using nude mice bearing xenografted human breast tumors. RESULTS: We showed that treatment of MCF-7 and triple-negative MDA-MB-231 human breast cancer cells with a GnRH-II antagonist results in apoptotic cell death in vitro via activation of stress-activated MAPK p38 and loss of mitochondrial membrane potential. In addition, we showed GnRH-II antagonist-induced activation of caspase-3 in MDA-MB-231 human breast cancer cells. After knockdown of GnRH-I receptor expression, GnRH-II antagonist-induced apoptosis and apoptotic signaling was only slightly reduced, indicating that an additional pathway mediating the effects of GnRH-II antagonists may exist. The GnRH-I receptor seems not to be the only target of GnRH-II antagonists. The antitumor effects of the GnRH-II antagonist could be confirmed in nude mice. The GnRH-II antagonist inhibited the growth of xenotransplants of human breast cancers in nude mice completely, without any apparent side effects. CONCLUSIONS: GnRH-II antagonists seem to be suitable drugs for an efficacious and less-toxic endocrine therapy for breast cancers, including triple-negative breast cancers.

Dose escalation and pharmacokinetic study of AEZS-108 (AN-152), an LHRH agonist linked to doxorubicin, in women with LHRH receptor-positive tumors.

OBJECTIVES: Receptors for luteinizing hormone-releasing hormone (LHRH) can be utilized for targeted chemotherapy of cytotoxic LHRH analogs. The compound AEZS-108 (previously AN-152) consists of [D-Lys6]LHRH linked to doxorubicin. The objectives of this first study in humans with AESZ-108 were to determine the maximum tolerated dose and to characterize the dose-limiting toxicity, pharmacokinetics, preliminary efficacy, and hormonal effects. METHODS: The study included 17 women with histologically confirmed epithelial cancer of the ovary, endometrium, or breast that was metastatic or unresectable and for which standard curative or palliative measures could not be used or were no longer effective or tolerated. In each patient, immunohistochemistry of primary tumor or metastatic lesion confirmed that the tumors expressed LHRH receptors. RESULTS: One patient each received intravenous doses of 10, 20, 40, or 80 mg/m² of AEZS-108, six received 160 mg/m² and seven 267 mg/m² at 3 week intervals. Dose-limiting leukopenia and neutropenia were observed at the highest dose. A total of 6 patients, 3 patients each in both upper dose groups, showed responses to AEZS-108. The half-life of AESZ-108 was estimated to be about 2h. CONCLUSIONS: The maximum tolerated dose of AESZ-108 in the absence of supportive medication is 267 mg/m² and this dose is recommended as starting dose for therapeutic Phase II studies.

Laparoscopy or laparotomy? A comparison of 240 patients with early-stage endometrial cancer.

BACKGROUND: This study aimed to compare the safety and efficacy of laparoscopy and laparotomy in the surgical treatment of early endometrial cancer, especially in obese women. METHODS: The results obtained after laparoscopic surgical treatment of early endometrial cancer (International Federation of Gynecology and Obstetrics (FIGO) stage 1 or 2) in patients between 1996 and 2007 were compared with an age- and tumour-matched historical group of patients treated with laparotomy between 1988 and 1996. All the patients underwent hysterectomy, bilateral salpingo-oophorectomy, and pelvic + or - paraaortic lymphadenectomy. RESULTS: Both groups included 120 patients with a preoperative diagnosis of early endometrial cancer. The postoperative diagnosis was endometrial cancer stage 1 or 2 for 89% of the cases in both groups. The mean operating time was 170 min for the laparotomy group compared with 178 min for the laparoscopy group (nonsignificant difference). The estimated intraoperative blood loss was significantly greater in the laparotomy group, and the hospital stay was significantly shorter in the laparoscopy group. CONCLUSIONS: The results show that early endometrial cancer can be treated effectively by laparoscopy. Because of this study's retrospective design, the results should be interpreted with caution. However, the advantages of this method for obese patients are evident. The age and weight of these patients should not be used as a contraindication for laparoscopy.

Gonadotropin-releasing hormone type II antagonists induce apoptotic cell death in human endometrial and ovarian cancer cells in vitro and in vivo.

In human endometrial and ovarian cancers, gonadotropin-releasing hormone type I (GnRH-I), GnRH-II, and their receptors are parts of a negative autocrine regulatory system of cell proliferation. Based on a tumor-specific signal transduction, GnRH-I and GnRH-II agonists inhibit the mitogenic signal transduction of growth factor receptors and related oncogene products associated with tyrosine kinase activity via activation of a phosphotyrosine phosphatase resulting in down-regulation of cancer cell proliferation. Induction of apoptosis is not involved. In this study, we show that treatment of human endometrial and ovarian cancer cells with GnRH-II antagonists results in apoptotic cell death via dose-dependent activation of caspase-3. The antitumor effects of the GnRH-II antagonists could be confirmed in nude mice. GnRH-II antagonists inhibited the growth of xenotransplants of human endometrial and ovarian cancers in nude mice significantly, without any apparent side effects. Thus, GnRH-II antagonists seem to be suitable drugs for an efficacious and less toxic endocrine therapy for endometrial and ovarian cancers.

Early onset vulvar Lichen Sclerosus in premenopausal women and oral contraceptives.

OBJECTIVE: For vulvar Lichen sclerosus (LS) immunological factors, genetic predisposition, and decreased 5 alpha-reductase activity have been discussed as aetiological factors. During the last decade an increase of LS in young women has been suspected. Aim of this study was to evaluate data of premenopausal women with early onset LS to find potential risk factors focussing on the use of oral contraceptives. STUDY DESIGN: We retrospectively analyzed the data of 40 premenopausal patients with early onset LS regarding use of oral contraceptives (OCPs), and first occurrence of LS. To compare these data in a case-control study we analyzed a matched control group of 110 healthy women. RESULTS: All our LS patients were using OCPs compared to 73 women (66.4%) in the control group. OCPs with anti-androgenic activity (chlormadinone acetate, cyproterone acetate, dienogest, and drospirenone) were used by 28 (70%) of the LS patients and by 35 (47.9%) of the 73 women using OCPs in the control group. Thus, the odds ratio for early onset LS for women using anti-androgenic OCPs was 2.53 (95% CI: 1.12-5.75). CONCLUSION: Our data suggest that disturbance of the androgen dependent growth of the vulvar skin by OCPs and especially by OCPs with anti-androgenic properties might trigger the early onset of LS in a subgroup of susceptible young women.

Hormonal heterogeneity of endometrial cancer.

Endometrial cancer is the most common malignant tumor of the female genital tract in the developed world. Increasing evidence suggests that the majority of cases can be divided into two different types ofendometrial cancer based on clinico-pathological and molecular characteristics. Type I is associated with an endocrine milieu of estrogen predominance. These tumors are ofendometroid histology and develop from endometrial hyperplasia. They have good prognosis and are sensitive to endocrine treatment. Type II endometrial cancers are not associated with a history of unopposed estrogens and develop from the atrophic endometrium of elderly women. Mainly, they are of serous papillary or clear cell morphology, have a poor prognosis and do not react to endocrine treatment. Both types of endometrial cancer probably differ markedly with regard to the molecular mechanisms of transformation. The transition from normal endometrium to a malignant tumor is thought to involve a stepwise accumulation of alterations in cellular mechanisms leading to dysfunctional cell growth. This chapter reviews the current knowledge of the molecular mechanisms commonly associated with development of type I and type II endometrial cancer.

GnRH-II agonist [D-Lys6]GnRH-II inhibits the EGF-induced mitogenic signal transduction in human endometrial and ovarian cancer cells.

The majority of human endometrial and ovarian cancers express receptors for GnRH type I (GnRH-I). Their proliferation is time- and dose-dependently reduced by GnRH-I and its analogs. GnRH-I analogs activate a phosphotyrosine-phosphatase (PTP) and inhibit EGF-induced mitogenic signal transduction. Recently we found that GnRH type II (GnRH-II) and its agonist [D-Lys6]GnRH-II also have antiproliferative effects on these tumor cells which are significantly greater than those of GnRH-I agonists. In a more recent study, we showed that the antiproliferative activity of GnRH-II on human endometrial and ovarian cancer cell lines is not mediated through the GnRH-I receptor. The underlying signal transduction mechanisms of GnRH-II are still unknown. In this study we showed that the mitogenic effects of growth factors in endometrial and ovarian cancer cell lines were counteracted by GnRH-II agonist [D-Lys6]GnRH-II, indicating an interaction with the mitogenic signal transduction. We showed that [D-Lys6]GnRH-II reduces EGF-induced auto-tyrosine-phosphorylation of EGF-receptors via activation of a PTP and that EGF-induced activation of mitogen-activated protein kinase was blocked in cells treated with [D-Lys6]GnRH-II. Furthermore, EGF-induced expression of the immediate early gene c-fos was inhibited by treatment with [D-Lys6]GnRH-II. After knock-out of GnRH-I receptor expression, GnRH-II agonist [D-Lys6]GnRH-II still activated PTP and inhibited the EGF-induced mitogenic signal transduction. These data indicate, that the effects of GnRH-II are not due to a cross-reaction with the GnRH-I receptor. In conclusion these data suggest that the signaling of GnRH-II agonist [D-Lys6]GnRH-II is comparable to that of GnRH-I analogs.

Acellular Dermal Matrix (Permacol®) for Heterologous Immediate Breast Reconstruction after Skin-Sparing Mastectomy in Patients with Breast Cancer: A Single-Institution Experience and a Review of the Literature.

OBJECTIVE: Skin-sparing mastectomy (SSM) with immediate heterologous reconstruction is a safe oncological option in surgical therapy of early breast cancer. Permacol® is an acellular dermal matrix (ADM) placed between the implant and the skin to improve lower pole projection and implant coverage. The aim of our study was to evaluate the outcome with a focus on patient satisfaction after 6 months and to analyze physical changes of ADM. METHODS: 10 patients who underwent SSM with Permacol® were analyzed retrospectively. All patients were followed using a satisfaction questionnaire and an ultrasound evaluation of the tissue thickness of the pectoralis muscle and the Permacol®. RESULTS: No intraoperative complications were observed. One patient required removal of the implant for necrosis after 3 months. Half of the patients underwent secondary corrective surgery. A statistically significant thinning of the pectoralis muscle was observed, compared to the thickening of the Permacol®. A majority of the patients were satisfied with the operation, and we found a correlation between lower body mass index and patient satisfaction. CONCLUSION: In our small case series Permacol®-assisted immediate reconstruction is shown to be an option for selected cases. Physical changes of Permacol® result in a symmetrical coverage of the implant, which may improve cosmetic outcome.

GnRH-II receptor-like antigenicity in human placenta and in cancers of the human reproductive organs.

We have recently demonstrated that the antiproliferative activity of GnRH-II on human endometrial and ovarian cancer cell lines is not mediated through the GnRH-I receptor. A functional receptor for human GnRH-II has not yet been identified. In this study, we have generated a polyclonal antiserum to the putative human GnRH-II receptor using a peptide (YSPTMLTEVPPC) corresponding to the third extracellular domain coupled to keyhole limpet haemocyanin via the Cys residue. A database search showed no identical peptide sequences in any other human gene. To avoid cross-reactions against two similar amino acid sequences the antiserum was pre-absorbed using these peptides. Immune histological sections of human placenta and human endometrial, ovarian and prostate cancers using rabbit anti-human GnRH-II receptor antiserum showed GnRH-II receptor-like staining. Western blot analysis of cell membrane preparations of human endometrial and ovarian cancer cell lines yielded a band at approximately 43 kDa whereas Western blot analysis of cell membrane preparations of ovaries obtained from the marmoset monkey (Callithrix jacchus) yielded a band at approximately 54 kDa. To identify the GnRH-II receptor-like antigen we used the photo-affinity labelling technique. Photochemical reaction of (125)I-labelled (4-azidobenzoyl)-N-hydroxysuccinimide-[d-Lys(6)]-GnRH-II (10(-9) M) with cell membrane preparations of human endometrial and ovarian cancer cells yielded a band at approximately 43 kDa. In competition experiments, the GnRH-I agonist Triptorelin (10(-7) M) showed a weak decrease of (125)I-labelled (4-azidobenzoyl)-N-hydroxysuccinimide-[d-Lys(6)]-GnRH-II binding to its binding site. The GnRH-I antagonist Cetrorelix (10(-7) M) showed a clearly stronger decrease, whereas GnRH-II agonist [d-Lys(6)]-GnRH-II (10(-7) M) was the most potent competitor. Western blot analysis of the same gel using rabbit anti-human GnRH-II receptor antiserum identified this band as GnRH-II receptor-like antigen.