Breast conservation and axillary management after primary systemic therapy in patients with early-stage breast cancer: the Lucerne toolbox.

Primary systemic therapy is increasingly used in the treatment of patients with early-stage breast cancer, but few guidelines specifically address optimal locoregional therapies. Therefore, we established an international consortium to discuss clinical evidence and to provide expert advice on technical management of patients with early-stage breast cancer. The steering committee prepared six working packages to address all major clinical questions from diagnosis to surgery. During a consensus meeting that included members from European scientific oncology societies, clinical trial groups, and patient advocates, statements were discussed and voted on. A consensus was reached in 42% of statements, a majority in 38%, and no decision in 21%. Based on these findings, the panel developed clinical guidance recommendations and a toolbox to overcome many clinical and technical requirements associated with the diagnosis, response assessment, surgical planning, and surgery of patients with early-stage breast cancer. This guidance could convince clinicians and patients of the major clinical advancements purported by primary systemic therapy, the use of less extensive and more targeted surgery to improve the lives of patients with breast cancer.

Characterization of molecular scores and gene expression signatures in primary breast cancer, local recurrences and brain metastases.

BACKGROUND: Breast cancer is a leading cause of cancer-related death in women worldwide. Despite extensive studies in all areas of basic, clinical and applied research, accurate prognosis remains elusive, thus leading to overtreatment of many patients. Diagnosis could be improved by introducing multigene molecular scores in standard clinical practice. Several tests that work with formalin-fixed tissue have become routine. Molecular scores usually include several genes representing processes, response to oestrogens, progestogens and human epidermal growth factor receptor 2 (Her2), respectively, which are combined additively in single values. These multi-gene scores have the advantage of being more robust and reproducible than single-gene scores. Their utility may be further enhanced by combining them with classical diagnostic parameters. Here, we present an exploratory study comparing the RISK and research versions of Oncotype DX recurrence score (RS), Prosigna Risk of Recurrence (ROR) and EndoPredict (EP) with respect to their prognostic potential for ipsilateral recurrence and/or distant relapse in brain, and we compared the scores to the intrinsic subtypes based on PAM50. METHODS: RNA was extracted from formalin-fixed, paraffin-embedded (FFPE) tissue cores of primary tumours, local recurrences and brain metastases. Gene expression was measured on a NanoString nCounter Analysis System. Intrinsic subtypes and molecular scores were computed according to published literature and RISK, RS, ROR and EP were compared against each other and to the intrinsic subtypes Luminal A (lumA), Luminal B (lumB), Her2-enriched (Her2↑), Basal-like (basal), and Normal-like (normal) of PAM50. Local recurrences and brain metastases were compared to their corresponding primary tumours. RESULTS: All four molecular scores were highly correlated. Highest correlations were observed among genes related to proliferation while lower correlations were found among oestrogen-related genes. The scores were significantly higher in primary tumours progressing to brain metastases as compared to recurrence-free primary tumours and primary tumours that relapsed as local recurrences. CONCLUSIONS: RISK and ROR-P are prognostic for primary tumours metastasizing to the brain. All four scores, RISK, RS, EP and ROR-P failed to discriminate between primary tumours that remained recurrence-free and primary tumours relapsing as local recurrences.

Oncoplastic Breast Consortium consensus conference on nipple-sparing mastectomy.

PURPOSE: Indications for nipple-sparing mastectomy (NSM) have broadened to include the risk reducing setting and locally advanced tumors, which resulted in a dramatic increase in the use of NSM. The Oncoplastic Breast Consortium consensus conference on NSM and immediate reconstruction was held to address a variety of questions in clinical practice and research based on published evidence and expert panel opinion. METHODS: The panel consisted of 44 breast surgeons from 14 countries across four continents with a background in gynecology, general or reconstructive surgery and a practice dedicated to breast cancer, as well as a patient advocate. Panelists presented evidence summaries relating to each topic for debate during the in-person consensus conference. The iterative process in question development, voting, and wording of the recommendations followed the modified Delphi methodology. RESULTS: Consensus recommendations were reached in 35, majority recommendations in 24, and no recommendations in the remaining 12 questions. The panel acknowledged the need for standardization of various aspects of NSM and immediate reconstruction. It endorsed several oncological contraindications to the preservation of the skin and nipple. Furthermore, it recommended inclusion of patients in prospective registries and routine assessment of patient-reported outcomes. Considerable heterogeneity in breast reconstruction practice became obvious during the conference. CONCLUSIONS: In case of conflicting or missing evidence to guide treatment, the consensus conference revealed substantial disagreement in expert panel opinion, which, among others, supports the need for a randomized trial to evaluate the safest and most efficacious reconstruction techniques.

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.

First international consensus conference on standardization of oncoplastic breast conserving surgery.

PURPOSE: To obtain consensus recommendations for the standardization of oncoplastic breast conserving surgery (OPS) from an international panel of experts in breast surgery including delegates from the German, Austrian and Swiss societies of senology. METHODS: A total of 52 questions were addressed by electronic voting. The panel's recommendations were put into context with current evidence and the report was circled in an iterative open email process until consensus was obtained. RESULTS: The panelists considered OPS safe and effective for improving aesthetic outcomes and broadening the indication for breast conserving surgery (BCS) towards larger tumors. A slim majority believed that OPS reduces the rate of positive margins; however, there was consensus that OPS is associated with an increased risk of complications compared to conventional BCS. The panel strongly endorsed patient-reported outcomes measurement, and recommended selected scales of the Breast-Q™-Breast Conserving Therapy Module for that purpose. The Clough bi-level classification was recommended for standard use in clinical practice for indicating, planning and performing OPS, and the Hoffmann classification for surgical reports and billing purposes. Mastopexy and reduction mammoplasty were the only two recognized OPS procedure categories supported by a majority of the panel. Finally, the experts unanimously supported the statement that every OPS procedure should be tailored to each individual patient. CONCLUSIONS: When implemented into clinical practice, the panel recommendations may improve safety and effectiveness of OPS. The attendees agreed that there is a need for prospective multicenter studies to optimize patient selection and for standardized criteria to qualify and accredit OPS training centers.

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.

Phase II study of fulvestrant 250 mg/month in patients with recurrent or metastatic endometrial cancer: a study of the Arbeitsgemeinschaft Gynäkologische Onkologie.

OBJECTIVES: The aim of this study is to evaluate the activity and toxicity of fulvestrant, a pure estrogen receptor antagonist in patients with advanced or recurrent endometrial cancer, expressing estrogen and/or progesterone receptors (ER/PR). METHODS: Eligible patients with advanced or recurrent endometrial cancer not amenable to curative surgery and/or radiotherapy were treated with fulvestrant at a dose of 250 mg by IM injection every 4 weeks for at least 12 weeks. Therapy was continued until disease progression, death, intolerable side effects or end of study. Response was assessed in patients with at least one target lesion according to WHO-criteria. RESULTS: Thirty-five patients were enrolled in this study and received at least one injection of fulvestrant (intention to treat-population, ITT). Twenty six patients received the intended 3 injections of fulvestrant (per protocol population, PP). There was no complete response but 4 partial responses (11.4% ITT) and 8 stable diseases. The median time to progression was 2.3 months (ITT). Overall survival was 13.2 months (ITT). Treatment was well tolerated. CONCLUSIONS: Fulvestrant at a dose of 250 mg IM every 4 weeks has marginal activity and good tolerability in patients with ER and/or PR positive advanced or recurrent endometrial cancer. A loading dose strategy and the use of 500 mg/4 weeks might improve the efficacy of this treatment.

Gestational and Non-gestational Trophoblastic Neoplasia. Guideline of the DGGG, OEGGG and SGGG (S2k-Level, AWMF Registry No. 032/049, April 2022).

Purpose The aim was to develop and update a guideline which would improve the quality of care offered to women with gestational and non-gestational trophoblastic disease, a group of diseases characterized by their rarity and biological heterogeneity. Methods In accordance with the method used to compile S2k-guidelines, the guideline authors carried out a search of the literature (MEDLINE) for the period 1/2020 to 12/2021 and evaluated the recent literature. No key questions were formulated. No structured literature search with methodical evaluation and assessment of the level of evidence was carried out. The text of the precursor version of the guideline from 2019 was updated based on the most recent literature, and new statements and recommendations were drafted. Recommendations The updated guideline contains recommendations for the diagnosis and therapy of women with hydatidiform mole (partial and complete moles), gestational trophoblastic neoplasia after pregnancy or without prior pregnancy, persistent trophoblastic disease after molar pregnancy, invasive moles, choriocarcinoma, placental site nodules, placental site trophoblastic tumor, hyperplasia at the implantation site und epithelioid trophoblastic tumor. Separate chapters cover the determination and assessment of human chorionic gonadotropin (hCG), histopathological evaluation of specimens, and the appropriate molecular pathological and immunohistochemical diagnostic procedures. Separate chapters on immunotherapy, surgical therapy, multiple pregnancies with simultaneous trophoblastic disease, and pregnancy after trophoblastic disease were formulated, and the corresponding recommendations agreed upon.

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.

Sonographic transvaginal bladder wall thickness: does the measurement discriminate between urodynamic diagnoses?

INTRODUCTION: Measurement of bladder wall thickness (BWT) using transvaginal ultrasound has previously been shown to discriminate between women with confirmed detrusor overactivity and those with urodynamic stress incontinence. Aim of the current study was to determine if vaginally measured BWT correlates with urodynamic diagnoses in a female population. PATIENTS AND METHODS: Between December 2008 and February 2010, adult female consecutive patients undergoing urogynaecologic investigation for lower urinary symptoms were approached to participate in this study. Ethical consent for the current study was obtained. Patients underwent multichannel urodynamics and transvaginal ultrasound measuring the bladder in three location with an emptied bladder. RESULTS: 123 patients were included in the study with a median age of 69 years (range 40-93), median parity of 2 (range 0-3) and a median body mass index of 29.5 kg/m(2) (range 23-38). Urodynamic stress incontinence was diagnosed in 59 patients, DO in 40 and obstruction in 24 cases. Bladder wall thickness was significantly higher in DO patients and in obstruction than in urodynamic stress incontinence. Detrusor pressure at maximum flow rate (pdet/Q(max) ) correlated significantly with BWT. CONCLUSION: Bladder wall thickness shows a significantly positive correlation to pdet/Q(max) and to urodynamic diagnoses of stress incontinence, DO and obstruction.

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.