Treatment of male and female precocious puberty (PP) by monthly injections of a continuous release preparation of D-Trp-6-LH-RH

Successful treatment of PP by daily subcutaneous (SC) administration of the LH-RH agonist D-Trp-6-LH-RH (Trp6) was reported (Kauli et al., ESPE 1983). After demonstration of its efficiency and innocuity in dogs, a long acting preparation designed for releasing continuously 100 μg Trp6 per 24 h, was given intramuscularly to 3 boys and 3 girls with PP, aged 3 to 8 years. 3 mg Trp6 were injected every 28 days, cyproterone acetate being associated during the first week. In boys testosterone levels (ng/ml) decreased from 2.2-5 to 0.1-0.2 within 2 months. Testis volume was unaffected in 1, decreased slighty in 2. In girls estradiol levels (pg/ml) decreased from 40-100 to 0-40 within 2 months and in a menstruating girl genital bleeding desappeared after 1 month. Breast enlargement was reduced in all. In all children, the gonadotropin responses to LH-RH were suppressed and the inhibition of gonadal secretion persisted after 6 months of treatment. The data demonstrate the ability of long acting Trp6 to suppress gonadal secretion by a monthly injection in children with PP

Pour quelles patientes peut-on envisager une désescalade dans la prise en charge des carcinomes canalaires in situ ?

International audienceDuctal carcinomas in situ (DCIS) of the breast account for 85% to 90% of breast cancer in situ. Current recommendations for the management of DCIS in France are based on surgical excision of the lesions, lumpectomy in healthy margins (margins of excision≥2mm) or mastectomy in case of extensive lesions. Radiation therapy is recommended after conservative surgical treatment. However, it seems relevant for some patients to discuss the benefit of a therapeutic de-escalation. Indeed, it has been reported that radiotherapy has no major impact on overall survival and that its interest could be discussed in the low-risk situations of invasive recurrence for which surgery alone could be sufficient, subject to sufficient margins. These questions call for the precise definition of low risk populations and to clarify the importance of taking into account decision support tools and new molecular markers. The place of scores like that of the University of Southern California - Van Nuys, and that of genomic tests such as the Oncotype test© DX DCIS (DCIS score) need to be specified. The expected results of several prospective studies could go in the direction of a significant therapeutic de-escalation for the management of DCIS in the years to come. In the meantime, however, it is advisable to remain cautious and the inclusion of patients in clinical trials should be favored.Les carcinomes canalaires in situ (CCIS) du sein représentent 85 % à 90 % des cancers in situ du sein. Les recommandations actuelles pour la prise en charge des CCIS en France, publiée en 2015 par l’Institut National du Cancer (INCa), reposent sur l’exérèse chirurgicale des lésions, par une tumorectomie en berges saines (marges d’exérèse ≥ 2 mm) ou par une mastectomie en cas de lésions étendue. La radiothérapie est recommandée après traitement chirurgical conservateur. Pour certaines patientes, une désescalade thérapeutique parait envisageable aux vues des données de la littérature. Ainsi, il a été rapporté que la radiothérapie n’a pas d’impact majeur sur la survie globale et que son intérêt pourrait être discuté dans les situations les moins à risque de récidive invasive pour lesquelles la chirurgie seule pourrait être suffisante, sous réserve de marges suffisantes. Ces interrogations imposent la définition précise de populations à bas risque et de préciser l’intérêt de la prise en compte des outils d’aide à la décision et des nouveaux marqueurs moléculaires. La place de scores comme celui de l’Université de Californie du Sud – Van Nuys, et celle des tests génomiques comme le test Oncotype© DX DCIS (DCIS score) doivent être précisées. Les résultats attendus de plusieurs études prospectives en cours d’inclusion pourraient aller dans le sens d’une désescalade thérapeutique significative pour la prise en charge adjuvante des CCIS dans les années à venir. Il convient toutefois en attendant ces résultats de rester prudents et de privilégier l’inclusion des patientes dans des essais thérapeutiques

191 PLASMA LEVELS OF D-TRP-6-LH-RH (DECAPEPTYL) AFTER INTRAMUSCULAR INJECTION OF LONG-ACTING MICROCAPSULES IN CHILDREN TREATED FOR PRECOCIOUS PUBERTY (PP)

The efficacy of periodic administration of Decapeptyl microcapsules upon symptoms of PP has been previously reported (Roger et al., ESPE meeting 1984, abstract 22). A sensitive radioimmuno assay of the analogue was developped using an antiserum raised in rabbit which exhibited unsignificant cross reactivity with native LH-RH or LH-RH fragments (Mason-Garcia et al.,Proc.Natl. Acad. Sci., USA, in press). Iodinated D-Trp-6-LH-RH was used as a tracer. Fifty μl antiserum diluted at 1/2500 , 50 μl tracer, 100 μl standard (or unknown plasma), 100 μl plasma pool (or phosphate buffer 0.01 M, pH 7.5) were incubated for 24 h. Free and bound were separated by PEG. NSB of the plasma pool and of 40 different child samples were respectively 6.2± 0.4 and 6.3± 0.4% (mean±SD). Bo was 20%. Intraassay CV were 12 and 7% for mean plasma levels of 100 and 370 pg/ml respectively. The detec tion limit was 57 pg/ml. Five children received intramuscularly (IM) on days 1, 21 and every 28 days thereafter, 1.5 mg Decapeptyl microcapsules. Plasma levels were on days 3, 7, 14, and 21 (pg/ml, mean±SEM) 312±57, 242±65, 145±78 and 171±87. Decapeptyl was undetectable in most of samples on day 28 after injection. This study demonstrates that significant Decapeptyl levels are maintained for at least 21 days after a single IM injection

Long term treatment of male and female precocious puberty by periodic administration of a long-acting preparation of D-Trp6-luteinizing hormone-releasing hormone microcapsules.

The efficacy and safety of a delayed release formulation of the LHRH agonist D-Trp6-LHRH (LHRH-A; im microcapsules) were tested in 16 girls, 0.9-8.8 yr old, and 10 boys, 2.0-10.5 yr old, with precocious puberty. All children had advanced bone age, breast or testis enlargement, and a pubertal LH response to LHRH. Precocious puberty was idiopathic in 19 subjects and secondary to a brain tumor or other central nervous system abnormality in 7. Nine girls and 6 boys had been previously treated unsuccessfully with medroxyprogesterone and/or cyproterone acetate. The microcapsules were made of 2% LHRH-A dispersed in a biocompatible biodegradable polymeric matrix of DL-lactide-coglycolide. Sixty micrograms of LHRH-A/kg BW were given im on days 1 and 21 and thereafter every 4 weeks for 10-27 months. Plasma LHRH-A levels were measured in 13 children by means of a specific RIA. On days 3, 7, 14, and 21, mean concentrations (+/- SEM) were 295 +/- 44, 218 +/- 31, 215 +/- 45, and 224 +/- 39 pg/ml, respectively. In girls, breast enlargement disappeared, and mean uterus size decreased from 44.4 +/- 2.5 to 38.1 +/- 3.1 mm (mean +/- SEM; P less than 0.02) within 6 months. Mean ovary length decreased from 23.0 +/- 1.5 to 16.2 +/- 1.5 mm (P less than 0.01). In boys, mean testis volume decreased from 8.1 +/- 1.2 to 6.7 +/- 1.2 ml (P less than 0.02) within 6 months. In both sexes, growth velocity decreased significantly, and bone maturation was generally reduced. Plasma levels of estradiol or testosterone and FSH levels decreased significantly within 3 weeks. The LH response to LHRH was reduced to normal prepubertal values after 7 weeks. No secondary clinical or biochemical escape occurred. In 1 boy, all biological features of puberty recurred within 1 month after omission of the fifth injection. No side-effects occurred, except for transient vaginal bleeding in girls after the first or second injection. No antibodies to LHRH-A were detected in the patients' sera. This study demonstrates the ability of a delayed release formulation of LHRH-A to achieve stable levels of the drug in plasma for at least 21 days after a single im injection and to suppress pituitary and gonadal secretion and pituitary response to LHRH for as long as 2 yr after therapy. This treatment appears to be more efficient in treating both clinical and biochemical abnormalities than does treatment with inhibitory steroids. Additionally, the method of administration is more practical and ensures better patient compliance

Call for Surgical Nodal Staging in Women with ESMO/ESGO/ESTRO High-Intermediate Risk Endometrial Cancer: A Multicentre Cohort Analysis from the FRANCOGYN Study Group

International audienceBackground - The European Society of Medical Oncology (ESMO)/European Society of Gynaecological Oncology (ESGO)/European Society for Radiotherapy & Oncology (ESTRO) classification for endometrial cancer (EC) now includes a high-intermediate risk (HIR) group of recurrence due to the adverse prognostic role of lymphovascular space involvement (LVSI) and grade 3 for women at intermediate risk. However, optimal surgical staging, and especially the place of lymphadenectomy, remains to be elucidated. We aimed to establish whether systematic nodal staging should be part of surgical staging for women with HIR EC. Methods - We abstracted from a prospectively maintained multicentre database the data of 181 women with HIR EC based on uterine factors (endometrioid type 1, grade 1-2 tumors with deep (≥50%) myometrial invasion and unequivocally positive LVSI, and those with grade 3 tumors with <50% myometrial invasion regardless of LVSI status), who received primary surgical treatment between January 2001 and December 2013. We recorded frequency of lymph node (LN) metastases in those who underwent nodal staging. The secondary outcomes were overall survival and recurrence patterns. Results - Overall, 145 (80.1%) women underwent nodal staging consisting of at least pelvic lymphadenectomy. Of these, 62 (42.7%) had LN disease (9.7% with micrometastases). The respective 5-year overall survival rates according to LN status were 85.0% (95% confidence interval [CI] 76.5-91.4), 71.8% (95% CI 61.9-80.4) and 36.0% (95% CI 26.6-46.2) for women with negative LN, positive LN, and unstaged (p = 0.047). Unstaged women were more likely to experience nodal recurrence than surgically staged/LN negative women (p = 0.05). Conclusions - Systematic nodal staging should be part of surgical staging for women with apparent ESMO/ESGO/ESTRO HIR EC. Sentinel LN biopsy (SLNB) could be an option in this specific setting that may possibly substitute comprehensive staging, for the identification of patients with lymphatic dissemination

Isolated lymph node recurrence in epithelial ovarian cancer: recurrence with better prognosis?

International audienceIntroduction The aim of this study was to compare overall survival (OS) between women with isolated lymph node recurrence (ILNR) and those with isolated peritoneal localization of recurrence (ICR), in patients managed for epithelial ovarian cancer.Methods Data from 1508 patients with ovarian cancer were collected retrospectively from1 January 2000 to 31 December 2016, from the FRANCOGYN database, pooling data from 11 centres specialized in ovary treatment. Median overall survival was determined using the Kaplan-Meier method. Univariate and multivariate analyses were performed to define prognostic factors of overall survival. Patients included had a first recurrence defined as ILNR or ICR during their follow up.Results 79 patients (5.2 %) presented with ILNR, and 247 (16.4 %) patients had isolated carcinomatosis recurrence. Complete lymphadenectomy was performed more frequently in the ILNR group vs. the ICR group (67.1 % vs. 53.4 %, p = 0.004) and the number of pelvic lymph nodes involved was higher (2.4 vs. 1.1, p = 0.008). The number of involved pelvic LN was an independent predictor of ILNR (OR = 1.231, 95 % CI [1.074–1.412], p = 0.0024). The 3-year and 5-year OS rates in the ILNR group were 85.2 % and 53.7 % respectively, compared to 68.1 % and 46.8 % in patients with ICR. There was no significant difference in terms of OS after initial diagnosis (p = 0.18). 3- year and 5-year OS rates after diagnosis of recurrence were 62.6 % and 15.6 % in the ILNR group, and 44 % and 15.7 % in patients with ICR (p = 0.21).Conclusion ILNR does not seem to be associated with a better prognosis in terms of OS