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Consensus of regulatory decisions on the same Marketing Authorization Application (MAA) are critical for stakeholders. In this context, regulatory decision patterns from the Swissmedic (SMC), the US Food and Drug Administration (FDA), and the European Medicines Agency (EMA) were analyzed for hemato‐oncology products (OP) and non‐oncology products (NOP). We compared 336 SMC regulatory decisions between 2009 and 2018 on new active substances with the EMA and the FDA for OP (n = 77) and NOP (n = 259) regarding approval rates, consensus, and divergent decisions. For OP MAA, we analyzed the underlying reasons for divergent decisions; for consensus decisions, the similarity and strictness of labeling. For OP, the approval rate for the SMC was 88.4%, the EMA 91.3%, and the FDA 95.7%. For NOP, the SMC had an approval rate of 86.2%, the EMA of 93.8%, and the FDA of 88.8%. The consensus decision rate among agencies was 88.4% for OP and 84.4% for NOP. The main clinical driver for divergent decisions for OP was nonrandomized trial design and low patient numbers. Comparing the approved indication wordings, the highest similarity was between the SMC and the EMA, and lowest for the FDA and the EMA. Investigating label strictness, the FDA numerically had the highest but not‐statistically significant number of strict labels. The approval rate stratified by disease area (OP and NOP) differed among the SMC, the EMA, and the FDA. High concordance in regulatory decisions was observed between agencies for OP as well as NOP. Reasons for divergent decisions regarding OP were mainly due to scientific uncertainties. Comparing strictness of indications, numerical but no statistically significant differences were observed between agencies. [ABSTRACT FROM AUTHOR]

This retrospective study attempts to establish if a correlation exists between osteoporosis and hematopoiesis before and after adjuvant chemotherapy in the context of non-metastatic breast cancer. Osteoporosis is interpreted both as a direct marker of osteoblastic decline and as an indirect marker of increased bone marrow adiposity within the hematopoietic microenvironment. Patients from the "Centre du Sein" at CHUV (Centre Hospitalier Universitaire Vaudois) undergoing adjuvant chemotherapy were included in this study. Evolution of blood counts was studied in correlation with the osteoporosis status. Toxicity of chemotherapy was coded according to published probability of febrile neutropenia. One hundred forty-three women were included: mean age 52.1 ± 12.5 years, mean BMI (body mass index) 24.4 ± 4.1. BMD (bone mineral density) scored osteoporotic in 32% and osteopenic in 45%. Prior to chemotherapy, BMD was positively correlated with neutrophil (p < 0.001) and thrombocyte (p = 0.01) count; TBS (trabecular bone score) was not correlated with blood count. After the first cycle of chemotherapy, an increase of one point in TBS correlated with a decrease of 57% on the time to reach leucocyte nadir (p = 0.004). There was a positive correlation between BMD and risk of infection (p < 0.001). Our data demonstrates an association between osteoporosis and lower blood counts in a younger cohort than previously published, extending it for the first time to neutrophil counts in females. Our results suggest that the healthier the bone, the earlier the lowest leucocyte count value, prompting further research on this area. [ABSTRACT FROM AUTHOR]

Introduction Chronic endometriosis is most commonly associated with clear cell neoplasms. Rarely, endometriosis can be complicated with endometrioid carcinoma. According to the literature, any abdominal structure can be involved. The vagina is rarely reported as the primary location of endometrioid adenocarcinoma associated with endometriosis with only six cases published in the last 20 years none of them with lymph node involvement. In this setting, staging and treatment references are missing. Here we present the diagnosis, surgical and adjuvant treatment of a patient with an endometrioid adenocarcinoma arising from endometriosis of the vaginal fornix with nodal involvement and extension to the Douglas pouch and rectal wall. Patients and methods A 56-year-old patient with a medical history of bilateral oophorectomy for endometriosis in 2002 was admitted to our gynecological department for investigation of progressive perineal pain with vaginal discharge developing over 5 months. Pelvic MRI and a PET-CT identified a mass of the posterior vaginal fornix infiltrating the Douglas pouch and possibly the rectal wall. There was no evidence of uterine involvement nor nodal or distant metastasis. Initial surgical debulking consisted in a laparoscopic posterior exenteration with bowel anastomosis and ileostomy, bilateral pelvic lymph-node dissection and vaginal reconstruction. The pathology report confirmed a grade1, endometrioid adenocarcinoma, measuring 30mm, with nodal involvement (1/25), infiltrating the perirectal fat but not the muscular layer, developed on an endometriosis lesion. There was no lymphovascular or perineural invasion and the surgical margins free of tumor. For this locally advanced ectopic endometrial adenocarcinoma, there is no specific staging system nor treatment guideline. The literature review for similar cases provids only scarce evidence, therefore we extended our research to endometrioid adenocarcinomas arising from endometriosis loci of other abdominal localization. Of the 13 published cases, three presented with nodal involvement and 8/13 had documented adjuvant treatment with chemotherapy and radiotherapy. The median progression free survival (PFS) of the treated cases was 24months [0-60] and 10months among the three cases with nodal involvement [6-28]. Results Based on these findings, for this high risk of relapse setting, we decided a sequential adjuvant treatment with 4-6 cycles of carboplatinum AUC5 - paclitaxel 175mg/m2 chemotherapy followed by EBRT and Brachytherapy. This approach was inspired by stage III endometrial carcinoma treatment. Because of a life-threatening anaphylactic reaction Introduction Chronic endometriosis is most commonly associated with clear cell neoplasms. Rarely, endometriosis can be complicated with endometrioid carcinoma. According to the literature, any abdominal structure can be involved. The vagina is rarely reported as the primary location of endometrioid adenocarcinoma associated with endometriosis with only six cases published in the last 20 years none of them with lymph node involvement. In this setting, staging and treatment references are missing. Here we present the diagnosis, surgical and adjuvant treatment of a patient with an endometrioid adenocarcinoma arising from endometriosis of the vaginal fornix with nodal involvement and extension to the Douglas pouch and rectal wall. Patients and methods A 56-year-old patient with a medical history of bilateral oophorectomy for endometriosis in 2002 was admitted to our gynecological department for investigation of progressive perineal pain with vaginal discharge developing over 5 months. Pelvic MRI and a PET-CT identified a mass of the posterior vaginal fornix infiltrating the Douglas pouch and possibly the rectal wall. There was no evidence of uterine involvement nor nodal or distant metastasis. Initial surgical debulking consisted in a laparoscopic posterior exenteration with bowel anastomosis and ileostomy, bilateral pelvic lymph-node dissection and vaginal reconstruction. The pathology report confirmed a grade1, endometrioid adenocarcinoma, measuring 30mm, with nodal involvement (1/25), infiltrating the perirectal fat but not the muscular layer, developed on an endometriosis lesion. There was no lymphovascular or perineural invasion and the surgical margins free of tumor. For this locally advanced ectopic endometrial adenocarcinoma, there is no specific staging system nor treatment guideline. The literature review for similar cases provids only scarce evidence, therefore we extended our research to endometrioid adenocarcinomas arising from endometriosis loci of other abdominal localization. Of the 13 published cases, three presented with nodal involvement and 8/13 had documented adjuvant treatment with chemotherapy and radiotherapy. The median progression free survival (PFS) of the treated cases was 24months [0-60] and 10months among the three cases with nodal involvement [6-28]. Results Based on these findings, for this high risk of relapse setting, we decided a sequential adjuvant treatment with 4-6 cycles of carboplatinum AUC5 - paclitaxel 175mg/m2 chemotherapy followed by EBRT and Brachytherapy. This approach was inspired by stage III endometrial carcinoma treatment. Because of a life-threatening anaphylactic reaction [ABSTRACT FROM AUTHOR]

Presents the correction to the article 'Inactivation of Notch1 in immature thymocytes does not perturb CD4 or CD8T cell development,' which appeared in the March 2001 issue of 'Nature Immunology.'

Consensus of regulatory decisions on the same Marketing Authorization Application (MAA) are critical for stakeholders. In this context, regulatory decision patterns from the Swissmedic (SMC), the US Food and Drug Administration (FDA), and the European Medicines Agency (EMA) were analyzed for hemato-oncology products (OP) and non-oncology products (NOP). We compared 336 SMC regulatory decisions between 2009 and 2018 on new active substances with the EMA and the FDA for OP (n = 77) and NOP (n = 259) regarding approval rates, consensus, and divergent decisions. For OP MAA, we analyzed the underlying reasons for divergent decisions; for consensus decisions, the similarity and strictness of labeling. For OP, the approval rate for the SMC was 88.4%, the EMA 91.3%, and the FDA 95.7%. For NOP, the SMC had an approval rate of 86.2%, the EMA of 93.8%, and the FDA of 88.8%. The consensus decision rate among agencies was 88.4% for OP and 84.4% for NOP. The main clinical driver for divergent decisions for OP was nonrandomized trial design and low patient numbers. Comparing the approved indication wordings, the highest similarity was between the SMC and the EMA, and lowest for the FDA and the EMA. Investigating label strictness, the FDA numerically had the highest but not-statistically significant number of strict labels. The approval rate stratified by disease area (OP and NOP) differed among the SMC, the EMA, and the FDA. High concordance in regulatory decisions was observed between agencies for OP as well as NOP. Reasons for divergent decisions regarding OP were mainly due to scientific uncertainties. Comparing strictness of indications, numerical but no statistically significant differences were observed between agencies., (© 2023 The Authors. Clinical and Translational Science published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Endometrial carcinoma is one of the most frequent women cancer. Its incidence is increasing due to the aging of the population and changes in life. Fortunately, these cancers are usually detected at an early stage due to post-menopausal bleeding. The prognostic factors are quite well determined : loco-regional and distant tumoral extension according to the FIGO classification, grade and histological type and the presence of lympho-vascular space invasions. These cancers, however, are usually of good prognosis because of an early diagnosis, and their treatment is based on surgery, preferably minimally invasive approach, whose extension is adapted to the prognostic factors from the pre-therapeutic assessment. The definitive histological examination will condition the adjuvant treatments., Competing Interests: Les auteurs n’ont declare aucun conflit d’interets en relation avec cet article.

The primary treatment of ovarian cancer consists in a complete surgical debulking followed by adjuvant chemotherapy combining platinum with taxanes. Despite this treatment, patient survival has remained stable over the last 20 years. Recently, advances in the sequence, regimens, and route of administration of treatment have enhanced effectiveness and reduced toxicity. Targeted anti-angiogenic therapy and recently PARP inhibitors are now complementing standard treatment and have improved patient progression-free survival. The development of immunotherapy, alone or in combination, brings new perspectives for the future treatment of ovarian cancer., Competing Interests: Les auteurs n’ont déclaré aucun conflit d’intérêts en relation avec cet article.

Endocrine therapy remains a mainstay in the treatment of endocrine-sensitive breast cancer. In the adjuvant setting, 5 years of endocrine therapy significantly reduces recurrence rate and mortality. Tamoxifen is the molecule of choice for premenopausal women, whereas for postmenopausal women aromatase inhibitors are currently part of the standard treatment. Endocrine therapy can induce side effects, which can affect patient's quality of life and lead to premature treatment interruption. Identification and adequately addressing these side effects is fundamental to maintain good treatment compliance and therefore improve breast cancer specific outcome.

Notch proteins influence cell fate decisions in many developmental systems. During lymphoid development, Notch1 signaling is essential to direct a bipotent T/B precursor toward the T cell fate, but the role of Notch1 at later stages of T cell development remains controversial. We have recently reported that tissue-specific inactivation of Notch1 in immature (CD44(-) CD25(+)) thymocytes does not affect subsequent T cell development. Here, we demonstrate that loss of Notch1 signaling at an earlier (CD44(+)CD25(+)) developmental stage results in severe perturbation of alpha beta but not gamma delta lineage development. Immature Notch1(-/-) thymocytes show impaired VDJ beta rearrangement and aberrant pre-TCR-independent survival. Collectively, our data demonstrate that Notch1 controls several nonredundant functions necessary for alpha beta lineage development.