No long-term effects of antenatal synthetic glucocorticoid exposure on epigenetic regulation of stress-related genes

Antenatal synthetic glucocorticoid (sGC) treatment is a potent modifier of the hypothalamic-pituitary-adrenal (HPA) axis. In this context, epigenetic modifications are discussed as potential regulators explaining how prenatal exposure to GCs might translate into persistent changes of HPA axis “functioning”. The purpose of this study was to investigate whether DNA methylation and gene expression profiles of stress-associated genes (NR3C1; FKBP5; SLC6A4) may mediate the persistent effects of sGC on cortisol stress reactivity that have been previously observed. In addition, hair cortisol concentrations (hairC) were investigated as a valid biomarker of long-term HPA axis activity. This cross-sectional study comprised 108 term-born children and adolescents, including individuals with antenatal GC treatment and controls. From whole blood, DNA methylation was analyzed by targeted deep bisulfite sequencing. Relative mRNA expression was determined by RT-qPCR experiments and qBase analysis. Acute stress reactivity was assessed by the Trier Social Stress Test (TSST) measuring salivary cortisol by ELISA and hairC concentrations were determined from hair samples by liquid chromatography coupled with tandem mass spectrometry. First, no differences in DNA methylation and mRNA expression levels of the stress-associated genes between individuals treated with antenatal sGC compared to controls were found. Second, DNA methylation and mRNA expression levels were neither associated with cortisol stress reactivity nor with hairC. These findings do not corroborate the belief that DNA methylation and mRNA expression profiles of stress-associated genes (NR3C1; FKBP5; SLC6A4) play a key mediating role of the persistent effects of sGC on HPA axis functioning

Pooled Analysis of the Prognostic Relevance of Disseminated Tumor Cells in the Bone Marrow of Patients With Ovarian Cancer

Objective: Detection of disseminated tumor cells (DTCs) in the bone marrow (BM) of patients with breast cancer is associated with poor outcomes. Recent studies demonstrated that DTCs may serve as a prognostic factor in ovarian cancer. The aim of this 3-center study was to evaluate the impact of BM status on survival in a large cohort of patients with ovarian cancer. Materials and Methods: Four hundred ninety-five patients with primary ovarian cancer were included in this 3-center prospective study. Bone marrow aspirates were collected intraoperatively from the iliac crest. Disseminated tumor cells were identified by antibody staining and by cytomorphology. Clinical outcome was correlated with the presence of DTCs. Results: Disseminated tumor cells were detected in 27% of all BM aspirates. The number of cytokeratin-positive cells ranged from 1 to 42 per 2 x 10(6) mononuclear cells. Disseminated tumor cell status did correlate with histologic subtype but not with any of the other established clinicopathologic factors. The overall survival was significantly shorter among DTC-positive patients compared to DTC-negative patients (51 months; 95% confidence interval, 37-65 months vs 33 months; 95% confidence interval, 23-43 months; P = 0.023). In the multivariate analysis, BM status, International Federation of Gynecology and Obstetrics stage, nodal status, resection status, and age were independent predictors of reduced overall survival, whereas only BM status, International Federation of Gynecology and Obstetrics stage, and resection status independently predicted progression-free survival. Conclusions: Tumor cell dissemination into the BM is a common phenomenon in ovarian cancer. Disseminated tumor cell detection has the potential to become an important biomarker for prognostication and disease monitoring in patients with ovarian cancer

Extracellular matrix components HAPLN1, lumican, and collagen I cause hyaluronic acid-dependent folding of the developing human Neocortex

Neocortical expansion, thought to underlie the cognitive traits unique to humans, is accompanied by cortical folding. This folding starts around gestational week (GW) 20, but what causes it remains largely unknown. Extracellular matrix (ECM) has been previously implicated in neocortical expansion and here we investigate the potential role of ECM in the formation of neocortical folds. We focus on three specific ECM components localized in the human fetal cortical plate (CP): hyaluronan and proteoglycan link protein 1 (HAPLN1), lumican and collagen I (collectively, HLC). Addition of HLC to cultures of human fetal neocortex (11–22 GW) caused local changes in tissue stiffness, induced CP folding, increased CP hyaluronic acid (HA), and required the HA-receptor CD168 and downstream ERK signaling. Importantly, loss of HA reduced HLC-induced and 22 GW physiological nascent folds. This was altered in samples with neurodevelopmental disorders, indicating it may be a useful system to study such disorders

European Society of Gynaecological Oncology quality indicators for surgical treatment of cervical cancer

Background: optimizing and ensuring the quality of surgical care is essential to improve the management and outcome of patients with cervical cancer.To develop a list of quality indicators for surgical treatment of cervical cancer that can be used to audit and improve clinical practice. Methods: quality indicators were developed using a four-step evaluation process that included a systematic literature search to identify potential quality indicators, in-person meetings of an ad hoc group of international experts, an internal validation process, and external review by a large panel of European clinicians and patient representatives. Results: fifteen structural, process, and outcome indicators were selected. Using a structured format, each quality indicator has a description specifying what the indicator is measuring. Measurability specifications are also detailed to define how the indicator will be measured in practice. Each indicator has a target which gives practitioners and health administrators a quantitative basis for improving care and organizational processes. Discussion: implementation of institutional quality assurance programs can improve quality of care, even in high-volume centers. This set of quality indicators from the European Society of Gynaecological Cancer may be a major instrument to improve the quality of surgical treatment of cervical cancer

Pooled Analysis of the Prognostic Relevance of Disseminated Tumor Cells in the Bone Marrow of Patients With Ovarian Cancer

Objective: Detection of disseminated tumor cells (DTCs) in the bone marrow (BM) of patients with breast cancer is associated with poor outcomes. Recent studies demonstrated that DTCs may serve as a prognostic factor in ovarian cancer. The aim of this 3-center study was to evaluate the impact of BM status on survival in a large cohort of patients with ovarian cancer. Materials and Methods: Four hundred ninety-five patients with primary ovarian cancer were included in this 3-center prospective study. Bone marrow aspirates were collected intraoperatively from the iliac crest. Disseminated tumor cells were identified by antibody staining and by cytomorphology. Clinical outcome was correlated with the presence of DTCs. Results: Disseminated tumor cells were detected in 27% of all BM aspirates. The number of cytokeratin-positive cells ranged from 1 to 42 per 2 x 10(6) mononuclear cells. Disseminated tumor cell status did correlate with histologic subtype but not with any of the other established clinicopathologic factors. The overall survival was significantly shorter among DTC-positive patients compared to DTC-negative patients (51 months; 95% confidence interval, 37-65 months vs 33 months; 95% confidence interval, 23-43 months; P = 0.023). In the multivariate analysis, BM status, International Federation of Gynecology and Obstetrics stage, nodal status, resection status, and age were independent predictors of reduced overall survival, whereas only BM status, International Federation of Gynecology and Obstetrics stage, and resection status independently predicted progression-free survival. Conclusions: Tumor cell dissemination into the BM is a common phenomenon in ovarian cancer. Disseminated tumor cell detection has the potential to become an important biomarker for prognostication and disease monitoring in patients with ovarian cancer

Rates of severe complications in patients undergoing colorectal surgery for deep endometriosis-a retrospective multicenter observational study.

INTRODUCTION Surgical experience and hospital procedure volumes have been associated with the risk of severe complications in expert centers for endometriosis in France. However, little is known about other certified units in Central European countries. MATERIAL AND METHODS This retrospective observational study included 937 women who underwent surgery for colorectal endometriosis between January 2018 and January 2020 in 19 participating expert centers for endometriosis. All women underwent complete excision of colorectal endometriosis by rectal shaving, discoid or segmental resection. Postoperative severe complications were defined as grades III-IV of the Clavien-Dindo classification system including anastomotic leakage, fistula, pelvic abscess and hematoma. Surgical outcomes of centers performing less than 40 (group 1), 40-59 (group 2) and ≥60 procedures (group 3) over a period of 2 years were compared. RESULTS The overall complication rate of grade III and IV complications was 5.1% (48/937), with rates of anastomotic leakage, fistula formation, abscess and hemorrhage in segmental resection, discoid resection and rectal shaving, respectively, as follows: anastomotic leakage 3.6% (14/387), 1.4% (3/222), 0.6% (2/328); fistula formation 1.6% (6/387), 0.5% (1/222), 0.9%; (3/328); abscess 0.5% (2/387), 0% (0/222) and 0.6% (2/328); hemorrhage 2.1% (8/387), 0.9% (2/222) and 1.5% (5/328). Higher overall complication rates were observed for segmental resection (30/387, 7.8%) than for discoid (6/222, 2.7%, P = 0.015) or shaving procedures (12/328, 3.7%, P = 0.089). No significant correlation was observed between the number of procedures performed and overall complication rates (rSpearman  = -0.115; P = 0.639) with a high variability of complications in low-volume centers (group 1). However, an intergroup comparison revealed a significantly lower overall severe complication rate in group 3 than in group 2 (2.9% vs 6.9%; P = 0.017) without significant differences between other groups. CONCLUSIONS A high variability in complication rates does exist in centers with a low volume of activity. Major complications may decrease with an increase in the volume of activity but this effect cannot be generally applied to all institutions and settings

Longer metaphase and fewer chromosome segregation errors in modern human than Neanderthal brain development

Since the ancestors of modern humans separated from those of Neanderthals, around 100 amino acid substitutions spread to essentially all modern humans. The biological significance of these changes is largely unknown. Here, we examine all six such amino acid substitutions in three proteins known to have key roles in kinetochore function and chromosome segregation and to be highly expressed in the stem cells of the developing neocortex. When we introduce these modern human-specific substitutions in mice, three substitutions in two of these proteins, KIF18a and KNL1, cause metaphase prolongation and fewer chromosome segregation errors in apical progenitors of the developing neocortex. Conversely, the ancestral substitutions cause shorter metaphase length and more chromosome segregation errors in human brain organoids, similar to what we find in chimpanzee organoids. These results imply that the fidelity of chromosome segregation during neocortex development improved in modern humans after their divergence from Neanderthals

Overcoming PARP inhibitor resistance in ovarian cancer: what are the most promising strategies?

Purpose!#!Ovarian cancer is the most lethal gynaecological malignancy. Despite the introduction of bevacizumab, standard chemotherapy has remained largely unchanged and the vast majority of patients will relapse within the first two years of diagnosis. However, results from recent clinical trials demonstrating clinical benefits of PARP inhibitor treatment are rapidly changing therapeutic options for many patients with ovarian cancer.!##!Methods!#!Given the introduction of new therapeutic options in the treatment of ovarian cancer, we critically review key clinical trials, areas of scientific research and its clinical relevance.!##!Results!#!Most notably, patients with BRCA1/2 mutant ovarian cancer benefit from maintenance treatment with PARP inhibitors after (complete or partial) response to platinum-based chemotherapy. Here, we discuss the mechanism of PARP inhibition, multiple drug resistance mechanisms, including BRCA reverse mutations, altered PARP expression, changes in DNA repair pathways, kinase activation and additional drug targets that may augment PARP inhibition.!##!Conclusion!#!Although the use of PARP inhibitors is a huge step forward, it is apparent that patients, both with and without BRCA-mutant ovarian cancer, will eventually become resistant to PARP inhibitors. Therefore, novel combination therapies may enhance PARP inhibitor efficacy and overcome resistance mechanisms