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A superenhancer at the retinoic acid receptor alpha (RARA) gene is associated with RARA mRNA overexpression in ∼30% of non-acute promyelocytic leukemia acute myeloid leukemia (AML) and in ∼50% of myelodysplastic syndromes (MDS). RARA overexpression is an actionable target for treatment with tamibarotene, an oral potent and selective RARα agonist. Sensitivity to the RARα agonist tamibarotene was demonstrated in RARA-high but not RARA-low preclinical AML models. The combination of oral tamibarotene plus azacitidine was evaluated in a phase 2 clinical study in 51 newly diagnosed unfit patients with AML identified as RARA-positive (n = 22) or RARA-negative (n = 29) for RARA mRNA overexpression in peripheral blasts using a blood-based biomarker test. In 18 response-evaluable RARA-positive patients, complete remission (CR)/CR with incomplete hematologic recovery rate was 61%, CR rate was 50%, and time to initial composite CR was rapid at 1.2 months. Transfusion independence was attained by 72% of RARA-positive patients. In contrast, 28 response-evaluable RARA-negative patients had response rates that were consistent with azacitidine monotherapy. Tamibarotene in combination with azacitidine was well tolerated. The majority of nonhematologic adverse events were low grade and hematologic adverse events were comparable to single-agent azacitidine, demonstrating that there was no additional myelosuppression when tamibarotene was combined with azacitidine. These results support further evaluation of tamibarotene-based treatment strategies in patients with AML or MDS with RARA overexpression to provide a targeted approach with the goal of improving patient outcomes. This trial was registered at www.clinicaltrials.gov as #NCT02807558.

“Placenta Accreta Spectrum” (PAS) is a rare but serious pregnancy condition where the placenta abnormally adheres to the uterine wall and fails to spontaneously release after delivery. When it occurs, PAS is associated with high maternal morbidity and mortality — as PAS management can be particularly challenging. This two-part review summarizes current evidence in PAS management, identifies its most challenging aspects, and offers evidence-based recommendations to improve management strategies and PAS outcomes. The first part of this two-part review highlighted the general anesthetic approach, surgical and interventional management strategies, specialized “centers of excellence,” and multidisciplinary PAS treatment teams. The high rates of PAS morbidity and mortality are often provoked by PAS-associated coagulopathies and peripartal hemorrhage (PPH). Anesthesiologists need to be prepared for massive blood loss, transfusion, and to manage potential coagulopathies. In this second part of this two-part review, we specifically reviewed the current literature pertaining to hemostatic changes, blood loss, transfusion management, and postpartum venous thromboembolism prophylaxis in PAS patients. Taken together, the two parts of this review provide a comprehensive survey of challenging aspects in PAS management for anesthesiologists.

Objectives Postpartum hemorrhage (PPH) is still one of the leading causes of maternal mortality worldwide. Recently effective PPH therapy with uterine packing with the chitosan-covered gauze was shown. This databased retrospective case–control study compares the therapy success of the chitosan tamponade with that of the balloon tamponade and medical therapy only. Methods All women who delivered at a university hospital between May 2016 and May 2019 with PPH were included. Based on the applied therapy, women were divided into three groups: medical therapy only, balloon tamponade and chitosan tamponade. The groups were compared in terms of therapy success, side-effects and reasons for PPH. Primary outcome was the need for surgical/radiological measures including hysterectomy, secondary outcomes were differences in hemoglobin levels, duration of inpatient stay, admission to intensive care unit, number of administered blood products and inflammation parameters. Results A total of 666 women were included in the study. 530 received medical therapy only, 51 the balloon tamponade and 85 the chitosan tamponade. There were no significant differences in the need for surgical therapy, but a significantly lower number of hysterectomies in the chitosan tamponade group than in the balloon tamponade group. There were no relevant differences in secondary outcomes and no adverse events related to the chitosan tamponade. Since the introduction of chitosan tamponade, the number of PPH related hysterectomies dropped significantly by 77.8%. Conclusions The chitosan tamponade is a promising treatment option for PPH. It reduces the postpartum hysterectomy rate without increased side effects compared to the balloon tamponade.

Olutasidenib (FT-2102) is a potent, selective, oral, small-molecule inhibitor of mutant isocitrate dehydrogenase 1 (mIDH1). Overall, 153 IDH-1 inhibitor naïve patients with mIDH1R132 relapsed/refractory (R/R) acute myeloid leukemia (AML) received olutasidenib monotherapy 150 mg twice daily in the pivotal cohort of this study. Median age (range) was 71 years (32-87) and the median number of prior regimens was 2 (1-7). The rate of complete remission (CR) plus complete remission with partial hematologic recovery (CRh) was 35% (n=51; 95% CI, 27.0-43.0) and the overall response rate was 48% (n=71; 95% CI, 40.0-56.7). Response rates were similar in patients who had and who had not received prior venetoclax. With 55% of patients censored at the time of data cut-off, median duration of CR/CRh was 25.9 months (95% CI, 13.5-NE). Median duration of overall response was 11.7 months (95% CI, 6.9-25.9). Median overall survival was 11.6 months (95% CI, 8.9-15.5). Of 86 patients who were transfusion-dependent at baseline, a 56-day transfusion independence was achieved in 29 (34%), including patients in all response groups. Grade 3/4 treatment-emergent adverse events (≥10%) were febrile neutropenia and anemia (n=31; 20% each), thrombocytopenia (n=25; 16%), and neutropenia (n=20; 13%). Differentiation syndrome adverse events of special interest occurred in 22 (14%) patients, with 14 (9%) grade ≥3 and 1 fatal case reported. Overall, olutasidenib induced durable remissions and transfusion independence with a well-characterized and manageable side-effect profile. The observed efficacy represents a therapeutic advance in this molecularly defined, poor-prognosis patient population with mIDH1 R/R AML. This trial is registered at www.clinicaltrials.gov as NCT02719574.

© 2023 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited., Summary of recommendations Corticosteroids should be administered to women at a gestational age between 24+0 and 33+6 weeks, when preterm birth is anticipated in the next seven days, as these have been consistently shown to reduce neonatal mortality and morbidity. (Strong-quality evidence; strong recommendation). In selected cases, extension of this period up to 34+6 weeks may be considered (Expert opinion). Optimal benefits are found in infants delivered within 7 days of corticosteroid administration. Even a single-dose administration should be given to women with imminent preterm birth, as this is likely to improve neurodevelopmental outcome (Moderate-quality evidence; conditional recommendation). Either betamethasone (12 mg administered intramuscularly twice, 24-hours apart) or dexamethasone (6 mg administered intramuscularly in four doses, 12-hours apart, or 12 mg administered intramuscularly twice, 24-hours apart), may be used (Moderate-quality evidence; Strong recommendation). Administration of two “all” doses is named a “course of corticosteroids”. Administration between 22+0 and 23+6 weeks should be considered when preterm birth is anticipated in the next seven days and active newborn life-support is indicated, taking into account parental wishes. Clear survival benefit has been observed in these cases, but the impact on short-term neurological and respiratory function, as well as long-term neurodevelopmental outcome is still unclear (Low/moderate-quality evidence; Weak recommendation). Administration between 34 + 0 and 34 + 6 weeks should only be offered to a few selected cases (Expert opinion). Administration between 35+0 and 36+6 weeks should be restricted to prospective randomized trials. Current evidence suggests that although corticosteroids reduce the incidence of transient tachypnea of the newborn, they do not affect the incidence of respiratory distress syndrome, and they increase neonatal hypoglycemia. Long-term safety data are lacking (Moderate quality evidence; Conditional recommendation). Administration in pregnancies beyond 37+0 weeks is not indicated, even for scheduled cesarean delivery, as current evidence does not suggest benefit and the long-term effects remain unknown (Low-quality evidence; Conditional recommendation). Administration should be given in twin pregnancies, with the same indication and doses as for singletons. However, existing evidence suggests that it should be reserved for pregnancies at high-risk of delivering within a 7-day interval (Low-quality evidence; Conditional recommendation). Maternal diabetes mellitus is not a contraindication to the use of antenatal corticosteroids (Moderate quality evidence; Strong recommendation). A single repeat course of corticosteroids can be considered in pregnancies at less than 34+0 weeks gestation, if the previous course was completed more than seven days earlier, and there is a renewed risk of imminent delivery (Low-quality evidence; Conditional recommendation).

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Pregnancy requires maternal adaptations to support fetal growth: whether these adaptations include temporal shifts in the gut microbiome is still unclear. We investigated the maternal gut microbiome longitudinally over the course of pregnancy and the impact of pre-pregnancy BMI (pBMI) and GWG. We also determined whether parity modulated observed associations. We show that the gut microbiota of participants with higher pBMI changed less over the course of pregnancy in primiparous, but not multiparous participants. This suggests that previous pregnancies may have persistent impacts on maternal adaptations to pregnancy. This ecological memory appears to be passed to the next generation, as parity modulated the impact of maternal GWG on the infant gut microbiome. This work supports a role for the gut microbiome in maternal adaptations to pregnancy and highlights the need for longitudinal sampling and accounting for parity as key considerations for studies of the microbiome in pregnancy and infants.

Objectives To analyze long-term effects of antenatal betamethasone (≤16 mg, =24 mg and >24 mg) in preterm twins on infant and childhood morbidity. Methods Retrospective cohort study among 198 preterm twins. Three follow up time points, including a total of 84 outcomes, were evaluated: first neonatal examination after birth and in the neonatal period up to 10 days after birth using data from the clinic charts; examination from the 21st to the 24th month of life and examination from the 60th to the 64th months, using data from copies of the children’s examination booklets sent back by the parents. Dosage-dependent and sex-specific long-term effects of antenatal betamethasone treatment on neonatal, infant and early childhood development and morbidity up to 5.3 years of age were analyzed. Results Dosage escalation of >24 mg was not associated with improved neonatal, infant or early child hood outcome, independent of twin pair structure. In contrast, higher doses >24 mg were significantly linked to increased rates of congenital infections (OR 5.867, 95% CI 1.895–18.167). Male sex as a factor was obvious for lower rates of apnea-bradycardia-syndrome in neonates, higher rates of no free steps after 15 months in infancy and highest rates of motor clumsiness in early childhood. Conclusions Betamethasone dosage escalation >24 mg in twins born between 23+5 and 33+6 weeks of gestation did not improve neonatal, infant or early childhood morbidity. In contrast, higher doses >24 mg total dose resulted in significantly higher rates of congenital infections and are not recommended. For males, 24 mg betamethasone appears to be the preferable dose.

Mouse models of chronic myeloid malignancies suggest that targeting mature cells of the malignant clone disrupts feedback loops that promote disease expansion. Here, we show that in chronic myelomonocytic leukemia (CMML), monocytes that accumulate in the peripheral blood show a decreased propensity to die by apoptosis. BH3 profiling demonstrates their addiction to myeloid cell leukemia-1 (MCL1), which can be targeted with the small molecule inhibitor S63845. RNA sequencing and DNA methylation pattern analysis both point to the implication of the mitogen-activated protein kinase (MAPK) pathway in the resistance of CMML monocytes to death and reveal an autocrine pathway in which the secreted cytokine-like protein 1 (CYTL1) promotes extracellular signal-regulated kinase (ERK) activation through C-C chemokine receptor type 2 (CCR2). Combined MAPK and MCL1 inhibition restores apoptosis of monocytes from patients with CMML and reduces the expansion of patient-derived xenografts in mice. These results show that the combined inhibition of MCL1 and MAPK is a promising approach to slow down CMML progression by inducing leukemic monocyte apoptosis.

VEXAS (vacuoles, E1 enzyme, X-LINKED, autoinflammatory, somatic) syndrome is a complex inflammatory disease associated with somatic mutations of the ubiquitin-like modifier activating enzyme 1 (UBA1) gene. A 75-year-old man with a medical history of thrombophlebitis, leukocytoclastic vasculitis, chronic inflammatory arthralgia, elevated inflammatory markers, and anemia was diagnosed with VEXAS syndrome. 18F-FDG PET/CT showed thoracic aortitis, a rare involvement during VEXAS syndrome. Corticosteroid therapy monitored with 18F-FDG PET/CT led to a complete metabolic response.

Objectives Histological examination of uterine scars provides insight into uterine wound healing and helps to develop prevention methods of uterine wall rupture after previous uterine surgery. Therefore, exact intraoperative scar identification is needed for specimen collection from the actual scar tissue. The aim of this study was to correlate pre- and intraoperative ultrasound measurements of the lower uterine segment (LUS) with histological findings of scar tissue and to evaluate the relevance of intraoperative ultrasound. Methods In a prospective observational study, preoperative and intraoperative sonographic measurements of the LUS thickness were performed in 33 women with a history of at least one cesarean delivery. Intraoperative ultrasound with a linear transducer placed directly on the uterus identified the scar area and uterotomy was performed 2 cm cranially. Tissue samples were taken after extraction of the fetus, embedded in paraffin wax, and stained according to Gomori Trichrome to identify scar tissue. Collagen content was evaluated with imaging software Fiji (NIH, Bethesda, USA). Preoperative and intraoperative sonographic measurements were correlated with histologic evidence of scar tissue. Results Histological evidence of scar tissue was found in 11 out of 33 samples with significantly lower ultrasonographic thickness of the lower uterine segment compared to the other 22 samples, both antepartum (1.4 mm [1.3–1.9] vs. 2.0 mm [1.6–2.6], p=0.03) and intrapartum (1.6 mm [1.3–1.9] vs. 3.7 mm [2.0–4.7], p Conclusions Intraoperative sonography identifies the uterine wall area with histologically confirmable scar tissue far better than preoperative sonography.

To design a simple and reproducible classifier predicting the overall survival (OS) of patients with acute myeloid leukemia (AML) ≥60 years of age treated with 7 + 3, we sequenced 37 genes in 471 patients from the ALFA1200 (Acute Leukemia French Association) study (median age, 68 years). Mutation patterns and OS differed between the 84 patients with poor-risk cytogenetics and the 387 patients with good (n = 13), intermediate (n = 339), or unmeasured (n = 35) cytogenetic risk. TP53 (hazards ratio [HR], 2.49; P = .0003) and KRAS (HR, 3.60; P = .001) mutations independently worsened the OS of patients with poor-risk cytogenetics. In those without poor-risk cytogenetics, NPM1 (HR, 0.57; P = .0004), FLT3 internal tandem duplications with low (HR, 1.85; P = .0005) or high (HR, 3.51; P < 10−4) allelic ratio, DNMT3A (HR, 1.86; P < 10−4), NRAS (HR, 1.54; P = .019), and ASXL1 (HR, 1.89; P = .0003) mutations independently predicted OS. Combining cytogenetic risk and mutations in these 7 genes, 39.1% of patients could be assigned to a “go-go” tier with a 2-year OS of 66.1%, 7.6% to the “no-go” group (2-year OS 2.8%), and 3.3% of to the “slow-go” group (2-year OS of 39.1%; P < 10−5). Across 3 independent validation cohorts, 31.2% to 37.7% and 11.2% to 13.5% of patients were assigned to the go-go and the no-go tiers, respectively, with significant differences in OS between tiers in all 3 trial cohorts (HDF [Hauts-de-France], n = 141, P = .003; and SAL [Study Alliance Leukemia], n = 46; AMLSG [AML Study Group], n = 223, both P < 10−5). The ALFA decision tool is a simple, robust, and discriminant prognostic model for AML patients ≥60 years of age treated with intensive chemotherapy. This model can instruct the design of trials comparing the 7 + 3 standard of care with less intensive regimens.

Microbial colonization of the human intestine impacts host metabolism and immunity; however, exactly when colonization occurs is unclear. Although many studies have reported bacterial DNA in first-pass meconium samples, these samples are typically collected hours to days after birth. Here, we investigated whether bacteria could be detected in meconium before birth. Fetal meconium (n = 20) was collected by rectal swab during elective breech caesarean deliveries without labour and before antibiotics and compared to technical and procedural controls (n = 5), first-pass meconium (neonatal meconium; n = 14) and infant stool (n = 25). Unlike first-pass meconium, no microbial signal distinct from negative controls was detected in fetal meconium by 16S ribosomal RNA gene sequencing. Additionally, positive aerobic (n = 10 of 20) and anaerobic (n = 12 of 20) clinical cultures of fetal meconium (13 of 20 samples positive in at least one culture) were identified as likely skin contaminants, most frequently Staphylococcus epidermidis, and not detected by sequencing in most samples (same genera detected by culture and sequencing in 2 of 13 samples with positive culture). We conclude that fetal gut colonization of healthy term infants does not occur before birth and that microbial profiles of neonatal meconium reflect populations acquired during and after birth. Fetal meconium does not have a detectable microbiota, as shown using 16S rRNA sequencing and culture of rectal swabs collected during elective breech caesarean sections without labour and before antibiotics, indicating that colonization occurs during and after birth.

Almost 10 years ago, clinicians at multiple locations all over Europe observed an increased number of antenatally undiagnosed cases of placenta accreta spectrum (PAS) resulting in significant morbidity and the occasional maternal death. Even with an improvement in antenatal imaging, the management of severe PAS remains challenging. One solution to improve understanding in rare but potentially lethal conditions is international collaboration. Consequently, a European working group was formed, which over the next few years grew into an international society, the IS-PAS. The collective goals are to develop a large shared database of cases, generate high-quality research into all aspects of PAS, and improve education of both healthcare professionals and patients. The first results of this collaboration are presented within this supplement. Non

Background: Due to their basal stress phenotype associated to transformation, cancer cells are addicted to non-mutated, non-oncogenic proteins that do not bear such vital functions in normal cells, a phenomenon referred as Non-Oncogenic Addiction (NOA). Targeting these NOAs could therefore induce selective killing of cancer cells, opening several therapeutic opportunities. Recent data suggest that the stress-related scaffold protein AAC-11 (anti-apoptosis clone 11, also known as Api5) is critically involved in cancer cells resistance to chemotherapies, metastatic potential and escape from the immune system. Methods: We have developed inactivating peptides based on the fusion of a cell penetrating sequence and portions of the leucine-zipper domain of AAC-11, which functions as a protein-protein interaction module. These peptides induce cancer cells death, through the inhibition of protein-protein interactions between AAC-11 and its partners, while sparing normal cells. We now describe further characterization of our lead peptide, JRT39, which contains residues 377 to 379 of AAC-11 linked to the cell-penetrating peptide “penetratin”. Results: In vitro, JRT39 causes cell death in a wide spectrum of cancer cell lines with IC50 ranging from 5 µM to 30 µM depending on tumor cell type. In particular, JRT39 showed selective efficacy towards primary cells from Acute Myeloid Leukemia (AML), Acute Lymphocytic Leukemia (ALL) or Sézary syndrome (SS) patients, while sparing normal hematopoietic cells, with an IC50 of 5-15 µM. Mechanistically, JRT39 induces membranolysis of cancer cells through binding to p21-activated kinase 1 (PAK1) in AML or SS cells plasma membrane, where PAK1 is overexpressed. In addition, JRT39 exerted potent anti-tumor activity in vivo in disseminated or subcutaneous AML, APL (Acute Promyelocytic Leukemia) and SS-patient derived preclinical murine models. Preliminary pharmacokinetic studies revealed that JRT39 is stable in human serum and has a plasma half-life of ~1.5-2.5 hours after intravenous (IV) administration to dogs or cynomolgus monkeys, with concentration-time data fitting 2-compartment model. Finally, JRT39 was well tolerated at 5 and 10 mg/kg after single or repeated (daily) IV injections. Conclusions: Combined, our preclinical data confirm that interfering with AAC-11-related survival pathways is a promising novel anticancer strategy and support the development of JRT39 for the treatment of cancer. Citation Format: Louise Jeammet, Emile Adicéam, Justine Habault, Anna Kaci, Jeannig Berrou, Mélanie Dupont, Nicolas Thonnart, Ewa Pasquereau-Kotula, Anne Marie-Cardine, Armand Bensussan, Marika Pla, Hervé Dombret, Claude Gardin, Martine Bagot, Jean-Christophe Rain, Hélène Sicard, Jérôme Tiollier, Thorsten Braun, Jean-Luc Poyet. AAC-11 survival pathways as therapeutic target in cancer: AAC-11 leucine-zipper domain derived peptides exert potent antitumor effects and exhibit favorable stability, pharmacokinetic and toxicology profiles [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 464.

“Placenta Accreta Spectrum” (PAS) describes abnormal placental adherence to the uterine wall without spontaneous separation at delivery. Though relatively rare, PAS presents a particular challenge to anesthesiologists, as it is associated with massive peripartum hemorrhage and high maternal morbidity and mortality. Standardized evidence-based PAS management strategies are currently evolving and emphasize: “PAS centers of excellence”, multidisciplinary teams, novel diagnostics/pharmaceuticals (especially regarding hemostasis, hemostatic agents, point-of-care diagnostics), and novel operative/interventional approaches (expectant management, balloon occlusion, embolization). Though available data are heterogeneous, these developments affect anesthetic management and must be considered in planed anesthetic approaches. This two-part review provides a critical overview of the current evidence and offers structured evidence-based recommendations to help anesthesiologists improve outcomes for women with PAS. This first part discusses PAS management in centers of excellence, multidisciplinary care team, anesthetic approach and monitoring, surgical approaches, patient safety checklists, temperature management, interventional radiology, postoperative care and pain therapy. The diagnosis and treatment of hemostatic disturbances and preoperative prepartum anemia, blood loss, transfusion management and postpartum venous thromboembolism will be addressed in the second part of this series.

By querying metabolic pathways associated with leukemic stemness and survival in multiple AML datasets, we nominated SLC7A11 encoding the xCT cystine importer as a putative AML dependency. Genetic and chemical inhibition of SLC7A11 impaired the viability and clonogenic capacity of AML cell lines in a cysteine-dependent manner. Sulfasalazine, a broadly available drug with xCT inhibitory activity, had anti-leukemic activity against primary AML samples in ex vivo cultures. Multiple metabolic pathways were impacted upon xCT inhibition, resulting in depletion of glutathione pools in leukemic cells and oxidative stress-dependent cell death, only in part through ferroptosis. Higher expression of cysteine metabolism genes and greater cystine dependency was noted in NPM1-mutated AMLs. Among eight anti-leukemic drugs, the anthracycline daunorubicin was identified as the top synergistic agent in combination with sulfasalazine in vitro. Addition of sulfasalazine at a clinically relevant concentration significantly augmented the anti-leukemic activity of a daunorubicin-cytarabine combination in a panel of 45 primary samples enriched in NPM1-mutated AML. These results were confirmed in vivo in a patient-derived xenograft model. Collectively, our results nominate cystine import as a druggable target in AML and raise the possibility to repurpose sulfasalazine for the treatment of AML, notably in combination with chemotherapy.

Isocitrate dehydrogenase 1 (IDH1) and 2 (IDH2) mutations in Myeloid Neoplams (MNs) exhibit DNA hypermethylation via 2-hydroxyglutarate (2HG) over-production. Clinical impact of azacitidine (AZA) re...

Fetale Pragung beschreibt den Zusammenhang zwischen dem Einfluss exogener und endogener Faktoren in sensiblen Phasen der Fetalentwicklung und dem Zellwachstum und der Organentwicklung, letztendlich mit dem Resultat einer anhaltenden postnatalen Veranderung in Organ- und Gewebsfunktionen. Hierbei kann eine Fehlanpassung mit dem Auftreten von Erkrankungen im gesamten spateren Leben assoziiert sein. Suboptimale intrauterine Bedingungen, wie etwa maternale Fehlernahrung, Hypoxie, psychischer Stress oder aber die GC(Glukokortikoid)-Exposition, konnen die fetale Entwicklung nachhaltig beeinflussen und sind haufig mit einer Verringerung des Geburtsgewichts assoziiert. Das mogliche Spektrum der Spatfolgen ist hierbei weit gefachert. Die antenatale Behandlung mit GC scheint mit einer geschlechtsspezifischen fetalen Wachstumsrestriktion sowie strukturellen und funktionellen Veranderungen in der Plazenta assoziiert zu sein, die potenziell die Gesundheit im spateren Leben beeinflussen konnen. Wahrend bei den weiblichen Feten eine eher kontinuierliche Sensibilitat gegenuber GC zu bestehen scheint, moglicherweise im Sinne einer praferentiellen Uberlebensstrategie zur Sicherung der Reproduktionsfahigkeit mit Spezieserhalt, scheint bei mannlichen Feten nach GC-Exposition die Plazenta zumindest temporar eine Resistenz gegenuber GC zu entwickeln. Die geschlechtsspezifische Sensibilitat gegenuber GC wird vermutlich durch ein unterschiedliches GR(GC-Rezeptoren)-Verteilungsmuster, Expression und/oder Interaktion verursacht und durch die Behandlung mit GC beeinflusst. Ein verbessertes Verstandnis fur die plazentavermittelten Signalwege, die zur fetalen Programmierung beitragen, wird von entscheidender Bedeutung bei den Bemuhungen sein, interventionelle Strategien fur Risikogruppen zu entwickeln.

International audience; In order to improve the outcome observed with azacitidine (AZA) in higher-risk Myelodysplastic syndrome (MDS), its combination with other drugs in MDS must be evaluated. So far, no combination has not been shown to be more effective than AZA alone. AZA-PLUS was a phase II trial that, in a "pick a winner" approach, randomly assigned patients with higher-risk MDS, CMML and low blast count AML to: AZA; AZA plus lenalidomide; AZA plus Valproic Acid or AZA plus Idarubicin. 322 patients were included. After six\,cycles, 69 (21.4%) CR\,+\,PR were observed with no benefit from any combination. Median EFS and OS were 17.2 and 19.7\,months in the whole cohort, respectively, with no difference across randomised arms. Infection and rates of hospitalisation during the first six\,cycles were higher in the AZA-LEN And AZA-IDA arm, related to increased myelosuppression. Factors associated with better response were IPSS, favourable or intermediate karyotype, haemoglobin, lower circulating blast count, fibrinogen level and lower LDH, while poorer survival was seen in therapy-related MDS and, in the case of TP53, PTPN11 or CSF3R mutation. The combinations used did not improve the outcome obtained with AZA alone. However, our "pick a winner" randomised strategy may remain useful with potentially more active drugs to be tested in combination with AZA.

The placenta is a central organ during early development, influencing trajectories of health and disease. DNA methylation (DNAm) studies of human placenta improve our understanding of how its function relates to disease risk. However, DNAm studies can be biased by cell type heterogeneity, so it is essential to control for this in order to reduce confounding and increase precision. Computational cell type deconvolution approaches have proven to be very useful for this purpose. For human placenta, however, an assessment of the performance of these estimation methods is still lacking. Here, we examine the performance of a newly available reference-based cell type estimation approach and compare it to an often-used reference-free cell type estimation approach, namely RefFreeEWAS, in placental genome-wide DNAm samples taken at birth and from chorionic villus biopsies early in pregnancy using three independent studies comprising over 1000 samples. We found both reference-free and reference-based estimated cell type proportions to have predictive value for DNAm, however, reference-based cell type estimation outperformed reference-free estimation for the majority of data sets. Reference-based cell type estimations mirror previous histological knowledge on changes in cell type proportions through gestation. Further, CpGs whose variation in DNAm was largely explained by reference-based estimated cell type proportions were in the proximity of genes that are highly tissue-specific for placenta. This was not the case for reference-free estimated cell type proportions. We provide a list of these CpGs as a resource to help researchers to interpret results of existing studies and improve future DNAm studies of human placenta.

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare and aggressive leukemia for which we developed a nationwide network to collect data from new cases diagnosed in France. In a retrospective, observational study of 86 patients (2000-2013), we described clinical and biological data focusing on morphologies and immunophenotype. We found expression of markers associated with plasmacytoid dendritic cell origin (HLA-DRhigh, CD303+, CD304+, and cTCL1+) plus CD4 and CD56 and frequent expression of isolated markers from the myeloid, B-, and T-lymphoid lineages, whereas specific markers (myeloperoxidase, CD14, cCD3, CD19, and cCD22) were not expressed. Fifty-one percent of cytogenetic abnormalities impact chromosomes 13, 12, 9, and 15. Myelemia was associated with an adverse prognosis. We categorized chemotherapeutic regimens into 5 groups: acute myeloid leukemia (AML)–like, acute lymphoid leukemia (ALL)–like, lymphoma (cyclophosphamide, doxorubicin, vincristine, and prednisone [CHOP])–like, high-dose methotrexate with asparaginase (Aspa-MTX) chemotherapies, and not otherwise specified (NOS) treatments. Thirty patients received allogeneic hematopoietic cell transplantation (allo-HCT), and 4 patients received autologous hematopoietic cell transplantation. There was no difference in survival between patients receiving AML-like, ALL-like, or Aspa-MTX regimens; survival was longer in patients who received AML-like, ALL-like, or Aspa-MTX regimens than in those who received CHOP-like regimens or NOS. Eleven patients are in persistent complete remission after allo-HCT with a median survival of 49 months vs 8 for other patients. Our series confirms a high response rate with a lower toxicity profile with the Aspa-MTX regimen, offering the best chance of access to hematopoietic cell transplantation and a possible cure.