Sex differences in DNA methylation across gestation: a large scale, cross-cohort, multi-tissue analysis.

Biological sex is a key variable influencing many physiological systems. Disease prevalence as well as treatment success can be modified by sex. Differences emerge already early in life and include pregnancy complications and adverse birth outcomes. The placenta is a critical organ for fetal development and shows sex-based differences in the expression of hormones and cytokines. Epigenetic regulation, such as DNA methylation (DNAm), may underlie the previously reported placental sexual dimorphism. We associated placental DNAm with fetal sex in three cohorts. Individual cohort results were meta-analyzed with random-effects modelling. CpG-sites differentially methylated with sex were further investigated regarding pathway enrichment, overlap with methylation quantitative trait loci (meQTLs), and hits from phenome-wide association studies (PheWAS). We evaluated the consistency of findings across tissues (CVS, i.e. chorionic villus sampling from early placenta, and cord blood) as well as with gene expression. We identified 10,320 epigenome-wide significant sex-differentially methylated probes (DMPs) spread throughout the epigenome of the placenta at birth. Most DMPs presented with lower DNAm levels in females. DMPs mapped to genes upregulated in brain, were enriched for neurodevelopmental pathways and significantly overlapped with meQTLs and PheWAS hits. Effect sizes were moderately correlated between CVS and placenta at birth, but only weakly correlated between birth placenta and cord blood. Sex differential gene expression in birth placenta was less pronounced and implicated genetic regions only marginally overlapped with those associated with differential DNAm. Our study provides an integrative perspective on sex-differential DNAm in perinatal tissues underscoring the possible link between placenta and brain.

Uterine packing with chitosan-covered tamponade to treat postpartum hemorrhage.

Postpartum hemorrhage remains a major cause of maternal mortality and morbidity worldwide with higher rates found in resource-challenged countries. Conventional use of uterotonics such as oxytocin, prostaglandins, and medications to support coagulation, such as fibrinogen and tranexamic acid, are helpful but may not be sufficient to arrest life-threatening postpartum hemorrhage. Severe postpartum hemorrhage leads to an increased need for blood transfusions and the use of invasive techniques, such as intrauterine balloon tamponade, compression sutures, and arterial ligation, as advanced steps in the management cascade. In extreme cases where hemorrhage is resistant to these therapies, a hysterectomy may be necessary to avoid possible maternal death. Uterine packing with a chitosan-covered tamponade is an emerging tool in the armamentarium of the obstetrical team, especially when resources for advance surgical and other invasive options may be limited. Modified chitosan-impregnated gauze was originally described in the management of acute hemorrhage in the field of military medicine, combining the physiological antihemorrhaging effect of modified chitosan with a compression tamponade for the acute treatment of wound bleeding. The first described use in obstetrics was in 2012, showing that the chitosan-covered tamponade is an effective intervention to arrest ongoing therapy-resistant postpartum hemorrhage. Further studies showed a reduction in hysterectomies and blood transfusions. The method is, however, underreported and is not yet an established method used worldwide. To demonstrate the step-by-step application of the intrauterine chitosan-covered tamponade in the management of therapy-resistant postpartum hemorrhage, we have produced a teaching video to illustrate the important steps and techniques to optimize the effectiveness and safety of this novel intervention.

Involvement of the JAK-STAT pathway in the molecular landscape of tyrosine kinase fusion-negative hypereosinophilic syndromes: A nationwide CEREO study.

We investigated using a custom NGS panel of 149 genes the mutational landscape of 64 consecutive adult patients with tyrosine kinase fusion-negative hypereosinophilia (HE)/hypereosinophilic syndrome (HES) harboring features suggestive of myeloid neoplasm. At least one mutation was reported in 50/64 (78%) patients (compared to 8/44 (18%) patients with idiopathic HE/HES/HEUS used as controls; p < .001). Thirty-five patients (54%) had at least one mutation involving the JAK-STAT pathway, including STAT5B (n = 18, among which the hotspot N642H, n = 13), JAK1 (indels in exon 13, n = 5; V658F/L, n = 2), and JAK2 (V617F, n = 6; indels in exon 13, n = 2). Other previously undescribed somatic mutations were also found in JAK2, JAK1, STAT5B, and STAT5A, including three patients who shared the same STAT5A V707fs mutation and features consistent with primary polycythemia. Nearly all JAK-STAT mutations were preceded by (or associated with) myelodysplasia-related gene mutations, especially in RNA-splicing genes or chromatin modifiers. In multivariate analysis, neurologic involvement (hazard ratio [HR] 4.95 [1.87-13.13]; p = .001), anemia (HR 5.50 [2.24-13.49]; p < .001), and the presence of a high-risk mutation (as per the molecular international prognosis scoring system: HR 6.87 [2.39-19.72]; p < .001) were independently associated with impaired overall survival. While corticosteroids were ineffective in all treated JAK-STAT-mutated patients, ruxolitinib showed positive hematological responses including in STAT5A-mutated patients. These findings emphasize the usefulness of NGS for the workup of tyrosine kinase fusion-negative HE/HES patients and support the use of JAK inhibitors in this setting. Updated classifications could consider patients with JAK-STAT mutations and eosinophilia as a new "gene mutated-entity" that could be differentiated from CEL, NOS, and idiopathic HES.

Prevalence of fetal anomalies, stillbirth, neonatal morbidity, or mortality in pregnancies complicated by placenta accreta spectrum disorders.

INTRODUCTION: Placenta accreta spectrum disorders (PAS) lead to major complications in pregnancy. While the maternal morbidity associated with PAS is well known, there is less information regarding neonatal morbidity in this setting. The aim of this study is to describe the neonatal outcomes (fetal malformations, neonatal morbidity, twin births, stillbirth, and neonatal death), using an international multicenter database of PAS cases. MATERIAL AND METHODS: This was a prospective, multicenter cohort study based on prospectively collected cases, using the international multicenter database of the International Society for PAS, carried out between January 2020 and June 2022 by 23 centers with experience in PAS care. All PAS cases were included, regardless of whether singleton or multiple pregnancies and were managed in each center according to their own protocols. Data were collected via chart review. Local Ethical Committee approval and Data Use Agreements were obtained according to local policies. RESULTS: There were 315 pregnancies eligible for inclusion, with 12 twin pregnancies, comprising 329 fetuses/newborns; 2 cases were excluded due to inconsistency of data regarding fetal abnormalities. For the calculation of neonatal morbidity and mortality, all elective pregnancy terminations were excluded, hence 311 pregnancies with 323 newborns were analyzed. In our cohort, 3 neonates (0.93%) were stillborn; of the 320 newborns delivered, there were 10 cases (3.13%) of neonatal death. The prevalence of major congenital malformations was 4.64% (15/323 newborns), most commonly, cardiovascular, central nervous system, and gastrointestinal tract malformations. The overall prevalence of major neonatal morbidity in pregnancies complicated by PAS was 47/311 (15.1%). There were no stillbirths, neonatal deaths, or fetal malformations in reported twin gestations. CONCLUSIONS: Although some outcomes may be too rare to detect within our cohort and data should be interpreted with caution, our observational data supports reassuring neonatal outcomes for women with PAS.

External validation of and improvement upon a model for the prediction of placenta accreta spectrum severity using prospectively collected multicenter ultrasound data.

INTRODUCTION: This study aimed to validate the Sargent risk stratification algorithm for the prediction of placenta accreta spectrum (PAS) severity using data collected from multiple centers and using the multicenter data to improve the model. MATERIAL AND METHODS: We conducted a multicenter analysis using data collected for the IS-PAS database. The Sargent model's effectiveness in distinguishing between abnormally adherent placenta (FIGO grade 1) and abnormally invasive placenta (FIGO grades 2 and 3) was evaluated. A new model was developed using multicenter data from the IS-PAS database. RESULTS: The database included 315 cases of suspected PAS, of which 226 had fully documented standardized ultrasound signs. The final diagnosis was normal placentation in 5, abnormally adherent placenta/FIGO grade 1 in 43, and abnormally invasive placenta/FIGO grades 2 and 3 in 178. The external validation of the Sargent model revealed moderate predictive accuracy in a multicenter setting (C-index 0.68), compared to its higher accuracy in a single-center context (C-index 0.90). The newly developed model achieved a C-index of 0.74. CONCLUSIONS: The study underscores the difficulty in developing universally applicable PAS prediction models. While models like that of Sargent et al. show promise, their reproducibility varies across settings, likely due to the interpretation of the ultrasound signs. The findings support the need for updating the current ultrasound descriptors and for the development of any new predictive models to use data collected by different operators in multiple clinical settings.

Opportunities for, and barriers to, uterus-preserving surgical techniques for placenta accreta spectrum.

INTRODUCTION: Placenta accreta spectrum (PAS) can lead to major peripartum morbidity. Appropriate management approaches depend on the clinical severity, each individual's preference, and the treating team's expertise. Peripartum hysterectomy is the most frequently used treatment option. However, it can impact psychological well-being and fertility. We investigated whether conservative treatment with focal resection or leaving the placenta in situ is associated with comparable or lower maternal morbidity than hysterectomy in centers of excellence within the International Society for placenta accreta spectrum (IS-PAS). Furthermore, a survey was conducted to explore potential barriers to conservative management in antenatal counseling and intraoperative decision-making. MATERIAL AND METHODS: Confirmed PAS cases in the prospective IS-PAS database from 22 registered centers between January 2020 and June 2022 were included in the analysis. A separate online survey with 21 questions was answered by the IS-PAS center experts about indications, diagnostic criteria, patient counseling, surgical practice, changes from the preoperative treatment plan, and why conservative management may not be offered. RESULTS: A total of 234 cases were included in the analysis: 186 women received hysterectomy and 38 women were treated by focal resection, and 10 by leaving the placenta in situ. Blood loss was lower in the focal resection group and in the placenta in situ group compared to the hysterectomy group (p = 0.04). 46.4% of the women initially planned for focal resection, and 35.7% of those initially planned for leaving the placenta in situ were ultimately treated by hysterectomy. Our survey showed that the IS-PAS centers preferred hysterectomy according to a woman's wishes (64%) and when they expected less blood loss and morbidity (41%). Eighteen percent of centers did not offer focal resection at all due to a lack of experience with this technique. Reasons for not offering to leave the placenta in situ were avoidance of unexpected reoperation (36%), puerperal infection (32%), or skepticism about the method (23%). CONCLUSIONS: Uterus-preserving treatment strategies such as focal resection appear to be safe alternatives to peripartum hysterectomy. However, less than half of the IS-PAS centers perform them. Acceptance of conservative treatments could be increased by standardized criteria for their implementation and by systematic training for PAS experts.

Trends in antenatal corticosteroid administration: did our timing improve?

OBJECTIVES: We aimed to analyze trends in the rate of effective antenatal corticosteroid prophylaxis (ACS) administrations across a spectrum of typical diagnoses associated with preterm birth. METHODS: In this retrospective study we utilized delivery data after ACS from 2014 to 2020 at Charité Berlin, Germany. We evaluated the rate of effective ACS administrations defined as ≤10 days between last dose of ACS and delivery as well as the rate of post-ACS births on/after 37 + 0 weeks. We explored conditions associated with high rates of ineffective ACS administrations (>10 days before delivery). We analyzed the trend of ACS-effectiveness during the study period in the overall cohort and in placental dysfunction and cervical insufficiency diagnoses. RESULTS: The overall rate of effective ACS administrations was 42 % (709/1,672). The overall percentage of deliveries after/at 37 + 0 weeks following ACS administration was 19 % (343). Placenta previa, twin pregnancy and isthmocervical insufficiency were associated with ineffective ACS (19-34 % effective i.e. ≤10 days before delivery). The overall ratio of effective ACS applications rose over time (p=0.002). Over the course of this study ACS effectiveness increased in placental dysfunction and isthmocervical insufficiency diagnoses (p=0.028; p=0.001). CONCLUSIONS: Compared to a previous publication we found a decrease of post-ACS deliveries after/at 37 + 0 weeks (19 vs. 27 %). Ineffective ACS administrations are still frequent in patients with placenta previa, twin pregnancy and isthmocervical insufficiency. It remains to be investigated in future trials if the introduction of new diagnostic tools such as soluble Fms-like tyrosinkinase-1/placental growth factor (sFlt-1/PlGF) testing and placental alpha-microglobulin-1 (PAMG-1) testing directly led to an increased ACS effectiveness.

Analysis of maternal mortality in Berlin, Germany - discrepancy between reported maternal mortality and comprehensive death certificate exploration.

OBJECTIVES: The Organisation for Economic Cooperation and Development (OECD) estimates an average maternal mortality rate (MMR) of around 3.4 maternal deaths per 100,000 live births for 2019-2021, based on relevant diagnoses on death certificates. However, Germany does not currently have a registry for recording the number of maternal deaths. The aim of this study is to identify the actual number of maternal deaths in Berlin between 2019 and 2022, as well as sources of underreporting and causes of death. METHODS: Potential maternal mortality cases were identified through a search at the Berlin Central Archive for Death Certificates, inquiring women aged 15-50 years with indications of present or recent pregnancy on the death certificate. To cross match the database, an additional search at the Charité University Hospital Berlin was carried out, checking each individual file for pregnancy-association. RESULTS: The data search resulted in 2,316 women, 18 of which presented an association to pregnancy. Of these, 12 could be classified as maternal mortality cases (MMR 7.8/100,000). The additional search in a university setting revealed two further maternal mortality cases without prior indication of pregnancy on the death certificate. This results in a total MMR of 9.1/100,000 live births, which is over double the official estimate by the OECD. CONCLUSIONS: Based on our findings in Berlin, it can be estimated that there is significant underreporting regarding maternal death cases in Germany. A more comprehensive recording system is needed to more accurately portray maternal mortality.

Venetoclax Combined with Intensive Chemotherapy: A New Hope for Refractory and/or Relapsed Acute Myeloid Leukemia?

Background. Primary resistance of acute myeloid leukemia (AML) to the conventional 3 + 7 intensive chemotherapy and relapses after first-line chemotherapy are two highly challenging clinical scenarios. In these cases, when allogeneic stem cell transplantation is feasible, patients are usually retreated with other chemotherapeutic regimens, as transplantation is still considered, nowadays, the only curative option. Methods. We discuss the mechanisms behind resistance to chemotherapy and offer a comprehensive review on current treatments of refractory/relapsed AML with a focus on novel approaches incorporating the BCL-2 inhibitor venetoclax. Results. Alas, complete remission rates after salvage chemotherapy remain relatively low, between 30 and 60% at best. More recently, the BCL-2 inhibitor venetoclax was combined either with hypomethylating agents or chemotherapy in refractory/relapsed patients. In particular, its combination with chemotherapy offered promising results by achieving higher rates of remission and bridging a substantial number of patients to transplantation. Conclusions. Venetoclax-based approaches might become, in the near future, the new standard of care for refractory/relapsed AML.

Short and long-term menstrual, reproductive, and mental health outcomes after the intrauterine use of chitosan tamponade or the Bakri balloon for severe postpartum hemorrhage: an observational study.

OBJECTIVE: This retrospective follow-up study analyzes the effect of intrauterine postpartum hemorrhage (PPH) therapy on menstrual, reproductive, and mental health outcomes. METHODS: All women who delivered at a university hospital between 2016 and 2021 with PPH and who needed intrauterine therapy were included. A questionnaire on well-being, menses, fertility, and reproductive outcomes was mailed to the patients. Those who did not reply were surveyed by telephone. RESULTS: A total of 214 women treated with chitosan-covered gauze (group A) and 46 women treated with a balloon tamponade (group B) were recruited, and their short-term courses were analyzed. For long-term follow-up, 71 women of group A (33%) and 21 women of group B (46%) could be reached. A total of 89% of group A and 95% of group B had regular menstrual bleeding in the most recent 12 months; 27% (group A) and 29% (group B) were trying to conceive again, and all of them did so successfully. There were 12 deliveries, 3 ongoing pregnancies, 3 miscarriages, and 2 terminations of pregnancies (TOP) in group A and 4 deliveries, 1 miscarriage, and 2 TOPs in group B. More than half of our study participants was sorted into grade II or III of the Impact of Events Scale, indicating they experienced clinical impacts in the form of psychological sequelae. One-quarter of patients had symptoms of post-traumatic stress disorder. CONCLUSION: Chitosan gauze as well as balloon tamponade appear to have few adverse effects on subsequent menstrual and reproductive function. Women after PPH are at increased risk of long-term adverse psychological outcomes.

Apoptosis Inhibitor 5: A Multifaceted Regulator of Cell Fate.

Apoptosis, or programmed cell death, is a fundamental process that maintains tissue homeostasis, eliminates damaged or infected cells, and plays a crucial role in various biological phenomena. The deregulation of apoptosis is involved in many human diseases, including cancer. One of the emerging players in the intricate regulatory network of apoptosis is apoptosis inhibitor 5 (API5), also called AAC-11 (anti-apoptosis clone 11) or FIF (fibroblast growth factor-2 interacting factor). While it may not have yet the same level of notoriety as some other cancer-associated proteins, API5 has garnered increasing attention in the cancer field in recent years, as elevated API5 levels are often associated with aggressive tumor behavior, resistance to therapy, and poor patient prognosis. This review aims to shed light on the multifaceted functions and regulatory mechanisms of API5 in cell fate decisions as well as its interest as therapeutic target in cancer.

Significance of Measurable Residual Disease in Adult Philadelphia Chromosome-Positive ALL: A GRAAPH-2014 Study.

PURPOSE: BCR::ABL1 quantification is widely regarded as the standard for monitoring measurable residual disease (MRD) in Philadelphia chromosome-positive (Ph+) ALL. However, recent evidence of BCR::ABL1 multilineage involvement questions the significance of BCR::ABL1 MRD. We aimed to define the prognostic role of MRD as assessed by BCR::ABL1 or lymphoid-specific immunoglobulin/T-cell receptor (IG/TR) gene markers. PATIENTS AND METHODS: We conducted BCR::ABL1 and IG/TR quantification after each treatment cycle in 264 patients treated in the GRAAPH-2014 trial, which used four cycles of reduced-intensity chemotherapy with nilotinib, followed by hematopoietic stem-cell transplantation (HSCT). RESULTS: Comparing BCR::ABL1 and IG/TR MRD revealed residual BCR::ABL1-positive non-ALL cells in 98 (43%) of 228 patients, defining multilineage Ph+ ALL. Despite poorer BCR::ABL1 responses, patients with multilineage Ph+ ALL had similar disease-free survival (DFS; hazard ratio [HR], 0.83 [95% CI, 0.49 to 1.41]; P = .50). Although BCR::ABL1 response failed to predict outcomes, IG/TR positivity (≥0.01%) was strongly associated with lower DFS (after cycle 2, HR, 2.49 [95% CI, 1.40 to 4.40]; P = .002; after cycle 4, HR, 4.13 [95% CI, 1.82 to 9.38]; P = .001). In multivariable analysis, both IG/TR positivity after cycle 2 and initial WBC count ≥30 × 109/L predicted poorer DFS, enabling to define a high-risk group having a 4-year DFS of 56.5% compared with 87.6% (HR, 3.72 [95% CI, 1.93 to 7.15]; P < .001). Moreover, allogeneic HSCT significantly improved DFS in the high-risk group (HR, 0.33 [95% CI, 0.18 to 0.60]; P < .001), whereas the standard-risk group had favorable outcomes regardless of allogeneic HSCT. CONCLUSION: Our findings challenge the significance of BCR::ABL1 monitoring in adult Ph+ ALL and demonstrate the prognostic role of IG/TR MRD. This study provides a framework for using MRD to guide treatment strategies in adults with Ph+ ALL.

Isatuximab, lenalidomide, dexamethasone and bortezomib in transplant-ineligible multiple myeloma: the randomized phase 3 BENEFIT trial.

CD38-targeting immunotherapy is approved in combination with lenalidomide and dexamethasone in patients with newly diagnosed multiple myeloma (NDMM) that are transplant ineligible (TI) and is considered the best standard of care (SOC). To improve current SOC, we evaluated the added value of weekly bortezomib (V) to isatuximab plus lenalidomide and dexamethasone (IsaRd versus Isa-VRd). This Intergroupe Francophone of Myeloma phase 3 study randomized 270 patients with NDMM that were TI, aged 65-79 years, to IsaRd versus Isa-VRd arms. The primary endpoint was a minimal residual disease (MRD) negativity rate at 10-5 by next-generation sequencing at 18 months from randomization. Key secondary endpoints included response rates, MRD assessment rates, survival and safety. The 18-month MRD negativity rates at 10-5 were reported in 35 patients (26%, 95% confidence interval (CI) 19-34) in IsaRd versus 71 (53%, 95% CI 44-61) in Isa-VRd (odds ratio for MRD negativity 3.16, 95% CI 1.89-5.28, P < 0.0001). The MRD benefit was consistent across subgroups at 10-5 and 10-6, and was already observed at month 12. The proportion of patients with complete response or better at 18 months was higher with Isa-VRd (58% versus 33%; P < 0.0001), as was the proportion of MRD negativity and complete response or better (37% versus 17%; P = 0.0003). At a median follow-up of 23.5 months, no difference was observed for survival times (immature data). The addition of weekly bortezomib did not significantly affect the relative dose intensity of IsaRd. Isa-VRd significantly increased MRD endpoints, including the 18-month negativity rate at 10-5, the primary endpoint, compared with IsaRd. This study proposes Isa-VRd as a new SOC for patients with NDMM that are TI. ClinicalTrials.gov identifier: NCT04751877 .