Publications by authors named "Thorsten Braun"

98 Publications

Dosage escalation of antenatal steroids in preterm twin pregnancies does not improve long-term outcome.

J Perinat Med 2021 Jul 13. Epub 2021 Jul 13.

Department of Obstetrics, Clinic of Obstetrics, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany.

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 and 33 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.
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http://dx.doi.org/10.1515/jpm-2020-0575DOI Listing
July 2021

Online survey on uterotomy closure techniques in caesarean section.

J Perinat Med 2021 Jul 7. Epub 2021 Jul 7.

Department of Obstetrics and Division of 'Experimental Obstetrics', Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health, Campus Virchow-Klinikum, Berlin, Germany.

Objectives: Uterine closure technique in caesarean section (CS) influences the rate of late complications in subsequent pregnancies. As no common recommendation on suture techniques exists, we developed a questionnaire to determine the techniques currently used and the frequencies of late complications.

Methods: The online questionnaire consisted of 13 questions and was sent to 648 obstetric hospitals (level I-IV) in Germany. Number of CS, rate of vaginal birth after caesarean section (VBAC), the type of uterus suturing technique and the frequency of uterine dehiscences, ruptures and placenta accreta spectrum (PAS) were queried. The answers were anonymous, and results were evaluated descriptively.

Results: The response rate was 24.7%. The mean CS rate was 27.3% (±6.2), the repeat CS rate 33.2% (±18.1). After CS, 46.2% (±20.2) women delivered vaginally. To close the uterotomy, 74.4% of hospitals used single layer continuous sutures, 16.3% single layer locked sutures, 3.8% interrupted sutures, 3.1% double layer continuous sutures and 2.5% used other suture techniques. The percentages of observed uterine dehiscences did not differ significantly between the different levels of care nor did the uterotomy suture techniques.

Conclusions: There is no uniform suturing technique in Germany. A detailed description of suture technique in surgery reports is required to evaluate complications in subsequent pregnancies. National online surveys on obstetric topics are feasible and facilitate the discussion on the need to define a standardized uterine closure technique for CS.
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http://dx.doi.org/10.1515/jpm-2021-0118DOI Listing
July 2021

Detection of Microplastic in Human Placenta and Meconium in a Clinical Setting.

Pharmaceutics 2021 Jun 22;13(7). Epub 2021 Jun 22.

Environment Agency Austria (Umweltbundesamt GmbH), 1090 Vienna, Austria.

Environmental pollution with microplastics (MPs) is a major and worldwide concern. Involuntary exposure to MPs by ingestion or inhalation is unavoidable. The effects on human health are still under debate, while in animals, cellular MP translocation and subsequent deleterious effects were shown. First reports indicate a potential intrauterine exposure with MPs, yet readouts are prone to contamination.

Method: To establish a thorough protocol for the detection of MPs in human placenta and fetal meconium in a real-life clinical setting, a pilot study was set up to screen for MPs > 50 µm in placental tissue and meconium sampled during two cesarean sections for breech deliveries. After chemical digestion of non-plastic material, Fourier-transform infrared (FTIR) microspectroscopy was used to analyze the presence of 10 common types of microplastic in placenta and stool samples.

Results: Human placenta and meconium samples were screened positive for polyethylene, polypropylene, polystyrene, and polyurethane, of which only the latter one was also detected as airborne fallout in the operating room-thus representing potential contamination.

Conclusion: We found MPs > 50 µm in placenta and meconium acquired from cesarean delivery. Critical evaluation of potential contamination sources is pivotal and may guide future clinical studies to improve the correct detection of MPs in organ tissue. Studies investigating nano-sized plastics in human tissue are warranted.
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http://dx.doi.org/10.3390/pharmaceutics13070921DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8308544PMC
June 2021

Never too late? Quadruplets at the age of 65 years.

Arch Gynecol Obstet 2021 Jun 19. Epub 2021 Jun 19.

Department of Obstetrics, Charité-Universitätsmedizin Berlin, 1335, 10117, Berlin, Germany.

Background: We discuss the challenges of multiple pregnancy at very advanced reproductive age.

Case Presentation: We present the case of a quadruplet pregnancy at the maternal age of 65 following in-vitro fertilization (IVF) with donor eggs and sperm, involving cross-border reproductive care. All children born were at 25 weeks' gestation and survived; however, poor neurodevelopmental outcome remains a major concern in one child.

Conclusions: The use of reproductive technology to achieve a multiple pregnancy at such an advanced post-menopausal age generated a debate on ethical, psychosocial and medical questions. We share this debate and highlight the need to reconsider international guidelines for women of advanced reproductive age.
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http://dx.doi.org/10.1007/s00404-021-06127-2DOI Listing
June 2021

The association between history of prenatal loss and maternal psychological state in a subsequent pregnancy: an ecological momentary assessment (EMA) study.

Psychol Med 2021 Jun 15:1-11. Epub 2021 Jun 15.

Institute of Medical Psychology, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin, Germany.

Background: Prenatal loss which occurs in approximately 20% of pregnancies represents a well-established risk factor for anxiety and affective disorders. In the current study, we examined whether a history of prenatal loss is associated with a subsequent pregnancy with maternal psychological state using ecological momentary assessment (EMA)-based measures of pregnancy-specific distress and mood in everyday life.

Method: This study was conducted in a cohort of N = 155 healthy pregnant women, of which N = 40 had a history of prenatal loss. An EMA protocol was used in early and late pregnancy to collect repeated measures of maternal stress and mood, on average eight times per day over a consecutive 4-day period. The association between a history of prenatal loss and psychological state was estimated using linear mixed models.

Results: Compared to women who had not experienced a prior prenatal loss, women with a history of prenatal loss reported higher levels of pregnancy-specific distress in early as well as late pregnancy and also were more nervous and tired. Furthermore, in the comparison group pregnancy-specific distress decreased and mood improved from early to late pregnancy, whereas these changes across pregnancy were not evident in women in the prenatal loss group.

Conclusion: Our findings suggest that prenatal loss in a prior pregnancy is associated with a subsequent pregnancy with significantly higher stress and impaired mood levels in everyday life across gestation. These findings have important implications for designing EMA-based ambulatory, personalized interventions to reduce stress during pregnancy in this high-risk group.
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http://dx.doi.org/10.1017/S0033291721002221DOI Listing
June 2021

Characteristics and outcome of patients with low-/intermediate-risk acute promyelocytic leukemia treated with arsenic trioxide - an international collaborative study.

Haematologica 2021 May 27. Epub 2021 May 27.

Gemeinschaftsklinikum Mittelrhein gGmbH, Koblenz.

The aim of this study was to characterize a large series of 154 patients with acute promyelocytic leukemia (APL; median age, 53 years; range, 18-90 years) and evaluate real-life outcome after up-front treatment with arsenic trioxide (ATO) and alltrans retinoic acid (ATRA). All patients were included in the prospective NAPOLEON registry (NCT02192619) between 2013 and 2019. APL was de novo in 91% (n=140) and therapy-related in 9% (n=14); 13% (n=20) were older than 70 years. At diagnosis bleeding/hemorrhage was present in 38% and thrombosis in 3%. Complete remission was achieved in 152 patients (99%), whereas two patients (1%) experienced induction death within 18 days after start of therapy. With a median follow-up of 1.99 years (95%-CI, 1.61-2.30 years) 1-year and 2-years overall survival (OS) rates were 97% (95%-CI, 94-100%) and 95% (95%-CI, 91-99%), respectively. Age above 70 years was associated with a significantly shorter OS (P<0.001) as compared to younger patients. So far no relapses were observed. Six patients (4%) died in CR after in median 0.95 years after diagnosis (range, 0.18-2.38 years). Our data confirm the efficiency and durability of ATO/ATRA in the primary management of adult low-/ intermediate-risk APL patients in the real life setting, irrespective of age.
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http://dx.doi.org/10.3324/haematol.2021.278722DOI Listing
May 2021

Genetic Identification of AML Patients Older than 60 years Achieving Long-term Survival with Intensive Chemotherapy.

Blood 2021 May 27. Epub 2021 May 27.

CHU Lille, INSERM, Lille, France.

To design a simple and reproducible classifier predicting the overall survival (OS) of AML patients ≥ 60 years old treated with 7+3, we sequenced 37 genes in 471 patients from the ALFA1200 study (NCT01966497, 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 unavailable (N=35) cytogenetic risk. TP53 (HR=2.49; P=0.0003) and KRAS (HR=3.60; P=0.001) mutations independently worsened OS of patients with poor-risk cytogenetics. In those without poor-risk cytogenetics, NPM1 (HR=0.57; P=0.0004), FLT3-ITDs with low (HR=1.85; P=0.0005) or high (HR=3.51; P<10-4) allelic ratio, DNMT3A (HR=1.86; P<10-4), NRAS (HR=1.54; P=0.019) and ASXL1 (HR=1.89; P=0.0003) 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%) while the 53.3% 'slow-go' patients had a 2-year OS of 39.1% (P<10-5). Across three independent validation cohorts, 31.2-37.7% and 11.2-13.5% of patients were assigned to the 'go-go' and the 'no-go' tiers respectively, with significant differences in OS between tiers in all 3 cohorts (HDF, N=141, P=0.003, SAL N=466 and AMLSG N=223, both P<10-5). The ALFA decision tool is a simple, robust and discriminant prognostic model for AML patients older than 60 years treated with intensive chemotherapy. This model can instruct the design of trials comparing the 7+3 standard of care with less intensive regimens.
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http://dx.doi.org/10.1182/blood.2021011103DOI Listing
May 2021

Fetal meconium does not have a detectable microbiota before birth.

Nat Microbiol 2021 Jul 10;6(7):865-873. Epub 2021 May 10.

Department of Obstetrics and Experimental Obstetrics, Charité-Universitätsmedizin Berlin, Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany.

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.
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http://dx.doi.org/10.1038/s41564-021-00904-0DOI Listing
July 2021

Prognostic significance of concurrent gene mutations in intensively treated patients with IDH-mutated AML: an ALFA study.

Blood 2021 May;137(20):2827-2837

Département d'Hématologie, Gustave Roussy, Université Paris-Saclay, Villejuif, France.

In patients with isocitrate dehydrogenase (IDH)-mutated acute myeloid leukemia (AML) treated by intensive chemotherapy (IC), prognostic significance of co-occurring genetic alterations and allogeneic hematopoietic stem cell transplantation (HSCT) are of particular interest with the advent of IDH1/2 mutant inhibitors. We retrospectively analyzed 319 patients with newly diagnosed AML (127 with IDH1, 135 with IDH2R140, and 57 with IDH2R172 mutations) treated with IC in 3 Acute Leukemia French Association prospective trials. In each IDH subgroup, we analyzed the prognostic impact of clinical and genetic covariates, and the role of HSCT. In patients with IDH1 mutations, the presence of NPM1 mutations was the only variable predicting improved overall survival (OS) in multivariate analysis (P < .0001). In IDH2R140-mutated AML, normal karyotype (P = .008) and NPM1 mutations (P = .01) predicted better OS. NPM1 mutations were associated with better disease-free survival (DFS; P = .0009), whereas the presence of DNMT3A mutations was associated with shorter DFS (P = .0006). In IDH2R172-mutated AML, platelet count was the only variable retained in the multivariate model for OS (P = .002). Among nonfavorable European LeukemiaNet 2010-eligible patients, 71 (36%) underwent HSCT in first complete remission (CR1) and had longer OS (P = .03) and DFS (P = .02) than nontransplanted patients. Future clinical trials testing frontline IDH inhibitors combined with IC may consider stratification on NPM1 mutational status, the primary prognostic factor in IDH1- or IDH2R140-mutated AML. HSCT improve OS of nonfavorable IDH1/2-mutated AML and should be fully integrated into the treatment strategy.
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http://dx.doi.org/10.1182/blood.2020010165DOI Listing
May 2021

Developing a database for multicenter evaluation of placenta accreta spectrum.

Acta Obstet Gynecol Scand 2021 03;100 Suppl 1:7-11

Department of Obstetrics and Gynecology, Fetomaternal Medical Center, Helsinki University Hospital and University of Helsinki, Finland.

Studies of rare, but complex clinical conditions require multicenter cooperation. The International Society for Placenta accreta spectrum (IS-PAS) have established a secure web-based database to analyze pregnancies complicated by PAS. By repeated in-person meetings of the IS-PAS, a core dataset was established. Then, a custom-made, secure online database, capable of receiving strictly anonymized patient-related textual and imaging data and allowing statistical queries was designed, tested, amended and implemented. Between 2008 and 2019, 14 IS-PAS centers across Europe and one center in the USA contributed data for all their PAS cases, containing pregnancy data for a total of 442 pregnant women. Data were analyzed by a designated data analysis sub-group of the IS-PAS. Center characteristics are presented. Based on experiences with previous versions, our new online database now allows an all-encompassing data collection. It has shown its usefulness in the current analysis project.
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http://dx.doi.org/10.1111/aogs.14085DOI Listing
March 2021

The relation between maternal obesity and placenta accreta spectrum: A multinational database study.

Acta Obstet Gynecol Scand 2021 03;100 Suppl 1:50-57

Department of Obstetrics and Gynaecology, Oxford University Hospitals NHS Foundation Trust, Oxford, UK.

Introduction: It has been suggested that women with obesity have increased risk of developing placenta accreta spectrum (PAS). It is unclear if this is independent of the increased risk of cesarean delivery seen with obesity itself. The aim of this study was to explore the association between maternal obesity and PAS, particularly severe PAS (percreta).

Material And Methods: This is a cohort study based on cases recorded in the International Society for Placenta Accreta Spectrum (IS-PAS) database between April 2008 and May 2019. Multivariable logistic regression was used to explore the effect of maternal obesity on severity of PAS; this model was adjusted for other known risk factors including previous cesarean deliveries, maternal age, and placenta previa. The estimated rate of obesity in a hypothetical cohort with similar characteristics (previous cesarean delivery and same parity) was calculated and compared with the observed rate of obesity in the women of the PAS cohort (one sample test of proportions).

Results: Of the 386 included women with PAS, 227 (58.8%) had severe disease (percreta). In univariable analysis, maternal obesity initially appeared to be associated with increased odds of developing the most severe type of PAS, percreta (odds ratio [OR] 1.87; 95% CI 1.14-3.09); however, this association was lost after adjustment for other risk factors including previous cesarean delivery (OR 1.44; 95% CI 0.85-2.44). There was no difference in the observed rate of obesity and the rate estimated based on the risk of cesarean delivery from obesity alone (31.3% vs 36.8%, respectively; P = .07).

Conclusions: Obesity does not seem to be an independent risk factor for PAS or severity for PAS. These findings are relevant for clinicians to provide accurate counseling to women with obesity regarding increased risks related to pregnancy.
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http://dx.doi.org/10.1111/aogs.14075DOI Listing
March 2021

When a rare condition creates a scientific society: The history of the International Society for Placenta Accreta Spectrum (IS-PAS).

Acta Obstet Gynecol Scand 2021 03;100 Suppl 1:3-6

Nuffield Department of Women's and Reproductive Health, University of Oxford, Oxford, UK.

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.
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http://dx.doi.org/10.1111/aogs.14077DOI Listing
March 2021

Performance of antenatal imaging to predict placenta accreta spectrum degree of severity.

Acta Obstet Gynecol Scand 2021 03;100 Suppl 1:21-28

Women's Division, Nancy Regional University Hospital (CHRU), Université de Lorraine, and Diagnosis and International Adaptive Imaging (IAD), Inserm, Université de Lorraine, Nancy, France.

Introduction: In cases of placenta accreta spectrum, a precise antenatal diagnosis of the suspected degree of invasion is essential for the planning of individual management strategies at delivery. The aim of this work was to evaluate the respective performances of ultrasonography and magnetic resonance imaging for the antenatal assessment of the severity of placenta accreta spectrum disorders included in the database. The secondary objective was to identify descriptors related to the severity of placenta accreta spectrum disorders.

Material And Methods: All the cases included in the database for which antenatal imaging data were available were analyzed. The rates of occurrence of each ultrasound and magnetic resonance imaging descriptor were reported and compared between the Group "Accreta-Increta" (FIGO grades 1 & 2) and the Group "Percreta" (FIGO grade 3).

Results: Antenatal imaging data were available for 347 women (347/442, 78.5%), of which 105 were included in the Group "Accreta - Increta" (105/347, 30.2%) and 213 (213/347, 61.4%) in the Group "Percreta". Magnetic resonance imaging was performed in addition to ultrasound in 135 women (135/347, 38.9%). After adjustment for all ultrasound descriptors in multivariate analysis, only the presence of a bladder wall interruption was associated with a significant higher risk of percreta (Odds ratio 3.23, Confidence interval 1.33-7.79). No magnetic resonance imaging sign was significantly correlated with the degree of severity.

Conclusions: The performance of ultrasound and magnetic resonance imaging to discriminate mild from severe placenta accreta spectrum disorders is very poor. To date, the benefit of additional magnetic resonance imaging has not been demonstrated.
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http://dx.doi.org/10.1111/aogs.14112DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8252006PMC
March 2021

Maternal and neonatal outcomes in planned versus emergency cesarean delivery for placenta accreta spectrum: A multinational database study.

Acta Obstet Gynecol Scand 2021 03 12;100 Suppl 1:41-49. Epub 2021 Mar 12.

Nuffield Department of Women's and Reproductive Health, University of Oxford, Oxford, UK.

Introduction: Placenta accreta spectrum (PAS) is a condition often resulting in severe maternal morbidity. Scheduled delivery by an experienced team has been shown to improve maternal outcomes; however, the benefits must be weighed against the risk of iatrogenic prematurity. The aim of this study is to investigate the rates of emergency delivery seen for antenatally suspected PAS and compare the resulting outcomes in the 15 referral centers of the International Society for PAS (IS-PAS).

Material And Methods: Fifteen centers provided cases between 2008 and 2019. The women included were divided into two groups according to whether they had a planned or an emergency cesarean delivery. Delivery was defined as "planned" when performed at a time and date to suit the team. All the remaining cases were classified as "emergency". Maternal characteristics and neonatal outcomes were compared between the two groups according to gestation at delivery.

Results: In all, 356 women were included. Of these, 239 (67%) underwent a planned delivery and 117 (33%) an emergency delivery. Vaginal bleeding was the indication for emergency delivery in 41 of the 117 women (41%). There were no significant differences in terms of blood loss, transfusion rates or major maternal morbidity between planned and emergency deliveries. However, the rate of maternal intensive therapy unit admission was increased with emergency delivery (45% vs 33%, P = .02). Antepartum hemorrhage was the only independent predictor of emergency delivery (aOR: 4.3, 95% confidence interval 2.4-7.7). Emergency delivery due to vaginal bleeding was more frequent with false-positive cases (antenatally suspected but not confirmed as PAS at delivery) and the milder grades of PAS (accreta/increta). The rate of infants experiencing any major neonatal morbidity was 25% at 34 to 36  weeks and 19% at >36  weeks.

Conclusions: Emergency delivery in centers of excellence did not increase blood loss, transfusion rates or maternal morbidity. The single greatest risk factor for emergency delivery was antenatal hemorrhage. When adequate expertise and resources are available, to defer delivery in women with no significant antenatal bleeding and no risk factors for pre-term birth until >36  weeks can be considered to improve fetal outcomes. Further studies are needed to investigate this fully.
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http://dx.doi.org/10.1111/aogs.14120DOI Listing
March 2021

Cytokine-like protein 1-induced survival of monocytes suggests a combined strategy targeting MCL1 and MAPK in CMML.

Blood 2021 Jun;137(24):3390-3402

INSERM U1287, Gustave Roussy Cancer Campus, Villejuif, France.

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.
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http://dx.doi.org/10.1182/blood.2020008729DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8233685PMC
June 2021

Feasibility of Umbilical Cord Blood Collection in Neonates at Risk of Brain Damage-A Step Toward Autologous Cell Therapy for a High-risk Population.

Cell Transplant 2021 Jan-Dec;30:963689721992065

Department of Obstetrics, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany.

Evidence for umbilical cord blood (UCB) cell therapies as a potential intervention for neurological diseases is emerging. To date, most existing trials worked with allogenic cells, as the collection of autologous UCB from high-risk patients is challenging. In obstetric emergencies the collection cannot be planned. In preterm infants, late cord clamping and anatomic conditions may reduce the availability. The aim of the present study was to assess the feasibility of UCB collection in neonates at increased risk of brain damage. Infants from four high-risk groups were included: newborns with perinatal hypoxemia, gestational age (GA) ≤30 + 0 weeks and/or birthweight <1,500 g, intrauterine growth restriction (IUGR), or monochorionic twins with twin-to-twin transfusion syndrome (TTTS). Feasibility of collection, quantity and quality of obtained UCB [total nucleated cell count (TNC), volume, sterility, and cell viability], and neonatal outcome were assessed. UCB collection was successful in 141 of 177 enrolled patients (hypoxemia = 10; GA ≤30 + 0 weeks = 54; IUGR = 71; TTTS = 6). Twenty-six cases were missed. The amount of missed cases per month declined over the time. Volume of collected UCB ranged widely (median: 24.5 ml, range: 5.0-102 ml) and contained a median of 0.77 × 10 TNC (range: 0.01-13.0 × 10). TNC and UCB volume correlated significantly with GA. A total of 10.7% (19/177) of included neonates developed brain lesions. To conclude, collection of UCB in neonates at high risk of brain damage is feasible with a multidisciplinary approach and intensive training. High prevalence of brain damage makes UCB collection worthwhile. Collected autologous UCB from mature neonates harbors a sufficient cell count for potential therapy. However, quality and quantity of obtained UCB are critical for potential therapy in preterm infants. Therefore, for extremely preterm infants alternative cell sources such as UCB tissue should be investigated for autologous treatment options because of the low yield of UCB.
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http://dx.doi.org/10.1177/0963689721992065DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7917411PMC
February 2021

Reply to: "Hysterectomy versus continuing conservative management: which is better for disseminated intravascular coagulation?"; Shinya Matsuzaki, MD, PhD, Yoshikazu Nagase, MD, Masayuki Endo, MD, PhD, Tadashi Kimura, MD, PhD.

Arch Gynecol Obstet 2021 Feb 5. Epub 2021 Feb 5.

Department of obstetrics (or anesthesiology or genecology…), Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Augustenburger Platz 1, 13353, Berlin, Germany.

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http://dx.doi.org/10.1007/s00404-021-05964-5DOI Listing
February 2021

Association of peripartum management and high maternal blood loss at cesarean delivery for placenta accreta spectrum (PAS): A multinational database study.

Acta Obstet Gynecol Scand 2021 03 21;100 Suppl 1:29-40. Epub 2021 Feb 21.

Department of Obstetrics, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany.

Introduction: Placenta accreta spectrum (PAS) carries a high burden of adverse maternal outcomes, especially significant blood loss, which can be life-threatening. Different management strategies have been proposed but the association of clinical risk factors and surgical management options during cesarean delivery with high blood loss is not clear.

Material And Methods: In this international multicenter study, 338 women with PAS undergoing cesarean delivery were included. Fourteen European and one non-European center (USA) provided cases treated retrospectively between 2008 and 2014 and prospectively from 2014 to 2019. Peripartum blood loss was estimated visually and/or by weighing and measuring of volume. Participants were grouped based on blood loss above or below the 75th percentile (>3500 ml) and the 90th percentile (>5500 ml).

Results: Placenta percreta was found in 58% of cases. Median blood loss was 2000 ml (range: 150-20 000 ml). Unplanned hysterectomy was associated with an increased risk of blood loss >3500 ml when compared with planned hysterectomy (adjusted OR [aOR] 3.7 [1.5-9.4], p = 0.01). Focal resection was associated with blood loss comparable to that of planned hysterectomy (crude OR 0.7 [0.2-2.1], p = 0.49). Blood loss >3500 ml was less common in patients undergoing successful conservative management (placenta left in situ, aOR 0.1 [0.0-0.6], p = 0.02) but was more common in patients who required delayed hysterectomy (aOR 6.5 [1.7-24.4], p = 0.001). Arterial occlusion methods (uterine or iliac artery ligation, embolization or intravascular balloons), application of uterotonic medication or tranexamic acid showed no significant effect on blood loss >3500 ml. Patients delivered by surgeons without experience in PAS were more likely to experience blood loss >3500 ml (aOR 3.0 [1.4-6.4], p = 0.01).

Conclusions: In pregnant women with PAS, the likelihood of blood loss >3500 ml was reduced in planned vs unplanned cesarean delivery, and when the surgery was performed by a specialist experienced in the management of PAS. This reinforces the necessity of delivery by an expert team. Conservative management was also associated with less blood loss, but only if successful. Therefore, careful patient selection is of great importance. Our study showed no consistent benefit of other adjunct measures such as arterial occlusion techniques, uterotonics or tranexamic acid.
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http://dx.doi.org/10.1111/aogs.14103DOI Listing
March 2021

A multicenter observational survey of management strategies in 442 pregnancies with suspected placenta accreta spectrum.

Acta Obstet Gynecol Scand 2021 03;100 Suppl 1:12-20

Department of Obstetrics and Gynecology, Division of Obstetrics and Prenatal Medicine, Erasmus MC, University Medical center Rotterdam, Rotterdam, the Netherlands.

Introduction: Management options for women with placenta accreta spectrum (PAS) comprise termination of pregnancy before the viable gestational age, leaving the placenta in situ for subsequent reabsorption of the placenta or delayed hysterectomy, manual removal of placenta after vaginal delivery or during cesarean section, focal resection of the affected uterine wall, and peripartum hysterectomy. The aim of this observational study was to describe actual clinical management and outcomes in PAS in a large international cohort.

Material And Methods: Data from women in 15 referral centers of the International Society of PAS (IS-PAS) were analyzed and correlated with the clinical classification of the IS-PAS: From Grade 1 (no PAS) to Grade 6 (invasion into pelvic organs other than the bladder). PAS was usually diagnosed antenatally and the operators performing ultrasound rated the likelihood of PAS on a Likert scale of 1 to 10.

Results: In total, 442 women were registered in the database. No maternal deaths occurred. Mean blood loss was 2600 mL (range 150-20 000 mL). Placenta previa was present in 375 (84.8%) women and there was a history of a previous cesarean in 329 (74.4%) women. The PAS likelihood score was strongly correlated with the PAS grade (P < .001). The mode of delivery in the majority of women (n = 252, 57.0%) was cesarean hysterectomy, with a repeat laparotomy in 20 (7.9%) due to complications. In 48 women (10.8%), the placenta was intentionally left in situ, of those, 20 (41.7%) had a delayed hysterectomy. In 26 women (5.9%), focal resection was performed. Termination of pregnancy was performed in 9 (2.0%), of whom 5 had fetal abnormalities. The placenta could be removed in 90 women (20.4%) at cesarean, and in 17 (3.9%) after vaginal delivery indicating mild or no PAS. In 34 women (7.7%) with an antenatal diagnosis of PAS, the placenta spontaneously separated (false positives). We found lower blood loss (P < .002) in 2018-2019 compared with 2009-2017, suggesting a positive learning curve.

Conclusions: In referral centers, the most common management for severe PAS was cesarean hysterectomy, followed by leaving the placenta in situ and focal resection. Prenatal diagnosis correlated with clinical PAS grade. No maternal deaths occurred.
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http://dx.doi.org/10.1111/aogs.14096DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8048500PMC
March 2021

Synergy of FLT3 inhibitors and the small molecule inhibitor of LIM kinase1/2 CEL_Amide in FLT3-ITD mutated Acute Myeloblastic Leukemia (AML) cells.

Leuk Res 2021 01 13;100:106490. Epub 2020 Dec 13.

Laboratoire de Transfert des Leucémies, EA3518, Institut de Recherche Saint Louis, University of Paris, Paris, France; Hematology Department, Hôpital Avicenne (Assistance Publique-Hôpitaux de Paris and University Paris XIII), Bobigny, France. Electronic address:

Patients with FLT3-ITD mutated (FLT3-ITD+) Acute Myeloid Leukemia (AML), have frequently relapsed or refractory disease and FLT3-ITD+ inhibitors have limited efficacy. Rho kinases (ROCK) are constitutively activated by FLT3-ITD+ in AML via PI3 kinase and Rho GTPase. Upon activation by ROCK, LIM kinases (LIMK) inactivate cofilin by phosphorylation which affects cytoskeleton dynamics, cell growth and apoptosis. LIMK inhibition leads to cofilin activation via dephosphorylation and activated cofilin localizes to mitochondria inducing apoptosis. Thus, we investigated the therapeutic potential of the LIMK1/2 inhibitor CEL_Amide (LIMKi) in FLT3-ITD+ AML. Expression of LIMK1/2 in FLT3-ITD+ cell lines MOLM-13 and MV-4-11 cells could be detected by RT-qPCR and at the protein level. IC50 after LIMKi monotherapy was 440 nM in MOLM-13 cells and 420 nM in MV4-11 cells. Treatment with LIMKi decreased LIMK1 protein levels and repression of inactivating phosphorylation of cofilin in FLT3-ITD+ cells. Combination experiments with LIMKi and FLT3 inhibitors including midostaurin, crenolanib and gilteritinib were synergistic for treatment of MOLM-13 cells while combinations with quizartinib were additive. Combinations of LIMKi and the hypomethylating agent azacitidine or the ROCK inhibitor fasudil were additive. In NOD-SCID mice engrafted with MOLM13-LUC cells, the FLT3 inhibitor midostaurin and LIMKi delayed MOLM13-LUC engraftment as detected by in vivo bioluminescence imaging and the LIMKi and midostaurin combination prolonged significantly survival of leukemic mice. LIMK1/2 inhibition by the small molecule CEL_Amide seems to have promising activity in combination with FLT3 inhibitors in vitro as well as in vivo and may constitute a novel treatment strategy for FLT3-ITD+ AML.
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http://dx.doi.org/10.1016/j.leukres.2020.106490DOI Listing
January 2021

Maternal Serum VEGF Predicts Abnormally Invasive Placenta Better than NT-proBNP: a Multicenter Case-Control Study.

Reprod Sci 2021 02 6;28(2):361-370. Epub 2020 Oct 6.

Department of Obstetrics, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Augustenburger Platz 1, 13353, Berlin, Germany.

The aim of this study was to test if maternal serum vascular endothelial growth factor (VEGF) or N-terminal pro B-type natriuretic peptide (NT-proBNP) predicts abnormally invasive placenta (AIP) better. Secondary objective was to test whether the serum levels of VEGF and NT-proBNP can predict the degree of invasion. In a multicenter case-control study design, gestational age-matched serum samples from pregnant women with AIP (n = 44) and uncomplicated pregnancies (n = 55) who had been enrolled at Charité - Universitätsmedizin Berlin, Germany and Centre Hospitalier Régional de la Citadelle in Liège, Belgium were analyzed. Maternal blood serum VEGF and NT-proBNP levels were immunoassayed from samples taken immediately before delivery (GA median: 35 weeks). Biomarker levels were compared between AIP and control group. The correlation of biomarker levels with the clinical AIP degree was assessed. The predictive biomarker ability was characterized through a multivariate regression model and receiver operating characteristic curves. Women with AIP had significantly lower maternal serum VEGF levels (AIP mean 285 pg/ml, 95% CI 248-322, vs. control: 391 pg/ml, 95% CI 356-426, p < 0.01) and higher NT-proBNP levels (AIP median 329 pg/ml, IQR 287-385, vs. control 295 pg/ml, IQR 273-356, p = 0.03). Maternal serum VEGF levels were able to predict AIP better (AUC = 0.729, 0.622-0.836, p < 0.001; VEGF + number of previous cesarean deliveries: AUC = 0.915, 0.853-0.977, p < 0.001). Maternal serum VEGF levels correlated inversely with the clinical AIP degree (r = - 0.32, p < 0.01). In short, maternal serum VEGF, more than NT-proBNP, can help in predicting AIP and hints at the degree of invasion.
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http://dx.doi.org/10.1007/s43032-020-00319-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7808970PMC
February 2021

Long term alterations of growth after antenatal steroids in preterm twin pregnancies.

J Perinat Med 2021 Feb 5;49(2):127-137. Epub 2020 Oct 5.

Clinic of Obstetrics, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany.

Objectives: To compare the long-term effects of antenatal betamethasone (ANS, ≤16 mg, =24 mg and >24 mg) in twins on infant and childhood growth.

Methods: A retrospective cohort follow up study among 198 twins after ANS including three time points: U1 first neonatal examination after birth and in the neonatal period; U7 examination from the 21st to the 24th month of life and U9 examination from the 60th to the 64th month of life using data from copies of the children's examination booklets. Inclusion criteria are twin pregnancies with preterm labor, cervical shortening, preterm premature rupture of membranes, or vaginal bleeding, and exposure to ANS between 23+5 and 33+6 weeks. Outcome measures are dosage-dependent and sex-specific effects of ANS on growth (body weight, body length, head circumference, body mass index and ponderal index) up to 5.3 years.

Results: Overall, 99 live-born twin pairs were included. Negative effects of ANS on fetal growth persisted beyond birth, altered infant and childhood growth, independent of possible confounding factors. Overall weight percentile significantly decreased between infancy and early childhood by 18.8%. Birth weight percentiles significantly changed in a dose dependent and sex specific manner, most obviously in female-female and mixed pairs. The ponderal index significantly decreased up to 42.9%, BMI index increased by up to 33.8%.

Conclusions: ANS results in long-term alterations in infant and childhood growth. Changes between infancy and early childhood in ponderal mass index and BMI, independent of dose or twin pair structure, might indicate an ANS associated increased risk for later life disease.

Synopsis: First-time report on long-term ANS administration growth effects in twin pregnancies, showing persisting alterations beyond birth in infant and childhood growth up to 5.3 years as potential indicator of later life disease risk.
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http://dx.doi.org/10.1515/jpm-2020-0204DOI Listing
February 2021

FDG PET/CT in a Patient With Mantle Cell Lymphoma and COVID-19: Typical Findings.

Clin Nucl Med 2020 Jul;45(7):e305-e306

Hematology, Avicenne Hospital, Hopitaux universitaires Paris Seine Saint Denis, AP-HP, France.

A 52-year-old woman with no medical history was admitted on March 18, 2020, presenting since 3 days asthenia, abdominal pain, and dry cough but no fever. Adenomegalies, splenomegaly, leukocytosis, and elevated LDH suggested mature lymphoproliferation. Considering the current health context, an RT-PCR testing for COVID-19 (coronavirus disease 2019) was performed and found to be positive. Early chest CT showed no sign of pulmonary infection but multiple adenomegalies. An F-FDG PET/CT performed 5 days later to assess the extent of the hemopathy revealed the apparition of FDG-avid bilateral ground glass and subpleural curvilinear opacities suggesting COVID-19-associated pneumopathy.
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http://dx.doi.org/10.1097/RLU.0000000000003113DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7268867PMC
July 2020

Added prognostic value of secondary AML-like gene mutations in ELN intermediate-risk older AML: ALFA-1200 study results.

Blood Adv 2020 05;4(9):1942-1949

Department of Hematology, Saint-Louis Institute for Research, Université de Paris, Hôpital Saint-Louis, Assistance Publique-Hôpitaux de Paris, Paris, France.

In this study, we aimed to refine prognostication of older with acute myeloid leukemia (AML) after intensive chemotherapy. Five hundred and nine patients aged 60 years or older (median age, 68 years) were prospectively enrolled in the intensive Acute Leukemia French Association (ALFA)-1200 trial between 2012 and 2016, and 471 patient samples were submitted to multigene analysis. Mutations in any of 8 genes frequently altered in myelodysplastic syndromes (MDS), including ASXL1, SRSF2, STAG2, BCOR, U2AF1, EZH2, SF3B1, and ZRSR2, defined a secondary AML (sAML)-like disease, as reported. Of the samples analyzed, 48% included sAML-like gene mutations. These mutations were associated with a shorter event-free survival, both overall (hazard ratio, 1.46; 95% confidence interval, 1.19-1.79; P < .001) and within the European LeukemiaNet (ELN)-2017 intermediate-risk subgroup (hazard ratio, 1.52; 95% confidence interval, 1.01-2.28; P = .044), which excludes ASXL1-mutated cases by definition. We therefore included patients with intermediate-risk AML carrying sAML-like mutations in a single high-risk patients group together with adverse-risk patients with AML, whereas other intermediate-risk patients were included in a standard-risk group together with favorable-risk patients (high-risk/standard-risk patient ratio, 1.00). Using this 2-class risk assessment, we observed that transplantation prolonged overall survival from remission in patients with high-risk AML only, not in patients with standard-risk AML. Routine analysis of sAML-like gene mutations may thus improve the definition of high-risk older patients with AML, and better identify the half of older patients who clearly derive survival benefit from allogeneic transplantation in first remission. This trial was registered at www.clinicaltrials.gov as #NCT01966497.
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http://dx.doi.org/10.1182/bloodadvances.2019001349DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7218423PMC
May 2020

Prophylactic and therapeutic antileukemic effects induced by the AAC-11-derived Peptide RT53.

Oncoimmunology 2020 2;9(1):1728871. Epub 2020 Mar 2.

INSERM UMRS976, Institut De Recherche Saint-Louis, Hôpital Saint-Louis, Paris, France.

Despite considerable progress, the treatment of acute leukemia continues to be a challenge for a significant majority of patients. Using a well-characterized preclinical mouse model of acute promyelocytic leukemia (APL), we evaluated here the antileukemic efficacy of RT53, an anticancer peptide with potential immunological properties. Our results indicate that RT53 possesses a direct antileukemic effect, even at a late stage. We also demonstrate that a single injection of a vaccine consisting of leukemic blasts exposed to RT53, which induces the hallmarks of immunogenic cell death, was highly effective in preventing leukemia development in both prophylactic and therapeutic settings. The vaccine comprising RT53-treated APL cells generated long-term antileukemic protection and depletion experiments indicated that CD4 + T cells were of crucial importance for vaccine efficacy. Combined, our results provide the rationale for the exploration of RT53-based therapies for the treatment of acute leukemia.
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http://dx.doi.org/10.1080/2162402X.2020.1728871DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7051191PMC
July 2021

Adult T-cell acute lymphoblastic leukemias with IL7R pathway mutations are slow-responders who do not benefit from allogeneic stem-cell transplantation.

Leukemia 2020 07 28;34(7):1730-1740. Epub 2020 Jan 28.

Université de Paris, Institut Necker-Enfants Malades, Institut National de Recherche Médicale U1151, Laboratory of Onco-Hematology, Assistance Publique-Hôpitaux de Paris, Hôpital Necker Enfants-Malades, Paris, France.

The prognostic value of IL7-receptor pathway (IL7Rp) mutations in T-cell acute lymphoblastic leukemia (T-ALL) remains unclear. We performed a comprehensive study of 200 adult patients with T-ALL included in the GRAALL2003/2005 protocols to address the clinical significance of IL7Rp mutations. Next-generation sequencing of the IL7Rp (IL7R/JAK1/JAK3/STAT5B) revealed that IL7Rp mutations were frequent in adult T-ALL (28%) particularly in immature/early T-cell progenitor (ETP)-ALL. They were associated with mutations of NOTCH-pathway, PHF6, and PRC2 components but not with K/NRAS. IL7Rp mutated (IL7Rp) T-ALL were slow-responders, with a high rate of M2/M3 day-8 marrow compared with IL7Rp non-mutated (IL7Rp) T-ALL (p = 0.002) and minimal residual disease positivity at 6-weeks (MRD1) (p = 0.008) but no difference in MRD2 positivity at 12-weeks. Despite this, no adverse prognosis was evidenced when censored for allogeneic hematopoietic stem cell transplantation (HSCT). In time-dependent analysis, HSCT did not benefit IL7Rp patients whereas it was of marked benefit to IL7Rp cases. IL7Rp-mutations identify a subgroup of slow-responder T-ALLs which benefit from post-induction chemotherapy regimens but not from HSCT. Our data suggest that prior knowledge of the mutation status of IL7Rp may influence HSCT decision and help to guide therapy reduction.
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http://dx.doi.org/10.1038/s41375-019-0685-4DOI Listing
July 2020

How should we diagnose and treat blastic plasmacytoid dendritic cell neoplasm patients?

Blood Adv 2019 12;3(24):4238-4251

Laboratoire d'Hématologie, CHU Estaing 1, Clermont-Ferrand, France.

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.
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http://dx.doi.org/10.1182/bloodadvances.2019000647DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6929390PMC
December 2019

BET inhibitors impair leukemic stem cell function only in defined oncogenic subgroups of acute myeloid leukaemias.

Leuk Res 2019 12 7;87:106269. Epub 2019 Nov 7.

INSERM/CNRS UMR 944/7212, Paris, France; Institut Universitaire d'Hématologie, Université Paris Diderot, Sorbonne Paris Cité, Paris Cancer Research Institute (PACRI), Paris, France; Département d'Hématologie, Hôpital Saint-Louis, Assistance Publique - Hopitaux de Paris, France. Electronic address:

Bromodomain and Extra-Terminal inhibitors (BETi) such as OTX015 are active in Acute Myeloid Leukaemias (AML). Their activity on Leukemic Stem Cells (LSCs) is less documented. We interrogated the anti-LSC activity of OTX015 in a niche-like long-term culture in 26 primary AML samples and validated our findings in vivo. OTX015 impaired LSCs in AMLs harbouring Core Binding Factor or KMT2A gene fusions, NPM1 or chromatin/spliceosome genes mutations, but not in those with aneuploidy/TP53 mutations. In four patients, we dissected the transcriptomic footprint of Bet inhibition on LSCs versus blasts. Our results can instruct future clinical trials of BETi in AML.
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http://dx.doi.org/10.1016/j.leukres.2019.106269DOI Listing
December 2019
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