Latest World Health Organization Research Articles

Delineating the Biomarker Potential and Therapeutic Significance of MicroRNAs in IDH-wildtype Glioblastoma as Defined by the WHO CNS5 Criteria

The World Health Organization (WHO) CNS5 classification, updated in 2021, has brought about a significant transformation in the diagnosis and treatment of IDH-wildtype glioblastoma, a subgroup of aggressive brain tumors. This new system, which incorporates molecular markers alongside traditional tissue analysis, provides a more refined approach that facilitates the identification of distinct glioblastoma subtypes with unique genetic profiles. Examples of these subtypes include IDH-mutant astrocytoma, IDH-mutant and 1p/19q-deleted oligodendroglioma, and IDH-wildtype glioblastoma. Despite advancements in genetics and targeted therapies, the treatment of these malignant tumors remains an ongoing quest. Therefore, the need for more specific diagnostic and therapeutic approaches is undeniable. MicroRNAs (miRNAs) are emerging as molecules that molecular biology has brought to the medical world in this context. These tiny molecules act as master regulators of gene expression and hold immense potential for glioblastoma diagnosis, prognosis prediction, and biomarker development. Recent research has highlighted the potential of miRNAs as therapeutic strategies, attracting scientific interest to this point. This review examines the current relationships of miRNAs in the context of IDH-wildtype glioblastoma within the framework of the WHO CNS5 classification. Utilizing extensive databases, this article investigates the intricate relationship between genetic abnormalities defined in the latest WHO classification and dysregulated miRNAs. By analyzing proposed molecular biomarkers and associated miRNA dysregulation, we aim to pave the way for the development of personalized miRNA-based therapies for this aggressive cancer type.

Ultrasound and cytopathological characteristics of thyroid tumours of uncertain malignant potential - from diagnosis to treatment.

The latest World Health Organization (WHO) classification from 2022 distinguishes the division of low-risk thyroid neoplasms such as non-invasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP), follicular tumour of uncertain malignant potential (FT-UMP), and well-differentiated tumour of uncertain malignant potential (WDT-UMP). The final diagnosis is made postoperatively according to histopathologic results. The aim of the study was the assessment of ultrasonographic and cytopathological features of borderline lesions to predict low-risk tumours preoperatively and plan the optimal treatment for that group of patients. A total of 35 patients (30 women; 5 men), aged 20-81 years with a mean age of 49 years, were enrolled in the study. The study evaluated 35 focal lesions of the thyroid gland, classified as low-risk neoplasms according to the WHO 2022 classification: FT-UMP (n = 21), NIFTP (n = 7), and WDT-UMP (n = 7). Ultrasonographic features of nodules including contrast-enhanced ultrasound (CEUS) and elastography were assessed by 2 specialists, and the risk of malignancy was evaluated according to EU-TIRADS-PL classification. Of the 35 focal thyroid lesions, most were categorised as low or intermediate risk of malignancy according to EU-TIRADS-PL, with dominant category 3 [n = 13 (37.2%)] and category 4 [n = 15 (42.8%)]. High-risk category 5 was assessed in 7 lesions (20%). In cytopathology nodules were categorised as follows (Bethesda System TBSRTC 2023): Bethesda II (n = 4), Bethesda III (n = 2), Bethesda IV (n = 25), Bethesda V (n = 3), and Bethesda VI (n = 1). In the CEUS study, contrasting patterns dominated compared to the surrounding parenchyma, such as enhancement equal to the parenchyma (66.6%) or intense (28.5%), heterogeneous (61.9%), centripetal (42.8%), or diffuse (57.1%) with fast (33.3%) or compared to parenchyma contrast wash-in (42.8%) and its fast (33.3%) or comparable to thyroid parenchyma wash-out (52.3%). The study indicates that lesions with uncertain malignant potential typically present features suggesting low to intermediate risk of malignancy based on EU-TIRADS-PL classification, with dominant cytopathologic Bethesda IV category. However, 20% of lesions were assessed tas EU-TIRADS-PL category 5. Low-risk tumours, including NIFTP, FT-UMP, and WDT-UMP, require careful observation and monitoring post surgical treatment due to their potential for recurrence and metastasis. The preoperatively prediction of borderline tumour may play an important role in proper treatment and follow-up.

Papillary thyroid carcinoma tall cell subtype (PTC-TC) and high-grade differentiated thyroid carcinoma tall cell phenotype (HGDTC-TC) have different clinical behaviour: aretrospective study of 1456 patients.

Papillary thyroid carcinoma, tall cell subtype (PTC-TC) is a potentially aggressive histotype. The latest World Health Organisation (WHO) classification introduced a novel class of tumours; namely, high-grade differentiated thyroid carcinoma (HGDTC), characterised by elevated mitotic count and/or necrosis, which can exhibit a tall cell phenotype (HGDTC-TC). We analysed the clinical outcomes in a large retrospective cohort of 1456 consecutive thyroid carcinomas with a tall cell phenotype, including PTC-TC and HGDTC-TC. HGDTC-TC is uncommon, accounting for 5.3% (77 of 1379) of carcinomas with tall cell morphology. HGDTC-TC was associated with significantly older age, larger tumour size, angioinvasion, gross extrathyroidal extension, higher AJCC pT stage, positive resection margin and nodal metastasis (P < 0.05). Compared with PTC-TC, HGDTC was associated with a significantly decreased DSS, LRDFS and distant metastasis-free survival (DMFS; P < 0.001). The 10-year DSS was 72 and 99%, the 10-year LRDFS was 61 and 92% and the 10-year DMFS was 53 and 97%, respectively, for HGDTC-TC and PTC-TC. On multivariate analysis, the classification (HGDTC-TC versus PTC-TC) was an independent adverse prognostic factor for DSS, LRDF, and DMFS when adjusted for sex, age, angioinvasion, margin status, AJCC pT and pN stage. Compared with PTC-TC, HGDTC-TC is associated with adverse clinicopathological features, a higher frequency of TERT promoter mutations (59% in HGDTC-TC versus 34% in PTC-TC) and incurs a significantly worse prognosis. HGDTC-TC is an independent prognostic factor for carcinoma with tall cell morphology. This validates the concept of HGDTC and the importance of tumour necrosis and high mitotic count for accurate diagnosis and prognosis of differentiated thyroid carcinomas.

Comparative analysis of newer classes of antidiabetics and the concept of pharmaceutical care – dealing with therapeutic problems

The prevalence of obesity is increasing rapidly. The latest World Health Organization – WHO report declares the disease as an epidemic. After pharmacodynamic, pharmacokinetic, clinical and pharmacoepidemiologic data analysis and comparison of the three classes of antidiabetic medicinal products: GLP-1 receptor agonists, DPP-4 inhibitors and SGLT2 inhibitors, a literature review of the topic, patient education and the concept of pharmaceutical care emerged as methods for dealing with the most common adverse drug reactions, safety concerns, and drug interactions.

Advances of pathological diagnosis and molecular pathology of lung neuroendocrine neoplasms

The pathological classification and diagnostic criteria for lung neuroendocrine neoplasms (NENs) in the 2021 World Health Organization (WHO) lung tumor classification are similar to the prior classifications. However, the advances on the molecular studies of lung NENs have shown that both small cell lung carcinoma and large cell neuroendocrine carcinoma are highly heterogeneous tumors with neuroendocrine characteristics and can be subclassified based on the features of genomics or transcriptomics, which are valuable in the diagnosis of lung NENs subtypes and patient treatment. In addition, it is necessary to interpret emerging concepts such as "lung neuroendocrine tumor G3" and "histological transformation" from pathological perspectives, as well as to know the novel neuroendocrine biomarkers such as INSM1 and POU2F3. This article summarized the diagnostic changes and the advances of molecular pathology of lung NENs based on the latest WHO classification and molecular research.

Impact of Traffic Noise and Apartment Building Features on the Quality of Life in Matsue City

Traffic noise has a significant impact on the health and quality of life of urban residents. Despite this, there has been limited research on the effects of vehicle-generated noise from roads and parking lots near buildings. This study aimed to examine the impact of traffic and parking noise on residents living in apartments along 11 roads in Matsue City, Japan. To achieve this, the residents' reactions to noise were investigated in relation to the distance of their apartments from main roads and parking lots, as well as the building design. Noise exposures were measured on the road shoulders in front of the properties for 24 hours, and short-term recordings were taken at various reference locations within the buildings. A questionnaire was distributed to 60 households residing in the targeted properties. The results showed that the residents living in apartments along the main roads, which exceeded the noise level limit recommended by the latest World Health Organization (WHO) environmental noise guidelines, expressed annoyance with the traffic noise. The study highlights that the noise issue cannot be solely determined by comparing it to the environmental standards recommended by prefectural standards. The findings suggest the need to review whether the current environmental standards are appropriate for each region.

Awareness and use of tranexamic acid in the management of postpartum hemorrhage among health care professionals in Enugu, Nigeria.

This study was conducted to determine the knowledge, practice, and barriers regarding the use of tranexamic acid (TXA) for the prevention and treatment of postpartum hemorrhage (PPH) among health care providers in Enugu, Nigeria. A cross-sectional study was conducted among health professionals (doctors, pharmacists, and nurses) in two Nigerian tertiary teaching hospitals (one federal and one state). A total of 220 questionnaires were distributed and 207 were returned (response rate: 94%) and analyzed using SPSS for inferential statistics with a level of significance of P < 0.05. Only 23.7% of the respondents had good knowledge of TXA use in PPH (P < 0.001), and awareness of the recent World Health Organization (WHO) recommendation on the use of TXA for PPH was low (19.8%, P < 0.001). The majority of the respondents had neither prescribed nor dispensed TXA (30%, P < 0.001). Very few respondents used TXA for all cases of PPH (16.4%, P < 0.001). Barriers against its use include nonawareness of the latest WHO recommendation, preference for other uterotonics, and cost of the drug. There was poor knowledge of TXA, poor awareness of its recommendation, and low use for PPH among different cadres of health care providers.

Urothelial carcinoma; an overview of histology, molecular subtypes, and clinical implications based on the latest WHO classification

The incidence of urothelial carcinoma is increasing worldwide (including in Iran). Bladder cancer can be classified in various manners according to the standardized histomorphology set by the World Health Organization (WHO). Various genetic modifications occurring at the DNA level and the resulting variations in RNA expression give rise to different subcategories that have important implications for diagnosis, prognosis, and treatment. The molecular basis of these morphologic variances is now better understood because of recent developments in molecular biology. With updates on the genetic and clinical characteristics, we highlight the histologic traits of the divergent differentiation and subtypes recognized by the most recent WHO classification (5th edition). Molecular subtypes of lower and upper tract cancer can be used to characterize their clinical behaviors and determine therapeutic responses to neoadjuvant chemotherapy. In this overview article, we also present a preliminary analysis of our ongoing data collection on molecular features of urothelial carcinoma.

Neuroimaging of pediatric tumors of the sellar region-A review in light of the 2021 WHO classification of tumors of the central nervous system.

Sellar/suprasellar tumors comprise about 10% of all pediatric Central Nervous System (CNS) tumors and include a wide variety of entities, with different cellular origins and distinctive histological and radiological findings, demanding customized neuroimaging protocols for appropriate diagnosis and management. The 5th edition of the World Health Organization (WHO) classification of CNS tumors unprecedently incorporated both histologic and molecular alterations into a common diagnostic framework, with a great impact in tumor classification and grading. Based on the current understanding of the clinical, molecular, and morphological features of CNS neoplasms, there have been additions of new tumor types and modifications of existing ones in the latest WHO tumor classification. In the specific case of sellar/suprasellar tumors, changes include for example separation of adamantinomatous and papillary craniopharyngiomas, now classified as distinct tumor types. Nevertheless, although the current molecular landscape is the fundamental driving force to the new WHO CNS tumor classification, the imaging profile of sellar/suprasellar tumors remains largely unexplored, particularly in the pediatric population. In this review, we aim to provide an essential pathological update to better understand the way sellar/suprasellar tumors are currently classified, with a focus on the pediatric population. Furthermore, we intend to present the neuroimaging features that may assist in the differential diagnosis, surgical planning, adjuvant/neoadjuvant therapy, and follow-up of this group of tumors in children.

WHO International Standard Terminologies on Traditional Chinese Medicine: Use in Context, Creatively

WHO International Standard Terminologies on Traditional Chinese Medicine: Use in Context, Creatively

Epigenetic Regulation in Primary CNS Tumors: An Opportunity to Bridge Old and New WHO Classifications.

Originally approved in 1979, a specific grading classification for central nervous system (CNS) tumors was devised by the World Health Organization (WHO) in an effort to guide cancer treatment and better understand prognosis. These "blue books" have since undergone several iterations based on tumor location, advancements in histopathology, and most recently, diagnostic molecular pathology in its fifth edition. As new research methods have evolved to elucidate complex molecular mechanisms of tumorigenesis, a need to update and integrate these findings into the WHO grading scheme has become apparent. Epigenetic tools represent an area of burgeoning interest that encompasses all non-Mendelian inherited genetic features affecting gene expression, including but not limited to chromatin remodeling complexes, DNA methylation, and histone regulating enzymes. The SWItch/Sucrose non-fermenting (SWI/SNF) chromatin remodeling complex is the largest mammalian family of chromatin remodeling proteins and is estimated to be altered in 20-25% of all human malignancies; however, the ways in which it contributes to tumorigenesis are not fully understood. We recently discovered that CNS tumors with SWI/SNF mutations have revealed an oncogenic role for endogenous retroviruses (ERVs), remnants of exogenous retroviruses that integrated into the germline and are inherited like Mendelian genes, several of which retain open reading frames for proteins whose expression putatively contributes to tumor formation. Herein, we analyzed the latest WHO classification scheme for all CNS tumors with documented SWI/SNF mutations and/or aberrant ERV expression, and we summarize this information to highlight potential research opportunities that could be integrated into the grading scheme to better delineate diagnostic criteria and therapeutic targets.

Molecular MRD Assessment in Acute Myeloid Leukemias

AbstractDetection of measurable residual disease (MRD) is of significant value in the management of acute myeloid leukemia (AML) patients. Along with multicolor flowcytometry (MFC), molecular techniques form an integral tool in AML MRD detection. Multiple studies have reiterated the role of molecular MRD evaluation in AML at defined timepoints during the course of therapy, helping in risk stratification, prediction of relapse, and as guide for pre-emptive therapy. The latest World Health Organization (WHO) classification (WHO-HEME5) has refined the classification of AML bringing forth newer entities defined by molecular abnormalities, especially fusions. AML is a clonally heterogeneous disease characterized by a spectrum of multiple molecular abnormalities including gene mutations and fusions. Accordingly, the molecular methods employed are also diverse and need robust technical standardization in clinical laboratories. Real-time quantitative polymerase chain reaction (PCR), digital PCR, and next-generation sequencing (NGS) are the major molecular platforms for AML MRD. The European LeukemiaNet (ELN) MRD Working Party consensus document recently updated in 2021 for the first time has reflected on the technical recommendations for NGS MRD in AML and stressed the value of an integrated approach. It is, therefore, desirable for physicians, scientists, and pathologists alike to thoroughly understand these molecular methods for appropriate utilization and interpretation. In this article, we discuss the various facets of molecular methods for MRD detection in AML including technical requirements, advantages, drawbacks, and applications.

Application of advanced diffusion models from diffusion weighted imaging in a large cohort study of breast lesions

BackgroundTo evaluate multiple parameters in multiple b-value diffusion-weighted imaging (DWI) in characterizing breast lesions and predicting prognostic factors and molecular subtypes.MethodsIn total, 504 patients who underwent 3-T magnetic resonance imaging (MRI) with T1-weighted dynamic contrast-enhanced (DCE) sequences, T2-weighted sequences and multiple b-value (7 values, from 0 to 3000 s/mm2) DWI were recruited. The average values of 13 parameters in 6 models were calculated and recorded. The pathological diagnosis of breast lesions was based on the latest World Health Organization (WHO) classification.ResultsTwelve parameters exhibited statistical significance in differentiating benign and malignant lesions. alpha demonstrated the highest sensitivity (89.5%), while sigma demonstrated the highest specificity (77.7%). The stretched-exponential model (SEM) demonstrated the highest sensitivity (90.8%), while the biexponential model demonstrated the highest specificity (80.8%). The highest AUC (0.882, 95% CI, 0.852–0.912) was achieved when all 13 parameters were combined. Prognostic factors were correlated with different parameters, but the correlation was relatively weak. Among the 6 parameters with significant differences among molecular subtypes of breast cancer, the Luminal A group and Luminal B (HER2 negative) group had relatively low values, and the HER2-enriched group and TNBC group had relatively high values.ConclusionsAll 13 parameters, independent or combined, provide valuable information in distinguishing malignant from benign breast lesions. These new parameters have limited meaning for predicting prognostic factors and molecular subtypes of malignant breast tumors.

Assays to Measure Insecticide Toxicity and Insecticide Resistance in Mosquitoes.

Mosquitoes' resistance to commonly used insecticides is now widespread, hampering control efforts and leading to substantial increases in human illness and mortality rates in many areas of the world. Insecticide bioassays are quantitative methodologies used to determine the dose-response relationship of insects to insecticides and to evaluate the susceptibility or resistance of mosquitoes to specific insecticides. They are frequently used to monitor the development of insecticide resistance in mosquitoes for both field resistance diagnoses (surveillance assays), in which the ability of mosquitoes to survive exposure to a standard dose or concentration of an insecticide is measured, and laboratory bioassays, in which responses to insecticides are tested in parallel populations of resistant (field) populations and laboratory susceptible strains using serial doses or concentrations. Metabolic detoxification, in which insecticides are metabolized by enzymes, including cytochrome P450s, hydrolases, and glutathione-S-transferases (GSTs), to become more polar and less toxic, is one resistance mechanism. Piperonyl butoxide (PBO), S,S,S-tributyl phosphorotrithioate (DEF), and diethyl maleate (DEM) are the inhibitors of P450s, hydrolases, and GSTs, respectively, and act as synergists for rapidly testing the involvement of these enzymes in insecticide resistance. Such synergistic assays are used to identify the detoxification enzyme that leads to resistance to a specific insecticide. This introduction and its associated protocols present a detailed discussion of appropriate methodologies and procedures for laboratory larval, adult, and synergistic bioassays and introduces the field surveillance tests used to monitor insecticide resistance as recommended by the latest World Health Organization (WHO) and U.S. Centers for Disease Control (CDC) guidelines.

Myxoid glioneuronal tumor: Histopathologic, neuroradiologic, and molecular features in a single center series

BackgroundMyxoid glioneuronal tumor (MGT) is a benign glioneuronal neoplasm recently introduced in the World Health Organization (WHO) classification of the central nervous system (CNS) tumors. MGTs are typically located in the septum pellucidum, foramen of Monro or periventricular white matter of the lateral ventricle. They were previously diagnosed as dysembryoplastic neuroepithelial tumors (DNT), showing histological features almost indistinguishable from classical cortical DNT. Despite that, MGTs have been associated with a specific dinucleotide substitution at codon 385 in the platelet-derived growth factor receptor alpha (PDGFRA) gene, replacing a lysine residue with either leucine or isoleucine (p. LysK385Leu/Iso). This genetic variation has never been described in any other CNS tumor. Materials and methodsThirty-one consecutive tumors, previously diagnosed as DNTs at the Meyer Children's Hospital IRCCS between January 2010 and June 2021 were collected for a comprehensive study of their clinical, imaging, pathological features, and molecular profile. ResultsIn six out of the thirty-one tumors we had previously diagnosed as DNTs, we identified the recurrent dinucleotide mutation in the PDGFRA. All six tumors were typically located within the periventricular white matter of the lateral ventricle and in the septum pellucidum. We then renamed these lesions as MGT, according to the latest WHO CNS classification. In all patients we observed an indolent clinical course, without recurrence. ConclusionMGT represent a rare but distinct group of neoplasm with a typical molecular profiling, a characteristic localization, and a relative indolent clinical course.

Recovering from the Unprecedented Backsliding in Immunization Coverage: Learnings from Country Programming in Five Countries through the Past Two Years of COVID-19 Pandemic Disruptions.

Between 2020 and 2021, the COVID-19 pandemic severely strained health systems across countries, leaving millions without access to essential healthcare services. Immunization programs experienced a 'double burden' of challenges: initial pandemic-related lockdowns disrupted access to routine immunization services, while subsequent COVID-19 vaccination efforts shifted often limited resources away from routine services. The latest World Health Organization (WHO) and United Nations Children's Fund (UNICEF) estimates suggest that 25 million children did not receive routine vaccinations in 2021, six million more than in 2019 and the highest number witnessed in nearly two decades. Recovering from this sobering setback requires a united push on several fronts. Intensifying the catch-up of routine immunization services is critical to reach children left behind during the pandemic and bridge large immunity gaps in countries. At the same time, we must strengthen the resilience of immunization systems to withstand future pandemics if we hope to achieve the goals of Immunization Agenda 2030 to ensure vaccinations are available for everyone, everywhere by 2030. In this article, leveraging the key actions for sustainable global immunization progress as a framework, we spotlight examples of strategies used by five countries-Cambodia, Cameroon, Kenya, Nigeria, and Uganda-who have exhibited exemplar performance in strengthening routine immunization programs and restored lost coverage levels in the last two years of the COVID-19 pandemic. The contents of this article will be helpful for countries seeking to maintain, restore, and strengthen their immunization services and catch up missed children in the context of pandemic recovery and to direct their focus toward building back a better resilience of their immunization systems to respond more rapidly and effectively, despite new and emerging challenges.

Borderline personality disorder in ICD-11 and DSM-5 – the relational nature of the criteria for the disorder

The paper illustrates the relational nature of the psychiatric category of borderline personality disorders based on the analysis of symptomatic criteria set out in the International Classification of Diseases and Related Health Problems, 11th Revision (ICD-11) issued by the World Health Organization (WHO), as well as the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) developed by the American Psychiatric Association (APA). We point to the appreciation of the relational nature of the phenomenon, which is noticeable already in a very cursory analysis, in the latest WHO and APA classification systems. The clinical manifestations of these criteria seem not only to be interconnected, but also to result from one another, suggesting a fundamentally structural nature of the phenomenon. All the described difficulties relate to interpersonal relationships – both in terms of the direct causes of disfunctions and long-term family and social consequences. This particularly applies to the borderlinetype emotionally unstable personality disorder, which is inseparably linked to emotional volatility and instability, and which is difficult to define using criteria in a way that does not give rise to diagnostic challenges. Therefore, we draw attention to difficulties with relationships, which are an important diagnostic criterion. Both ICD-11 and DSM-5 contain separate diagnostic categories for relationship problems, which, as it turns out, not necessarily coexist with other disorders. Linking relationship pathology with personality disorders may be of great importance for establishing the correct diagnosis and therefore choosing an appropriate treatment strategy.

Molecular pathology and clinical implications of diffuse glioma.

The prognosis for diffusely infiltrating gliomas at World Health Organization (WHO) grade 2-4 remains dismal due to their heterogeneity. The rapid development of genome-wide molecular-profiling-associated studies has greatly promoted the accuracy of glioma classification. Thus, the latest version of the WHO classification of the central nervous system tumors published in 2021 has incorporated more molecular biomarkers together with histological features for the diagnosis of gliomas. Advanced usage of molecular pathology in clinical diagnostic practice provides also new opportunities for the therapy of patients with glioma, including surgery, radiotherapy and chemotherapy, targeted therapy, immunotherapy, and more precision clinical trials. Herein, we highlight the updates in the classification of gliomas according to the latest WHO guidelines and summarize the clinically relevant molecular markers by focusing on their applications in clinical practice. We also review the advances in molecular features of gliomas, which can facilitate the development of glioma therapies, thereby discussing the challenges and future directions of molecular pathology toward precision medicine for patients with glioma.

The Adverse Effect of Myelodysplasia-Related Mutations in De Novo Acute Myeloid Leukemia Is Associated with Higher Variant Allelic Frequency (VAF): A Proposal for a Numeric Cutoff for Variant Allelic Frequency

Mutations in myelodysplasia-related genes ASXL1, BCOR, EHZH2, RUNX1, SF3B1, SRSF2, STAG2, U2AF1 and ZRSR2 (MRmut) are class-defining alterations in acute myeloid leukemia (AML) in the latest World Health Organization (WHO, with the exception of RUNX1) and International Consensus Classification (ICC) schemes and indicate adverse-risk per European Leukemia Net (ELN) 2022 guidelines, unless occurring in favorable-risk AML. The lower limit of detection (LOD) for most clinical-grade next generation sequencing (NGS) is ~1-2% variant allelic frequency (VAF); however, data on the prognostic significance of MRmut relative to VAF is lacking. No guidelines that provide a numeric cutoff for VAF are available for utilizing these mutations to classify AML. Our aim was to define a clinically meaningful VAF cutoff for MR mutations in de novo AML. We included patients (pts) with de novo, untreated AML with MRmut treated at our institution between 2017 to 2022. We excluded pts with acute promyelocytic leukemia, core binding factor AML, and other ELN adverse-risk categories (adverse karyotype and/or TP53 mutation). NGS at baseline was performed using a panel of 81 genes recurrently mutated in myeloid neoplasms (LOD ~1-2%). We performed a best fit classifier on individual MRmut to determine optimal VAF cutoffs using event-free survival (EFS) and overall survival (OS) as endpoints. VAF for MRmut involving X-linked genes was adjusted for men. Pts (n=145) included 92 (63%) men and 53 (37%) women with a median age of 68 years (range, 58-75). 85 (59%) pts had diploid karyotype AML, 51 (35%) had other intermediate-risk non-diploid karyotype AML, and 9(6%) had insufficient metaphases for analysis. 34 (23%) pts had ELN favorable-risk and 111(77%) had ENL adverse-risk AML. Pts were treated with low-intensity+venetoclax (VEN) (72/50%), low-intensity (26/18%), high-intensity (22/15%), and high-intensity+VEN (12/17%) regimens. Median follow-up was 26.9 months (range, 13.9 - 40.8). 72 (49%) pts had 1 MRmut; the remaining had 2-4 concurrent MRmut. MRmut had the following frequencies and VAFs: ASXL1 (28%; median VAF: 26%, [range 2-48%]); BCOR (18%; median VAF 37% [3-100%]); EHZH2 (9%; median VAF 7% [1-55%]), RUNX1 (32%; median VAF 47% [1-96%]), SF3B1 (9%; median VAF: 38% [1-55%]), SRSF2 (46%; median VAF: 37% [1-76%]), STAG2 (20%; median VAF: 44% [15-98%]), U2AF1 (12%; median VAF: 33% [2-43%]) and ZRSR2 (2%; median VAF: 94% [93-95%]). 34 (23%) pts had ELN favorable-risk AML including 28 (23%) with mutated NPM1 without FLT3-ITD and 6 (4%) with CEBPA bZIP mutations, respectively; in 12/34 pts NPM1 or CEBPA bZIP mutations were subclonal compared with clonal MR mutation(s). A summary of baseline genetic and treatment data is provided in Fig 1A. The overall composite remission rate (CR+CRi) was 88% (64% and 24%, respectively) Median OS was 30.3 months and estimated 12/24 month OS were 77%/60%. The median EFS was 24.6 months and estimated 12/24 month EFS were 65%/51%. Pts with ELN favorable-risk AML with MRmut had longer OS and EFS compared with the adverse-risk group (median OS 34.9 vs 27.5 months, median EFS 34.9 vs 22.9 months) but the difference was not significant (p=0.60 and 0.30, respectively). The VAF cutoff for MRmut associated with EFS and OS, respectively, was: ASXL1: 21%/21%, BCOR 25%/25% , EHZH2 15%/15%, RUNX1 25%/27%, SF3B1 31%/31%, SRSF2 32%/35%, STAG2 40%/21%, U2AF1 44%/44% and ZRSR2 47/47%.There was no significant difference in OS or EFS between pts with 1 MRmut vs those involving ≥2 MR genes. Pts treated with high-intensity, high intensity+ VEN and low intensity+VEN regimens had longer OS (Fig 1B) and EFS compared with pts treated with low intensity regimens without VEN (OS: not reached, 31.7 months, 31.4 months vs 8.9 months, respectively, p<0.001; EFS: not reached, 31.7 months, 29.6 months vs 3.7 months, respectively, p<0.001). Our data suggest that the poor prognostic effect of MRmut in de novo AML is associated with higher VAF and not a binary presence or absence of MRmut. The minimum VAFs associated with worse outcome for each MRmut ranged from 15-47%. Additional analysis to create predictive models is in progress to determine the optimal VAF cutoff when using MRmut to assign AML to the WHO/ICC MR categories and to ELN adverse-risk group. Importantly, our results suggest that pts with MRmut and non-adverse karyotype have significantly better outcomes when treated with high-intensity and/or venetoclax-based treatment regimens. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Interventions to support the re-establishment of breastfeeding and their application in humanitarian settings: A systematic review.

In 1998, the World Health Organisation (WHO) published general guidelines proposing essential measures to achieve relactation. Yet, increased knowledge about the practical set-up of relactation support interventions in different contexts is needed, especially in humanitarian settings, where nonbreastfed infants are particularly at risk. This study aimed to compile and assess the characteristics, outcomes and factors influencing the implementation of relactation support interventions reported sincethe latest WHO recommendations. We conducted a systematic review following Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) guidelines, undertaking a search from Medline, Embase, PubMed Central, Web of Science, Global Health and CINAHL electronic databases. Studies published in English and Spanish, reporting characteristics and outcomes of relactation support provided to non-(breastfeeding) BF mothers with infants aged less than 6 months were included. Data were analysed by narrative synthesis and the Johanna Briggs Institute Critical Appraisal Tools were used for quality assessment. Overall, 16 studies met the inclusion criteria. Most were observational and conducted in middle-income countries, only one focused on humanitarian settings. Studies reported inpatient and community-based interventions, which generally followed WHO recommendations for relactation. In 13 out of 16 studies, over 80% of mothers restarted BFafter receiving relactation support. Enabling factors included younger infant age, shorter lactation gap, mother's strong motivation, family support, and continuous skilled support. Although current literature suggests that intensive relactation support can contribute to re-establish BF, its application and effectiveness in humanitarian settings remain uncertain. Further research is needed to explore the effectiveness, feasibility and acceptability of different approaches to relactation support, especially in humanitarian settings.