Dental Profile of Brazilian Patients with Rare Skeletal Genetic Disorders: Clinical Features and Associated Factors.

The aim of this study is to compare the dental profiles of Brazilian patients with rare genetic skeletal disorders and normotypical patients. A cross-sectional study was carried out with 210 individuals aged between 2 and 54 years old [105 with rare diseases (Mucopolysaccharidosis/MPS n = 27 and Osteogenesis Imperfecta/OI n = 78) and 105 without rare diseases] and their parents/caregivers. The parents/caregivers answered a questionnaire about individual aspects of their child and the dental profile was identified from questions related to dental history and the presence/absence of dental problems. The patients' oral cavity was also examined by three examiners for dental caries, malocclusion, gingivitis, and dental anomalies. The average age of individuals with a rare disease was 14.1 years (±12.2) and the median was 9.5 years. Participants who had already used the public health system (SUS) dental care services had a 2.24 times higher chance of belonging to the group with a rare disease (OR = 2.24; 95% CI: 1.07-4.89). Patients with rare diseases are 14.86 times more likely to have difficulty receiving dental treatment (OR = 14.86; 95% CI: 5.96-27.03) and 10.38 times more likely to have one or more dental problems (OR = 10.38; 95% CI: 1.95-35.17). Individuals with rare disorders have a greater history of difficulty in accessing dental treatment, using the SUS, and were diagnosed with more dental problems compared to normotypical individuals.

Health-related quality of life metrics as endpoints in surgical trials: hype or hope?

The management of gynecological cancer has evolved considerably over the past decades in almost every field of treatment. Surgery plays a major role in the treatment algorithm. However, these invasive interventions can have profound implications for the quality of life (QoL) of affected individuals. The routine implementation of QoL measurements in clinical trials has become common, reflecting a new research 'standard', despite the fact that all available QoL instruments were not designed nor validated prospectively for surgical trials. This review seeks to address whether patient reported outcomes and QoL measurements rightfully take center stage in current surgical trials, leading to direct implementation for the benefit of patient care, or are they simply more of a researcher's hope. We will also provide an 'action plan' to better implement QoL measurements in future surgical trials.

Cardiophrenic lymph nodes in advanced ovarian cancer.

Epithelial ovarian cancer most commonly presents at advanced stages, and prognosis is influenced by residual disease following cytoreduction. The significance of cardiophrenic lymph node resection at the time of cytoreductive surgery in advanced ovarian cancer remains a topic of debate. Enlarged cardiophrenic lymph nodes are detected through high-resolution imaging; however, the optimal imaging technique in determining feasibility of node resection remains uncertain. Similarly, the impact of excision of cardiophrenic lymph nodes on progression-free and overall survival remains elusive. The indications for resection of cardiophrenic lymph nodes are not addressed in standard ovarian cancer guidelines. Patients with cardiophrenic lymph nodes exceeding 1 cm in size may be considered for resection if complete intra-abdominal cytoreduction is feasible to no gross residual. The surgical approach might be either by open access or by video-assisted thoracoscopic surgery (minimally invasive approach), and major complications following cardiophrenic lymph nodes resection are low. Pathological cardiophrenic lymph nodes are associated with a poorer overall prognosis and can serve as a prognostic parameter; however, the therapeutic benefit of cardiophrenic lymph nodes resection remains inconclusive.

Impact of gynecological cancers on health-related quality of life: historical context, measurement instruments, and current knowledge.

Gynecologic cancers, comprising 14.4% of newly diagnosed cancer cases in women globally, are substantial causes of both mortality and morbidity, with a profound impact on the quality of life (QoL) of survivors. Over the past few decades, advancements in interdisciplinary and interprofessional care have contributed to an increase in the average life expectancy of gynecological cancer patients. However, the disease and its treatments have a profound impact on patients, leading to physical changes and psychological consequences, including psychosocial and psychosexual effects, which negatively affect their QoL.The primary objective of management strategies is to minimize harm while improving survival rates and enhancing QoL during the survivorship stage. QoL measures play a crucial role in enhancing our comprehension of how cancer and its treatments affect individuals. Consequently, various measurement instruments, such as the EORTC QLQ 30, PROMIS-29, FACT-G, and QOL-CS, have been developed to assess health-related quality of life (HRQoL). Pre- and post-treatment HRQoL measurements have been shown to be predictive factors for post-operative complications and prognostic factors for overall survival and progression-free survival in gynecological oncology patients. Patient-reported outcomes related to HRQoL are essential tools for measuring patient outcomes and enabling patient-centered clinical decision-making.This article focuses on HRQoL, providing a historical context, summarizing measurement instruments, and discussing the current understanding of the impact of gynecological cancers on HRQoL.

εγ-Thalassemia, a New Hemoglobinopathy Category.

BACKGROUND: Large ß-globin gene cluster deletions (hereditary persistence of fetal hemoglobin [Hb] or ß-, δß-, γδß-, and ϵγδß-thalassemia), are associated with widely disparate phenotypes, including variable degrees of microcytic anemia and Hb F levels. When present, increased Hb A2 is used as a surrogate marker for ß-thalassemia. Notably, ϵγδß-thalassemias lack the essential regulatory locus control region (LCR) and cause severe transient perinatal anemia but normal newborn screen (NBS) results and Hb A2 levels. Herein, we report a novel deletion of the ϵ, Aγ, Gγ, and ψß loci with intact LCR, δ-, and ß-regions in 2 women and newborn twins. METHODS: Capillary electrophoresis (CE), high-performance liquid chromatography (HPLC), DNA sequencing, multiplex ligation-dependent probe amplification (MLPA), gap-polymerase chain reaction (gap-PCR), and long-read sequencing (LRS) were performed. RESULTS: NBS showed an Hb A > Hb F pattern for both twins. At 20 months, Hb A2 was increased similarly to that in the mother and an unrelated woman. Unexplained microcytosis was absent and the twins lacked severe neonatal anemia. MLPA, LRS, and gap-PCR confirmed a 32 599 base pair deletion of ϵ (HBE1) through ψß (HBBP1) loci. CONCLUSIONS: This deletion represents a hemoglobinopathy category with a distinct phenotype that has not been previously described, an ϵγ-thalassemia. Both the NBS Hb A > F pattern and the subsequent increased Hb A2 without microcytosis are unusual. A similar deletion should be considered when this pattern is encountered and appropriate test methods selected for detection. Knowledge of the clinical impact of this new category will improve genetic counselling, with distinction from the severe transient anemia associated with ϵγδß-thalassemia.

Avaliação de um material educativo sobre higiene bucal e transtorno do espectro autista sob a ótica dos critérios do BR-CDC-CCI / Evaluation of an educational material on oral hygiene and autism spectrum disorder from the perspective of the BR-CDC-CCI criteria

Objetivo: avaliar a clareza e a qualidade das informações de um material educativo sobre higiene bucal voltado para pacientes com Transtorno do Espectro Autista (TEA) sob a ótica de critérios preconizados da versão brasileira do Índice de Comunicação Clara em Saúde (BR-CDC-CCI). Materiais e Métodos: foi realizada uma busca no sítio de busca Google (www.google.com) no dia 4 de março de 2023, utilizando os unitermos "cartilha", "higiene bucal" e "pessoa com deficiência". O critério de inclusão envolveu material educativo direcionado a cuidadores de pessoas com TEA desenvolvido por instituição brasileira. Foram excluídos materiais educativos direcionados para profissionais de saúde ou educação, bem como materiais não disponibilizados online. A primeira página de busca revelou um material educativo em saúde bucal para cuidadores de pessoas com TEA, disponibilizado online. O BR-CDC-CCI foi utilizado de forma independente, por duas cirurgiãs-dentistas, para se avaliar o material a partir dos critérios de "Mensagem principal e chamada para ação", "Linguagem", "Design da informação", "Estado da ciência (conhecimento científico), "Recomendações de comportamento", "Números" e "Riscos". Os escores obtidos pelo consenso das avaliadoras para o material, em uma escala de zero a vinte, foram alcançados em uma reunião. Resultados: o material apresentou 100% de conformidade com os critérios exigidos pelo instrumento como mensagem principal destacada, linguagem simples, design atraente, recomendações comportamentais, evidência científica atual, riscos e abordagem adequada da numeracia, demonstrando clareza e qualidade das informações. Conclusão: o material educativo intitulado "Higiene Bucal Para Pessoas Com TEA", apresentou excelente qualidade de acordo com os critérios utilizados. O mesmo cumpre seu objetivo de ajudar pais e profissionais nos cuidados à higiene bucal das pessoas com TEA.

Objective: to evaluate the clarity and quality of information in one educational material on oral hygiene aimed at patients with Autism Spectrum Disorder (ASD) according to the criteria recommended by the Brazilian version of the Clear Communication in Health Index (BR-CDC-CCI). Materials and Methods: a electronic search was carried out on the Google search site (www.google.com) on March 4th, 2023, using the keywords "cartilha", "higiene bucal" and "pessoa com deficiência". The inclusion criterion involved educational material directed to caregivers of people with ASD developed by a Brazilian institution. Educational materials directed to health or education professionals were excluded, as well as materials not available online. The first search page revealed one oral health educational material for caregivers of people with ASD, available online. The BR-CDC-CCI was used independently by two dentists to assess the material using the criteria of "Main message and call to action", "Language", "Information design", "State of the science (scientific knowledge)", "Behavior recommendations", "Numbers", and "Risks". The scores obtained by the consensus of the evaluators for the material, on a scale of zero to twenty, were reached in a meeting. Results: the material showed 100% compliance with the criteria required by the instrument as highlighted main message, simple language, attractive design, behavioral recommendations, current scientific evidence, risks and appropriate approach to numeracy, demonstrating clarity and quality of information. Conclusion: the educational material entitled "Oral Hygiene for People with Autism" proved to be excellent material and could fulfill its goal of helping parents and professionals in the oral hygiene of people with ASD.

Association between management, human resources, and care provided to patients with special healthcare needs in dental specialty centers in Brazil: A cross-sectional study.

AIMS: This study aimed to identify the association between management and human resource factors with the performance of dental care provided to patients with special health care needs (SHCN) in secondary care in Brazil in the second cycle of the Program for Quality Improvement and Access to Dental Specialty Centers (PMAQ-CEO). METHODS AND RESULTS: This study is a secondary data analysis from the second cycle from PMAQ-CEO, which evaluated 1097 Dental Specialty Centers (DSCs), conducted in 2018. Seventeen independent variables taken from dentists' training, and dental team management characteristics were analyzed to assess their influence on the reported "Performance of care for SHCN patients". An estimated score was generated from their performance on 23 questions related to the physical and human structure and work processes in the oral health care of SHCN patients in the DSCs. Negative binomial regression model with values p ≤ 0.05 were considered significant. Data analysis included residual deviation to the degree of freedom and the chi-square test. The patient care performance score with SHCN increases significantly when the DSC has a manager (RR = 1.019; CI = 1.011-1.026) and goal monitoring and analysis (RR = 1.012; CI = 1.007-1.005). By contrast, the DSCs in which the dentist is a statutory public servant (RR = 0.998; CI = 0.997-1.000) and performs additional unhealthy or hazardous duties (RR = 0.998; CI = 0.996-0.999) are less likely to provide a higher quality care. CONCLUSION: The heterogeneity and low-performance scores for dental care provided to SHCN was identified in Brazilian health services. It was possible to verify that management and human resource factors of the DSCs were associated with the performance of dental care provided to SHCN patients.

Associação entre gestão, recursos humanos e cuidados prestados a pacientes com necessidades especiais de saúde em centros de especialidades odontológicas no Brasil: um estudo transversal / Association between management, human resources, and care provided to patients with special healthcare needs in Dental Specialty Centers in Brazil: a cross-sectional study

Este estudo visou identificar a associação entre a gestão e os fatores de recursos humanos com o desempenho dos cuidados odontológicos prestados a pacientes com necessidades especiais (PNE) na atenção secundária no Brasil no segundo ciclo do Programa de Melhoria da Qualidade e Acesso a Centros de Especialidades Odontológicas (PMAQ-CEO). Trata-se de uma análise de dados secundários do segundo ciclo do PMAQ-CEO, que avaliou 1.097 Centros de Especialidades Odontológicas (CEOs), realizado em 2018. Foram analisadas 17 variáveis independentes retiradas da formação de cirurgiões-dentistas e as características de gestão de equipes odontológicas para avaliar a sua influência descrito como "Desempenho dos cuidados aos PNE". Foi gerada uma pontuação estimada a partir do seu desempenho em 23 questões relacionadas com a estrutura física e humana e processos de trabalho nos cuidados de saúde bucal de PNE nos CEOs. Foi utilizado o modelo de regressão binomial negativo e valores de p≤0.05 foram considerados significativos. A análise da qualidade do modelo incluiu o desvio residual ao grau de liberdade e o teste do qui-quadrado. A pontuação do desempenho dos cuidados de saúde dos pacientes com PNE aumenta significativamente quando o CEO tem um gestor (RR=1,019; IC=1,011-1,026) e monitorização e análise de objetivos (RR=1.012; IC=1,007-1,005). Pelo contrário, os CEOs que o dentista é funcionário público estatutário (RR=0,998; IC=0,997-1,000) e que recebe adicional de insalubridade ou periculosidade (RR=0,998; IC=0,996-0,999) possui menor probabilidade de prestar cuidados de maior qualidade. A heterogeneidade e a baixa pontuação de desempenho nos cuidados dentários prestados à PNE foi identificada nos serviços de saúde brasileiros. Foi possível verificar que os fatores de gestão e recursos humanos dos CEOs foram associados ao desempenho dos cuidados em saúde bucal prestados aos PNE.

This study aimed to identify the association between management and human resource factors with the performance of dental care provided to patients with special health care needs (SHCN) in secondary care in Brazil in the second cycle of the Program for Quality Improvement and Access to Dental Specialty Centers (PMAQCEO). Secondary data analysis from the second cycle from PMAQ-CEO, which evaluated 1,097 Dental Specialty Centers (DSCs), conducted in 2018. Seventeen independent variables taken from dentists' training, and dental team management characteristics were analyzed to assess their influence on the reported "Performance of care for SHCN patients". An estimated score was generated from their performance on 23 questions related to the physical and human structure and work processes in the oral health care of SHCN patients in the DSCs. Negative binomial regression model with values p≤0.05 were considered significant. Data analysis included residual deviation to the degree of freedom and the chi-square test. The patient care performance score with SHCN increases significantly when the DSC has a manager (RR=1.019; CI=1.011-1.026) and goal monitoring and analysis (RR=1.012; CI=1.007-1.005). By contrast, the DSCs in which the dentist is a statutory public servant (RR=0.998; CI=0.997-1.000) and performs additional unhealthy or hazardous duties (RR=0.998; CI=0.996-0.999) are less likely to provide a higher quality care. The heterogeneity and low performance scores for dental care provided to SHCN was identified in Brazilian health services. It was possible to verify that management and human resource factors of the DSCs were associated with the performance of dental care provided to SHCN patients.

Isolated anemia in patients with large granular lymphocytic leukemia (LGLL).

Patients with large granular lymphocytic leukemia (LGLL) frequently present with neutropenia. When present, anemia is usually accompanied by neutropenia and/or thrombocytopenia and isolated anemia is uncommon. We evaluated a cohort of 244 LGLL patients spanning 15 years and herein report the clinicopathologic features of 34 (14%) with isolated anemia. The patients with isolated anemia showed a significantly male predominance (p = 0.001), a lower level of hemoglobulin (p < 0.0001) and higher MCV (p = 0.017) and were less likely to have rheumatoid arthritis (p = 0.023) compared to the remaining 210 patients. Of the 34 LGLL patients with isolated anemia, 13 (38%) presented with pure red cell aplasia (PRCA), markedly decreased reticulocyte count and erythroid precursors, and more transfusion-dependence when compared to non-PRCA patients. There was no other significant clinicopathologic difference between PRCA and non-PRCA patients. 32 patients were followed for a median duration of 51 months (6-199). 24 patients were treated (11/11 PRCA and 13/21 non-PRCA patients, p < 0.02). The overall response rate to first-line therapy was 83% [8/11 (72.7%) for PRCA, 12/13 (92.3%) for non-PRCA], including 14 showing complete response and 6 showing partial response with a median response duration of 48 months (12-129). Half of non-PRCA patients who were observed experienced progressive anemia. During follow-up, no patients developed neutropenia; however, 5/27 (18.5%) patients developed thrombocytopenia. No significant difference in overall survival was noted between PRCA and non-PRCA patients. In summary, this study demonstrates the unique features of LGLL with isolated anemia and underscores the importance of recognizing LGLL as a potential cause of isolated anemia, which may benefit from disease-specific treatment. LGLL patients with PRCA were more likely to require treatment but demonstrated similar clinicopathologic features, therapeutic responses, and overall survival compared to isolated anemia without PRCA, suggesting PRCA and non-PRCA of T-LGLL belong to a common disease spectrum.

Improved Characterization of Complex ß-Globin Gene Cluster Structural Variants Using Long-Read Sequencing.

Complex insertion-deletion (indel) events in the globin genes manifest in widely variable clinical phenotypes. Many are incompletely characterized because of a historic lack of efficient methods. A more complete assessment enables improved prediction of clinical impact, which guides emerging therapeutic choices. Current methods have limited capacity for breakpoint assignment and accurate assessment of mutation extent, especially in cases containing duplications or multiple deletions and insertions. Technology, such as long-read sequencing, holds promise for significant impact in the characterization of indel events because of read lengths that span large regions, resulting in improved resolution. Four known complex ß-globin gene cluster indel types were assessed using single-molecule, real-time sequencing technology and showed high correlation with previous reports, including the Caribbean locus control deletion (g.5,305,478_5,310,336del), a large ß-gene duplication containing the Hb S mutation (g.4,640,335_5,290,171dup with g.5,248,232T>A, c.20A>T; variant allele fraction, 64%), and two nested variants (double deletions with intervening inversion): the Indian Gγ(Aγδß)0-thalassemia (g.5,246,804-5,254,275del, g.5,254,276_5,269,600inv, and g.5,269,601_5,270,442del) and the Turkish/Macedonian (δß)0 thalassemia (g.5,235,064_5,236,652del, g.5,236,653_5,244,280inv, and g.5,244,281_5,255,766del). Our data confirm long-read sequencing as an efficient and accurate method to identify these clinically significant complex events. Limitations include high-complexity sample preparation requirements, which hinder routine use in clinical laboratories. Continued improvements in sample and data workflow processes are needed to accommodate volumes in a tertiary clinical laboratory.

High-oxygen-affinity hemoglobinopathy-associated erythrocytosis: Clinical outcomes and impact of therapy in 41 cases.

We describe presenting features, treatment strategies, and follow-up events involving 41 patients (median age 39 years, range 1-81; 54% males) with high oxygen affinity (HOA) hemoglobinopathy-associated erythrocytosis, seen at our institution (1973-2020). Thirty-four (83%) patients carried ß-chain (13 Malmo, 4 Olympia, 3 San Diego, 2 Wood) and 7 (17%) α-chain (4 Dallas and one each Columbia-Missouri, Jackson, and Wayne) variants. Median (range) hemoglobin (Hgb)/hematocrit (Hct), serum erythropoietin and p50 were 18 g/dL/52.9% (16-21.9/48-66), 10.4 mIU (4-36.3), and 20 mmHg (12-25), respectively. Family history was documented in 24 patients and history of thrombosis in two (5%). Treatment included phlebotomy in 23 and antiplatelet therapy in 21 patients. At a median follow-up of 10 years, 23 (56%) patients reported one or more symptoms that were thought to be related to their increased Hct while thrombosis was documented in 10 (24%) patients. Neither Hgb/Hct level nor active phlebotomy showed a significant correlation with either thrombotic or nonthrombotic symptoms (p > .1 in all instances). Among 23 pregnancies recorded, 78% resulted in live births and no fetal loss was attributed to erythrocytosis. The current study does not implicate Hgb/Hct level as a major contributor of morbidity in HOA hemoglobinopathy-associated erythrocytosis and suggests limited therapeutic value for phlebotomy.

Clinical Heterogeneity of the VEXAS Syndrome: A Case Series.

The objective of this study is to describe the clinical features and outcomes of patients with the newly defined vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic (VEXAS) syndrome. Nine men with somatic mutations in the UBA1 gene were identified; the most frequent variant was p.Met41Thr (7 of 9, 78%). The median age at VEXAS diagnosis was 74 (67, 76.5) years, and patients had a median duration of symptoms for 4 years before diagnosis. Refractory constitutional symptoms (88%), ear and nose chondritis (55%), and inflammatory arthritis (55%) were common clinical features. Vasculitis was noted in 44%. All patients had significantly elevated inflammatory markers and macrocytic anemia. Thrombocytopenia was present in 66% at diagnosis of VEXAS. Eight patients had bone marrow biopsies performed. All bone marrows were hypercellular, and there was vacuolization of the erythroid (100%) or myeloid precursors (75%). Glucocorticoids attenuated symptoms at prednisone doses ≥20 mg per day, but no other immunosuppressive agent showed consistent long-term control of disease. One patient with coexisting plasma-cell myeloma received plasma-cell-directed therapy with improvement of the inflammatory response, which is a novel finding. In conclusion, VEXAS syndrome is a clinically heterogeneous, treatment-refractory inflammatory condition caused by somatic mutation of the UBA1 gene. Patients often present with overlapping rheumatologic manifestations and persistent hematologic abnormalities. As such, internists and subspecialists, including pathologists, should be aware of this condition to avert diagnostic delay, now that the etiology of this syndrome is known.

Spectrum of hematological malignancies, clonal evolution and outcomes in 144 Mayo Clinic patients with germline predisposition syndromes.

Germline predisposition syndromes (GPS) result from constitutional aberrations in tumor suppressive and homeostatic genes, increasing risk for neoplasia in affected kindred. In this study, we present clinical and genomic data on 144 Mayo Clinic patients with GPS; 59 evaluated prospectively using an algorithm-based diagnostic approach in the setting of a dedicated GPS/ inherited bone marrow failure syndrome (IBMFS) clinic. Seventy-two (50%) patients had IBMFS (telomere biology disorders-32,Fanconi anemia-18, Diamond Blackfan Anemia - 11, congenital neutropenia-5, Schwachman-Diamond Syndrome-5 and Bloom Syndrome-1), 27 (19%) had GPS with antecedent thrombocytopenia (RUNX1-FPD-15, ANKRD26-6, ETV6-2, GATA1-1, MPL-3), 28 (19%) had GPS without antecedent thrombocytopenia (GATA2 haploinsufficiency-16, DDX41-10, CBL-1 and CEBPA-1) and 17 (12%) had general cancer predisposition syndromes (ataxia telangiectasia-7, heterozygous ATM variants-3, CHEK2-2, TP53-2, CDK2NA-1, NF1-1 and Nijmegen Breakage Syndrome-1). Homozygous and heterozygous ATM pathogenic variants were exclusively associated with lymphoproliferative disorders (LPD), while DDX41 GPS was associated with LPD and myeloid neoplasms. The use of somatic NGS-testing identified clonal evolution in GPS patients, with ASXL1, RAS pathway genes, SRSF2 and TET2 being most frequently mutated. Fifty-two (91%) of 59 prospectively identified GPS patients had a change in their management approach, including additional GPS-related screening in 42 (71%), referral for allogenic HSCT workup and screening of related donors in 16 (27%), medication initiation and selection of specific conditioning regimens in 14 (24%), and genetic counseling with specific intent of fertility preservation and preconceptual counseling in 10 (17%) patients; highlighting the importance of dedicated GPS screening, detection and management programs for patients with hematological neoplasms.

Interpreting sulfhemoglobin and methemoglobin in patients with cyanosis: An overview of patients with M-hemoglobin variants.

INTRODUCTION: Methemoglobin (MetHb) and sulfhemoglobin (SHb) measurements are useful in the evaluation of cyanosis. When one or both values are elevated, additional analysis is important to establish the etiology of the disorder. Methemoglobinemia occurs from acquired or hereditary causes with diverse treatment considerations, while true sulfhemoglobinemia is only acquired and treatment is restricted to toxin removal. Some toxic exposures can result in a dual increase in MetHb and SHb. Hereditary conditions, such as M-Hemoglobin variants (M-Hbs), can result in increased MetHb and/or SHb values but are clinically compensated and do not require treatment if they are cyanotic but otherwise clinically well. METHODS: Herein, we report 53 hemoglobin variant cases that have associated MetHb and SHb levels measured by an adapted Evelyn-Malloy laboratory assay method. RESULTS: Our data indicate M-Hbs cause variable patterns of MetHb and SHb elevation in a fairly reproducible pattern for the particular variant. In particular, α globin chain M-Hbs can mimic acquired sulfhemoglobinemia due to an isolated increased SHb value. CONCLUSION: If the patient appears clinically well other than cyanosis, M-Hbs should be considered early in the evaluation process to differentiate from acquired conditions to avoid unnecessary testing and treatment regimens and prompt genetic counseling.

Genetic and Clinical Studies of Patients With Increased Multinucleated Megakaryocytes in Bone Marrow as an Isolated Finding: A Diagnostic Pitfall for Myelodysplastic Syndrome.

The presence of increased multinucleated megakaryocytes (aka osteoclast-like) is considered a dysplastic feature in myelodysplastic syndrome; however, its clinical significance in isolation is uncertain. Herein, we report the clinicopathologic and genetic features of 18 such cases of 40,539 bone marrow biopsies spanning 10 years. All 18 patients had ≥25% multinucleated megakaryocytes in otherwise normal bone marrow biopsies, which were evaluated for plasma cell neoplasms (n=9), lymphoma (n=4), or anemia/neutropenia (n=5). None of the 17 patients tested showed acquired cytogenetic abnormalities. Sixteen patients underwent targeted gene panel next-generation sequencing: 9 patients had no pathogenic mutations; 3 harbored a single pathogenic mutation with variant allele frequencies of 7.5%, 7.6%, and 10.7%, likely representing clonal hematopoiesis of indeterminate potential; 1 had 2 pathogenic mutations, 1 of which had a variant allele frequency >20%. Fourteen of 18 patients had a follow-up period >6 months (median: 36.5 mo, range: 7 to 110 mo) and no patients developed a new-onset cytopenia, a progressive cytopenia, or a myeloid neoplasm. The patient with 2 mutations had persistent anemia, worrisome for an emerging MDS. However, given the absence of thrombocytopenia, increased multinucleated megakaryocytes in this patient could be an unrelated incidental finding. Our study indicates that increased multinucleated megakaryocytes as an isolated finding is a rare phenomenon, and this sole morphologic finding is not diagnostic of myelodysplastic syndrome. Diagnostic approaches in the presence of increased multinucleated megakaryocytes are proposed based on different clinical and pathologic scenarios.

Pathologic Spectrum and Molecular Landscape of Myeloid Disorders Harboring SF3B1 Mutations.

OBJECTIVES: SF3B1 mutations are the most common mutations in myelodysplastic syndromes (MDS). The International Working Group for the Prognosis of MDS (IWG-PM) recently proposed SF3B1-mutant MDS (SF3B1-mut-MDS) as a distinct disease subtype. We evaluated the spectrum and molecular landscape of SF3B1-mutated myeloid disorders and assessed the prognostication in MDS harboring SF3B1 mutations (MDS-SF3B1). METHODS: Cases were selected by retrospective review. Clinical course and laboratory and clinical findings were collected by chart review. SF3B1-mut-MDS was classified following IWG-PM criteria. RESULTS: SF3B1 mutations were identified in 75 of 955 patients, encompassing a full spectrum of myeloid disorders. In MDS-SF3B1, Revised International Prognostic Scoring System (IPSS-R) score greater than 3 and transcription factor (TF) comutations were adverse prognostic markers by both univariate and multivariate analyses. We confirmed the favorable outcome of IWG-PM-defined SF3B1-mut-MDS. Interestingly, it did not show sharp prognostic differentiation within MDS-SF3B1. CONCLUSIONS: SF3B1 mutations occur in the full spectrum of myeloid disorders. We independently validated the favorable prognostication of IWG-PM-defined SF3B1-mut-MDS. However it may not provide sharp prognostication within MDS-SF3B1 where IPSS-R and TF comutations were prognostic-informative. Larger cohort studies are warranted to verify these findings and refine MDS-SF3B1 prognostication.