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ABSTRACT: Thrombophilia is one of the principal features of paroxysmal nocturnal hemoglobinuria (PNH) and constitutes the main cause of disease morbidity/mortality. Anticomplement treatment has revolutionized the natural history of PNH, with control of the hemolytic process and abolition of thrombotic events (TEs). However, no guidelines exist for the management of thromboembolic complications in this setting, with type and duration of anticoagulation depending on individual practices. Besides, a scarcity of data is present on the efficacy of direct oral anticoagulants (DOACs). Herein, we accrued a large real-world cohort of patients with PNH from 4 US centers to explore features, predictors of TE, and anticoagulation strategies. Among 267 patients followed up for a total of 2043 patient-years, 56 (21%) developed TEs. These occurred at disease onset in 43% of cases, involving more frequently the venous system, typically as Budd-Chiari syndrome. Rate of TEs was halved in patients receiving complement inhibitors (21 vs 40 TEs per 1000 patient-years in untreated cases, with a 2-year cumulative incidence of thrombosis of 3.9% vs 18.3%, respectively), and varied according to PNH granulocytes and erythrocytes clone size, type, disease activity parameters, as well as number (≥2 mutations, or less) and variant allelic frequency of PIGA mutations. Anticoagulation with warfarin (39%), DOACs (37%), and low-molecular weight heparin (16%) was administered for a median of 29 months (interquartile range [IQR], 9-61.8). No thrombotic recurrence was observed in 19 patients treated with DOACs at a median observation of 17.1 months (IQR, 8.9-45) whereas 14 cases discontinued anticoagulation without TE recurrence at a median time of 51.4 months (IQR, 29.9-86.8).
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Anticoagulantes , Hemoglobinuria Paroxística , Trombosis , Humanos , Hemoglobinuria Paroxística/complicaciones , Hemoglobinuria Paroxística/tratamiento farmacológico , Masculino , Femenino , Persona de Mediana Edad , Trombosis/etiología , Trombosis/tratamiento farmacológico , Adulto , Anciano , Anticoagulantes/uso terapéutico , Estudios de SeguimientoRESUMEN
Idiopathic aplastic anemia (IAA) is a rare autoimmune bone marrow failure (BMF) disorder initiated by a human leukocyte antigen (HLA)-restricted T-cell response to unknown antigens. As in other autoimmune disorders, the predilection for certain HLA profiles seems to represent an etiologic factor; however, the structure-function patterns involved in the self-presentation in this disease remain unclear. Herein, we analyzed the molecular landscape of HLA complexes of a cohort of 300 IAA patients and almost 3000 healthy and disease controls by deeply dissecting their genotypic configurations, functional divergence, self-antigen binding capabilities, and T-cell receptor (TCR) repertoire specificities. Specifically, analysis of the evolutionary divergence of HLA genotypes (HED) showed that IAA patients carried class II HLA molecules whose antigen-binding sites were characterized by a high level of structural homology, only partially explained by specific risk allele profiles. This pattern implies reduced HLA binding capabilities, confirmed by binding analysis of hematopoietic stem cell (HSC)-derived self-peptides. IAA phenotype was associated with the enrichment in a few amino acids at specific positions within the peptide-binding groove of DRB1 molecules, affecting the interface HLA-antigen-TCR ß and potentially constituting the basis of T-cell dysfunction and autoreactivity. When analyzing associations with clinical outcomes, low HED was associated with risk of malignant progression and worse survival, underlying reduced tumor surveillance in clearing potential neoantigens derived from mechanisms of clonal hematopoiesis. Our data shed light on the immunogenetic risk associated with IAA etiology and clonal evolution and on general pathophysiological mechanisms potentially involved in other autoimmune disorders.
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Anemia Aplásica/genética , Genes MHC Clase II , Antígenos HLA-D/genética , Adulto , Alelos , Estudios de Cohortes , Femenino , Genotipo , Humanos , Masculino , Persona de Mediana EdadRESUMEN
While red blood cells (RBCs) and granulocytes have been more studied, platelets and reticulocytes are not commonly used in paroxysmal nocturnal hemoglobinuria (PNH) flow-cytometry and less is known about susceptibility to complement-mediated destruction and effects of anti-complement therapy on these populations. We performed flow-cytometry of RBCs and granulocytes in 90 PNH patients and of platelets and reticulocytes in a subgroup (N = 36), to unveil perturbations of these populations during PNH disease course before and after anti-complement treatment. We found that platelets and reticulocytes were less sensitive to complement-mediated lysis than RBCs but not as resistant as granulocytes, as shown by mean sensitive fraction (difference in a given PNH population vs. PNH granulocyte clone size). In treated patients, reticulocytes, platelets, RBCs (with differences between type II and III) and granulocytes significantly increased post-treatment, confirming the role of PNH hematopoiesis within the context of anti-complement therapy. Moreover, we found that PNH platelet clone size reflects PNH granulocyte clone size. Finally, we established correlations between sensitive fraction of PNH cell-types and thrombosis. In sum, we applied a flow-cytometry panel for investigation of PNH peripheral blood populations' perturbations before and after eculizumab treatment to explore complement-sensitivity and kinetics of these cells during the disease course.
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Anticuerpos Monoclonales Humanizados/uso terapéutico , Células Sanguíneas/efectos de los fármacos , Inactivadores del Complemento/uso terapéutico , Hemoglobinuria Paroxística/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Anticuerpos Monoclonales Humanizados/farmacología , Células Sanguíneas/citología , Plaquetas/citología , Plaquetas/efectos de los fármacos , Inactivadores del Complemento/farmacología , Eritrocitos/citología , Eritrocitos/efectos de los fármacos , Células Eritroides/citología , Células Eritroides/efectos de los fármacos , Femenino , Citometría de Flujo , Granulocitos/citología , Granulocitos/efectos de los fármacos , Hemoglobinuria Paroxística/sangre , Humanos , Masculino , Persona de Mediana Edad , Reticulocitos/citología , Reticulocitos/efectos de los fármacos , Adulto JovenRESUMEN
The nucleoside analogue decitabine can deplete the epigenetic regulator DNA methyltransferase 1 (DNMT1), an effect that occurs, and is saturated at, low concentrations/doses. A reason to pursue this molecular-targeted effect instead of the DNA damage/cytotoxicity produced with high concentrations/doses, is that non-cytotoxic DNMT1-depletion can cytoreduce even p53-null myeloid malignancies while sparing normal haematopoiesis. We thus identified minimum doses of decitabine (0·1-0·2 mg/kg) that deplete DNMT1 without off-target anti-metabolite effects/cytotoxicity, and then administered these well-tolerated doses frequently 1-2X/week to increase S-phase dependent DNMT1-depletion, and used a Myeloid Malignancy Registry to evaluate long-term outcomes in 69 patients treated this way. Consistent with the scientific rationale, treatment was well-tolerated and durable responses were produced (~40%) in genetically heterogeneous disease and the very elderly.
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Antimetabolitos Antineoplásicos/uso terapéutico , Decitabina/uso terapéutico , Trastornos Mieloproliferativos/tratamiento farmacológico , Anciano , Anciano de 80 o más Años , Antimetabolitos Antineoplásicos/farmacología , Decitabina/farmacología , Femenino , Humanos , MasculinoRESUMEN
The therapy algorithm for severe aplastic anaemia (sAA) is established but moderate AA (mAA), which likely reflects a more diverse pathogenic mechanism, often represents a treatment/management conundrum. A cohort of AA patients (n = 325) was queried for those with non-severe disease using stringent criteria including bone marrow hypocellularity and chronic persistence of moderately depressed blood counts. As a result, we have identified and analyzed pathological and clinical features in 85 mAA patients. Progression to sAA and direct clonal evolution (paroxysmal nocturnal haemoglobinuria/acute myeloid leukaemia; PNH/AML) occurred in 16%, 11% and 1% of mAA cases respectively. Of the mAA patients who received immunosuppressive therapy, 67% responded irrespective of time of initiation of therapy while conservatively managed patients showed no spontaneous remissions. Genomic analysis of mAA identified evidence of clonal haematopoiesis with both persisting and remitting patterns at low allelic frequencies; with more pronounced mutational burden in sAA. Most of the mAA patients have autoimmune pathogenesis similar to those with sAA, but mAA contains a mix of patients with diverse aetiologies. Although progression rates differed between mAA and sAA (P = 0·003), cumulative incidences of mortalities were only marginally different (P = 0·095). Our results provide guidance for diagnosis/management of mAA, a condition for which no current standard of care is established.
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Anemia Aplásica/patología , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Algoritmos , Anemia Aplásica/sangre , Anemia Aplásica/genética , Anemia Aplásica/terapia , Enfermedades Autoinmunes/genética , Enfermedades Autoinmunes/patología , Benzoatos/uso terapéutico , Transfusión Sanguínea , Médula Ósea/patología , Niño , Preescolar , Evolución Clonal , Terapia Combinada , Danazol/uso terapéutico , Manejo de la Enfermedad , Progresión de la Enfermedad , Femenino , Hematopoyesis , Trasplante de Células Madre Hematopoyéticas , Células Madre Hematopoyéticas/patología , Hemoglobinuria Paroxística/etiología , Hemoglobinuria Paroxística/patología , Humanos , Hidrazinas/uso terapéutico , Inmunosupresores/uso terapéutico , Estimación de Kaplan-Meier , Leucemia Mieloide Aguda/patología , Masculino , Persona de Mediana Edad , Mutación , Pirazoles/uso terapéutico , Índice de Severidad de la Enfermedad , Adulto JovenAsunto(s)
Médula Ósea/patología , Inmunoglobulina M/análisis , Gammopatía Monoclonal de Relevancia Indeterminada/complicaciones , Aplasia Pura de Células Rojas/complicaciones , Anciano , Humanos , Masculino , Persona de Mediana Edad , Gammopatía Monoclonal de Relevancia Indeterminada/patología , Aplasia Pura de Células Rojas/patología , Macroglobulinemia de Waldenström/complicaciones , Macroglobulinemia de Waldenström/patologíaRESUMEN
Haematological profile of patients with oral sub mucous fibrosis (OSMF) and its correlation with the severity of OSMF is evaluated. The study comprised of sixty participants with clinical diagnoses. They were divided into smaller groups based on the OSMF stage. Sixty age and gender matched healthy controls were chosen among patients presenting for routine hematological examinations and free of systemic illnesses. Assessment of iron, hemoglobin, and red cell indices in all study participants was carried out. It was observed that the values of haematological tests like (Hb (g/dL), PCV, MCV (fl), MCH, MCHC, Iron (mg/dL) and Vitamin B12 (pg/Ml) was greater in normal subjects as compared to OSMF patients. Values were found to decrease further as the severity (staging) of OSMF increased among OSMF patients. The findings were statistically significant showing decrease in the values of different haematological parameters as the stage of OSMF progressed from stage I to stage III.
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Immuno-histochemical evaluation of CD34 in oral lichen planus (OLP) and Oral Submucous Fibrosis (OSMF) is of interest to dentist.20 specimens of normal oral mucosa (buccal mucosa/gingiva tissue) from patients who had extractions performed as part of orthodontic treatment comprised Group I, the control group. Group II comprised 30 individuals with a diagnosis of oral lichen planus. 30 OSMF cases with diagnoses is Group III. These 80 specimens were all given consideration when choosing for CD34immuno-histochemical staining. The CD34 was greater in all categories of OLP and OSMF when compared to normal controls. Maximum CD34 expression was observed in erosive OLP (147.41±17.60) followed by OSMF (116.01 ±11.72) and reticular OLP (105.01±11.62). Data was statistically significant (p<0.001).Immunohistochemistry of CD34 evaluation is a potential diagnostic marker for OLP and OSMF.
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ABSTRACT: Severe aplastic anemia (SAA) is a rare hematologic condition for which there is no clear management algorithm. A panel of 11 experts on adult and pediatric aplastic anemia was assembled and, using the RAND/University of California, Los Angeles modified Delphi panel method, evaluated >600 varying patient care scenarios to develop clinical recommendations for the initial and subsequent management of patients of all ages with SAA. Here, we present the panel's recommendations to rule out inherited bone marrow failure syndromes, on supportive care before and during first-line therapy, and on first-line (initial management) and second-line (subsequent management) therapy of acquired SAA, focusing on when transplant vs medical therapy is most appropriate. These recommendations represent the consensus of 11 experts informed by published literature and experience. They are intended only as general guidance for experienced clinicians who treat patients with SAA and are in no way intended to supersede individual physician and patient decision making. Current and future research should validate this consensus using clinical data. Once validated, we hope these expert panel recommendations will improve outcomes for patients with SAA.
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Anemia Aplásica , Consenso , Técnica Delphi , Manejo de la Enfermedad , Anemia Aplásica/terapia , Anemia Aplásica/diagnóstico , HumanosAsunto(s)
Alemtuzumab/administración & dosificación , Enfermedades de la Médula Ósea/tratamiento farmacológico , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Alemtuzumab/efectos adversos , Anemia Aplásica/tratamiento farmacológico , Enfermedades de la Médula Ósea/etiología , Enfermedades de la Médula Ósea/mortalidad , Femenino , Estudios de Seguimiento , Humanos , Leucemia Linfocítica Granular Grande/tratamiento farmacológico , Masculino , Persona de Mediana Edad , Aplasia Pura de Células Rojas/tratamiento farmacológico , Terapia Recuperativa/métodos , Análisis de Supervivencia , Resultado del Tratamiento , Adulto JovenRESUMEN
Even if local anesthetic is still the mainstay of pain management in dentistry, research will keep striving for novel and effective pain management techniques. The majority of research efforts are focused on improving anesthetic medications, delivery systems, and related methods. There are more recent technologies available that can assist the dentist in providing better pain relief with fewer unpleasant injections and fewer negative adverse effects. The purpose of the current review of the literature is to compile evidence that will convince dentists to employ modern local anesthetics, as well as other methods and techniques to reduce patient discomfort while administering anesthesia.
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Background: To compare and correlate the relationship between body mass index (BMI) and blood and salivary glucose (mean values) in patients with diabetes and non-diabetic control group patients. Materials and Methods: In the study, 100 patients were included, 50 patients each-patients with diabetes and non-diabetic control group. Each patient had their BMI measured as well as unstimulated whole saliva collected and blood drawn. Results: When compared to BMI, blood glucose (mean), and salivary glucose (mean) in healthy controls, BMI, blood glucose, and salivary glucose values in diabetic patients were considerably higher. Conclusion: Patients who have a higher BMI are more likely to develop diabetes.
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PURPOSE: Secondary myeloid neoplasms (sMNs) remain the most serious long-term complications in patients with aplastic anemia (AA) and paroxysmal nocturnal hemoglobinuria (PNH). However, sMNs lack specific predictors, dedicated surveillance measures, and early therapeutic interventions. PATIENTS AND METHODS: We studied a multicenter, retrospective cohort of 1,008 patients (median follow-up 8.6 years) with AA and PNH to assess clinical and molecular determinants of clonal evolution. RESULTS: Although none of the patients transplanted upfront (n = 117) developed clonal complications (either sMN or secondary PNH), the 10-year cumulative incidence of sMN in nontransplanted cases was 11.6%. In severe AA, older age at presentation and lack of response to immunosuppressive therapy were independently associated with increased risk of sMN, whereas untreated patients had the highest risk among nonsevere cases. The elapsed time from AA to sMN was 4.5 years. sMN developed in 94 patients. The 5-year overall survival reached 40% and was independently associated with bone marrow blasts at sMN onset. Myelodysplastic syndrome with high-risk phenotypes, del7/7q, and ASXL1, SETBP1, RUNX1, and RAS pathway gene mutations were the most frequent characteristics. Cross-sectional studies of clonal dynamics from baseline to evolution revealed that PIGA/human leukocyte antigen lesions decreased over time, being replaced by clones with myeloid hits. PIGA and BCOR/L1 mutation carriers had a lower risk of sMN progression, whereas myeloid driver lesions marked the group with a higher risk. CONCLUSION: The risk of sMN in AA is associated with disease severity, lack of response to treatment, and patients' age. sMNs display high-risk morphological, karyotypic, and molecular features. The landscape of acquired somatic mutations is complex and incompletely understood and should be considered with caution in medical management.
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Anemia Aplásica , Hemoglobinuria Paroxística , Humanos , Anemia Aplásica/genética , Anemia Aplásica/patología , Anemia Aplásica/terapia , Hemoglobinuria Paroxística/genética , Estudios Retrospectivos , Estudios Transversales , Evolución Clonal/genéticaRESUMEN
Genomic mutations drive the pathogenesis of myelodysplastic syndromes and acute myeloid leukemia. While morphological and clinical features have dominated the classical criteria for diagnosis and classification, incorporation of molecular data can illuminate functional pathobiology. Here we show that unsupervised machine learning can identify functional objective molecular clusters, irrespective of anamnestic clinico-morphological features, despite the complexity of the molecular alterations in myeloid neoplasia. Our approach reflects disease evolution, informed classification, prognostication, and molecular interactions. We apply machine learning methods on 3588 patients with myelodysplastic syndromes and secondary acute myeloid leukemia to identify 14 molecularly distinct clusters. Remarkably, our model shows clinical implications in terms of overall survival and response to treatment even after adjusting to the molecular international prognostic scoring system (IPSS-M). In addition, the model is validated on an external cohort of 412 patients. Our subclassification model is available via a web-based open-access resource ( https://drmz.shinyapps.io/mds_latent ).
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Leucemia Mieloide Aguda , Síndromes Mielodisplásicos , Trastornos Mieloproliferativos , Humanos , Síndromes Mielodisplásicos/diagnóstico , Síndromes Mielodisplásicos/genética , Síndromes Mielodisplásicos/patología , Mutación , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patologíaRESUMEN
Using a range of health-related quality of life (HRQoL) instruments, most - but not all - studies of myelodysplastic syndromes (MDS) have reported that lower hemoglobin levels and red blood cell transfusion dependency are associated with worse HRQoL. In addition, some MDS treatments may significantly improve HRQoL, particularly among those patients who respond to therapy; however, the majority of these studies were underpowered for this secondary endpoint. Furthermore, decreased HRQoL has been associated with worse survival outcomes, and HRQoL scores can be used to refine classical prognostic systems. Despite the subjective nature of HRQoL, the importance and validity of measuring it in trials and clinical practice are increasingly being recognized, but properly validated MDS-specific instruments are required. We describe what is currently known about HRQoL in patients with MDS, and the limitations of measuring HRQoL, and we provide some recommendations to improve the measurement of this outcome in future trials.
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Síndromes Mielodisplásicos , Calidad de Vida , Transfusión de Eritrocitos/métodos , Humanos , Síndromes Mielodisplásicos/diagnóstico , Síndromes Mielodisplásicos/terapia , PronósticoRESUMEN
Application of next generation sequencing (NGS) has shed light on the molecular heterogeneity of hematological malignancies. NGS panels targeting recurrent mutations have become common in many large centers and commercial laboratories. However, its impact in clinical practice is unclear. We sought to characterize the use of NGS at a tertiary care center in an observational study of 343 patients with suspected hematological malignancies. We found that NGS changed or refined the clinical and pathologic diagnosis in 9% of patients and affected management decisions in 65% (including clinical trial eligibility, targeted therapy selection, and consideration for stem cell transplantation). This study emphasizes early incorporation of NGS in clinical practice while also highlighting the present limitations. As our understanding of these disorders increases and more clinically relevant genetic targets emerge, it will be important to refine the molecular testing strategy to deliver personalized medicine given the high cost associated with this technology.
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Neoplasias Hematológicas , Secuenciación de Nucleótidos de Alto Rendimiento , Neoplasias Hematológicas/diagnóstico , Neoplasias Hematológicas/genética , Neoplasias Hematológicas/terapia , Humanos , Técnicas de Diagnóstico Molecular , MutaciónRESUMEN
TCR repertoire diversification constitutes a foundation for successful immune reconstitution after allogeneic hematopoietic cell transplantation (allo-HCT). Deep TCR Vß sequencing of 135 serial specimens from a cohort of 35 allo-HCT recipients/donors was performed to dissect posttransplant TCR architecture and dynamics. Paired analysis of clonotypic repertoires showed a minimal overlap with donor expansions. Rarefied and hyperexpanded clonotypic patterns were hallmarks of T cell reconstitution and influenced clinical outcomes. Donor and pretransplant TCR diversity as well as divergence of class I human leukocyte antigen genotypes were major predictors of recipient TCR repertoire recovery. Complementary determining region 3-based specificity spectrum analysis indicated a predominant expansion of pathogen- and tumor-associated clonotypes in the late post-allo-HCT phase, while autoreactive clones were more expanded in the case of graft-versus-host disease occurrence. These findings shed light on post-allo-HCT adaptive immune reconstitution processes and possibly help in tracking alloreactive responses.
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Inmunidad Adaptativa , Regiones Determinantes de Complementariedad/inmunología , Enfermedad Injerto contra Huésped/inmunología , Antígenos HLA/inmunología , Trasplante de Células Madre Hematopoyéticas , Receptores de Antígenos de Linfocitos T alfa-beta/inmunología , Células Clonales/inmunología , Epítopos , Perfil Genético , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Trasplante de Células Madre Hematopoyéticas/métodos , Humanos , Reconstitución Inmune , Receptores de Antígenos de Linfocitos T/inmunología , Análisis de Secuencia de Proteína , Trasplante Homólogo/efectos adversos , Trasplante Homólogo/métodosRESUMEN
PURPOSE OF REVIEW: The lack of fully effective therapies to alter the natural course of myelodysplastic syndromes (MDS) leads to chronic morbidity, mortality and affects quality of life (QoL). Since existing therapies outside of hematopoietic cell transplantation (HCT) are not curative, there is a growing interest in incorporating patient-reported outcomes (PROs) as meaningful endpoints for these patients in research and clinical practice. RECENT FINDINGS: Currently, there are limited numbers of studies reporting the impact of MDS therapeutics on PROs to guide clinical decision-making and increase patient satisfaction. However, clinical trials that have incorporated QoL outcomes have demonstrated positive results with the use of growth factors, hypomethylating agents, and lenalidomide. Here we review and highlight the importance of harnessing the power of PROs as part of a comprehensive efficacy evaluation to ultimately deliver superior patient-centered care across the spectrum of MDS. As our understanding of MDS continues to increase, adapting the metrics of these outcome measurements will be equally important as the alteration of the natural history in developing new therapies.