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1.
Medicine (Baltimore) ; 99(40): e22505, 2020 Oct 02.
Artigo em Inglês | MEDLINE | ID: mdl-33019449

RESUMO

RATIONALE: Neuroblastoma (NB) can occur in any part of the sympathetic nervous system, and it is highly heterogeneous. Tumors that only involve bone marrow and bone lesions without solid masses have rarely been reported. PATIENT CONCERNS: A 2-year-old girl child presented with recurrent fever, accompanied by pain in both lower limbs for more than 1 month. DIAGNOSE: Bone marrow examination revealed NB cell invasion. Femoral and multiple vertebral lesions were observed by MRI, while head MRI, chest CT, abdominal CT, and pelvic CT showed no solid mass. INTERVENTIONS: The child received the standard therapy for high-risk NB. OUTCOMES: She was sensitive to the initial chemotherapy protocol. Two years later, a bone marrow examination confirmed NB recurrence. LESSONS: The prognosis of this special type of NB was not improved mainly based on common chemotherapy and local radiotherapy, and new treatment strategies should be explored.


Assuntos
Medula Óssea/patologia , Neoplasias Ósseas/diagnóstico por imagem , Neoplasias Ósseas/patologia , Neuroblastoma/patologia , Exame de Medula Óssea , Neoplasias Ósseas/diagnóstico , Pré-Escolar , Feminino , Humanos , Imagem por Ressonância Magnética , Neuroblastoma/diagnóstico , Tomografia Computadorizada por Raios X
4.
Medicine (Baltimore) ; 99(39): e22299, 2020 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-32991435

RESUMO

INTRODUCTION: Hemophagocytic lymphohistiocytosis (HLH) is a condition characterized by a hyperinflammatory state and persistent macrophage activation, resulting in reactive phagocytosis of the hematopoietic elements. In children, it is usually a hereditary disorder, while in adults it is usually acquired secondary to viral infections, collagenoses, or tumors. Although accounting for 10% of hematologic malignancies, HLH is rarely associated with multiple myeloma (MM) and other plasmacytic dyscrasias. PATIENT CONCERNS: A 64-year-old Brazilian man seeked medical care with a 3-month history of intermittent fever, weight loss, night sweats, and progressive anemic symptoms. DIAGNOSIS: Total blood count showed severe bicytopenia (normocytic-normochromic anemia and thrombocytopenia), biochemical exams showed elevation of creatinine, as well as monoclonal peak in serum protein electrophoresis, high IgA dosage, and serum immunofixation with IgA kappa paraprotein. Bone marrow biopsy showed 30% of monoclonal and phenotypically anomalous plasmocytes, confirming the diagnosis of MM. Diagnosis of HLH was established by the presence of clinical and laboratory criteria: fever, splenomegaly, cytopenias, hypofibrinogenemia, hyperferritinemia, elevation of triglycerides, and several figures of erythrophagocytosis in bone marrow aspirate. INTERVENTIONS: The patient experienced pulse therapy with methylprednisolone for hemophagocytic lymphohistiocytosis, followed by initial therapy for multiple myeloma with cyclophosphamide and dexamethasone. OUTCOMES: Once the diagnosis of MM and secondary hemophagocytic syndrome was established, the patient had a rapid clinical deterioration despite the established therapeutic measures, evolving with cardiovascular failure, acute liver failure, acute disseminated intravascular coagulation, worsening renal dysfunction requiring dialysis support, respiratory dysfunction, and lowering of consciousness, characterizing rapid multiple organ dysfunction, ultimately leading to the death of the patient. INNOVATION: Here, we aimed to describe the sixth reported case of HLH associated with MM, according to cases cataloged in the PubMed database, and the first case evaluated by 18-fluordeoxyglucose positron emission tomography (18-FDG-PETCT). CONCLUSION: Our case report seeks to provide support for a better clinical and laboratory characterization of this rare paraneoplastic entity associated with MM, and aims to call the attention of hematologists and intensivists to this condition that falls within the scope of the differential diagnosis of rapid onset multiple organ failure in patients with plasmacytic neoplasms.


Assuntos
Linfo-Histiocitose Hemofagocítica/tratamento farmacológico , Linfo-Histiocitose Hemofagocítica/etiologia , Mieloma Múltiplo/complicações , Mieloma Múltiplo/tratamento farmacológico , Anemia/sangue , Anemia/etiologia , Antineoplásicos Alquilantes/administração & dosagem , Antineoplásicos Alquilantes/uso terapêutico , Medula Óssea/patologia , Brasil/epidemiologia , Ciclofosfamida/administração & dosagem , Ciclofosfamida/uso terapêutico , Dexametasona/administração & dosagem , Dexametasona/uso terapêutico , Quimioterapia Combinada , Evolução Fatal , Febre/diagnóstico , Febre/etiologia , Glucocorticoides/administração & dosagem , Glucocorticoides/uso terapêutico , Humanos , Linfo-Histiocitose Hemofagocítica/sangue , Linfo-Histiocitose Hemofagocítica/diagnóstico , Masculino , Metilprednisolona/administração & dosagem , Metilprednisolona/uso terapêutico , Pessoa de Meia-Idade , Mieloma Múltiplo/metabolismo , Insuficiência de Múltiplos Órgãos/complicações , Paraproteinemias/sangue , Plasmócitos/patologia , Esplenomegalia/diagnóstico , Esplenomegalia/etiologia , Trombocitopenia/sangue , Trombocitopenia/etiologia , Perda de Peso
5.
PLoS One ; 15(8): e0237155, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32866200

RESUMO

BACKGROUND: Stringent complete response (sCR) is used as a deeper response category than complete response (CR) in multiple myeloma (MM) but may be of limited value in the era of minimal residual disease (MRD) testing. METHODS: Here, we used 4-colour multiparametric flow cytometry (MFC) or next-generation sequencing (NGS) of immunoglobulin genes to analyse and compare the prognostic impact of sCR and MRD monitoring. We included 193 treated patients in two institutions achieving CR, for which both bone marrow aspirates and biopsies were available. RESULTS: We found that neither the serum free light chain ratio, clonality by immunohistochemistry (IHC) nor plasma cell bone marrow infiltration identified CR patients at distinct risk. Patients with sCR had slightly longer progression-free survival. Nevertheless, persistent clonal bone marrow disease was detectable using MFC or NGS and was associated with significantly inferior outcomes compared with MRD-negative cases. CONCLUSION: Our results confirm that sCR does not predict a different outcome and indicate that more sensitive techniques are able to identify patients with differing prognoses. We suggest that MRD categories should be implemented over sCR for the future classification of MM responses.


Assuntos
Mieloma Múltiplo/terapia , Adulto , Idoso , Idoso de 80 Anos ou mais , Medula Óssea/patologia , Confiabilidade dos Dados , Feminino , Citometria de Fluxo/métodos , Seguimentos , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Humanos , Cadeias Leves de Imunoglobulina/sangue , Cadeias Leves de Imunoglobulina/genética , Masculino , Pessoa de Meia-Idade , Neoplasia Residual , Plasmócitos/imunologia , Prognóstico , Intervalo Livre de Progressão , Estudos Retrospectivos
6.
Medicine (Baltimore) ; 99(34): e21876, 2020 Aug 21.
Artigo em Inglês | MEDLINE | ID: mdl-32846844

RESUMO

BACKGROUND: Cancer continues to be a severe global health problem and the leading cause of death worldwide. Chemotherapy as the main treatment has various side effects, of which marrow suppression is the most common one. Acupuncture had shown clinical effects for marrow suppression after chemotherapy in many studies. However, the efficacy and safety of acupuncture therapy for marrow suppression after chemotherapy remains unclear. OBJECTIVE: This protocol aims to evaluate the efficacy and safety of acupuncture for marrow suppression after chemotherapy according to the existing randomized controlled trials. METHODS AND ANALYSIS: The randomized controlled trials on acupuncture therapy for marrow suppression after chemotherapy will be searched in the database of Embase, PubMed and Cochrane Library, Allied and Complementary Medicine Database (AMED), Chinese Biomedical Literature Database (CBM), China Science and Technology Journal Database (VIP), China National Knowledge Infrastructure (CNKI), WanFang Database (WF), and related registration platforms (WHO ICTRP, Clinical Trials, and Chinese Clinical Trial Register [ChiCTR]), Grey Literature Database from inception to 1 August 2020. The primary outcomes will be assessed using white blood cell (WBC) count, platelet count, hemoglobin count and the number of neutrophils (N). Review Manager V.5.3 software will be applied for statistical analyses. We will measure the risk of bias of the included studies with Cochrane Collaboration Risk of Bias Tool. Finally, Grades of Recommendation, Assessment, Development, and Evaluation (GRADE) will be used to grade the overall quality of evidence. And we will use the intra-group correlation coefficient to assess the consistency of reviewers. RESULT: This systematic review and meta-analysis will put a high-quality synthesis of the efficacy and safety of acupuncture treatment in marrow suppression after chemotherapy. CONCLUSION: The conclusion of this systematic review will provide evidence to assess acupuncture therapy is an efficacy and safe intervention to treat and control marrow suppression after chemotherapy. PROSPERO REGISTRATION NUMBER: PROSPERO CRD42020163336.


Assuntos
Terapia por Acupuntura/métodos , Antineoplásicos/efeitos adversos , Células da Medula Óssea/efeitos dos fármacos , Medula Óssea/efeitos dos fármacos , Medula Óssea/patologia , Tratamento Farmacológico/métodos , Feminino , Hemoglobinas/análise , Humanos , Contagem de Leucócitos/métodos , Masculino , Neoplasias/tratamento farmacológico , Neutrófilos/citologia , Contagem de Plaquetas/métodos , Ensaios Clínicos Controlados Aleatórios como Assunto , Segurança , Resultado do Tratamento
7.
Ann Hematol ; 99(10): 2303-2313, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32856141

RESUMO

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare hematologic disease characterized by a deregulated complement system, chronic Coombs-negative, intravascular hemolysis, and a variable clinical course with substantial risk to develop thromboembolic events. We analyzed diagnostic and prognostic parameters as well as clinical endpoints in 59 adult patients suffering from PNH in 5 hematology centers in Austria (observation period: 1978-2015). Median follow-up time was 5.6 years. The median clone size at diagnosis amounted to 55% and was higher in patients with classical PNH (81%) compared to patients with PNH associated with aplastic anemia (AA) or myelodysplastic syndromes (MDS) (50%). The clone size also correlated with lactate dehydrogenase (LDH) levels. In one patient, anemia improved spontaneously and disappeared with complete normalization of LDH after 16 years. Seventeen patients received therapy with eculizumab. The rate of thromboembolic events was higher in the pre-eculizumab era compared with eculizumab-treated patients but did not correlate with the presence of age-related clonal hematopoiesis or any other clinical or laboratory parameters. Peripheral blood colony-forming progenitor cell counts were lower in PNH patients compared with healthy controls. Only two patients with classical PNH developed MDS. Overall, 7/59 patients died after 0.5-32 years. Causes of death were acute pulmonary hypertension, Budd-Chiari syndrome, and septicemia. Overall survival (OS) was mainly influenced by age and was similar to OS measured in an age-matched healthy Austrian control cohort. Together, compared with previous times, the clinical course and OS in PNH are favorable, which may be due to better diagnosis, early recognition, and eculizumab therapy.


Assuntos
Hemoglobinúria Paroxística/epidemiologia , Lesão Renal Aguda/sangue , Lesão Renal Aguda/etiologia , Adulto , Anemia Aplástica/epidemiologia , Anticorpos Monoclonais Humanizados/uso terapêutico , Áustria/epidemiologia , Medula Óssea/patologia , Causas de Morte , Células Clonais/patologia , Ensaio de Unidades Formadoras de Colônias , Terapia Combinada , Inativadores do Complemento/uso terapêutico , Creatinina/sangue , Progressão da Doença , Feminino , Seguimentos , Hematopoese , Transplante de Células-Tronco Hematopoéticas , Hemoglobinúria Paroxística/complicações , Hemoglobinúria Paroxística/tratamento farmacológico , Hemoglobinúria Paroxística/terapia , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/epidemiologia , Gravidez , Complicações Hematológicas na Gravidez/epidemiologia , Prognóstico , Tromboembolia/etiologia
8.
Ann Hematol ; 99(10): 2417-2427, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32862286

RESUMO

For most acute myeloid leukemia (AML) patients, an allogeneic hematopoietic stem cell transplantation (HSCT) offers the highest chance of sustained remissions and long-term survival. At diagnosis, high expression of the AML-associated genes BAALC (brain and acute leukemia, cytoplasmic) and MN1 (meningioma-1) were repeatedly linked to inferior outcomes in patients consolidated with chemotherapy while data for patients receiving HSCT remain limited. Using clinically applicable digital droplet PCR assays, we analyzed the diagnostic BAALC/ABL1 and MN1/ABL1 copy numbers in 302 AML patients. High BAALC/ABL1 and MN1/ABL1 copy numbers associated with common adverse prognostic factors at diagnosis. However, while high diagnostic copy numbers of both genes associated with shorter event free survival (EFS) and overall survival (OS) in patients receiving chemotherapy, there was no prognostic impact in patients undergoing HSCT. Our data suggests that the adverse prognostic impact of high BAALC and MN1 expression are mitigated by allogeneic HSCT. But preHSCT BAALC/ABL1 and MN1/ABL1 assessed in remission prior to HSCT remained prognosticators for EFS and OS independent of the diagnostic expression status. Whether allogeneic HSCT may improve survival for AML patients with high diagnostic BAALC or MN1 expression should be investigated prospectively and may improve informed decisions towards individualized consolidation options in AML.


Assuntos
Medula Óssea/patologia , Leucemia Mieloide Aguda/terapia , Proteínas de Neoplasias/genética , Transplante de Células-Tronco de Sangue Periférico , Transativadores/genética , Proteínas Supressoras de Tumor/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Aloenxertos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Medula Óssea/química , Terapia Combinada , Citarabina/administração & dosagem , Intervalo Livre de Doença , Feminino , Dosagem de Genes , Regulação Neoplásica da Expressão Gênica , Humanos , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/mortalidade , Masculino , Pessoa de Meia-Idade , Proteínas de Neoplasias/biossíntese , Reação em Cadeia da Polimerase/métodos , Prognóstico , Proteínas Proto-Oncogênicas c-abl/genética , Transativadores/biossíntese , Resultado do Tratamento , Proteínas Supressoras de Tumor/biossíntese , Adulto Jovem
9.
PLoS One ; 15(8): e0235503, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32760083

RESUMO

PURPOSE: We evaluated the outcomes of decitabine as first-line treatment in older patients with acute myeloid leukemia (AML) and investigated the predictors, including a baseline mini nutritional assessment short form (MNA-SF) score, of response and survival. PATIENTS AND METHODS: Between 2010 and 2018, 96 AML patients aged 65 and above who received decitabine treatment at 6 centers in Korea were retrospectively evaluated. Response rates, hematologic improvements (HI), progression-free survival (PFS), and overall survival (OS) were analyzed. RESULTS: The median age at diagnosis was 73.9 years, and the median number of decitabine treatments administered to the patients was 4 (range, 1-29). Of 85 patients, 15 patients (17.6%) achieved complete remission (CR) or CR with incomplete blood count recovery. Twelve patients (14.1%) showed partial remission (PR), and 18 (21.2%) demonstrated HI without an objective response. The median PFS and OS were 7.0 (95% confidence interval [CI], 4.9-9.0) and 10.6 (95% CI, 7.7-13.5%) months, respectively. In multivariate analyses, MNA-SF score ≥ 8 and the absence of peripheral blood (PB) blasts were significant predictors for improved PFS and OS. CONCLUSIONS: For older patients with newly diagnosed AML, a high MNA-SF score and the absence of PB blasts were independently associated with improved survival.


Assuntos
Antimetabólitos Antineoplásicos/administração & dosagem , Decitabina/administração & dosagem , Leucemia Mieloide Aguda/tratamento farmacológico , Indução de Remissão/métodos , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Antimetabólitos Antineoplásicos/efeitos adversos , Contagem de Células Sanguíneas , Medula Óssea/patologia , Decitabina/efeitos adversos , Esquema de Medicação , Feminino , Humanos , Leucemia Mieloide Aguda/sangue , Leucemia Mieloide Aguda/mortalidade , Leucemia Mieloide Aguda/patologia , Masculino , Avaliação Nutricional , Intervalo Livre de Progressão , República da Coreia/epidemiologia , Estudos Retrospectivos , Perda de Peso
10.
Platelets ; 31(8): 1085-1089, 2020 Nov 16.
Artigo em Inglês | MEDLINE | ID: covidwho-733448

RESUMO

Coronavirus disease 2019 (COVID-19) is a global public health emergency with many clinical facets, and new knowledge about its pathogenetic mechanisms is deemed necessary; among these, there are certainly coagulation disorders. In the history of medicine, autopsies and tissue sampling have played a fundamental role in order to understand the pathogenesis of emerging diseases, including infectious ones; compared to the past, histopathology can be now expanded by innovative techniques and modern technologies. For the first time in worldwide literature, we provide a detailed postmortem and biopsy report on the marked increase, up to 1 order of magnitude, of naked megakaryocyte nuclei in the bone marrow and lungs from serious COVID-19 patients. Most likely related to high interleukin-6 serum levels stimulating megakaryocytopoiesis, this phenomenon concurs to explain well the pulmonary abnormal immunothrombosis in these critically ill patients, all without molecular or electron microscopy signs of megakaryocyte infection.


Assuntos
Betacoronavirus/patogenicidade , Medula Óssea/patologia , Infecções por Coronavirus/patologia , Síndrome da Liberação de Citocina/patologia , Coagulação Intravascular Disseminada/patologia , Pulmão/patologia , Pneumonia Viral/patologia , Trombose/patologia , Adulto , Idoso , Autopsia , Betacoronavirus/imunologia , Medula Óssea/imunologia , Medula Óssea/virologia , Núcleo Celular/imunologia , Núcleo Celular/patologia , Núcleo Celular/virologia , Infecções por Coronavirus/complicações , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/virologia , Estado Terminal , Síndrome da Liberação de Citocina/complicações , Síndrome da Liberação de Citocina/imunologia , Síndrome da Liberação de Citocina/virologia , Coagulação Intravascular Disseminada/complicações , Coagulação Intravascular Disseminada/imunologia , Coagulação Intravascular Disseminada/virologia , Evolução Fatal , Interações Hospedeiro-Patógeno/imunologia , Humanos , Interleucina-6/biossíntese , Interleucina-6/imunologia , Pulmão/imunologia , Pulmão/virologia , Masculino , Megacariócitos/imunologia , Megacariócitos/patologia , Megacariócitos/virologia , Pessoa de Meia-Idade , Pandemias , Pneumonia Viral/complicações , Pneumonia Viral/imunologia , Pneumonia Viral/virologia , Índice de Gravidade de Doença , Trombopoese/imunologia , Trombose/complicações , Trombose/imunologia , Trombose/virologia
11.
Platelets ; 31(8): 1085-1089, 2020 Nov 16.
Artigo em Inglês | MEDLINE | ID: mdl-32857624

RESUMO

Coronavirus disease 2019 (COVID-19) is a global public health emergency with many clinical facets, and new knowledge about its pathogenetic mechanisms is deemed necessary; among these, there are certainly coagulation disorders. In the history of medicine, autopsies and tissue sampling have played a fundamental role in order to understand the pathogenesis of emerging diseases, including infectious ones; compared to the past, histopathology can be now expanded by innovative techniques and modern technologies. For the first time in worldwide literature, we provide a detailed postmortem and biopsy report on the marked increase, up to 1 order of magnitude, of naked megakaryocyte nuclei in the bone marrow and lungs from serious COVID-19 patients. Most likely related to high interleukin-6 serum levels stimulating megakaryocytopoiesis, this phenomenon concurs to explain well the pulmonary abnormal immunothrombosis in these critically ill patients, all without molecular or electron microscopy signs of megakaryocyte infection.


Assuntos
Betacoronavirus/patogenicidade , Medula Óssea/patologia , Infecções por Coronavirus/patologia , Síndrome da Liberação de Citocina/patologia , Coagulação Intravascular Disseminada/patologia , Pulmão/patologia , Pneumonia Viral/patologia , Trombose/patologia , Adulto , Idoso , Autopsia , Betacoronavirus/imunologia , Medula Óssea/imunologia , Medula Óssea/virologia , Núcleo Celular/imunologia , Núcleo Celular/patologia , Núcleo Celular/virologia , Infecções por Coronavirus/complicações , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/virologia , Estado Terminal , Síndrome da Liberação de Citocina/complicações , Síndrome da Liberação de Citocina/imunologia , Síndrome da Liberação de Citocina/virologia , Coagulação Intravascular Disseminada/complicações , Coagulação Intravascular Disseminada/imunologia , Coagulação Intravascular Disseminada/virologia , Evolução Fatal , Interações Hospedeiro-Patógeno/imunologia , Humanos , Interleucina-6/biossíntese , Interleucina-6/imunologia , Pulmão/imunologia , Pulmão/virologia , Masculino , Megacariócitos/imunologia , Megacariócitos/patologia , Megacariócitos/virologia , Pessoa de Meia-Idade , Pandemias , Pneumonia Viral/complicações , Pneumonia Viral/imunologia , Pneumonia Viral/virologia , Índice de Gravidade de Doença , Trombopoese/imunologia , Trombose/complicações , Trombose/imunologia , Trombose/virologia
12.
Ann Hematol ; 99(10): 2405-2416, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32813071

RESUMO

Predictive factors of response to hypomethylating agents (HMA) in elderly acute myeloid leukemia (AML) patients remain unclear in the real-life setting and no direct comparison between azacitidine (AZA) and decitabine (DEC) has been carried out. We retrospectively evaluated 110 AML patients treated with HMA (78 AZA, 32 DEC) as first-line therapy outside of clinical trials. Median age was 75 years (range 58-87). The median overall survival (OS) of the entire cohort was 8.0 months (95% CI 6.1-10), without significant differences among the subgroups: AZA 8.8 months vs DEC 6.3 months (p = 0.291). HMA treatment yielded an overall response rate (ORR) of 40% (AZA 37% vs DEC 47%, p = 0.237). A stable disease (SD) after 4 HMA cycles was not associated with a worse survival outcome compared with an early optimal response. Factors independently associated with a better OS were transfusion independence during treatment (p = 0.049), achievement of an optimal response to treatment (p < 0.001), and a baseline hemoglobin level ≥ 9.25 (p = 0.018). A bone marrow (BM) blast count ≥ 30% (p < 0.001) and a therapy-related AML (p = 0.008) remain poor survival predictors. Of the available biologic features, an adverse risk category according to the ELN classification was significantly associated with a shorter survival over the intermediate risk category (p = 0.034). Disease progression remains the primary cause of death. Infectious complications were more severe (p = 0.036) and occurred earlier (p = 0.006) in the DEC group compared with that of the AZA group. In conclusion, clinical prognostic factors associated to response and survival have been identified without significant associations concerning overall outcomes between the two HMAs.


Assuntos
Antimetabólitos Antineoplásicos/uso terapêutico , Azacitidina/uso terapêutico , Metilação de DNA/efeitos dos fármacos , DNA de Neoplasias/efeitos dos fármacos , Decitabina/uso terapêutico , Leucemia Mieloide Aguda/tratamento farmacológico , Idoso , Idoso de 80 Anos ou mais , Medula Óssea/patologia , Causas de Morte , Contagem de Células , DNA de Neoplasias/química , Progressão da Doença , Intervalo Livre de Doença , Feminino , Hemoglobinas/análise , Humanos , Infecções/etiologia , Infecções/mortalidade , Estimativa de Kaplan-Meier , Leucemia Mieloide Aguda/mortalidade , Masculino , Pessoa de Meia-Idade , Células-Tronco Neoplásicas , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Resultado do Tratamento
13.
PLoS One ; 15(8): e0236338, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32785215

RESUMO

Dysregulation of BCL2 is a pathophysiology observed in haematological malignancies. For implementation of available treatment-options it is preferred to know the relative quantification of BCL2 mRNA with appropriate reference genes. For the choice of reference genes-(i) Reference Genes were selected by assessing variation of >60,000 genes from 4 RNA-seq datasets of haematological malignancies followed by filtering based on their GO biological process annotations and proximity of their chromosomal locations to known disease translocations. Selected genes were experimentally validated across various haematological malignancy samples followed by stability comparison using geNorm, NormFinder, BestKeeper and RefFinder. (ii) 43 commonly used Reference Genes were obtained from literature through extensive systematic review. Levels of BCL2 mRNA was assessed by qPCR normalized either by novel reference genes from this study or GAPDH, the most cited reference gene in literature and compared. The analysis showed PTCD2, PPP1R3B and FBXW9 to be the most unregulated genes across lymph-nodes, bone marrow and PBMC samples unlike the Reference Genes used in literature. BCL2 mRNA level shows a consistent higher expression in haematological malignancy patients when normalized by these novel Reference Genes as opposed to GAPDH, the most cited Reference Gene. These reference genes should also be applicable in qPCR platforms using Taqman probes and other model systems including cell lines and rodent models. Absence of sample from healthy-normal individual in diagnostic cases call for careful selection of Reference Genes for relative quantification of a biomarker by qPCR.BCL2 can be used as molecular diagnostics only if normalized with a set of reference genes with stable yet low levels of expression across different types of haematological malignancies.


Assuntos
Biomarcadores Tumorais/isolamento & purificação , Neoplasias Hematológicas/diagnóstico , Proteínas Proto-Oncogênicas c-bcl-2/isolamento & purificação , RNA Mensageiro/isolamento & purificação , RNA-Seq/normas , Animais , Biomarcadores Tumorais/sangue , Biomarcadores Tumorais/genética , Medula Óssea/patologia , Linhagem Celular Tumoral , Conjuntos de Dados como Assunto , Modelos Animais de Doenças , Estudos de Viabilidade , Regulação Neoplásica da Expressão Gênica , Genes Essenciais , Neoplasias Hematológicas/sangue , Neoplasias Hematológicas/genética , Neoplasias Hematológicas/patologia , Humanos , Leucócitos Mononucleares , Proteínas Proto-Oncogênicas c-bcl-2/sangue , Proteínas Proto-Oncogênicas c-bcl-2/genética , RNA Mensageiro/sangue , RNA Mensageiro/genética , Reação em Cadeia da Polimerase em Tempo Real/normas , Padrões de Referência
14.
Nat Commun ; 11(1): 3702, 2020 07 24.
Artigo em Inglês | MEDLINE | ID: mdl-32710081

RESUMO

Spinal cord injury (SCI) causes immune dysfunction, increasing the risk of infectious morbidity and mortality. Since bone marrow hematopoiesis is essential for proper immune function, we hypothesize that SCI disrupts bone marrow hematopoiesis. Indeed, SCI causes excessive proliferation of bone marrow hematopoietic stem and progenitor cells (HSPC), but these cells cannot leave the bone marrow, even after challenging the host with a potent inflammatory stimulus. Sequestration of HSPCs in bone marrow after SCI is linked to aberrant chemotactic signaling that can be reversed by post-injury injections of Plerixafor (AMD3100), a small molecule inhibitor of CXCR4. Even though Plerixafor liberates HSPCs and mature immune cells from bone marrow, competitive repopulation assays show that the intrinsic long-term functional capacity of HSPCs is still impaired in SCI mice. Together, our data suggest that SCI causes an acquired bone marrow failure syndrome that may contribute to chronic immune dysfunction.


Assuntos
Transtornos da Insuficiência da Medula Óssea/etiologia , Medula Óssea/metabolismo , Traumatismos da Medula Espinal/complicações , Animais , Medula Óssea/patologia , Células da Medula Óssea , Transtornos da Insuficiência da Medula Óssea/patologia , Proliferação de Células , Quimiocina CXCL12 , Modelos Animais de Doenças , Feminino , Hematopoese , Células-Tronco Hematopoéticas/metabolismo , Compostos Heterocíclicos/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos NOD , Camundongos Transgênicos , Receptores CXCR4/antagonistas & inibidores , Transdução de Sinais , Traumatismos da Medula Espinal/imunologia
17.
PLoS One ; 15(7): e0235658, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32649712

RESUMO

Medical diagnostic X-rays are an important source of ionizing radiation (IR) exposure in the general population; however, it is unclear if the resulting low patient doses increase lymphoma risk. We examined the association between lifetime medical diagnostic X-ray dose and lymphoma risk, taking into account potential confounding factors, including medical history. The international Epilymph study (conducted in the Czech-Republic, France, Germany, Ireland, Italy, and Spain) collected self-reported information on common diagnostic X-ray procedures from 2,362 lymphoma cases and 2,465 frequency-matched (age, sex, country) controls. Individual lifetime cumulative bone marrow (BM) dose was estimated using time period-based dose estimates for different procedures and body parts. The association between categories of BM dose and lymphoma risk was examined using unconditional logistic regression models adjusting for matching factors, socioeconomic variables, and the presence of underlying medical conditions (atopic, autoimmune, infectious diseases, osteoarthritis, having had a sick childhood, and family history of lymphoma) as potential confounders of the association. Cumulative BM dose was low (median 2.25 mGy) and was not positively associated with lymphoma risk. Odds ratios (ORs) were consistently less than 1.0 in all dose categories compared to the reference category (less than 1 mGy). Results were similar after adjustment for potential confounding factors, when using different exposure scenarios, and in analyses by lymphoma subtype and by type of control (hospital-, population-based). Overall no increased risk of lymphoma was observed. The reduced ORs may be related to unmeasured confounding or other sources of systematic bias.We found little evidence that chronic medical conditions confound lymphoma risk and medical radiation associations.


Assuntos
Linfoma/etiologia , Exposição à Radiação/efeitos adversos , Radiação Ionizante , Adulto , Idoso , Medula Óssea/patologia , Medula Óssea/efeitos da radiação , Estudos de Casos e Controles , Feminino , Humanos , Modelos Logísticos , Linfoma/diagnóstico , Masculino , Pessoa de Meia-Idade , Razão de Chances , Doses de Radiação , Fatores de Risco
18.
PLoS One ; 15(7): e0235786, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32639975

RESUMO

In front-line treatment of diffuse large B-cell lymphoma (DLBCL), prior studies suggest that concordant but not discordant involvement of the bone marrow (BM) portends a poor prognosis. The prognostic impact of bone marrow infiltration (BMI) in recurrent or refractory DLBCL (r/rDLBCL) and transformed indolent lymphoma (r/rTRIL) patients is less clear. Thus, we examined the prognostic significance of the infiltration of bone marrow (BMI) by concordant, large B-cells (conBMI) and discordant, small B-cells (disBMI) in this patient group. We performed a single center retrospective analysis of the prognostic impact of BMI diagnosed before start of second-line treatment as well as multiple clinicopathologic variables in 82 patients with r/rDLBCL or r/rTRIL intended to treat with autologous SCT. Twenty-five of 82 patients (30.5%) had BMI. Out of these, 19 (76%) had conBMI and 6 (24%) had disBMI. In patients with conBMI but not disBMI, uni- and multivariate analysis revealed inferior progression free survival (PFS) and overall survival (OS) compared to patients without BMI (median PFS, 9.2 vs 17.45 months, log rank: p = 0.049; Hazard Ratio, 2.34 (Confidence Interval, 1.24-4.44), p = 0.009; median OS 14.72 vs 28.91 months, log rank: p = 0.017; Hazard Ratio, 2.76 (Confidence Interval, 1.43-5.31), p = 0.002). ConBMI was strongly associated with nonGCB subtype as classified by the Hans algorithm (82.4% vs 17.6%, p = 0.01). ConBMI comprised an independent predictor of poor prognosis in primary and secondary r/rDLBCL. Incorporating conBMI in the pretherapeutic risk assessment for r/rDLBCL and r/rTRIL patients may be useful for prognostication, for stratification in clinical trials, and to assess new therapies for this high-risk patient subset that might not benefit from SCT in second-line treatment.


Assuntos
Medula Óssea/patologia , Linfoma Difuso de Grandes Células B/diagnóstico , Linfoma não Hodgkin/diagnóstico , Recidiva Local de Neoplasia/diagnóstico , Adulto , Idoso , Linfócitos B/patologia , Feminino , Humanos , Linfoma Difuso de Grandes Células B/patologia , Linfoma não Hodgkin/patologia , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/patologia , Prognóstico , Estudos Retrospectivos , Adulto Jovem
19.
Am J Clin Pathol ; 154(4): 466-474, 2020 09 08.
Artigo em Inglês | MEDLINE | ID: mdl-32681166

RESUMO

OBJECTIVES: A subset of coronavirus disease 2019 (COVID-19) patients exhibit clinical features of cytokine storm. However, clinicopathologic features diagnostic of hemophagocytic lymphohistiocytosis (HLH) have not been reported. We studied the reticuloendothelial organs of 4 consecutive patients who died of COVID-19 and correlated with clinical and laboratory parameters to detect HLH. METHODS: Autopsies were performed on 4 patients who died of COVID-19. Routine H&E staining and immunohistochemical staining for CD163 were performed to detect hemophagocytosis. Clinical and laboratory results from premortem blood samples were used to calculate H-scores. RESULTS: All 4 cases demonstrated diffuse alveolar damage within the lungs. Three of the 4 cases had histologic evidence of hemophagocytosis within pulmonary lymph nodes. One case showed hemophagocytosis in the spleen but none showed hemophagocytosis in liver or bone marrow. Lymphophagocytosis was the predominant form of hemophagocytosis observed. One patient showed diagnostic features of HLH with an H-score of 217, while a second patient likely had HLH with a partial H-score of 145 due to a missing triglyceride level. The remaining 2 patients had H-scores of 131 and 96. CONCLUSIONS: This is the first report of severe acute respiratory syndrome coronavirus 2-associated HLH. Identification of HLH in a subset of patients with severe COVID-19 will inform clinical trials of therapeutic strategies.


Assuntos
Betacoronavirus , Infecções por Coronavirus/diagnóstico , Infecções por Coronavirus/patologia , Linfo-Histiocitose Hemofagocítica/patologia , Linfo-Histiocitose Hemofagocítica/virologia , Pneumonia Viral/diagnóstico , Pneumonia Viral/patologia , Idoso , Idoso de 80 Anos ou mais , Autopsia , Medula Óssea/patologia , Infecções por Coronavirus/complicações , Evolução Fatal , Feminino , Humanos , Fígado/patologia , Pulmão/patologia , Linfonodos/patologia , Linfo-Histiocitose Hemofagocítica/diagnóstico , Masculino , Pessoa de Meia-Idade , Pandemias , Pneumonia Viral/complicações , Baço/patologia
20.
Nat Commun ; 11(1): 3549, 2020 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-32669548

RESUMO

Refractory metastatic rhabdomyosarcoma is largely incurable. Here we analyze the response of a child with refractory bone marrow metastatic rhabdomyosarcoma to autologous HER2 CAR T cells. Three cycles of HER2 CAR T cells given after lymphodepleting chemotherapy induces remission which is consolidated with four more CAR T-cell infusions without lymphodepletion. Longitudinal immune-monitoring reveals remodeling of the T-cell receptor repertoire with immunodominant clones and serum autoantibodies reactive to oncogenic signaling pathway proteins. The disease relapses in the bone marrow at six months off-therapy. A second remission is achieved after one cycle of lymphodepletion and HER2 CAR T cells. Response consolidation with additional CAR T-cell infusions includes pembrolizumab to improve their efficacy. The patient described here is a participant in an ongoing phase I trial (NCT00902044; active, not recruiting), and is 20 months off T-cell infusions with no detectable disease at the time of this report.


Assuntos
Imunoterapia Adotiva/métodos , Neoplasias Musculares/terapia , Recidiva Local de Neoplasia/terapia , Receptor ErbB-2/imunologia , Rabdomiossarcoma/terapia , Linfócitos T/transplante , Biópsia , Medula Óssea/patologia , Criança , Ensaios Clínicos Fase I como Assunto , Humanos , Masculino , Neoplasias Musculares/imunologia , Neoplasias Musculares/patologia , Recidiva Local de Neoplasia/imunologia , Receptores de Antígenos Quiméricos/imunologia , Indução de Remissão/métodos , Rabdomiossarcoma/imunologia , Rabdomiossarcoma/secundário , Linfócitos T/imunologia , Linfócitos T/metabolismo , Transplante Autólogo/métodos , Resultado do Tratamento
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