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1.
Toxicol Lett ; 318: 92-98, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31678399

RESUMO

Sulfur mustard (SM) is a vesicant chemical warfare agent. Recent studies reported alleged use of SM by non-state actors in Syria and Iraq. It has been shown that SM induced immunological and hematological complications. The aim of this study was to determine acute toxic effects of SM exposure on hematological parameters. Blood samples from a group of Syrian exposed to SM in 2016 were taken daily during the follow-up of the patients in intensive care unit. Initial leukocytosis was observed in all patients (100%) on the first 48 h after exposure. Following leukocytosis, isolated lymphopenia was observed in all patients (100%) between 2nd and 4th days. A decrease in hemoglobin level was noted in five patients (62.5%) between 4th and 5th days. Thrombocytopenia was observed in 75% of patients between 4th and 6th days for mild cases and between 9th and 11th days for severe cases. Three patients (37.5%) developed distinct leucopenia/neutropenia on 11th and 12th days. It was observed that human exposure to high dose of SM has direct toxic effect on hematological cells and bone marrow. New strategies on treatment of SM-induced myelosuppression could reduce the effects of hematological complications and could increase the survival rate in these patients.


Assuntos
Medula Óssea/efeitos dos fármacos , Terrorismo Químico , Substâncias para a Guerra Química/envenenamento , Leucocitose/induzido quimicamente , Leucopenia/induzido quimicamente , Linfopenia/induzido quimicamente , Gás de Mostarda/envenenamento , Trombocitopenia/induzido quimicamente , Adolescente , Adulto , Biomarcadores/sangue , Medula Óssea/patologia , Feminino , Hemoglobinas/metabolismo , Humanos , Leucocitose/sangue , Leucocitose/patologia , Leucopenia/sangue , Leucopenia/patologia , Linfopenia/sangue , Linfopenia/patologia , Masculino , Síria , Trombocitopenia/sangue , Trombocitopenia/patologia , Adulto Jovem
4.
Rinsho Ketsueki ; 60(9): 1166-1175, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31597840

RESUMO

The classical myeloproliferative neoplasms (MPN), polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF), are characterized by clonal myeloproliferation without features of myelodysplasia. The diagnostic approach proposed by the World Health Organization (WHO) uses clinical features, peripheral blood counts and smear analysis, bone marrow (BM) morphology, karyotype and molecular genetic tests to classify MPN subtypes. The detection of characteristic driver mutations like JAK2V617F, JAK2 exon 12, MPL, and calrecticulin (CALR) is a major diagnostic feature. JAK2 mutations are detected in more than 90% of patients with PV and are therefore used as highly sensitive clonal marker in this subtype. However, JAK2 mutations may also occur in ET and PMF, while CALR is virtually not seen in PV. Therefore, BM remains the central diagnostic platform and is essential for distinguishing ET from pre-fibrotic PMF and diagnosing cases which do not express JAK2, MPL or CALR ('wild-type' or 'triple-negative' MPN). The standardization of relevant BM features is mandatory to recognize characteristic and easy to assess patterns that enable an accurate discrimination between the MPN subtypes. Key parameters include cellularity, erythropoiesis and neutrophil granulopoiesis in context with specific features of megakaryocytes as well as the BM fiber content, especially in early stage MPN that present with thrombocytosis and clinically mimic essential thrombocythemia.


Assuntos
Transtornos Mieloproliferativos/diagnóstico , Medula Óssea/patologia , Calreticulina/genética , Diagnóstico Diferencial , Eritropoese , Humanos , Janus Quinase 2/genética , Megacariócitos/citologia , Mutação , Neutrófilos/citologia , Policitemia Vera , Trombocitemia Essencial , Organização Mundial da Saúde
5.
Cancer Immunol Immunother ; 68(12): 1971-1978, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31650199

RESUMO

Acute myeloid leukemia (AML) is a common and lethal hematopoietic malignancy that is highly dependent on the bone marrow (BM) microenvironment. Infiltrating immune and stromal cells are important components of the BM microenvironment and significantly influence the progression of AML. This study aimed to elucidate the value of immune/stromal cell-associated genes for AML prognosis by integrated bioinformatics analysis. We obtained expression profiles from The Cancer Genome Atlas (TCGA) database and used the ESTIMATE algorithm to calculate immune scores and stromal scores; we then identified differentially expressed genes (DEGs) based on these scores. Overall survival analysis was applied to reveal common DEGs of prognostic value. Subsequently, we conducted a functional enrichment analysis, generated a protein-protein interaction (PPI) network and performed an interrelation analysis of immune system processes, showing that these genes are mainly associated with the immune/inflammatory response. Finally, eight genes (CD163, CYP27A1, KCNA5, PPM1J, FOLR1, IL1R2, MYOF, VSIG2) were verified to be significantly associated with AML prognosis in the Gene Expression Omnibus (GEO) database. In summary, we identified key microenvironment-related genes that affect the outcomes of AML patients and might serve as therapeutic targets.


Assuntos
Medula Óssea/patologia , Inflamação/genética , Leucemia Mieloide Aguda/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Biologia Computacional , Feminino , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Humanos , Imunidade Celular/genética , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/mortalidade , Masculino , Pessoa de Meia-Idade , Prognóstico , Mapas de Interação de Proteínas , Análise de Sobrevida , Microambiente Tumoral , Adulto Jovem
6.
F1000Res ; 82019.
Artigo em Inglês | MEDLINE | ID: mdl-31583083

RESUMO

Myelofibrosis is the advanced stage of the Philadelphia chromosome-negative myeloproliferative neoplasms (MPNs), characterized by systemic inflammation, hematopoietic failure in the bone marrow, and development of extramedullary hematopoiesis, mainly in the spleen. The only potentially curative therapy for this disease is hematopoietic stem cell transplantation, an option that may be offered only to those patients with a compatible donor and with an age and functional status that may face its toxicity. By contrast, with the Philadelphia-positive MPNs that can be dramatically modified by inhibitors of the novel BCR-ABL fusion-protein generated by its genetic lesion, the identification of the molecular lesions that lead to the development of myelofibrosis has not yet translated into a treatment that can modify the natural history of the disease. Therefore, the cure of myelofibrosis remains an unmet clinical need. However, the excitement raised by the discovery of the genetic lesions has inspired additional studies aimed at elucidating the mechanisms driving these neoplasms towards their final stage. These studies have generated the feeling that the cure of myelofibrosis will require targeting both the malignant stem cell clone and its supportive microenvironment. We will summarize here some of the biochemical alterations recently identified in MPNs and the novel therapeutic approaches currently under investigation inspired by these discoveries.


Assuntos
Mielofibrose Primária/terapia , Microambiente Tumoral , Medula Óssea/patologia , Proteínas de Fusão bcr-abl/antagonistas & inibidores , Hematopoese Extramedular , Transplante de Células-Tronco Hematopoéticas , Humanos , Transtornos Mieloproliferativos
7.
Medicine (Baltimore) ; 98(37): e16936, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31517814

RESUMO

The study aimed to investigate the effect of ratios of marrow cavity diameter to intramedullary nail diameter from different layers on hidden blood loss (HBL), overt blood loss (OBL) and total blood loss (TBL) during using proximal femoral nail antirotation-Asian version (PFNA)-II for femoral intertrochanteric fractures.We retrospectively studied 70 patients treated in our hospital recently. We recorded postoperative hematocrit (Hct) and OBL during operation. TBL and HBL were calculated using CROSS equation. The ratios of marrow cavity diameter to intramedullary nail diameter from different layers, including start of funnel, end of funnel and femoral isthmus, were measured. The mean of the ratio from frontal and lateral X-ray were designated as R. We classified all included participants into a high and a low matching group according to z-score of R within each layer. TBL, HBL, and OBL were compared between the 2 groups. We applied multiple linear regression analysis between the HBL as a dependent variable and gender, age, body mass index, fracture type, and R as independent variables.The present study indicated a significant reduction in the HBL and TBL in the high matching group compared to low matching group on three layers, whereas it showed no significant difference in OBL between the 2 groups on three layers. It showed that R values from start of funnel and end of funnel were significantly associated with HBL.Matching rate of PFNA II at the funnel might be an important factor for HBL and TBL postoperatively.


Assuntos
Perda Sanguínea Cirúrgica , Medula Óssea/diagnóstico por imagem , Fraturas do Fêmur/diagnóstico por imagem , Fraturas do Fêmur/cirurgia , Idoso , Idoso de 80 Anos ou mais , Perda Sanguínea Cirúrgica/prevenção & controle , Medula Óssea/patologia , Feminino , Fraturas do Fêmur/patologia , Humanos , Interpretação de Imagem Assistida por Computador , Masculino , Pessoa de Meia-Idade , Tamanho do Órgão , Hemorragia Pós-Operatória/patologia , Hemorragia Pós-Operatória/terapia , Estudos Retrospectivos
8.
J Cancer Res Clin Oncol ; 145(10): 2529-2539, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31485768

RESUMO

PURPOSE: This study aimed to determine the potential of positron emission tomography/computed tomography (PET/CT) in replacing routine bone-marrow biopsies (BMB) in newly diagnosed extranodal natural killer/T-cell lymphoma (ENKTCL). METHODS: Newly diagnosed patients underwent PET/CT imaging and routine BMB to assess bone/bone marrow involvement (BMI). Clinical stage and treatment plan were determined, and survival was compared. RESULTS: In a total of 101 patients, 78 were diagnosed as stage I/II and 23 as stage III/IV without using the BMB results. No BMB-positive patients were identified in stages I/II, and therefore, the BMB results did not alter the stage and treatment choice in any patients. The sensitivity and specificity of focal skeletal PET/CT lesion(s) in assessing BMI was 100% and 92.8%, respectively, taking routine BMB as the reference standard. The overall survival (OS) and progression-free survival (PFS) of BMB-positive patients was significantly inferior (P = 0.0011 and 0.0465, respectively, in advanced-stage patients; both P < 0.0001 in all patients), and this was corroborated by the PET/CT findings (P = 0.0006 and 0.0116, respectively, in advanced-stage patients; both P < 0.0001 in all patients). CONCLUSIONS: Based on the results, PET/CT demonstrated satisfactory predictive performance in terms of staging and prognosis in ENKTCL. BMB did not influence staging and treatment in newly diagnosed ENKTCL, and routine non-targeted BMB is not obligatory for early stage patients undergoing PET/CT. Targeted BMB is recommended to confirm BMI in advanced-stage patients.


Assuntos
Medula Óssea/diagnóstico por imagem , Medula Óssea/patologia , Linfoma Extranodal de Células T-NK/diagnóstico , Tomografia Computadorizada com Tomografia por Emissão de Pósitrons , Adolescente , Adulto , Idoso , Biomarcadores , Biópsia , Feminino , Humanos , Linfoma Extranodal de Células T-NK/mortalidade , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Tomografia Computadorizada com Tomografia por Emissão de Pósitrons/métodos , Prognóstico , Modelos de Riscos Proporcionais , Sensibilidade e Especificidade , Análise de Sobrevida , Adulto Jovem
9.
Hematol Oncol ; 37(4): 483-486, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31408541

RESUMO

In absence of red blood cells disease or immune defect, parvovirus B19 (PVB-19) is usually considered as a benign condition. Here, we report the case of a 10-year-old boy, previously healthy, presenting with a PVB-19 infection revealed by a bicytopenia and a voluminous axillary adenopathy. Pathophysiology examination showed reactional lymphoid population. Nine months later and in the absence of remission, a new biopsy of the same adenopathy revealed a Hodgkin lymphoma with area of T-cell rich aggressive large B-cell lymphoma. This case suggests PVB-19 as potential trigger of this malignant childhood hemopathy. Although no definitive conclusion can be drawn, our clinical case questions the role of PVB-19 in lymphomagenesis.


Assuntos
Eritema Infeccioso/complicações , Doença de Hodgkin/etiologia , Linfoma de Células B/etiologia , Neoplasias Primárias Múltiplas/etiologia , Viremia/complicações , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Linfócitos B/patologia , Medula Óssea/patologia , Medula Óssea/virologia , Criança , Eritema Infeccioso/sangue , Eritema Infeccioso/patologia , Eritema Infeccioso/virologia , Doença de Hodgkin/patologia , Humanos , Linfoma de Células B/patologia , Masculino , Neoplasias Primárias Múltiplas/patologia , Pancitopenia/etiologia , Pseudolinfoma/etiologia , Indução de Remissão , Rituximab/administração & dosagem , Linfócitos T/patologia , Sequenciamento Completo do Exoma
10.
Anticancer Res ; 39(8): 4455-4462, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31366544

RESUMO

BACKGROUND/AIM: Platinum-based chemotherapy often fails due to its severe adverse effects. The aim of this study was to examine the adverse effects profile and efficacy of dicycloplatin and compare them to those of cisplatin and carboplatin. MATERIALS AND METHODS: Cystoscopy surveillance of the first American cancer patient treated with dicycloplatin was performed quarterly. In vitro and in vivo studies were conducted using immunoblotting and flow cytometry to assess immune status of spleen and bone marrow of mice treated with dicycloplatin, cisplatin and carboplatin. RESULTS: The American patient did not suffer clinically significant myelosuppression; dicycloplatin has sustained remission in this patient to date. Experimental studies showed that dicycloplatin is less toxic to bone marrow and spleen of mice than cisplatin and carboplatin. CONCLUSION: Dicycloplatin is a promising drug in cancer chemotherapy with less aggressive side-effects than those typically associated with cisplatin and carboplatin. This is an important therapeutic advantage in cancer chemotherapy. Clinical investigation of dicycloplatin as an alternative to cisplatin or carboplatin is warranted.


Assuntos
Medula Óssea/efeitos dos fármacos , Glutamatos/administração & dosagem , Neoplasias/tratamento farmacológico , Compostos Organoplatínicos/administração & dosagem , Baço/efeitos dos fármacos , Animais , Medula Óssea/patologia , Carboplatina/administração & dosagem , Carboplatina/efeitos adversos , Cisplatino/administração & dosagem , Cisplatino/efeitos adversos , Cistoscopia , Modelos Animais de Doenças , Combinação de Medicamentos , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Feminino , Glutamatos/efeitos adversos , Humanos , Camundongos , Compostos Organoplatínicos/efeitos adversos , Baço/patologia
12.
Hematol Oncol ; 37(4): 401-408, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31291481

RESUMO

Multiple myeloma (MM) is malignant tumor with abnormal proliferation of bone marrow plasma cells. The existing clinical tools used to determine treatment response and tumor relapse are limited in sensitivity. We investigated the CD138+ microparticles (MPs) of MM patients to find out whether MPs could provide a novel means to monitor the malignant cells in MM patients. Our study showed that the levels of MPs were significantly elevated in MM patients. The MP counts in peripheral blood from new diagnosed MM patients were significantly higher than patients in CR and HD. Consist with the total MPs, the number of the PC-derived MPs (CD138+) increased in BM from MM patients compared with CR and HD. The ratio of the PC-derived MPs (CD138+) in BM increased in MM patients compared with CR and HD. The correlation test revealed that the CD138+ MPs in BM and PB were all positively correlated with the plasmacyte ratio in bone marrow (BMPC) and the ß2 -MG. New diagnosed MM patients and controls were compared, and ROC curves were used to identify cutoff points with optimal sensitivity and specificity concerning the ratios and counts of CD138+ MPs in BM and PB. The AUC of the CD138+ MP counts in BM was 0.767, and in PB was 0.680. The AUC of the CD138+ MP ratios in BM was 0.714, and in PB was 0.666. According to this, the counts of CD138+ MPs in BM showed to be a powerful marker of diagnosis. We demonstrated that CD138+ MPs from the plasma provide support for a potential monitoring biomarker of MM.


Assuntos
Células da Medula Óssea/química , Medula Óssea/patologia , Micropartículas Derivadas de Células/química , Mieloma Múltiplo/sangue , Proteínas de Neoplasias/sangue , Sindecana-1/sangue , Adulto , Idoso , Idoso de 80 Anos ou mais , Área Sob a Curva , Biomarcadores Tumorais/sangue , Separação Celular/métodos , Feminino , Citometria de Fluxo/métodos , Humanos , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/diagnóstico , Mieloma Múltiplo/patologia , Plasmócitos/patologia , Curva ROC , Sensibilidade e Especificidade , Sindecana-1/análise , Microglobulina beta-2/análise
13.
Hematol Oncol ; 37(4): 474-482, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31325181

RESUMO

LncRNAs play critical roles in various pathophysiological and biological processes, such as protein translation, RNA splicing, and epigenetic modification. Indeed, abundant evidences demonstrated that lncRNA act as competing endogenous RNAs (ceRNAs) to participate in tumorigenesis. However, little is known about the underlying function of lncRNA in nonhomologous end joining (NHEJ) pathway 1 (LINP1) in pediatric and adolescent acute myeloid leukemia (AML). The expression of LINP1 was examined in AML patient samples by qRT-PCR. Cell proliferation was examined by CCK-8 and Edu assays. ß-Galactosidase senescence assay, mGlucose uptake assay, lactate production assay, and Gene Ontology (GO) analysis were performed for functional analysis. We found that LINP1 was significantly overexpressed in AML patients at diagnosis, whereas downregulated after complete remission (CR). Furthermore, knockdown of LINP1 expression remarkably suppressed glucose uptake and AML cell maintenance. Mechanistically, LINP1 was found to inhibit the glucose metabolism by suppressing the expression of HNF4a. Both LINP1 and HNF4a knockdown reduced the expression levels of AMPK phosphorylation and WNT5A, indicating for the first time that LINP1 strengthened the HNF4a-AMPK/WNT5A signaling pathway involved in cell glucose metabolism modulation and AML cell survival. Taken together, our results indicated that LINP1 promotes the malignant phenotype of AML cells and stimulates glucose metabolism, which can be regarded as a potential prognostic marker and therapeutic target for AML.


Assuntos
Adenilato Quinase/fisiologia , Fator 4 Nuclear de Hepatócito/fisiologia , Leucemia Mieloide Aguda/genética , RNA Longo não Codificante/fisiologia , RNA Neoplásico/fisiologia , Transdução de Sinais/fisiologia , Proteína Wnt-5a/fisiologia , Adolescente , Animais , Medula Óssea/patologia , Divisão Celular , Criança , Regulação Leucêmica da Expressão Gênica , Técnicas de Silenciamento de Genes , Ontologia Genética , Glucose/metabolismo , Fator 4 Nuclear de Hepatócito/biossíntese , Fator 4 Nuclear de Hepatócito/genética , Humanos , Leucemia Mieloide Aguda/metabolismo , Leucemia Mieloide Aguda/patologia , Masculino , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Transplante de Neoplasias , Púrpura Trombocitopênica Idiopática/metabolismo , Interferência de RNA , RNA Longo não Codificante/biossíntese , RNA Longo não Codificante/genética , RNA Neoplásico/biossíntese , RNA Neoplásico/genética , RNA Interferente Pequeno/genética , Distribuição Aleatória , Indução de Remissão , Transdução de Sinais/genética , Células THP-1
14.
Hematol Oncol ; 37(4): 368-374, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31325190

RESUMO

In 2009, the four laboratories of the Fondazione Italiana Linfomi (FIL) minimal residual disease (MRD) Network started a collaborative effort to harmonize and standardize their methodologies at the national level, performing quality control (QC) rounds for follicular lymphoma (FL) and mantle cell lymphoma (MCL) MRD assessment. In 16 QC rounds between 2010 and 2017, the four laboratories received 208 bone marrow (BM) samples (126 FL; 82 MCL); 187 were analyzed, according to the EuroMRD Consortium guidelines, by both nested (NEST) polymerase chain reaction (PCR) and real-time quantitative (RQ) PCR for BCL2/IGH MBR or IGHV rearrangements. Here, we aimed at analyzing the samples that challenged the interlaboratory reproducibility and data interpretation. Overall, 156/187 BM samples (83%) were concordantly classified as NEST+/RQ+ or NEST-/RQ- by all the four laboratories. The remaining 31 samples (17%) resulted alternatively positive and negative in the interlaboratory evaluations, independently of the method and the type of rearrangement, and were defined "borderline" (brd) samples: 12 proved NEST brd/RQ brd, 7 NEST-/RQ brd, 10 NEST brd/RQ positive not quantifiable (PNQ), and 2 NEST brd/RQ-. Results did not change even increasing the number of replicates/sample. In 6/31 brd samples, droplet digital PCR (ddPCR) was tested and showed no interlaboratory discordance. Despite the high interlaboratory reproducibility in the MRD analysis obtained and maintained by the QC round strategy, samples with the lowest MRD levels can still represent a challenge: 17% (31/187) of our samples showed discordant results in interlaboratory assessments, with 6.4% (12/187) remained brd even applying the two methods. Thus, although representing a minority, brd samples are still problematic, especially when a clinically oriented interpretation of MRD results is required. Alternative, novel methods such as ddPCR and next-generation sequencing have the potential to overcome the current limitations.


Assuntos
Exame de Medula Óssea , Medula Óssea/patologia , Ensaio de Proficiência Laboratorial , Linfoma não Hodgkin/patologia , Reação em Cadeia da Polimerase , Exame de Medula Óssea/normas , Células Clonais , Rearranjo Gênico de Cadeia Pesada de Linfócito B , Genes de Imunoglobulinas , Genes bcl-2 , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Cadeias Pesadas de Imunoglobulinas/genética , Região Variável de Imunoglobulina/genética , Itália/epidemiologia , Linfoma não Hodgkin/genética , Neoplasia Residual , Proteínas de Fusão Oncogênica/análise , Reação em Cadeia da Polimerase/métodos , Reação em Cadeia da Polimerase/normas , Proteínas Proto-Oncogênicas c-bcl-2/genética , Garantia da Qualidade dos Cuidados de Saúde , Reprodutibilidade dos Testes , Translocação Genética
15.
Hematol Oncol ; 37(4): 456-463, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31348835

RESUMO

To illustrate the clinical and genetic features of elderly and secondary acute myeloid leukemia (AML) patients, we compared 145 elderly AML (e-AML) and 55 secondary AML (s-AML) patients with 451 young de novo AML patients. Both e-AML and s-AML patients showed lower white blood cell (WBC) and bone marrow (BM) blasts at diagnosis. NPM1, DNMT3A, and IDH2 mutations were more common while biallelic CEBPA and IDH1 mutations were less seen in e-AML patients. s-AML patients carried a higher frequency of KMT2A-AF9. In treatment response and survival, e/s-AML conferred a lower complete remission (CR) rate and shorter duration of event-free survival (EFS) and overall survival (OS) compared with young patients. In multivariate analysis, s-AML was an independent risk factor for OS but not EFS in the whole cohort. Importantly, intensive therapy tended to improve the survival of e/s-AML patients without increasing the risk of early death, and hematopoietic stem cell transplantation (HSCT) could rescue the prognosis of s-AML, which should be recommended for the treatment of fit patients.


Assuntos
Leucemia Mieloide Aguda/genética , Segunda Neoplasia Primária/genética , Adolescente , Adulto , Fatores Etários , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Medula Óssea/patologia , Aberrações Cromossômicas , Feminino , Genes Neoplásicos , Humanos , Estimativa de Kaplan-Meier , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/patologia , Contagem de Leucócitos , Masculino , Pessoa de Meia-Idade , Mutação , Neoplasia Residual , Segunda Neoplasia Primária/tratamento farmacológico , Segunda Neoplasia Primária/patologia , Células-Tronco Neoplásicas/patologia , Prognóstico , Intervalo Livre de Progressão , Indução de Remissão , Resultado do Tratamento , Adulto Jovem
16.
Hematol Oncol ; 37(4): 424-433, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31359447

RESUMO

Currently available prognostic scoring systems in primary myelofibrosis (PMF) do not integrate clinical, histological, and molecular data, or they also required information on "other" mutations that are available in the clinical practice only in a very limited number of laboratories. In the present multicenter study, including 401 PMF patients, an integrated International Prognostic Scoring System (I-IPSS) was developed by combining IPSS, grade of bone marrow fibrosis (GBMF), and driver mutations molecular status (MS) to define PMF prognosis at diagnosis. Four prognostic categories were identified: I-IPSS-low risk (113 patients), I-IPSS-intermediate-1 risk (56 patients), I-IPSS-intermediate-2 risk (154 patients), and I-IPSS-high risk (78 patients). Median overall survival was 26.7 years in I-IPSS-intermediate-1, 10.8 in I-IPSS-intermediate-2, and 6.4 in I-IPSS-high-risk patients (log-rank test <0.0001); instead, it was not reached in the I-IPSS-low-risk cohort because of the extremely low number of registered deaths. The addition of GBMF and MS to IPSS improved the efficacy for predicting the risk of death. Indeed, the sensitivity of I-IPSS was significantly higher (P < .05) than that of IPSS, considering both total deaths and 5- and 10-year mortality. This comprehensive approach allows clinicians to evaluate mutual interactions between IPSS, GBMF, and MS and identify high-risk patients with poor prognosis who may benefit from aggressive treatments. More importantly, this integrated score can be easily applicable worldwide as it only required information that represent the good clinical practice in the management of PMF patients.


Assuntos
Mielofibrose Primária/diagnóstico , Índice de Gravidade de Doença , Adulto , Idoso , Biomarcadores , Medula Óssea/patologia , Calreticulina/genética , Feminino , Humanos , Janus Quinase 2/genética , Masculino , Pessoa de Meia-Idade , Mutação , Proteínas de Neoplasias/genética , Mielofibrose Primária/genética , Mielofibrose Primária/mortalidade , Mielofibrose Primária/patologia , Prognóstico , Receptores de Trombopoetina/genética , Reticulina/ultraestrutura , Estudos Retrospectivos , Fatores de Risco
17.
Vet Microbiol ; 235: 136-142, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31282371

RESUMO

Infectious Bursal Disease Virus (IBDV) of the ITA genotype (G6) was shown to have peculiar molecular characteristics and, despite a subclinical course, aggressiveness towards lymphoid tissues after experimental infection of specific-pathogen-free (SPF) chickens. The aim of the present study was to evaluate and compare with a Classical IBDV strain, ITA IBDV distribution and persistence in various tissues (bursa of Fabricious, spleen, thymus, bone marrow, caecal tonsils, Harderian gland, kidney, liver and proventriculus), its cloacal shedding and the involvement of gut TLR-3 in duodenum tissues. The 35-day-old SPF chickens were experimentally infected and sampled up to 28 days post infection (dpi) for IBDV detection and TLR-3 quantification by qRT-PCR. The ITA IBDV strain was detected in lymphoid and most non-lymphoid tissues up to the end of the trial, with higher loads compared to the Classical IBDV. Most of those differences were found during the first 2 weeks post-infection. Notably, bone marrow and caecal tonsils presented higher viral loads until 28 dpi, allowing to speculate that these organs may serve as non-bursal lymphoid tissues supporting virus replication. Differences in relative TLR-3 gene expression between ITA IBDV-infected birds and Classical-IBDV infected ones were observed at 4, 14 and 21 dpi, being initially higher in Classical group and later in ITA group. Our results provide new insights into IBDV pathogenesis showing that IBDV of ITA genotype leads to a high and persistent viral load in lymphoid tissues and to a delayed antiviral response.


Assuntos
Infecções por Birnaviridae/veterinária , Vírus da Doença Infecciosa da Bursa/genética , Tecido Linfoide/virologia , Doenças das Aves Domésticas/imunologia , Carga Viral , Animais , Infecções por Birnaviridae/imunologia , Medula Óssea/patologia , Medula Óssea/virologia , Galinhas , Ensaio de Imunoadsorção Enzimática , Genótipo , Vírus da Doença Infecciosa da Bursa/patogenicidade , Tonsila Palatina/virologia , Doenças das Aves Domésticas/virologia , Organismos Livres de Patógenos Específicos , Receptor 3 Toll-Like/genética , Replicação Viral
18.
Cancer Sci ; 110(9): 2748-2759, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31301081

RESUMO

In hepatocarcinogenesis induced by diethylnitrosamine (DEN) in B6C3F1 mice, the BrafV637E mutation, corresponding to the human BRAFV600E mutation, plays a pivotal role. The livers of transgenic mice with a hepatocyte-specific human BRAFV600E mutation weighed 4.5 times more than that of normal mice and consisted entirely of hepatocytes, resembling DEN-induced preneoplastic hepatocytes. However, these transgenic mice spontaneously died 7 wk after birth, therefore this study aimed to clarify the causes of death. In the transgenic mice, the liver showed thrombopoietin (TPO) overexpression, which is associated with eventual megakaryocytosis and thrombocytosis, and activated platelets were deposited in hepatic sinusoids. TPO was also overexpressed in the DEN-induced hepatic tumors, and sinusoidal platelet deposition was observed in the hepatic tumors of humans and mice. Podoplanin was expressed in some of the Kupffer cells in the liver of the transgenic mice, indicating that platelet activation occurred via the interaction of podoplanin with C-type lectin receptor 2 (CLEC-2) on the platelet membrane. Additionally, erythrocyte dyscrasia and glomerulonephropathy/interstitial pneumonia associated with platelet deposition were observed. In the transgenic mice, aspirin (Asp) administration prevented platelet activation, reduced the liver/body weight ratio, decreased the platelet deposition in the liver, kidney, and lung, and prevented erythrocyte dyscrasia and ameliorated the renal/pulmonary changes. Thrombopoietin overproduction by BRAFV600E-mutated hepatocytes may contribute to hepatocyte proliferation via thrombocytosis, platelet activation, and the interaction of platelets with hepatic sinusoidal cells, while hematologic, renal, and pulmonary disorders due to aberrant platelet activation may lead to spontaneous death in the transgenic mice.


Assuntos
Carcinogênese/genética , Neoplasias Hepáticas Experimentais/patologia , Fígado/patologia , Proteínas Proto-Oncogênicas B-raf/genética , Trombopoetina/metabolismo , Animais , Biópsia , Plaquetas/patologia , Medula Óssea/patologia , Capilares/patologia , Carcinógenos/administração & dosagem , Carcinógenos/toxicidade , Proliferação de Células/genética , Dietilnitrosamina/administração & dosagem , Dietilnitrosamina/toxicidade , Feminino , Regulação Neoplásica da Expressão Gênica , Hepatectomia , Hepatócitos/patologia , Humanos , Fígado/irrigação sanguínea , Fígado/citologia , Neoplasias Hepáticas Experimentais/induzido quimicamente , Neoplasias Hepáticas Experimentais/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos , Camundongos Transgênicos , Ativação Plaquetária/genética , Cultura Primária de Células , Proteínas Proto-Oncogênicas B-raf/metabolismo , Células Tumorais Cultivadas
19.
Rinsho Ketsueki ; 60(6): 559-564, 2019.
Artigo em Japonês | MEDLINE | ID: mdl-31281144

RESUMO

Classic hairy cell leukemia (classic HCL) is a rare disease associated with indolent mature B-cell lymphoma. A 50-year-old man presented with pancytopenia for 3 years and was diagnosed with classic HCL because his lymphoid cells showed a hairy morphology with oval nuclei and indistinct nucleoli both in the peripheral blood and bone marrow (BM) smears. Flow cytometric analysis revealed that these cells expressed CD11c, CD25, and CD103, and the Sanger sequence method detected BRAF V600E mutation. Cladribine (0.09 mg/kg/day) was initiated for 7 days via continuous intravenous injection. On day 13, the patient died from bloodstream infection caused by methicillin-resistant Staphylococcus epidermidis. Autopsy findings revealed BM necrosis without residual leukemia cells caused by classic HCL, severe infection, and agents, such as cladribine and granulocyte-colony stimulating factor; however, its cause remained undetermined. Both early diagnosis and immediate clinical intervention are required to improve the clinical outcomes in classic HCL. The cause of hematopoiesis disturbance should also be identified using BM biopsy or magnetic resonance imaging before initiating treatment in classic HCL with severe pancytopenia.


Assuntos
Medula Óssea/patologia , Cladribina/administração & dosagem , Leucemia de Células Pilosas/diagnóstico , Infecções Estafilocócicas , Antineoplásicos/administração & dosagem , Evolução Fatal , Humanos , Masculino , Staphylococcus aureus Resistente à Meticilina , Pessoa de Meia-Idade
20.
Rev Med Chil ; 147(3): 275-280, 2019 Mar.
Artigo em Espanhol | MEDLINE | ID: mdl-31344163

RESUMO

BACKGROUND: Waldenström macroglobulinemia (WM) is an uncommon indolent B-cell lymphoma, due to the proliferation of lymphoplasmacytic cells, and secretion of a monoclonal IgM protein. AIM: To evaluate the clinical characteristics, management and results of treatment of patients with WM at a public hospital in Chile. PATIENTS AND METHODS: Review of medical records of 31 patients aged 43 to 85 years (16 males) with WM diagnosed between 2002 and 2017. Clinical features and survival were recorded. RESULTS: All patients had bone marrow compromise, and 31%, extranodal involvement. According to the International Prognostic Score System for WM (IPSSWM) 16, 58 and 26% were at low, intermediate and high risk, respectively. Twenty-five patients (81%) were treated, 32% with plasmapheresis and 36% with rituximab. Four cases (16%) achieved complete remission. Median follow up was 35 months (range 6-159). Estimated overall survival (OS) at 5 and 10 years was 74% and 53%, respectively. According to IPSSWM, the estimated five-year OS was 80, 92 and 39%, for low, intermediate and high-risk patients, respectively. CONCLUSIONS: OS was similar to that reported abroad, except for low risk patients, probably due to the low number of cases and short follow up. An improved survival should be expected with the routine use of immunochemotherapy.


Assuntos
Macroglobulinemia de Waldenstrom/diagnóstico , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos Imunológicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biópsia , Medula Óssea/patologia , Chile/epidemiologia , Ciclofosfamida/uso terapêutico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Prednisona/uso terapêutico , Estudos Retrospectivos , Rituximab/uso terapêutico , Taxa de Sobrevida , Resultado do Tratamento , Vincristina/uso terapêutico , Macroglobulinemia de Waldenstrom/tratamento farmacológico , Macroglobulinemia de Waldenstrom/mortalidade
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