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1.
Isr Med Assoc J ; 22(10): 645-647, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-33070490

RESUMO

BACKGROUND: Histiocytic sarcoma (HS) is a rare hematopoietic malignancy originating from the monocyte/macrophage bone marrow lineage. HS can occur in isolation or in association with other hematological neoplasms such as non-Hodgkin lymphoma (NHL), myelodysplasia, or acute leukemia. Clinically, HS can affect lymph nodes, gastrointestinal tract, skin, bone marrow, and spleen as well as the central nervous system. Most cases of HS follow an aggressive clinical course, with most patients dying of progressive disease within one year of diagnosis.


Assuntos
Medula Óssea/patologia , Sarcoma Histiocítico/patologia , Linfonodos/patologia , Biópsia por Agulha , Diagnóstico Diferencial , Feminino , Sarcoma Histiocítico/diagnóstico , Sarcoma Histiocítico/terapia , Humanos , Imuno-Histoquímica , Linfoma não Hodgkin/patologia , Linfoma não Hodgkin/terapia , Masculino , Síndromes Mielodisplásicas/patologia , Síndromes Mielodisplásicas/terapia , Prognóstico , Doenças Raras , Medição de Risco , Tomografia Computadorizada por Raios X/métodos
2.
Lancet Haematol ; 7(8): e566-e574, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32735836

RESUMO

BACKGROUND: The median overall survival of patients with high-risk myelodysplastic syndromes refractory to hypomethylating agents is less than 6 months. Currently, no standard therapy for such patients exists. Preclinical studies have shown that inhibition of the nuclear export protein exportin 1 (XPO1) causes nuclear accumulation of p53 and disruption of NF-κB signalling, both relevant targets for myelodysplastic syndromes. We therefore aimed to assess the safety and activity of selinexor in patients with myelodysplastic syndromes or oligoblastic acute myeloid leukaemia refractory to hypomethylating agents. METHODS: We did a single-centre, single-arm, phase 2 trial at the Memorial Sloan Kettering Cancer Center in the USA. We included patients 18 years or older with high-risk myelodysplastic syndromes or oligoblastic acute myeloid leukaemia (defined as blasts ≥20% but ≤30%) refractory to hypomethylating agents and with an Eastern Cooperative Oncology Group performance status score of 0-2. Eligible patients received 3-week long cycles of oral selinexor (60 mg twice per week for 2 weeks, followed by 1 week off). The primary outcome was overall response rate. Complete remission, partial remission, marrow complete remission, or haematological improvement were included in the response categories for assessing the primary endpoint. The activity analysis included all patients who completed at least one full-scheduled post-treatment disease assessment. All patients who were given selinexor were included in the safety analysis. This study is registered with ClinicalTrials.gov, NCT02228525. FINDINGS: Between Sept 23, 2014, and March 13, 2018, 25 patients were enrolled on this study. The median follow-up was 8·5 months (IQR 3·1-12·2). Two patients did not meet the full eligibility criteria after baseline assessment; therefore, 23 patients were evaluable for activity assessment. In the 23 evaluable patients, overall response rate was 26% (95% CI 10-48) in six patients with marrow complete remission, with an additional 12 patients (52%, 95% CI 31-73) achieving stable disease. The most common grade 3 or 4 adverse events were thrombocytopenia (eight [32%] of 25 patients) and hyponatraemia (five [20%]). There were no drug-related serious adverse events and no treatment-related deaths. INTERPRETATION: Selinexor showed responses in patients with myelodysplastic syndromes or oligoblastic acute myeloid leukaemia refractory to hypomethylating agents. Adverse events were manageable with supportive care implementation. Further studies are needed to compare selinexor with supportive care alone, and to identify patient subgroups that might benefit the most from selinexor treatment. FUNDING: Karyopharm Therapeutics.


Assuntos
Azacitidina/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Hidrazinas/uso terapêutico , Leucemia Mieloide Aguda/tratamento farmacológico , Síndromes Mielodisplásicas/tratamento farmacológico , Triazóis/uso terapêutico , Idoso , Idoso de 80 Anos ou mais , Antimetabólitos Antineoplásicos/farmacologia , Feminino , Seguimentos , Humanos , Leucemia Mieloide Aguda/patologia , Masculino , Síndromes Mielodisplásicas/patologia , Segurança do Paciente , Prognóstico , Taxa de Sobrevida
3.
Medicine (Baltimore) ; 99(34): e21900, 2020 Aug 21.
Artigo em Inglês | MEDLINE | ID: mdl-32846854

RESUMO

BACKGROUND: Gene mutations with important prognostic roles have been identified in patients with myelodysplastic syndrome (MDS). Overall, it is not yet fully clear whether enhancer of zeste homolog 2 (EZH2) is affected and contributes to the disease in MDS patients. Thus, we performed a meta-analysis to investigate the effects of EZH2 mutations on the prognosis of patients with MDS. METHODS: We searched English-language databases (PubMed, Embase, and Cochrane Library) for studies published on the effects of EZH2 mutations in MDS patients. The study had to include at least 1 of the following indices as therapeutic evaluation data: overall survival (OS), transformation time to leukemia, and International Prognostic Scoring System risk. Revman, version 5.2 software was used for all statistical processing. We calculated the risk ratio and the 95% confidence interval (CI) of continuous variables, and determined the hazard ratio and 95% CI of time-to-event data. RESULTS: We included 5 studies with a total enrolment of 994 patients. There was a significant adverse effect on OS in the EZH2-mutation group compared to the unmutated group (hazard ratio = 2.47, 95% CI: 1.37-4.47, P < .00001), while the heterogeneity was relatively high (I = 68%). There was no significant correlation between EZH2 mutations and IPSS risk (low/int-1 vs int-2/high) (odds ratio: 0.69, 95% CI: 0.14-3.39, P = .65), with significant heterogeneity (I = 78%). The analysis did not show significant publication bias in the studies. CONCLUSION: This meta-analysis indicated an adverse effect of EZH2 mutations with regard to OS in patients with MDS. However, larger cohort trials are still needed to better understand the prognostic impacts of EZH2 mutations on MDS patients.


Assuntos
Proteína Potenciadora do Homólogo 2 de Zeste/genética , Síndromes Mielodisplásicas/genética , Síndromes Mielodisplásicas/mortalidade , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Síndromes Mielodisplásicas/patologia , Razão de Chances , Prognóstico , Análise de Sobrevida , Adulto Jovem
4.
Anticancer Res ; 40(7): 3883-3888, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32620628

RESUMO

BACKGROUND/AIM: The insulin-like growth factor type 1 receptor (IGF-1R) is overexpressed in myelodysplastic syndrome (MDS) cells, and 765IGF-Methotrexate (IGF-MTX) is a conjugate of methotrexate and a variant of insulin-like growth factor-1 (IGF-1) designed to selectively target cancer cells through binding to IGF-1R. The aim of this study was to determine whether IGF-MTX would be effective to treat MDS. PATIENTS AND METHODS: In this phase I clinical trial, two patients with high grade MDS or oligoblastic acute myeloid leukemia (O-AML) that had failed standard therapy were treated with IGF-MTX. RESULTS: No dose-limiting toxicity was observed. Both patients had stable or improved cell counts and CD34+ myelodysplastic cell counts and exceeded their life expectancy (both alive at 1.9 years despite a life expectancy of less than 6 months). Bone marrow blast counts decreased from 22% to 5% in one patient, and from 17% to 16% in the other. CONCLUSION: In conclusion, IGF-MTX at 0.20 µM equivalents per kg was well tolerated, caused no cytopenia, and produced stable disease and extension of life.


Assuntos
Imunoconjugados/administração & dosagem , Metotrexato/administração & dosagem , Síndromes Mielodisplásicas/tratamento farmacológico , Idoso , Idoso de 80 Anos ou mais , Humanos , Imunoconjugados/efeitos adversos , Imunoconjugados/imunologia , Fator de Crescimento Insulin-Like I/administração & dosagem , Fator de Crescimento Insulin-Like I/imunologia , Masculino , Metotrexato/efeitos adversos , Terapia de Alvo Molecular , Síndromes Mielodisplásicas/sangue , Síndromes Mielodisplásicas/imunologia , Síndromes Mielodisplásicas/patologia , Gradação de Tumores , Receptor IGF Tipo 1/biossíntese , Receptor IGF Tipo 1/imunologia
5.
Hematol Oncol ; 38(4): 541-553, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32495951

RESUMO

Higher-risk Myelodysplastic syndromes (MDS) patients undergoing treatment with 5-azacytidine (AZA) are typically elderly with several comorbidities. However, the effect of comorbidities on the effectiveness and safety of AZA in real-world settings remains unclear. We analyzed data from 536 AZA-treated patients with higher-risk MDS, Myelodysplastic/Myeloproliferative neoplasms and low blast count Acute Myeloid Leukemia enrolled to the Hellenic National Registry of Myelodysplastic and Hypoplastic Syndromes. Multivariate analysis adjusted also for the International Prognostic Scoring System (IPSS), its revised version (IPSS-R) and the French Prognostic Scoring System (FPSS), demonstrated independent associations of overall and leukemia-free survival with estimated glomerular filtration rate (eGFR) <45 mL min-1 /1.73 m2 (P = .039, P = .023, respectively), ECOG performance status <2 (P = .015, P = .006), and presence of peripheral blood blasts (P = .008, P = .034), while secondary MDS also correlated with significantly shorter leukemia-free survival (P = .039). Addition of eGFR <45 mL min-1 /1.73 m2 , in IPSS-R and FPSS increased the predictive power of both models. Only FPSS ≤2 and eGFR <45 mL min-1 /1.73 m2 predicted worse response to AZA in multivariate analysis, whereas eGFR <45 mL min-1 /1.73 m2 correlated significantly with death from hemorrhage (P = .003) and cardiovascular complications (P = .006). In conclusion, in the second largest real-world series of AZA-treated MDS patients, we show that an eGFR <45 mL min-1 /1.73 m2 is an independent predictor of worse response and survival. This higher cut-off, instead of the commonly used serum creatinine >2 mg/dL, can be utilized as a more precise indicator of renal comorbidity during AZA therapy. Incorporation of eGFR in the prognostic assessment of AZA-treated MDS patients may prove useful not only in routine practice, but also for the appropriate patient stratification in clinical trials with AZA combinations.


Assuntos
Antimetabólitos Antineoplásicos/efeitos adversos , Azacitidina/efeitos adversos , Taxa de Filtração Glomerular , Nefropatias/mortalidade , Síndromes Mielodisplásicas/mortalidade , Sistema de Registros/estatística & dados numéricos , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Seguimentos , Humanos , Nefropatias/induzido quimicamente , Nefropatias/patologia , Masculino , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/tratamento farmacológico , Síndromes Mielodisplásicas/patologia , Prognóstico , Taxa de Sobrevida
6.
Gene ; 754: 144881, 2020 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-32526259

RESUMO

OBJECTIVE: This study aims to investigate the roles of Sonic hedgehog (Shh) signaling pathway in the occurrence and progression of Myelodysplastic Syndrome (MDS) and further evaluate using jervine as therapeutic strategy for MDS by inhibiting Shh pathway. METHODS: CD34+ cells from the bone marrow of 53 MDS patients were counted by flow cytometry and isolated by magnetic bead sorting. Shh, Smo, Ptch-1 and Gli-1 (involved in Shh pathway) in CD34+ cells were examined by RT-qPCR. Besides, the relationship between Shh pathway-related genes and the clinical features or prognosis of MDS were analyzed. Further, the effects of jervine on MUTZ-1 cells regarding their proliferation, apoptosis and cell cycle as well as Shh pathway-related gene and protein expression were analyzed. RESULTS: Gene expression level of Shh, Gli-1 and Smo was significantly increased in MDS patients. Herein, Smo and Gli-1 were correlated with chromosome karyotype classification and IPSS. MDS patients with high expression of Smo or Gli-1 had a poor prognosis. Jervine inhibited gene and protein expression of Shh, Smo, Ptch-1 and Gli-1. Besides, jervine suppressed the proliferation and promoted the apoptosis of MUTZ-1 cells, as well as inhibited the transition of cells from G1 to S phase. CONCLUSION: Shh signaling pathway of MDS patients is abnormally activated and participated in the occurrence and progression of MDS. Jervine intervention is a potential therapeutic strategy for MDS.


Assuntos
Biomarcadores Tumorais/metabolismo , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Proteínas Hedgehog/metabolismo , Síndromes Mielodisplásicas/tratamento farmacológico , Síndromes Mielodisplásicas/patologia , Alcaloides de Veratrum/farmacologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Apoptose , Biomarcadores Tumorais/genética , Ciclo Celular , Proliferação de Células , Feminino , Proteínas Hedgehog/genética , Humanos , Masculino , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/metabolismo , Receptor Patched-1/genética , Receptor Patched-1/metabolismo , Prognóstico , Transdução de Sinais , Receptor Smoothened/genética , Receptor Smoothened/metabolismo , Células Tumorais Cultivadas , Adulto Jovem , Proteína GLI1 em Dedos de Zinco/genética , Proteína GLI1 em Dedos de Zinco/metabolismo
8.
J Cancer Res Ther ; 16(1): 173-176, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32362632

RESUMO

Myelodysplastic syndromes (MDSs) are characteristically defined by the presence of specific karyotypic abnormalities, based on which they have been prognosticated. Translocation t(9;22)(q34;q11.2) (Philadelphia positive [Ph +ve]) and corresponding BCR-ABL fusion transcript is the defining parameter of chronic myeloid leukemia. It is also seen in a fair proportion of adult acute lymphoblastic leukemia. Occurrence of a Ph +ve MDS is very uncommon, and that too is seen mostly on progression to higher stage/acute leukemia. Even rarer is the de novo presence of Ph positivity in an MDS. A literature search through PubMed has shown only about forty cases of Ph +ve MDS among which less than half had shown Ph positivity at the time of initial diagnosis. Due to its rarity, this entity has not yet found its space in current WHO 2008 classification and is still under "yet to be validated phase" in current practice of hematological malignancies. The benefit of using a tyrosine kinase inhibitor in such a situation is also debatable. We report here two such cases of de novo Ph +ve MDS, diagnosed in last 1½ year at our institute along with brief literature review.


Assuntos
Proteínas de Fusão bcr-abl/genética , Síndromes Mielodisplásicas/patologia , Cromossomo Filadélfia , Translocação Genética , Adulto , Progressão da Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/genética
9.
Cell Prolif ; 53(5): e12819, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32372504

RESUMO

OBJECTIVE: The objective of this study was to explore characteristics of bone marrow mesenchymal stromal cells (BM-MSCs) derived from patients with myelodysplastic syndrome (MDS) and multiple myeloma (MM). METHODS: BM-MSCs were recovered from 17 of MDS patients, 23 of MM patients and 9 healthy donors and were passaged until proliferation stopped. General characteristics and gene expression profiles of MSCs were analysed. In vitro, ex vivo coculture, immunohistochemistry and knockdown experiments were performed to verify gene expression changes. RESULTS: BM-MSCs failed to culture in 35.0% of patients and 50.0% of recovered BM-MSCs stopped to proliferate before passage 6. MDS- and MM-MSCs shared characteristics including decreased osteogenesis, increased angiogenesis and senescence-associated molecular pathways. In vitro and ex vivo experiments showed disease-specific changes such as neurogenic tendency in MDS-MSCs and cardiomyogenic tendency in MM-MSCs. Although the age of normal control was younger than patients and telomere length was shorter in patient's BM-MSCs, they were not different according to disease category nor degree of proliferation. Specifically, poorly proliferation BM-MSCs showed CDKN2A overexpression and CXCL12 downregulation. Immunohistochemistry of BM biopsy demonstrated that CDKN2A was intensely accumulation in perivascular BM-MSCs failed to culture. Interestingly, patient's BM-MSCs revealed improved proliferation activity after CDKN2A knockdown. CONCLUSION: These results collectively indicate that MDS-MSCs and MM-MSCs have common and different alterations at various degrees. Hence, it is necessary to evaluate their alteration status using representative markers such as CDKN2A expression.


Assuntos
Medula Óssea/patologia , Células-Tronco Mesenquimais/patologia , Mieloma Múltiplo/patologia , Síndromes Mielodisplásicas/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Medula Óssea/metabolismo , Células da Medula Óssea/metabolismo , Células da Medula Óssea/patologia , Diferenciação Celular/fisiologia , Proliferação de Células/fisiologia , Células Cultivadas , Quimiocina CXCL12/metabolismo , Feminino , Humanos , Masculino , Células-Tronco Mesenquimais/metabolismo , Pessoa de Meia-Idade , Mieloma Múltiplo/metabolismo , Síndromes Mielodisplásicas/metabolismo , Osteogênese/fisiologia , Adulto Jovem
10.
Hematol Oncol ; 38(4): 531-540, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32469434

RESUMO

Patients with acute myeloid leukemia (AML) evolving from myelodysplastic syndrome (MDS) or higher-risk MDS have limited treatment options and poor prognosis. Our previous single-center study of decitabine followed by low dose idarubicin and cytarabine (D-IA) in patients with myeloid neoplasms showed promising primary results. We therefore conducted a multicenter study of D-IA regimen in AML evolving from MDS and higher-risk MDS. Patients with AML evolving from MDS or refractory anemia with excess blasts type 2 (RAEB-2) (based on the 2008 WHO classification) were included. The D-IA regimen (decitabine, 20 mg/m2 daily, days 1 to 3; idarubicin, 6 mg/m2 daily, days 4 to 6; cytarabine 25 mg/m2 every 12 hours, days 4 to 8; granulocyte colony stimulating factor [G-CSF], 5 µg/kg, from day 4 until neutrophil count increased to 1.0 × 109 /L) was administered as induction chemotherapy. Seventy-one patients were enrolled and treated, among whom 44 (62.0%) had AML evolving from MDS and 27 (38.0%) had RAEB-2. Twenty-eight (63.6%) AML patients achieved complete remission (CR) or complete remission with incomplete blood count recovery (CRi): 14 (31.8%) patients had CR and 14 (31.8%) had CRi. Six (22.2%) MDS patients had CR and 15 (55.6%) had marrow complete remission. The median overall survival (OS) was 22.4 months for the entire group, with a median OS of 24.2 months for AML and 20.0 months for MDS subgroup. No early death occurred. In conclusion, the D-IA regimen was effective and well tolerated, representing an alternative option for patients with AML evolving from MDS or MDS subtype RAEB-2.


Assuntos
Anemia Refratária com Excesso de Blastos/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biomarcadores Tumorais/genética , Evolução Clonal , Epigênese Genética , Leucemia Mieloide Aguda/tratamento farmacológico , Síndromes Mielodisplásicas/tratamento farmacológico , Adulto , Idoso , Anemia Refratária com Excesso de Blastos/genética , Anemia Refratária com Excesso de Blastos/patologia , Citarabina/administração & dosagem , Decitabina/administração & dosagem , Feminino , Seguimentos , Regulação Neoplásica da Expressão Gênica , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Idarubicina/administração & dosagem , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patologia , Masculino , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/genética , Síndromes Mielodisplásicas/patologia , Prognóstico , Estudos Prospectivos , Taxa de Sobrevida , Adulto Jovem
11.
Exp Hematol ; 86: 21-27.e2, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32437909

RESUMO

Our previous study revealed that expression of G protein-coupled receptor 68 (GPR68) was upregulated in MDSL cells, a cell line representing myelodysplastic syndromes (MDS), in response to lenalidomide (LEN), and mediated a calcium/calpain proapoptotic pathway. Isx, a GPR68 agonist, enhanced the sensitivity to LEN in MDSL cells. The fact that Isx is not a U.S. Food and Drug Administration-approved drug prompts us to look for alternative candidates that could enhance the sensitivity of LEN in MDS as well as other hematologic malignancies, such as acute myeloid leukemia (AML). In the study described here, we found that regulator of calcineurin 1 (RCAN1), an endogenous inhibitor of calcineurin (CaN), was upregulated in MDSL cells in response to LEN, possibly through degradation of IKZF1. Consistently, cyclosporin (Cys), a pharmacological inhibitor of CaN, inhibited the activity of CaN and induced apoptosis in MDSL cells, indicating that CaN provided a prosurvival signal in MDSL cells. In addition, Cys enhanced the cytotoxic effect of LEN in MDS/AML cell lines as well as primary bone marrow cells from MDS patients and AML patient-derived xenograft models. Intriguingly, pretreatment with LEN reversed the suppressive effect of Cys on T-cell activation. Our study suggests a novel mechanism of action of LEN in mediating cytotoxicity in MDS/AML via upregulation of RCAN1, thus inhibiting the CaN prosurvival pathway. Our study also suggests that Cys enhances the sensitivity to LEN in MDS/AML cells without compromising T-cell activation.


Assuntos
Ciclosporina/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Lenalidomida/farmacologia , Leucemia Mieloide Aguda , Síndromes Mielodisplásicas , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Ciclosporina/agonistas , Proteínas de Ligação a DNA/biossíntese , Regulação Leucêmica da Expressão Gênica/efeitos dos fármacos , Humanos , Fator de Transcrição Ikaros/biossíntese , Lenalidomida/agonistas , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/metabolismo , Leucemia Mieloide Aguda/patologia , Camundongos , Camundongos Endogâmicos NOD , Proteínas Musculares/biossíntese , Síndromes Mielodisplásicas/tratamento farmacológico , Síndromes Mielodisplásicas/metabolismo , Síndromes Mielodisplásicas/patologia , Proteínas de Neoplasias/biossíntese , Regulação para Cima/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
12.
Am J Clin Pathol ; 154(1): 5-14, 2020 06 08.
Artigo em Inglês | MEDLINE | ID: mdl-32458977

RESUMO

OBJECTIVES: Myelodysplastic syndromes (MDS) are a group of myeloid neoplasms that are often difficult to diagnose due to their pathologic and clinical heterogeneity. The key features of MDS are peripheral blood cytopenias, ineffective hematopoiesis manifesting as morphologic dysplasia, and clonal genetic abnormalities. The most difficult diagnostic dilemmas often arise in low-grade MDS cases (lacking excess blasts), which can be difficult to distinguish from other causes of cytopenia. This distinction requires the integration of information from the peripheral blood (both CBC parameters and morphology), bone marrow morphology, genetic studies, and interrogation of the clinical record to exclude secondary causes. METHODS: We discuss the approach to the diagnosis of low-grade MDS (cases lacking increased blasts), including a diagnostic algorithm and two illustrative cases. RESULTS: The appropriate use of ancillary studies is important to support or dispute the likelihood of low-grade MDS in conjunction with the findings of morphologic dysplasia. Interpreting the results of cytogenetics and next-generation sequencing can be challenging and must incorporate the emerging knowledge of clonal hematopoiesis of indeterminate potential. CONCLUSIONS: The role of pathologists in integrating data from multiple sources in the diagnosis of low-grade MDS is evolving and becoming increasingly complex; in this challenging diagnostic setting, it is important to feel comfortable with uncertainty and maintain a conservative approach.


Assuntos
Síndromes Mielodisplásicas/diagnóstico , Idoso , Idoso de 80 Anos ou mais , Humanos , Masculino , Síndromes Mielodisplásicas/genética , Síndromes Mielodisplásicas/patologia
13.
Leuk Res ; 94: 106369, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32442785

RESUMO

Phase 1 results from a Phase 1/2 study comprise 18 patients with myelodysplastic syndromes (MDS; n = 9), acute myeloid leukemia (AML; n = 8), and chronic myelomonocytic leukemia (CMML; n = 1) who were either hypomethylating agent naïve (n = 10) or relapsed/refractory following prior hypomethylating agent therapy (n = 8) (NCT01926587). Patients received oral rigosertib, an inhibitor of Ras-effector pathways, in 3 successive cohorts (140 mg twice daily, 280 mg twice daily, or 840 mg/day [560 mg morning/280 mg evening]) for 3 weeks of a 4-week cycle. Patients received parenteral azacitidine (75 mg/m2/day × 7 days) during the second week; the cycle repeated every 4 weeks. The combination was well tolerated for a median of 4 (range 1-41) cycles, with 72% of patients experiencing ≥1 serious adverse events. No dose-limiting toxicities were observed. Thus, no maximum tolerated dose was reached. The most frequently reported adverse events were diarrhea (50%), constipation, fatigue, and nausea (each 44%), and pneumonia and back pain (each 33%). Sequential administration demonstrated an overall response rate of 56% in evaluable patients, with responses observed in 7/9 MDS/CMML patients (78%) and 2/7 AML patients (29%). Further clinical studies are warranted to investigate this doublet therapy in patients with myeloid malignancies.


Assuntos
Azacitidina/administração & dosagem , Glicina/análogos & derivados , Leucemia Mieloide Aguda/tratamento farmacológico , Síndromes Mielodisplásicas/tratamento farmacológico , Sulfonas/administração & dosagem , Adulto , Idoso , Idoso de 80 Anos ou mais , Azacitidina/efeitos adversos , Feminino , Glicina/administração & dosagem , Glicina/efeitos adversos , Humanos , Leucemia Mielogênica Crônica BCR-ABL Positiva/sangue , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Leucemia Mielogênica Crônica BCR-ABL Positiva/patologia , Leucemia Mieloide Aguda/sangue , Leucemia Mieloide Aguda/patologia , Masculino , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/sangue , Síndromes Mielodisplásicas/patologia , Sulfonas/efeitos adversos
16.
Biol Blood Marrow Transplant ; 26(7): 1312-1317, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32283185

RESUMO

The COVID-19 pandemic has created significant barriers to timely donor evaluation, cell collection, and graft transport for allogeneic hematopoietic stem cell transplantation (allo-HCT). To ensure availability of donor cells on the scheduled date of infusion, many sites now collect cryopreserved grafts before the start of pretransplantation conditioning. Post-transplantation cyclophosphamide (ptCY) is an increasingly used approach for graft-versus-host disease (GVHD) prophylaxis, but the impact of graft cryopreservation on the outcomes of allo-HCT using ptCY is not known. Using the Center for International Blood and Marrow Transplant Research (CIBMTR) database, we compared the outcomes of HCT using cryopreserved versus fresh grafts in patients undergoing HCT for hematologic malignancy with ptCY. We analyzed 274 patients with hematologic malignancy undergoing allo-HCT between 2013 and 2018 with cryopreserved grafts and ptCY. Eighteen patients received bone marrow grafts and 256 received peripheral blood stem cell grafts. These patients were matched for age, graft type, disease risk index (DRI), and propensity score with 1080 patients who underwent allo-HCT with fresh grafts. The propensity score, which is an assessment of the likelihood of receiving a fresh graft versus a cryopreserved graft, was calculated using logistic regression to account for the following: disease histology, Karnofsky Performance Score (KPS), HCT Comorbidity Index, conditioning regimen intensity, donor type, and recipient race. The primary endpoint was overall survival (OS). Secondary endpoints included acute and chronic graft-versus-host disease (GVHD), non-relapse mortality (NRM), relapse/progression and disease-free survival (DFS). Because of multiple comparisons, only P values <.01 were considered statistically significant. The 2 cohorts (cryopreserved and fresh) were similar in terms of patient age, KPS, diagnosis, DRI, HCT-CI, donor/graft source, and conditioning intensity. One-year probabilities of OS were 71.1% (95% confidence interval [CI], 68.3% to 73.8%) with fresh grafts and 70.3% (95% CI, 64.6% to 75.7%) with cryopreserved grafts (P = .81). Corresponding probabilities of OS at 2 years were 60.6% (95% CI, 57.3% to 63.8%) and 58.7% (95% CI, 51.9% to 65.4%) (P = .62). In matched-pair regression analysis, graft cryopreservation was not associated with a significantly higher risk of mortality (hazard ratio [HR] for cryopreserved versus fresh, 1.05; 95% CI, .86 to 1.29; P = .60). Similarly, rates of neutrophil recovery (HR, .91; 95% CI, .80 to 1.02; P = .12), platelet recovery (HR, .88; 95% CI, .78 to 1.00; P = .05), grade III-IV acute GVHD (HR, .78; 95% CI, .50 to 1.22; P = .27), NRM (HR, 1.16; 95% CI, .86 to 1.55; P = .32) and relapse/progression (HR, 1.21; 95% CI, .97 to 1.50; P = .09) were similar with cryopreserved grafts versus fresh grafts. There were somewhat lower rates of chronic GVHD (HR, 78; 95% CI, .61 to .99; P = .04) and DFS (HR for treatment failure, 1.19; 95% CI, 1.01 to 1.29; P = .04) with graft cryopreservation that were of marginal statistical significance after adjusting for multiple comparisons. Overall, our data indicate that graft cryopreservation does not significantly delay hematopoietic recovery, increase the risk of acute GVHD or NRM, or decrease OS after allo-HCT using ptCY.


Assuntos
Transplante de Medula Óssea/métodos , Infecções por Coronavirus/epidemiologia , Criopreservação/métodos , Doença Enxerto-Hospedeiro/prevenção & controle , Transplante de Células-Tronco Hematopoéticas/métodos , Leucemia/terapia , Linfoma/terapia , Síndromes Mielodisplásicas/terapia , Pneumonia Viral/epidemiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Ciclofosfamida/uso terapêutico , Feminino , Doença Enxerto-Hospedeiro/imunologia , Doença Enxerto-Hospedeiro/mortalidade , Doença Enxerto-Hospedeiro/patologia , Teste de Histocompatibilidade , Humanos , Leucemia/imunologia , Leucemia/mortalidade , Leucemia/patologia , Linfoma/imunologia , Linfoma/mortalidade , Linfoma/patologia , Masculino , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/imunologia , Síndromes Mielodisplásicas/mortalidade , Síndromes Mielodisplásicas/patologia , Pandemias , Irmãos , Análise de Sobrevida , Condicionamento Pré-Transplante/métodos , Transplante Homólogo , Estados Unidos/epidemiologia , Doadores não Relacionados/provisão & distribução
17.
Cancer Res ; 80(12): 2523-2536, 2020 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-32341038

RESUMO

RUNX3, a RUNX family transcription factor, regulates normal hematopoiesis and functions as a tumor suppressor in various tumors in humans and mice. However, emerging studies have documented increased expression of RUNX3 in hematopoietic stem/progenitor cells (HSPC) of a subset of patients with myelodysplastic syndrome (MDS) showing a worse outcome, suggesting an oncogenic function for RUNX3 in the pathogenesis of hematologic malignancies. To elucidate the oncogenic function of RUNX3 in the pathogenesis of MDS in vivo, we generated a RUNX3-expressing, Tet2-deficient mouse model with the pancytopenia and dysplastic blood cells characteristic of MDS in patients. RUNX3-expressing cells markedly suppressed the expression levels of Runx1, a critical regulator of hemaotpoiesis in normal and malignant cells, as well as its target genes, which included crucial tumor suppressors such as Cebpa and Csf1r. RUNX3 bound these genes and remodeled their Runx1-binding regions in Tet2-deficient cells. Overexpression of RUNX3 inhibited the transcriptional function of Runx1 and compromised hematopoiesis to facilitate the development of MDS in the absence of Tet2, indicating that RUNX3 is an oncogene. Furthermore, overexpression of RUNX3 activated the transcription of Myc target genes and rendered cells sensitive to inhibition of Myc-Max heterodimerization. Collectively, these results reveal the mechanism by which RUNX3 overexpression exerts oncogenic effects on the cellular function of and transcriptional program in Tet2-deficient stem cells to drive the transformation of MDS. SIGNIFICANCE: This study defines the oncogenic effects of transcription factor RUNX3 in driving the transformation of myelodysplastic syndrome, highlighting RUNX3 as a potential target for therapeutic intervention.


Assuntos
Transformação Celular Neoplásica/genética , Subunidade alfa 2 de Fator de Ligação ao Core/metabolismo , Subunidade alfa 3 de Fator de Ligação ao Core/metabolismo , Células-Tronco Hematopoéticas/patologia , Síndromes Mielodisplásicas/patologia , Animais , Medula Óssea/patologia , Proteínas de Ligação a DNA/genética , Modelos Animais de Doenças , Humanos , Células Jurkat , Camundongos , Camundongos Knockout , Síndromes Mielodisplásicas/genética , Cultura Primária de Células , Proteínas Proto-Oncogênicas/genética , Transcrição Genética
18.
Int J Hematol ; 112(2): 238-242, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32246278

RESUMO

A 70-year-old male was referred to our hospital for marked thrombocytosis without anemia. The patient simultaneously presented with an MPL W515L mutation, one of the major driver mutations in essential thrombocythemia (ET), and deletion of 5q, a characteristic cytogenetic abnormality in myelodysplastic syndrome (MDS). Bone marrow examination showed a combination of both mature hyperlobulated megakaryocytes, as found in ET, and small hypolobulated megakaryocytes, typically found in MDS with del(5q). The present case is consistent with the recently proposed category of myeloid neoplasms with isolated del(5q) and an MPN driver mutation.


Assuntos
Mutação , Receptores de Trombopoetina/genética , Trombocitemia Essencial/diagnóstico , Trombocitemia Essencial/genética , Idoso , Deleção Cromossômica , Cromossomos Humanos Par 5/genética , Humanos , Masculino , Megacariócitos/patologia , Síndromes Mielodisplásicas/diagnóstico , Síndromes Mielodisplásicas/genética , Síndromes Mielodisplásicas/patologia , Trombocitemia Essencial/patologia , Organização Mundial da Saúde
20.
Cardiovasc Pathol ; 47: 107211, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32268262

RESUMO

Immune checkpoint inhibitor (ICI)-induced myocarditis carries a poor prognosis and is not fully understood. Similar to lymphocytic myocarditis and acute cellular rejection in heart transplant, ICI-induced myocarditis requires immune suppressive strategies. We aimed to describe ICI-induced myocarditis by presenting findings of comprehensive cardiovascular evaluations and outcomes of patients following a therapeutic approach similar to autoimmune disorders or allograft transplant rejection, and to discuss the molecular basis of the benefits of immune modulation and statins in ICI-myocarditis. Three patients with ICI-induced myocarditis (2 with positive biopsies and 1 based on cardiac magnetic resonance imaging with negative biopsy) underwent a complete cardiovascular workup, including cardiac catheterization with endomyocardial biopsy. Treatment was with intravenous immunoglobulins (IVIG) and statins in all cases, with additional colchicine (2 cases) or hydroxychloroquine (1 case). Immunohistochemical analysis demonstrated varied subsets of T cells involved in the inflammatory response. Therapy with IVIG and statins led to symptom resolution and cardiac function normalization at 1-month follow-up in all patients. Cancer therapy was resumed in all patients. One patient expired 10 months after the myocarditis episode due to advanced malignancy; two patients were alive, free of heart failure symptoms and cancer progression, at 1-year follow-up, and 1 patient was rechallenged with ICI. We suggest that treatment with IVIG and statins may allow for a prompt resumption of anti-cancer therapy (including ICI) and improve outcomes.


Assuntos
Antineoplásicos Imunológicos/efeitos adversos , Fatores Imunológicos/uso terapêutico , Ipilimumab/efeitos adversos , Melanoma/tratamento farmacológico , Síndromes Mielodisplásicas/tratamento farmacológico , Miocardite/tratamento farmacológico , Nivolumabe/efeitos adversos , Neoplasias Cutâneas/tratamento farmacológico , Idoso , Cardiotoxicidade , Colchicina/uso terapêutico , Feminino , Humanos , Hidroxicloroquina/uso terapêutico , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Imunoglobulinas Intravenosas/uso terapêutico , Masculino , Melanoma/imunologia , Melanoma/secundário , Síndromes Mielodisplásicas/imunologia , Síndromes Mielodisplásicas/patologia , Miocardite/induzido quimicamente , Miocardite/imunologia , Miocardite/patologia , Neoplasias Cutâneas/imunologia , Neoplasias Cutâneas/patologia , Resultado do Tratamento
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