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1.
Nefrologia (Engl Ed) ; 44(3): 373-381, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-39002996

RESUMO

INTRODUCTION: Lupus nephritis (LN) is known to be one of the most serious complications of SLE and it is a major predictor of poor prognosis. Despite the improvement in understanding the pathophysiology of lupus nephritis and greater improvement in diagnostic approaches, lupus nephritis patients have poorer outcomes. OBJECTIVES: Study the relation between renal resistive index (RRI) and renal function and histopathological parameters in lupus nephritis (LN) patients. Also to investigate the usefulness of RRI in predicting response to treatment. PATIENTS AND METHODS: This study included 126 patients who were split into two groups (group 1: 101 LN patients and group 2: 25 SLE patients without renal affection); and 100 healthy controls (group 3). The RRI was measured for all participants through a colored Doppler ultrasound examination. LN patients underwent renal biopsy and received their therapy and were followed up for 6 months. RESULTS: The RRI was significantly greater in the LN group (mean±SD; 0.64±0.07) than in SLE patients without nephritis (0.5884±0.04) (P<0.0001). The RRI was greater in LN class IV (P<0.0001). RRI significantly correlated with the chronicity index (r=0.704, P<0.0001), activity index (r=0.310, P=0.002), and serum creatinine (r=0.607, P<0.0001) and negatively correlated with eGFR (r=-0.719, P<0.0001). Almost eighty-five percent (84.8%) of LN patients responded to induction therapy. RRI was significantly greater in the nonresponder group (mean±SD, 0.73±0.02) than that in the responder group (0.63±.07) (P<0.0001). All non-responders to induction therapy while only 29.8% of responders had an RRI of ˃0.7. RRI, according to regression analysis was a significant predictor of response to treatment in LN patients. CONCLUSION: RRI was significantly greater in the LN group and significantly correlated with kidney function and histopathological parameters. RRI can predict response to induction therapy in LN patients.


Assuntos
Nefrite Lúpica , Artéria Renal , Resistência Vascular , Humanos , Nefrite Lúpica/fisiopatologia , Nefrite Lúpica/diagnóstico por imagem , Feminino , Masculino , Adulto , Prognóstico , Artéria Renal/diagnóstico por imagem , Artéria Renal/fisiopatologia , Adulto Jovem , Rim/fisiopatologia , Rim/diagnóstico por imagem , Rim/patologia , Pessoa de Meia-Idade
2.
Nat Commun ; 15(1): 1832, 2024 Feb 28.
Artigo em Inglês | MEDLINE | ID: mdl-38418452

RESUMO

PHF6 mutations (PHF6MT) are identified in various myeloid neoplasms (MN). However, little is known about the precise function and consequences of PHF6 in MN. Here we show three main findings in our comprehensive genomic and proteomic study. Firstly, we show a different pattern of genes correlating with PHF6MT in male and female cases. When analyzing male and female cases separately, in only male cases, RUNX1 and U2AF1 are co-mutated with PHF6. In contrast, female cases reveal co-occurrence of ASXL1 mutations and X-chromosome deletions with PHF6MT. Next, proteomics analysis reveals a direct interaction between PHF6 and RUNX1. Both proteins co-localize in active enhancer regions that define the context of lineage differentiation. Finally, we demonstrate a negative prognostic role of PHF6MT, especially in association with RUNX1. The negative effects on survival are additive as PHF6MT cases with RUNX1 mutations have worse outcomes when compared to cases carrying single mutation or wild-type.


Assuntos
Leucemia Mieloide Aguda , Neoplasias , Humanos , Masculino , Feminino , Proteínas Repressoras/genética , Subunidade alfa 2 de Fator de Ligação ao Core/genética , Subunidade alfa 2 de Fator de Ligação ao Core/metabolismo , Proteômica , Mutação , Leucemia Mieloide Aguda/genética
3.
EJHaem ; 4(1): 165-173, 2023 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-36819163

RESUMO

Several FLT3 inhibitors(i) are available to treat relapsed/refractory (R/R) FLT3-internal tandem duplicated acute myeloid leukemia (AML). This study analyzes the efficacies of various FLT3i (types 1 and 2) tested in clinical trials in treating R/R AML and high-risk myelodysplastic syndromes (HR-MDS). PubMed and EMBASE databases were searched for single/double-arm phase I/II/III R/R AML or HR-MDS clinical trials published between 1/1/2000 and 6/1/2021. The outcomes studied were composite response rate (CRc) and overall response rate (ORR). Toxicities were compared based on the organ system. The 28 studies analyzed had 1927 patients. The pooled ORR and (CRc) for all FLT3i were 53% (95% CI, 43%-63%) and 34% (95% CI, 26%-44%). Pooled ORR and CRc were 37% (95% CI, 25%-51%) and 35% (95% CI, 21%-52%) for type 1 and 58% (95% CI, 43%-71%) and 38% (95% CI, 27%-50%) for type 2, respectively. Gastrointestinal (GI) and hematological toxicity occurred in 22% (95% CI, 19%-25.4%) and 74.6% (95% CI, 70%-79%) with type 1 and 13.9% (95% CI, 12%-16%) and 57.7% (95% CI, 54.6%-60.8%) with type 2 FLT3i. QTc prolongation occurred in 2.06% (95% CI, 1.03%-3.65%) with type 1 and 7% (95% CI, 5.3%-9%) with type 2 FLT3i. Type 2 FLT3i had less GI toxicity but more QTc prolongation. Prospective studies are needed to compare the efficacy of type 1 and 2 FLT3i.

5.
Hematol Rep ; 14(4): 294-299, 2022 Oct 02.
Artigo em Inglês | MEDLINE | ID: mdl-36278519

RESUMO

Classic dyskeratosis congenita is a hereditary disease where the majority of patients present with bone marrow failure and mucocutaneous changes: mainly skin pigmentation, nail dystrophy, oral premalignant leukoplakia, in addition to increased risk for malignancies. A 63-year-old man with a long history of untreated chronic pulmonary disease, a smoker in the past, presented initially with pancytopenia and a clinical diagnosis of myelodysplastic syndrome with excess blasts returned a month later with leukocytosis (WBC 215.9 × 106/µL) and diagnosed with acute myeloid leukemia (AML) with deletion of chromosome 7 and FLT3-TKD mutation. The patient's mother and sister died in their 6th decade from rapidly progressing fulminant pulmonary fibrosis. He had abnormal skin pigmentation and oral leukoplakia on presentation. He was induced with 7 + 3 chemotherapy and started on midostaurin but experienced prolonged cytopenias, complicated by hypoxic acute on chronic respiratory failure requiring intubation and mechanical ventilation. D + 28 and D + 36 bone marrow examination showed trilineage hypoplasia but no blasts, though the D + 28 bone marrow biopsy revealed one metaphase with del (7) that was cleared on D + 35. The constellation of clinical features and strong family history along with del 7 and FLT3-TKD AML with preceding MDS highly suggests a germline predisposition state dyskeratosis congenita. Germline predispositions are often underrecognized as delayed onset conditions leading to AML and may have treatment and preventative implications especially genetic counseling for blood-related family members.

6.
Egypt J Immunol ; 28(3): 114-126, 2021 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-34185460

RESUMO

Chronic lymphocytic leukemia (CLL) has variable clinical presentations, and molecular and biological prognostic markers. The C-X-C chemokine receptor 4 (CXCR4) and its ligand stromal cell-derived factor-1 (SDF-1) play an important role in trafficking of lymphocytes and monocytes. The aim was to study lymphocyte expression of CXCR4 and its prognostic value in CLL. A case control study was carried out on 30 newly diagnosed CLL cases and 30 healthy controls. Fludarabine, cyclophosphamide, and rituximab (FCR) was the standard treatment. Flowcytometric measurement of CXCR4 expression on lymphocytes was done. CXCR4 was significantly higher in patients than controls (81.67 ± 17.95 vs. 11.78 ± 2.78; P< 0.001). CXCR4 was significantly higher (P<0.001) in high risk CLL (93.63 ± 6.78) vs. intermediate risk (82.50 ± 7.13) and low risk (75.84 ± 12.23). CXCR4 was significantly higher (P<0.001) in non-responders (91.63 ± 6.98) vs. partial responders (83.11 ± 5.55) and complete responders (70.11 ± 4.44). CXCR4 was significantly lower in survivors vs. non-survivors (80.89 ± 5.09 vs. 85.43 ± 5.51; P< 0.001. CXCR4 had significant positive correlation with WBCs (r=0.45, P=0.01) and lymphocytes (r=0.40, P=0.01) measured at diagnosis. In conclusions, expression of CXCR4 in newly diagnosed CLL is significantly high. CXCR4 increased expression is associated with poor prognosis and resistance to the therapy.so it can be used as prognostic tool.


Assuntos
Leucemia Linfocítica Crônica de Células B , Estudos de Casos e Controles , Egito , Humanos , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Prognóstico , Receptores CXCR4
7.
J Blood Med ; 12: 225-234, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33880072

RESUMO

INTRODUCTION: A positive direct antiglobulin test (DAT) with or without autoimmune hemolytic anemia is a frequent finding in chronic lymphocytic leukemia (CLL). The heterogenic clinical course of CLL mainly depends on different pathogenetic mechanisms which appears in a form of variable biological and clinical features. These features allow stratification of patients into subsets with different outcomes. PATIENTS AND METHODS: We evaluated the DAT as a prognostic marker in 120 CLL patients treated with chemoimmunotherapy. Clinical and laboratory features, treatment response, and survival outcomes of CLL patients were assessed in relation to their DAT test status. Additionally, the English literature was extensively reviewed regarding the prognostic impact of a positive DAT in CLL. RESULTS: DAT positivity was detected in 36 patients (30%) and was associated advanced disease staging (P = 0.03). No correlations were found with other clinical, laboratory, or biological factors such as ZAP-70 or CD38. Both a positive DAT and an Eastern Cooperative Oncology Group performance status >2 were predictors for non-response to first-line treatment in the multivariate analysis (OR = 0.3, 95% CI: 0.12-0.8 and OR = 0.2, 95% CI: 0.08-0.8, respectively). The five-year progression-free survival was significantly lower in the DAT-positive group (P = 0.004). No significant association was found with overall survival (P = 0.2). Sixteen reports analyzing more than 11,000 patients were identified in our review. CONCLUSION: In conclusion, DAT positivity in CLL patients is associated with poor response to treatment and disease progression.

8.
Nat Commun ; 10(1): 5386, 2019 11 26.
Artigo em Inglês | MEDLINE | ID: mdl-31772163

RESUMO

Myelodysplastic syndromes (MDS) arise in older adults through stepwise acquisitions of multiple somatic mutations. Here, analyzing 1809 MDS patients, we infer clonal architecture by using a stringent, the single-cell sequencing validated PyClone bioanalytic pipeline, and assess the position of the mutations within the clonal architecture. All 3,971 mutations are grouped based on their rank in the deduced clonal hierarchy (dominant and secondary). We evaluated how they affect the resultant morphology, progression, survival and response to therapies. Mutations of SF3B1, U2AF1, and TP53 are more likely to be dominant, those of ASXL1, CBL, and KRAS are secondary. Among distinct combinations of dominant/secondary mutations we identified 37 significant relationships, of which 12 affect clinical phenotypes, 5 cooperatively associate with poor prognosis. They also predict response to hypomethylating therapies. The clonal hierarchy has distinct ranking and the resultant invariant combinations of dominant/secondary mutations yield novel insights into the specific clinical phenotype of MDS.


Assuntos
Mutação , Síndromes Mielodisplásicas/etiologia , Idoso , Feminino , Hematopoese/genética , Humanos , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patologia , Masculino , Síndromes Mielodisplásicas/tratamento farmacológico , Síndromes Mielodisplásicas/genética , Síndromes Mielodisplásicas/patologia , Fenótipo , Fosfoproteínas/genética , Mielofibrose Primária/genética , Fatores de Processamento de RNA/genética , Fator de Processamento U2AF/genética , Resultado do Tratamento , Proteína Supressora de Tumor p53/genética , Sequenciamento do Exoma
9.
Blood Adv ; 3(14): 2164-2178, 2019 07 23.
Artigo em Inglês | MEDLINE | ID: mdl-31320321

RESUMO

Somatic mutations of the CUT-like homeobox 1 (CUX1) gene (CUX1 MT) can be found in myeloid neoplasms (MNs), in particular, in myelodysplastic syndromes (MDSs). The CUX1 locus is also deleted in 3 of 4 MN cases with -7/del(7q). A cohort of 1480 MN patients was used to characterize clinical features and clonal hierarchy associated with CUX1 MT and CUX1 deletions (CUX1 DEL) and to analyze their functional consequences in vitro. CUX1 MT were present in 4% of chronic MNs. CUX1 DEL were preferentially found in advanced cases (6%). Most MDS and acute myeloid leukemia (AML) patients with -7/del(7q) and up to 15% of MDS patients and 5% of AML patients diploid for the CUX1 locus exhibited downmodulated CUX1 expression. In 75% of mutant cases, CUX1 MT were heterozygous, whereas microdeletions and homozygous and compound-heterozygous mutations were less common. CUX MT/DEL were associated with worse survival compared with CUX1 WT Within the clonal hierarchy, 1 of 3 CUX1 MT served as founder events often followed by secondary BCOR and ASXL1 subclonal hits, whereas TET2 was the most common ancestral lesion, followed by subclonal CUX1 MT Comet assay of patients' bone marrow progenitor cells and leukemic cell lines performed in various experimental conditions revealed that frameshift mutations, hemizygous deletions, or experimental CUX1 knockdown decrease the repair of oxidized bases. These functional findings may explain why samples with either CUX1 MT or low CUX1 expression coincided with significantly higher numbers of somatic hits by whole-exome sequencing. Our findings implicate the DNA repair dysfunction resulting from CUX1 lesions in the pathogenesis of MNs, in which they lead to a mutator phenotype.


Assuntos
Suscetibilidade a Doenças , Proteínas de Homeodomínio/genética , Transtornos Mieloproliferativos/diagnóstico , Transtornos Mieloproliferativos/etiologia , Proteínas Repressoras/genética , Fatores de Transcrição/genética , Biomarcadores , Aberrações Cromossômicas , Evolução Clonal/genética , Feminino , Perfilação da Expressão Gênica , Estudos de Associação Genética , Predisposição Genética para Doença , Proteínas de Homeodomínio/metabolismo , Humanos , Estimativa de Kaplan-Meier , Leucócitos Mononucleares , Perda de Heterozigosidade , Masculino , Mutação , Transtornos Mieloproliferativos/mortalidade , Transtornos Mieloproliferativos/patologia , Fenótipo , Polimorfismo de Nucleotídeo Único , Prognóstico , Proteínas Repressoras/metabolismo , Deleção de Sequência , Fatores de Transcrição/metabolismo
10.
Blood Adv ; 3(3): 339-349, 2019 02 12.
Artigo em Inglês | MEDLINE | ID: mdl-30709865

RESUMO

Somatic TET2 mutations (TET2 MT) are frequent in myeloid neoplasia (MN), particularly chronic myelomonocytic leukemia (CMML). TET2 MT includes mostly loss-of-function/hypomorphic hits. Impaired TET2 activity skews differentiation of hematopoietic stem cells toward proliferating myeloid precursors. This study was prompted by the observation of frequent biallelic TET2 gene inactivations (biTET2 i ) in CMML. We speculated that biTET2 i might be associated with distinct clinicohematological features. We analyzed TET2 MT in 1045 patients with MN. Of 82 biTET2 i cases, 66 were biTET2 MT, 13 were hemizygous TET2 MT, and 3 were homozygous TET2 MT (uniparental disomy); the remaining patients (denoted biTET2 - hereafter) were either monoallelic TET2 MT (n = 96) or wild-type TET2 (n = 823). Truncation mutations were found in 83% of biTET2 i vs 65% of biTET2 - cases (P = .02). TET2 hits were founder lesions in 72% of biTET2 i vs 38% of biTET2 - cases (P < .0001). In biTET2 i , significantly concurrent hits included SRSF2 MT (33%; P < .0001) and KRAS/NRAS MT (16%; P = .03) as compared with biTET2 - When the first TET2 hit was ancestral in biTET2 i , the most common subsequent hits affected a second TET2 MT, followed by SRSF2 MT, ASXL1 MT, RAS MT, and DNMT3A MT BiTET2 i patients without any monocytosis showed an absence of SRSF2 MT BiTET2 i patients were older and had monocytosis, CMML, normal karyotypes, and lower-risk disease compared with biTET2 - patients. Hence, while a second TET2 hit occurred frequently, biTET2 i did not portend faster progression but rather determined monocytic differentiation, consistent with its prevalence in CMML. Additionally, biTET2 i showed lower odds of cytopenias and marrow blasts (≥5%) and higher odds of myeloid dysplasia and marrow hypercellularity. Thus, biTET2 i might represent an auxiliary assessment tool in MN.


Assuntos
Proteínas de Ligação a DNA/genética , Síndromes Mielodisplásicas/genética , Proteínas Proto-Oncogênicas/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Proteínas de Ligação a DNA/metabolismo , Dioxigenases , Feminino , Inativação Gênica , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Síndromes Mielodisplásicas/sangue , Síndromes Mielodisplásicas/patologia , Fenótipo , Prognóstico , Proteínas Proto-Oncogênicas/metabolismo , Adulto Jovem
12.
Haematologica ; 103(2): 221-230, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-29217782

RESUMO

Pure red cell aplasia is an orphan disease, and as such lacks rationally established standard therapies. Most cases are idiopathic; a subset is antibody-mediated. There is overlap between idiopathic cases and those with T-cell large granular lymphocytic leukemia, hypogammaglobulinemia, and low-grade lymphomas. In each of the aforementioned, the pathogenetic mechanisms may involve autoreactive cytotoxic responses. We selected 62 uniformly diagnosed pure red cell aplasia patients and analyzed their pathophysiologic features and responsiveness to rationally applied first-line and salvage therapies in order to propose diagnostic and therapeutic algorithms that may be helpful in guiding the management of prospective patients, 52% of whom were idiopathic, while the others involved large granular lymphocytic leukemia, thymoma, and B-cell dyscrasia. T-cell-mediated responses ranged between a continuum from polyclonal to monoclonal (as seen in large granular lymphocytic leukemia). During a median observation period of 40 months, patients received a median of two different therapies to achieve remission. Frequently used therapy included calcineurin-inhibitors with a steroid taper yielding a first-line overall response rate of 76% (53/70). Oral cyclophosphamide showed activity, albeit lower than that produced by cyclosporine. Intravenous immunoglobulins were effective both in parvovirus patients and in hypogammaglobulinemia cases. In salvage settings, alemtuzumab is active, particularly in large granular lymphocytic leukemia-associated cases. Other potentially useful salvage options include rituximab, anti-thymocyte globulin and bortezomib. The workup of acquired pure red cell aplasia should include investigations of common pathological associations. Most effective therapies are directed against T-cell-mediated immunity, and therapeutic choices need to account for associated conditions that may help in choosing alternative salvage agents, such as intravenous immunoglobulin, alemtuzumab and bortezomib.


Assuntos
Algoritmos , Gerenciamento Clínico , Aplasia Pura de Série Vermelha/terapia , Terapia de Salvação/métodos , Adulto , Idoso , Idoso de 80 Anos ou mais , Alemtuzumab/uso terapêutico , Antineoplásicos/uso terapêutico , Bortezomib/uso terapêutico , Feminino , Humanos , Imunoglobulinas Intravenosas/uso terapêutico , Imunossupressores/uso terapêutico , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos
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