RESUMO
Background: Frail elderly patients with newly diagnosed multiple myeloma (NDMM) have inferior survival and less benefit from high-dose therapies. This prospective study aimed to investigate the efficacy, safety, and quality of life (QoL) of induction treatment of ixazomib/lenalidomide/dexamethasone (IRd) and ixazomib/pegylated liposomal doxorubicin/dexamethasone (IDd) followed by ixazomib/dexamethasone (Id) maintenance therapy in frail, elderly patients with NDMM. Methods: From July 2019 to December 2021, this non-randomized concurrent controlled clinical study enrolled 120 NDMM patients aged ≥65 years with frailty defined by the International Myeloma Working Group (IMWG) frailty score or Mayo geriatric scoring system. The enrolled patients received 6-8 cycles of IRd or IDd followed by Id maintenance therapy for a minimum of 2 years at the discretion of physicians based on patient's clinical characteristics (chiCTR1900024917). Findings: The median age was 71 years and 55% of the patients were males. The overall response rate (ORR) was 82% and 77%, complete response (CR) rate was 25% and 12% for IRd and IDd groups, respectively. The difference in ORR of the Idd group minus the IRd group was -5.36% (95% CI: -18.9% to 8.19%), indicating that the ORR of the IDd group was neither inferior nor non-inferior to the IRd group. After a median follow-up of 34.3 months, the median progression-free survival (PFS) was 21.6 and 13.9 months, OS was not reached and 29.2 months in IRd and IDd groups, respectively. 28 and 33 patients discontinued induction therapy, 20 and 19 discontinued maintenance therapy in IRd and IDd groups, respectively. Cumulative Grade 3 or higher hematological adverse events (AEs) occurred in 10 of the 60 patients (17%) and non-hematological AEs occurred in 15 of the 60 patients (25%) in the IRd group, while 13 of the 60 patients (22%) and 21 of the 60 patients (35%) in the IDd group. Patients were observed with clinically significant improvement in QoL when compared with that at baseline in both IRd and IDd groups by evaluation per cycle (P < 0.0001). Interpretation: The results demonstrated that compared with IRd regimen, IDd regimen showed no significant advantage, but the survival of the IDd group was shorter than that of the IRd group, indicating an all-oral outpatient triplet regimen with IRd, which has low toxicity and has improved QoL, could be the viable first-line treatment option for frail NDMM patients. Funding: The Young Elite Scientist sponsorship program by bast of Beijing Association for Science and Technology (No. BYESS2023116) and Beijing Medical Award Foundation (No. YXJL-2018-0539-0073).
Assuntos
Mieloma Múltiplo , Insuficiência Renal , Humanos , Mieloma Múltiplo/complicações , Mieloma Múltiplo/diagnóstico , Mieloma Múltiplo/tratamento farmacológico , Bortezomib/efeitos adversos , Talidomida/efeitos adversos , Insuficiência Renal/complicações , Insuficiência Renal/diagnóstico , Dexametasona/efeitos adversosRESUMO
OBJECTIVE: To investigate the biological function of miR-203a-5p and the underlying mechanism in multiple myeloma (MM). METHODS: Three miRNA expression profiles (GSE16558, GSE24371 and GSE17498) were downloaded from the GEO database. The three miRNA expression profiles contained 131 MM samples and 17 normal plasmacyte samples. The robust rank aggregation (RRA) method was used to identify the differentially expressed miRNAs between MM and normal plasmacytes. In order to carry out cytological experiments, MM cell line with stable over-expression of miR-203a-5p was constructed with lentivirus. Expression levels of miR-203a-5p in MM cells were quantified by qRT-PCR. The effects of miR-203a-5p on MM cells were investigated using assays of cell viability and cell cycle. Cell proliferation was measured using the Cell Counting kit (CCK)8 assay. The percentage of cells in each cell cycle was measured with a FACSCalibur system. Xenograft tumor models were established to evaluate the role of miR-203a-5p in tumorigenesis in vivo . To elucidate the underlying molecular mechanisms of miR-203a-5p in mediating cell proliferation inhibition and cell cycle arrest in MM, we used TargetScan and miRanda to predict the candidate targets of miR-203a-5p. The potential target of miR-203a-5p in MM cells was explored using the luciferase reporter assay, qRT-PCR, and Western blot. RESULTS: An integrated analysis of three MM miRNA expression datasets showed that the levels of miR-203a-5p in MM were notably downregulated compared with those in normal plasmacytes. Accordingly, the relative expression levels of miR-203a-5p were decreased in MM cell lines. In addition, overexpression of miR-203a-5p inhibited the proliferation and cell cycle progression of RPMI8226 and U266 cells. In vivo experiments demonstrated that upregulation of miR-203a-5p expression could significantly inhibit the tumorigenesis of subcutaneous myeloma xenografts in nude mice. Mechanistic investigation led to the identification of Jagged 1 (JAG1) as a novel and direct downstream target of miR-203a-5p. Interestingly, the reintroduction of JAG1 abrogated miR-203a-5p-induced MM cell growth inhibition and cell cycle arrest. CONCLUSION: Our data demonstrate that miR-203a-5p inhibits cell proliferation and cell cycle progression in MM cells by targeting JAG1, supporting the utility of miR-203a-5p as a novel and potential therapeutic agent for miRNA-based MM therapy.
Assuntos
MicroRNAs , Mieloma Múltiplo , Animais , Camundongos , Humanos , Mieloma Múltiplo/genética , Mieloma Múltiplo/patologia , Linhagem Celular Tumoral , Camundongos Nus , MicroRNAs/genética , MicroRNAs/metabolismo , Divisão Celular , Proliferação de Células , Modelos Animais de Doenças , Carcinogênese/genética , Regulação Neoplásica da Expressão Gênica , Proteína Jagged-1/genética , Proteína Jagged-1/metabolismoRESUMO
Intracranial hemorrhage (ICH) is a rare and life-threatening hemorrhagic event in patients with immune thrombocytopenia (ITP). However, its mortality and related risk factors remain unclear. Herein, we conducted a nationwide multicenter real-world study of ICH in adult ITP patients. According to data from 27 centers in China from 2005 to 2020, the mortality rate from ICH was 33.80% (48/142) in ITP adults. We identified risk factors by logistic univariate and multivariate logistic regression for 30-day mortality in a training cohort of 107 patients as follows: intraparenchymal hemorrhage (IPH), platelet count ≤10 × 109/L at ICH, a combination of serious infections, grade of preceding bleeding events, and Glasgow coma scale (GCS) level on admission. Accordingly, a prognostic model of 30-day mortality was developed based on the regression equation. Then, we evaluated the performance of the prognostic model through a bootstrap procedure for internal validation. Furthermore, an external validation with data from a test cohort with 35 patients from 11 other centers was conducted. The areas under the receiver operating characteristic (ROC) curves for the internal and external validation were 0.954 (95% confidence interval [CI], 0.910-0.998) and 0.942 (95% CI, 0.871-1.014), respectively. Both calibration plots illustrated a high degree of consistency in the estimated and observed risk. In addition, the decision curve analysis showed a considerable net benefit for patients. Thus, an application (47.94.162.105:8080/ich/) was established for users to predict 30-day mortality when ICH occurred in adult patients with ITP.
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Púrpura Trombocitopênica Idiopática , Adulto , Hemorragia Cerebral/complicações , Escala de Coma de Glasgow , Humanos , Hemorragias Intracranianas/etiologia , Púrpura Trombocitopênica Idiopática/complicações , Púrpura Trombocitopênica Idiopática/epidemiologia , Curva ROCRESUMO
The study aimed to compare the efficacy and safety of all-trans retinoic acid (ATRA) plus low-dose rituximab (LD-RTX) with LD-RTX monotherapy in corticosteroid-resistant or relapsed immune thrombocytopenia (ITP) patients. Recruited patients were randomized at a ratio of 2:1 into 2 groups: 112 patients received LD-RTX plus ATRA, and 56 patients received LD-RTX monotherapy. Overall response (OR), defined as achieving a platelet count of ≥30 × 109/L confirmed on ≥2 separate occasions (≥7 days apart), at least a doubling of the baseline platelet count without any other ITP-specific treatment, and the absence of bleeding within 1 year after enrollment, was observed in more patients in the LD-RTX plus ATRA group (80%) than in the LD-RTX monotherapy group (59%) (between-group difference, 0.22; 95% CI, 0.07-0.36). Sustained response (SR), defined as maintenance of a platelet count >30 × 109/L, an absence of bleeding, and no requirement for any other ITP-specific treatment for 6 consecutive months after achievement of OR during 1 year following enrollment, was achieved by 68 (61%) patients in the combination group and 23 (41%) patients in the monotherapy group (between-group difference, 0.20; 95% CI, 0.04-0.35). The 2 most common adverse events (AEs) for the combination group were dry skin and headache or dizziness. Our findings demonstrated that ATRA plus LD-RTX significantly increased the overall and sustained response, indicating a promising treatment option for corticosteroid-resistant or relapsed adult ITP. This study is registered at www.clinicaltrials.gov as #NCT03304288.
Assuntos
Antineoplásicos/uso terapêutico , Fatores Imunológicos/uso terapêutico , Púrpura Trombocitopênica Idiopática/tratamento farmacológico , Rituximab/uso terapêutico , Tretinoína/uso terapêutico , Corticosteroides/uso terapêutico , Adulto , Antineoplásicos/administração & dosagem , Resistência a Medicamentos , Quimioterapia Combinada , Feminino , Humanos , Fatores Imunológicos/administração & dosagem , Masculino , Pessoa de Meia-Idade , Recidiva , Rituximab/administração & dosagem , Prevenção Secundária , Tretinoína/administração & dosagemRESUMO
Intracranial hemorrhage (ICH) is a devastating complication of immune thrombocytopenia (ITP). However, information on ICH in ITP patients under the age of 60 years is limited, and no predictive tools are available in clinical practice. A total of 93 adult patients with ITP who developed ICH before 60 years of age were retrospectively identified from 2005 to 2019 by 27 centers in China. For each case, 2 controls matched by the time of ITP diagnosis and the duration of ITP were provided by the same center. Multivariate analysis identified head trauma (OR = 3.216, 95%CI 1.296-7.979, P =.012), a platelet count ≤ 15,000/µL at the time of ITP diagnosis (OR = 1.679, 95%CI 1.044-2.698, P =.032) and severe/life-threatening bleeding (severe bleeding vs. mild bleeding, OR = 1.910, 95%CI 1.088-3.353, P =.024; life-threatening bleeding vs. mild bleeding, OR = 2.620, 95%CI 1.360-5.051, P =.004) as independent risk factors for ICH. Intraparenchymal hemorrhage (OR = 5.191, 95%CI 1.717-15.692, P =.004) and a history of severe bleeding (OR = 4.322, 95%CI 1.532-12.198, P =.006) were associated with the 30-day outcome of ICH. These findings may facilitate ICH risk stratification and outcome prediction in patients with ITP.
Assuntos
Hemorragias Intracranianas/etiologia , Púrpura Trombocitopênica Idiopática/complicações , Feminino , Humanos , Hemorragias Intracranianas/patologia , Masculino , Pessoa de Meia-Idade , Prognóstico , Fatores de Risco , Resultado do TratamentoRESUMO
Immune-mediated thrombotic thrombocytopenic purpura (iTTP) is a rare and life-threatening haematological emergency. Although therapeutic plasma exchange together with corticosteroids achieve successful outcomes, a considerable number of patients remain refractory to this treatment and require early initiation of intensive therapy. However, a method for the early identification of refractory iTTP is not available. To develop and validate a model for predicting the probability of refractory iTTP, a cohort of 265 consecutive iTTP patients from 17 large medical centres was retrospectively identified. The derivation cohort included 94 patients from 11 medical centres. For the validation cohort, we included 40 patients from the other six medical centres using geographical validation. An easy-to-use risk score system was generated, and its performance was assessed using internal and external validation cohorts. In the multivariable logistic analysis of the derivation cohort, three candidate predictors were entered into the final prediction model: age, haemoglobin and creatinine. The prediction model had an area under the curve of 0.886 (95% CI: 0.679-0.974) in the internal validation cohort and 0.862 (95% CI: 0.625-0.999) in the external validation cohort. The calibration plots showed a high agreement between the predicted and observed outcomes. In conclusion, we developed and validated a highly accurate prediction model for the early identification of refractory iTTP. It has the potential to guide tailored therapy and is a step towards more personalized medicine.
Assuntos
Creatinina/sangue , Bases de Dados Factuais , Hemoglobinas/metabolismo , Modelos Biológicos , Púrpura Trombocitopênica Trombótica/sangue , Adulto , Fatores Etários , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Medição de Risco , Fatores de RiscoRESUMO
To establish a nomogram for predicting the overall survival (OS) of patients with newly diagnosed multiple myeloma (MM), 304 patients with newly diagnosed MM were recruited between June 1, 2010, and June 30, 2015, from the Beijing Chaoyang Hospital, Capital Medical University, and randomly divided into training (n=214) and validation (n=90) cohorts. The Kaplan-Meier method and the Cox proportional hazards regression model were used to evaluate the prognostic effects of multiple clinical and laboratory parameters on survival. Significant prognostic factors were combined to build a nomogram. The discriminative ability and predictive accuracy of the nomogram were evaluated using the index of concordance (C-index) and calibration curves and compared with the five staging systems currently used for MM. Multivariate analysis of the training cohort revealed that the age at diagnosis, clonal bone marrow plasma cells, serum lactate dehydrogenase, serum ß2-microglobulin, and del (17p) were independent risk factors for OS and were used to establish the nomogram. The C-index value of the nomogram for predicting OS was 0.749, which was significantly higher than the C-indices of the five most common staging systems currently used for MM. In the validation cohort, the C-index for nomogram-based predictions was 0.711 for OS, and the nomogram discrimination was better than the above mentioned five staging systems (P<0.001). All calibration curves revealed good consistency between predicted and actual survivals. The proposed nomogram is more accurate in predicting the prognoses of patients with newly diagnosed MM.
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Mieloma Múltiplo/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/metabolismo , Estadiamento de Neoplasias/métodos , Nomogramas , Prognóstico , Modelos de Riscos ProporcionaisRESUMO
The survival of individuals with tumors may be predicted by the peripheral blood lymphocyte-to-monocyte ratio (LMR) upon diagnosis in recent studies. For patients with multiple myeloma (MM) in the era of novel agents, the prognostic significance of LMR remains unclear. In this study, the prognostic impact of LMR is evaluated by 285 patients with MM who are treated with proteasome inhibitor and/or immunomodulatory drug. LMR is a proven predictor of survival using the receiver operating characteristic curve, with 4.2 as the cutoff point. Patients with LMR ≤ 4.2 at diagnosis had poorer overall survival (OS) and progression-free survival (PFS) than those with LMR > 4.2. In addition, multivariate analysis showed that LMR less than 4.2 is an independent predictor for the OS (hazard ratio [HR]: 1.703; 95% confidence interval [CI]: 1.020-2.842; P = 0.042) and PFS (HR: 1.831; 95% CI: 1.098-3.053; P = 0.021). According to the test, the LMR at diagnosis, which functions as a simple index reflecting host systemic immunity, can predict clinical outcomes in patients with MM who are treated with new agents.
Assuntos
Leucócitos Mononucleares/patologia , Linfócitos/patologia , Monócitos/patologia , Mieloma Múltiplo/patologia , Idoso , Intervalo Livre de Doença , Feminino , Humanos , Contagem de Linfócitos/métodos , Masculino , Análise Multivariada , Prognóstico , Modelos de Riscos ProporcionaisRESUMO
The aim of this study was to establish nomograms, based on significant clinicopathologic parameters, for predicting the overall survival (OS) and the cancer-specific survival (CSS) of patients with classical Hodgkin lymphoma (CHL). The data of 43,330 CHL patients, diagnosed between 1983 and 2014, were obtainedfrom the database of the Surveillance, Epidemiology, and End Results (SEER) program. These patients were randomly divided into training (n = 30,339) and validation (n = 12,991) cohorts. The Kaplan-Meier method and Cox proportional hazards regression model were used to evaluate the prognostic effects of multiple clinicopathologic parameters on survival. Significant prognostic factors were combined to build nomograms. The predictive performance of nomograms was evaluated using the index of concordance (C-index) and calibration curves. In the training cohort, on univariate and multivariate analyses, age at diagnosis, gender, race, Ann Arbor stage, and histological type significantly correlated with the survival outcomes. These characteristics were used to establish nomograms. The nomograms showed good accuracy in predicting 1-, 5-, and 10-year OS and CSS, with a C-index of 0.794 (95% confidence interval [CI], 0.789-0.799) for OS and 0.760 (95% CI, 0.753-0.767) for CSS. In the validation cohort, the C-index for nomogram-based predictions was 0.787 (95% CI, 0.779-0.795) for OS and 0.769 (95% CI, 0.758-0.780) for CSS. All calibration curves revealed excellent consistency between predicted and actual survival. In summary, novel nomograms were established and validated to predict OS and CSS for patients with CHL. These new prognostic models could aid in improved prediction of survival outcomes leading to reasonable treatment recommendations.
RESUMO
OBJECTIVE: This study was aimed to investigate the roles of PDCD5 (programmed cell death 5) in pathogenesis of acute myeloid leukemia (AML) and the relevance of PDCD5 with the clinical characteristics and prognosis of patients by testing the PDCD5 expression in adult AML patients. METHODS: The mRNA and intracellular protein levels of PDCD5 from 36 newly diagnosed AML patients were analyzed by real-time fluorescence quantitative polymerase chain reaction (RQ-PCR) and flow cytometry (FCM), respectively. The correlation of mRNA levels and intracellular protein levels of PDCD5 with the clinical characteristics and survival time of patients were analyzed. RESULTS: The intracellular protein expression levels of PDCD5 in AML patients were significantly higher than those in normal controls (P < 0.05). The PDCD5 mRNA levels were not significantly different between patients and controls (P > 0.05). The mRNA and protein levels of PDCD5 did not significantly correlate with sex, age, WBC count, FAB subtype, extramedullary infiltration, WT1 gene, NPM1 gene mutation and the patients response to induction therapy. The patients with positive FLT3/ITD mutation displayed higher protein levels of PDCD5 as compared with negative FLT3/ITD mutation patients (P < 0.05). CONCLUSION: The intracellular protein of PDCD5 significantly increased in AML patients. However, the increased PDCD5 does not exert the pro-apoptotic effects on AML cells. The patients with positive FLT3/ITD mutation show higher protein levels of PDCD5.
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Leucemia Mieloide Aguda , Proteínas Reguladoras de Apoptose , Humanos , Mutação , Proteínas de Neoplasias , Nucleofosmina , Prognóstico , RNA Mensageiro , Reação em Cadeia da Polimerase em Tempo Real , Indução de Remissão , Tirosina Quinase 3 Semelhante a fmsRESUMO
This study was aimed to investigate the role of B-cell lymphoma 2 (BCL-2) in pathogenesis of hyperleukocytic acute myeloid leukemia (AML). The levels of intracellular BCL-2 in 48 AML patients were detected by flow cytometry (FCM). Serum levels of BCL-2 in 40 AML patients were measured by enzyme-linked immunosorbent assay (ELISA). The results showed that the serum levels of BCL-2 in hyperleukocytic AML and non-hyperleukocytic AML patients were significantly higher than that in normal controls (P < 0.05), but intracellular BCL-2 levels were not significantly different, as compared with normal controls (P > 0.05). There were no difference of intracellular and serum BCL-2 levels between hyperleukocytic and non-hyperleukocytic AML patients (P > 0.05). The serum and intracellular levels of BCL-2 between hyperleukocytic AML, non-hyperleukocytic AML patients and normal controls were not statistically correlated. It is concluded that leukemic cells in AML patients produce and secrete too much BCL-2, which may be involved in the pathogenesis of leukemia disease. However, the anti-apoptosis effect of BCL-2 has no significant impact on the pathogenesis of hyperleukocytic AML.