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1.
Clin Cancer Res ; 2019 Aug 23.
Artigo em Inglês | MEDLINE | ID: mdl-31444250

RESUMO

PURPOSE: Anti-CD19 chimeric antigen receptor (CAR) T cells represent a novel immunotherapy and are highly effective in treating relapsed/refractory B-cell non- Hodgkin's lymphoma (B-NHL). How tumor microenvironment influences clinical response to CAR T therapy remains great interests. EXPERIMENTAL DESIGN: Aphase 1, first-in-human, dose-escalation studyof anti-CD19 JWCAR029was conductedinrefractory B-NHL (NCT03355859)and 10 patients received CAR T cells at an escalating dose of 2.5X107(n=3), 5X107(n=4), and 1X108(n=3) cells.Core needle biopsy was performed on tumor samples collected from diffuse large B-cell lymphomapatients onDay -6 (one day before lymphodepletion) and on Day 11 after CAR T cell infusion when adequate CAR T cell expansion was detected. RESULTS: The overall response rate was 100%, with 6 of 9 (66.7%) evaluable patients achieved complete remission. The most common adverse events of grade 3 or higher were neutropenia (10/10, 100%), anemia (3/10, 30%), thrombocytopenia (3/10, 30%), and hypofibrinogenemia (2/10, 20%). Grade 1 CRS occurred in all patientsand grade 3 neurotoxicity in one patient. The average peak levels of peripheral blood CAR T cells and cytokines were similar in three different dose levels,but CART cells were significantly higher in patients achieved CR on Day 29. Meanwhile, RNA sequencing identified gene expression signatures differentially enriched in complete and partial remission patients.Increased tumor-associated macrophage infiltration was negatively associated with remission status. CONCLUSIONS: JWCAR029was effective and safe in treating refractory B-NHL. The composition of the tumor microenvironment has a potential impact inCAR T therapy response.

3.
Lung Cancer ; 132: 39-44, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31097092

RESUMO

BACKGROUND: Pulmonary lymphoma arises primarily from the lung, which is extremely rare, or be secondarily involved by lymphoma. The clinical features, management, and prognostic factors have not been clearly identified. METHODS: Sixty-three patients with primary pulmonary lymphoma (PPL) and 117 patients with secondary pulmonary lymphoma (SPL) treated in our institution between June 2003 and December 2017 were retrospectively reviewed. RESULTS: MALT (67%) was the most common pathological subtype of PPL, while DLBCL (48%) was the most common subtype of SPL. Compared to the patients with PPL, the presence of B symptoms, advanced disease stage, intermediate-high or high risks of IPI and NCCN-IPI, elevated inflammatory parameters, and elevated cytokine levels were all observed in patients with SPL. Consolidation was the most frequent radiological finding in PPL cases, while nodules were the most frequent finding in SPL. With a median follow-up of 35 months (range 2-176), the estimated 3-year OS rates were 95%, 100%, 70% and 50% in indolent PPL, indolent SPL, aggressive PPL, and aggressive SPL, respectively. In indolent pulmonary lymphoma, none of the prognostic factors we studied significantly influenced survival of the patients. In aggressive pulmonary lymphoma, univariate analysis showed that NCCN-IPI was related to OS in PPL. Multivariate analysis showed that ß2-MG was an independent prognostic factor for OS in SPL. CONCLUSIONS: Primary and secondary pulmonary lymphoma differ in their clinical features and outcome. Furthermore, ß2-MG is the independent prognostic factor for OS in patients with aggressive SPL.

4.
Lancet Haematol ; 6(6): e328-e337, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31126528

RESUMO

BACKGROUND: Anthracycline dose optimisation in the treatment of diffuse large B-cell lymphoma has rarely been tested. We aimed to find out whether R-CEOP70 was non-inferior to R-CHOP50 with less cardiotoxicity, and whether R-CEOP90 had a superior efficacy to R-CHOP50 or R-CEOP70 with acceptable toxic effects. METHODS: In this multicentre, phase 3, randomised, controlled study (NHL-001), patients with newly diagnosed diffuse large B-cell lymphoma or follicular lymphoma grade 3B were enrolled from 20 centres of the Multicenter Hematology-Oncology Programs Evaluation System in China. Young patients (16-60 years) were randomly assigned 1:1:1 (block size of six) to six courses of R-CHOP50, R-CEOP70, or R-CEOP90, and older patients (61-80 years) were assigned 1:1 (block size of four) to R-CHOP50 or R-CEOP70. Patients were randomly assigned using computer-assisted permuted-block randomisation. Investigators and patients were not masked to treatment assignment. In the R-CHOP50 group, patients were given rituximab 375 mg/m2 intravenously on day 0, cyclophosphamide 750 mg/m2, doxorubicin 50 mg/m2, and vincristine 1·4 mg/m2 (maximum dose 2 mg) intravenously on day 1, and prednisone 60 mg/m2 (maximum dose 100 mg) orally from day 1-5; in the R-CEOP70 group, epirubicin 70 mg/m2 replaced doxorubicin; and in the R-CEOP90 group, high dose epirubicin 90 mg/m2 replaced doxorubicin. All patients received two additional courses of rituximab 375 mg/m2 intravenously every 21 days. Consolidation radiotherapy was given to patients with bulky disease at diagnosis or residual disease at the end of treatment. The primary endpoint was 2-year progression-free survival. The non-inferiority margin for R-CEOP70 versus R-CHOP50 was defined by hazard ratio [HR] as the upper limit of its 95% CI being no greater than 1·50. Analysis of efficacy and safety were of the intention-to-treat population. This study is registered with ClinicalTrials.gov, number NCT01852435. FINDINGS: From May 15, 2013, to March 16, 2016, a total of 648 patients were enrolled, including 404 (62%) young patients (R-CHOP50 [n=135], R-CEOP70 [n=134], or R-CEOP90 [n=135]), and 244 (38%) older patients (R-CHOP50 [n=122] or R-CEOP70 [n=122]). Four patients were excluded from the study for consent withdrawal and one patient for misdiagnosis before treatment. The 2-year progression-free survival in the R-CHOP50 group was 72·5% (95% CI 66·6-77·6) and in the R-CEOP70 group was 72·4% ([66·5-77·5]; HR 1·00 [0·73-1·38]; p=0·99). The non-inferiority was met and adverse events were similar between the two groups. Fewer patients in the R-CEOP70 group (14 [13%] of 110) presented with over 10% decrease in left ventricular ejection fraction (LVEF) than those in the R-CHOP50 group (31 [29%] of 108) at 3 years after remission. For young patients, the 2-year progression-free survival in the R-CEOP90 group was 88·8% (82·1-93·1) and was significantly improved compared with the R-CHOP50 group (75·9% [67·7-82·3]; 0·44 [0·25-0·76]; p=0·0047) and the R-CEOP70 group (77·4% [69·4-83·7%]; 0·49 [0·27-0·86]; p=0·017). Grade 3-4 neutropenia occurred more frequently in the R-CEOP90 group (97 [72%] of 134) than in the R-CHOP50 group (87 [65%] of 133) and R-CEOP70 group (84 [63%] of 133) in young patients but without further increase of clinically significant infections. Fewer patients in the R-CEOP70 group (7 [11%] of 66) and in the R-CEOP90 group (10 [13%] of 79) presented with more than 10% decrease in LVEF than those in the R-CHOP50 group (17 [26%] of 66) at 3 years after remission. INTERPRETATION: R-CEOP70 could serve as an alternative regimen to R-CHOP50 with mild long-term cardiotoxicity. Young patients with diffuse large B-cell lymphoma might benefit from high-dose epirubicin. Epirubicin is an alternative drug to doxorubicin in regular R-CHOP with mild long-term cardiotoxicity. FUNDING: National Natural Science Foundation of China, National Key Research and Development Program, Shanghai Commission of Science and Technology, Shanghai Municipal Education Commission Gaofeng Clinical Medicine Grant Support, Multicenter Clinical Research Project by Shanghai Jiao Tong University School of Medicine, Clinical Research Plan of Shanghai Hospital Development Center, and Chang Jiang Scholars Program.

5.
Food Chem ; 288: 347-353, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-30902303

RESUMO

The objective of this study is to report a molecularly imprinted polymer-based chemiluminescence method for determination of Sudan dyes. A dummy-template molecularly imprinted polymer capable of recognizing seven Sudan dyes was first synthesized and its recognition mechanism was studied by using computation simulation method. The polymer was coated in the wells of conventional microplate to prepare a chemiluminescence sensor and the assay process consisted of only one sample-loading step prior to signal acquisition. The optimized sensor was used to determine the seven dyes in egg yolk and the results were confirmed with a high performance liquid chromatography. Results showed that this sensor achieved ultrahigh sensitivity (1.0-5.0 pg/mL), rapid assay process (10 min) and satisfactory recovery (70.5%-92.2%). Furthermore, the sensor could be reused for 5 times. Therefore, this sensor could be used as a useful tool for screening the residues of Sudan dyes in egg.


Assuntos
Corantes/análise , Gema de Ovo/química , Medições Luminescentes/métodos , Impressão Molecular , Polímeros/química , Animais , Cromatografia Líquida de Alta Pressão , Contaminação de Alimentos/análise
6.
Theranostics ; 9(4): 1115-1124, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30867819

RESUMO

Rationale: Epstein-Barr virus (EBV) is associated with multiple malignancies with expression of viral oncogenic proteins and chronic inflammation as major mechanisms contributing to tumor development. A less well-studied mechanism is the integration of EBV into the human genome possibly at sites which may disrupt gene expression or genome stability. Methods: We sequenced tumor DNA to profile the EBV sequences by hybridization-based enrichment. Bioinformatic analysis was used to detect the breakpoints of EBV integrations in the genome of cancer cells. Results: We identified 197 breakpoints in nasopharyngeal carcinomas and other EBV-associated malignancies. EBV integrations were enriched at vulnerable regions of the human genome and were close to tumor suppressor and inflammation-related genes. We found that EBV integrations into the introns could decrease the expression of the inflammation-related genes, TNFAIP3, PARK2, and CDK15, in NPC tumors. In the EBV genome, the breakpoints were frequently at oriP or terminal repeats. These breakpoints were surrounded by microhomology sequences, consistent with a mechanism for integration involving viral genome replication and microhomology-mediated recombination. Conclusion: Our finding provides insight into the potential of EBV integration as an additional mechanism mediating tumorigenesis in EBV associated malignancies.

7.
Mol Cancer ; 18(1): 54, 2019 03 30.
Artigo em Inglês | MEDLINE | ID: mdl-30925928

RESUMO

BACKGROUND: MicroRNAs (miRs) are involved in lymphoma progression by regulating tumor cell interaction with microenvironment. MiR155 is overexpressed in diffuse large B-cell lymphoma (DLBCL) and its biological effect on tumor microenvironment needs to be futher investigated. METHODS: MiR155 was detected by quantitative real-time PCR in patients with newly diagnosed DLBCL. The mechanism of action of miR155 on lymphoma progression and tumor microenvironment was examined in vitro in B-lymphoma cell lines and in vivo in a murine xenograft model. RESULTS: Serum miR155 was significantly elevated, correlated with tumor miR155 expression, and indicated poor disease outcome in DLBCL. MiR155 overexpression was associated with decreased peripheral blood CD8+T cells and inhibition of T-cell receptor signaling. Of note, EBV-positive patients showed higher serum miR155 than EBV-negative patients. In co-culture systems of B-lymphoma cells with immune cells, miR155 induced Fas-mediated apoptosis of CD8+T cells, which could be targeted by anti-PD-1 and anti-PD-L1 antibodies. Moreover, miR155 enhanced lymphoma cell PD-L1 expression, recruited CD8+T cells by PD-1/PD-L1 interaction and inhibited CD8+T cell function via dephosphorylating AKT and ERK. MiR155-induced AKT/ERK inactivation was more obvious in CD8+T cells co-cultured with EBV-infected B-lymphoma cells. In vivo in a murine xenograft model established with subcutaneous injection of A20 cells, PD-L1 blockade particularly retarded miR155-overexpressing tumor growth, consistent with maintenance of CD8+T cells and their function. CONCLUSIONS: As a oncogenic biomarker of B-cell lymphoma, serum miR155 was related to lymphoma progression through modulating PD-1/PD-L1-mediated interaction with CD8+T cells of tumor microenvironment, indicating the sensitivity of B-cell lymphoma to PD-L1 blockade. Also CD8+T cells could be a therapeutic mediator of immune checkpoint inhibitors in treating EBV-associated lymphoid malignancies.


Assuntos
Antineoplásicos Imunológicos/farmacologia , Antígeno B7-H1/antagonistas & inibidores , Linfócitos T CD8-Positivos/imunologia , Comunicação Celular , Resistencia a Medicamentos Antineoplásicos/genética , Linfoma Difuso de Grandes Células B/tratamento farmacológico , MicroRNAs/genética , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Animais , Apoptose , Antígeno B7-H1/imunologia , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Linfócitos T CD8-Positivos/efeitos dos fármacos , Estudos de Casos e Controles , Proliferação de Células , Estudos de Coortes , Feminino , Seguimentos , Humanos , Linfócitos/efeitos dos fármacos , Linfócitos/imunologia , Linfócitos/metabolismo , Linfoma Difuso de Grandes Células B/genética , Linfoma Difuso de Grandes Células B/imunologia , Linfoma Difuso de Grandes Células B/patologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Pessoa de Meia-Idade , Prognóstico , Receptor de Morte Celular Programada 1/imunologia , Transdução de Sinais , Taxa de Sobrevida , Células Tumorais Cultivadas , Microambiente Tumoral , Ensaios Antitumorais Modelo de Xenoenxerto
8.
J Hematol Oncol ; 11(1): 134, 2018 Dec 04.
Artigo em Inglês | MEDLINE | ID: mdl-30514323

RESUMO

Natural-killer/T cell lymphoma (NKTCL) represents the most common subtype of extranodal lymphoma with aggressive clinical behavior. Prevalent in Asians and South Americans, the pathogenesis of NKTCL remains to be fully elucidated. Using system biology techniques including genomics, transcriptomics, epigenomics, and metabolomics, novel biomarkers and therapeutic targets have been revealed in NKTCL. Whole-exome sequencing studies identify recurrent somatic gene mutations, involving RNA helicases, tumor suppressors, JAK-STAT pathway molecules, and epigenetic modifiers. Another genome-wide association study reports that single nucleotide polymorphisms mapping to the class II MHC region on chromosome 6 contribute to lymphomagenesis. Alterations of oncogenic signaling pathways janus kinase-signal transducer and activator of transcription (JAK-STAT), nuclear factor-κB (NF-κB), mitogen-activated protein kinase (MAPK), WNT, and NOTCH, as well as epigenetic dysregulation of microRNA and long non-coding RNAs, are also frequently observed in NKTCL. As for metabolomic profiling, abnormal amino acids metabolism plays an important role on disease progression of NKTCL. Of note, through targeting multiple omics aberrations, clinical outcome of NKTCL patients has been significantly improved by asparaginase-based regimens, immune checkpoints inhibitors, and histone deacetylation inhibitors. Future investigations will be emphasized on molecular classification of NKTCL using integrated analysis of system biology, so as to optimize targeted therapeutic strategies of NKTCL in the era of precision medicine.

9.
Int J Nanomedicine ; 13: 5673-5683, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30288040

RESUMO

Purpose: Cardiac side effects of doxorubicin (Dox) have limited its clinical application. The aim of this study was to explore new Dox-loaded dextran-based nano-carriers (NCs) in efficiently targeting tumor growth with less cardiac toxicity. Methods: Inspired by recent reports that polymeric NCs could function as sustained, controlled and targeted drug delivery systems, we developed Dox-loaded NCs which displayed a 2-fold release ratio of Dox in the mimic tumor site condition (pH 5.0 with 10 mM glutathione, GSH) as much as that in systemic circulation condition (pH 7.4). Results: Lymphoma cells treated with Dox-NCs had significantly higher intracellular Dox concentrations and more apoptotic induction, with lower P-gp expression, when compared with those treated with Dox alone. The identified mechanism of action, apoptosis, was triggered through survivin reduction and caspase-3 activation. Even in the Dox-resistant cells, Dox-NCs could significantly inhibit cell growth and induce apoptosis. In murine lymphoma xenograft models, Dox-NCs also remarkably significantly retarded tumor growth, assessed by murine weight, and demonstrated less cytotoxicity. Noticeably, apoptotic myocardial cells were decreased in the Dox-NCs-treated group, when compared with the control group, which was consistent with low intracellular Dox concentration in the cardiac cell line H9C2. Conclusion: Dox-NCs showed an anti-lymphoma effect with reduced cardiac toxicity in both in vivo and in vitro models and, therefore, could be a potential therapeutic agent in the treatment of lymphoma.


Assuntos
Cardiotoxicidade/tratamento farmacológico , Dextranos/química , Doxorrubicina/uso terapêutico , Portadores de Fármacos/química , Linfoma/tratamento farmacológico , Linfoma/patologia , Nanopartículas/química , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Animais , Apoptose/efeitos dos fármacos , Cardiotoxicidade/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Regulação para Baixo/efeitos dos fármacos , Doxorrubicina/farmacologia , Sistemas de Liberação de Medicamentos , Humanos , Proteínas Inibidoras de Apoptose/metabolismo , Camundongos Nus , Nanopartículas/ultraestrutura , Survivina , Ensaios Antitumorais Modelo de Xenoenxerto
10.
EBioMedicine ; 33: 94-104, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29936139

RESUMO

Immunotherapeutic agents have demonstrated encouraging signs of clinical utility in non-Hodgkin lymphoma. The goal of this study is to analyze the immune characteristics of Chinese patients with diffuse large B-cell lymphoma (DLBCL) to inform the development of immunotherapies in this patient population. Tumor samples from 211 DLBCL patients were analyzed for cell of origin (COO) and immune characteristics using the NanoString platform as well as MYC protein expression through immunohistochemistry. Lower incidence of the germinal center B-cell (GCB) subtype (93/211, 44.1%) was observed in this cohort. Compared to the GCB subtype, the activated B-cell (ABC) subtype was associated with significantly increased expression of multiple pro-inflammatory gene signatures and decreased expression of anti-inflammatory gene signatures. Instead of affecting the pro-inflammatory genes, MYC protein overexpression showed a negative correlation with the expression of T-cell receptor (TCR) and T regulatory genes as well as the OX40 gene. Regardless of COO, higher PD-L1 or IDO1 gene expression correlated with increased expression of T effector and Interferon-γ gene signatures while the expression of multiple oncogenes including ACTR3B, ERBB2, AKT2 and SMARCD1 was down-regulated. Our findings may thus be helpful in guiding further development of immunotherapies for the different subsets of Chinese DLBCL patients.


Assuntos
Antígeno B7-H1/genética , Centro Germinativo/imunologia , Indolamina-Pirrol 2,3,-Dioxigenase/genética , Linfoma Difuso de Grandes Células B/imunologia , Ligante OX40/genética , Proteínas Proto-Oncogênicas c-myc/metabolismo , Adolescente , Adulto , Idoso , China , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Linfoma Difuso de Grandes Células B/genética , Masculino , Pessoa de Meia-Idade , Proteínas Proto-Oncogênicas c-myc/genética , Regulação para Cima , Adulto Jovem
11.
EBioMedicine ; 28: 5-6, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-29397369
12.
Haematologica ; 103(4): 679-687, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29305415

RESUMO

Due to heterogeneous morphological and immunophenotypic features, approximately 50% of peripheral T-cell lymphomas are unclassifiable and categorized as peripheral T-cell lymphomas, not otherwise specified. These conditions have an aggressive course and poor clinical outcome. Identification of actionable biomarkers is urgently needed to develop better therapeutic strategies. Epigenetic alterations play a crucial role in tumor progression. Histone modifications, particularly methylation and acetylation, are generally involved in chromatin state regulation. Here we screened the core set of genes related to histone methylation (KMT2D, SETD2, KMT2A, KDM6A) and acetylation (EP300, CREBBP) and identified 59 somatic mutations in 45 of 125 (36.0%) patients with peripheral T-cell lymphomas, not otherwise specified. Histone modifier gene mutations were associated with inferior progression-free survival time of the patients, irrespective of chemotherapy regimens, but an increased response to the histone deacetylase inhibitor chidamide. In vitro, chidamide significantly inhibited the growth of EP300-mutated T-lymphoma cells and KMT2D-mutated T-lymphoma cells when combined with the hypomethylating agent decitabine. Mechanistically, decitabine acted synergistically with chidamide to enhance the interaction of KMT2D with transcription factor PU.1, regulated H3K4me-associated signaling pathways, and sensitized T-lymphoma cells to chidamide. In a xenograft KMT2D-mutated T-lymphoma model, dual treatment with chidamide and decitabine significantly retarded tumor growth and induced cell apoptosis through modulation of the KMT2D/H3K4me axis. Our work thus contributes to the understanding of aberrant histone modification in peripheral T-cell lymphomas, not otherwise specified and the stratification of a biological subset that can benefit from epigenetic treatment.

13.
Mediators Inflamm ; 2017: 7960907, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29109622

RESUMO

Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous group of lymphoma, with different clinical manifestation and prognosis. The International Prognostic Index (IPI), an index designed during the prerituximab era for aggressive lymphoma, showed variable values in the prediction of patient clinical outcomes. The aim of this study was to analyze the prognostic value and causes of pretreatment liver injury in 363 de novo DLBCL patients in our institution. Pretreatment liver impairment, commonly detected in lymphoma patients, showed significant association with poor outcomes and increased serum inflammatory cytokines in DLBCL patients but had no relation to hepatitis B virus replication nor lymphomatous hepatic infiltration. Multivariate analysis revealed that liver dysfunction, advanced Ann Arbor stage, and elevated lactate dehydrogenase (LDH) were independent adverse prognostic factors of both PFS and OS. Accordingly, a new liver-IPI prognostic model was designed by adding liver injury as an important factor in determining IPI score. Based on Kaplan-Meier curves for PFS and OS, the liver-IPI showed better stratification in DLBCL patients than either the IPI or the revised IPI in survival prediction.


Assuntos
Fígado/lesões , Fígado/patologia , Linfoma Difuso de Grandes Células B/mortalidade , Linfoma Difuso de Grandes Células B/patologia , Anticorpos Monoclonais Murinos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Estudos de Casos e Controles , Ciclofosfamida/uso terapêutico , Intervalo Livre de Doença , Doxorrubicina/uso terapêutico , Feminino , Humanos , Estimativa de Kaplan-Meier , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Prednisona/uso terapêutico , Prognóstico , Estudos Retrospectivos , Vincristina/uso terapêutico
14.
EBioMedicine ; 25: 41-49, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-29056540

RESUMO

BACKGROUND: A phase II study of methotrexate, etoposide, dexamethasone, and pegaspargase (MESA) sandwiched with radiotherapy for newly diagnosed, stage IE-IIE extranodal natural-killer/T-cell lymphoma, nasal-type (ENKTL) was conducted to explore its clinical efficacy and safety, as well as novel serum biomarkers upon anti-metabolic treatment. METHODS: Four cycles of MESA sandwiched with radiotherapy were administered. The primary end point was the overall response rate (ORR). Serum metabolomic profiles were assessed by liquid chromatography-mass spectrometry, with specific metabolites quantified by targeted metabolic analysis. FINDINGS: Forty patients were enrolled and the ORR was 92.1% (95%CI, 83.1%-100.0%). The 2-year progression-free survival (PFS) rate was 89.1% and overall survival (OS) rate was 92.0%. Grade 3/4 non-hematologic and hematologic toxicities were observed in 17 (42.5%) and 26 patients (65·0%) during chemotherapy, and in 9 (22.5%) and 0 (0.0%) patients during radiotherapy, respectively. Fifty-six significantly decreased and 59 increased metabolites were identified in ENKTL, as compared to healthy volunteers. A predictive principal components analysis model of asparaginase-associated metabolites, asparaginase-associated metabolic score (AspM), was established, including alanine, aspartate, glutamate, and succinic acid. Patients with high AspM score displayed superior survival and prognostic significance of AspM was validated in a historical cohort of early and advanced-stage ENKTL treated with asparaginase-based regimens. Multivariate analysis confirmed AspM as a prognostic score independent of PINK and PINK combined with Epstein-Barr virus DNA. INTERPRETATION: MESA sandwiched with radiotherapy is an effective and safe regimen for early-stage ENKTL. AspM score may be a promising prognostic index of serum metabolites in addition to clinical prognostic index in ENKTL.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Linfoma Extranodal de Células T-NK/tratamento farmacológico , Linfoma Extranodal de Células T-NK/radioterapia , Prognóstico , Adulto , Idoso , Asparaginase/administração & dosagem , Terapia Combinada , Dexametasona/administração & dosagem , Intervalo Livre de Doença , Etoposídeo/administração & dosagem , Feminino , Herpesvirus Humano 4/patogenicidade , Humanos , Linfoma Extranodal de Células T-NK/patologia , Masculino , Metotrexato/administração & dosagem , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Polietilenoglicóis/administração & dosagem
15.
Sci Rep ; 7(1): 7433, 2017 Aug 07.
Artigo em Inglês | MEDLINE | ID: mdl-28785100

RESUMO

Cancer stem cells play an important role on tumor progression. Biomarkers of stem cell property and their relationship to extranodal involvement of malignant lymphocytes are undefined in diffuse large B-cell lymphoma (DLBCL). Here we showed that junctional adhesion molecule-A (JAM-A) was highly expressed in DLBCL patients with multiple extranodal lesions. JAM-A maintained B-lymphoma cell stemness and was associated with cell invasion and epithelial-to-mesenchymal transition both in vitro and in vivo. As mechanism of action, JAM-A overexpression selectively activated transforming growth factor-ß (TGF-ß)/NODAL signaling, thereby enhanced B-lymphoma cell aggressiveness and induced extranodal involvement to mesoendoderm-derived organs in DLBCL. Lenalidomide downregulated JAM-A and downstream NODAL expression, resulting in inhibition of B-lymphoma cell invasion and epithelial-to-mesenchymal transition. In a murine xenograft model established with subcutaneous injection of JAM-A-overexpressing B-lymphoma cells, lenalidomide retarded tumor growth and prevented cell invasion to mesoendoderm-derived organs, consistent with the downregulation of JAM-A and NODAL expression. Collectively, these findings indicated that JAM-A was related to extranodal involvement in DLBCL through modulating TGF-ß/NODAL signaling. Identified as a biomarker of stem cell property, JAM-A indicated the sensitivity of B-lymphoma cells to lenalidomide. Therapeutic targeting of JAM-A/NODAL axis could thus be a promising clinical strategy to impede tumor progression in DLBCL.

16.
Zhongguo Shi Yan Xue Ye Xue Za Zhi ; 25(4): 1036-1041, 2017 Aug.
Artigo em Chinês | MEDLINE | ID: mdl-28823264

RESUMO

OBJECTIVE: To analyze the clinical features and prognostic factors of patients with mantle cell lymphoma(MCL). METHODS: The clinical data of 66 MCL patients were collected from the Department of Hematology of Shanghai Ruijin Hospital, Shanghai Jiaotong University Medical School from January 2000 to December 2014. The clinical characteristics, treatment efficiency and survival rate were analyzed retrospectively. RESULTS: The sex ratio of male to female in these 66 MCL patients was 3.71:1, the nosopoietic median age was 59 years old, and most cases were diagnosed as MCL in Ann Arbor stage III-IV(90.9%). "R-HperCVAD" regimen had the highest CR-rate reached to 55.6%, and CR rate of "R-CHOP" reached to 44.4%. The total prospective 5-year overall survival and progress-free survival rates were 35.5%±11.5% and 8.8%±5.6%, respectively. Leukocyte count abnormality(>10×109/L or <4×109/L), B symptom, LDH level, bone marrow involvement, Ki-67 and high risk group of MIPI scores, and therapy combined with or without rituximab were the independent prognostic factors. CONCLUSION: The prognosis of MCL patients is poor, and the incidence is higher in men. The extranodal sites of bone marrow and gastrointestinal tract are involved more easily. The treatment combined with rituximab can increase survival rate for these patients.

17.
J Exp Clin Cancer Res ; 36(1): 82, 2017 06 21.
Artigo em Inglês | MEDLINE | ID: mdl-28637496

RESUMO

BACKGROUND: MicroRNAs (miRs) are involved in tumor progression by regulating tumor cells and tumor microenvironment. MiR21 is overexpressed in diffuse large B-cell lymphoma (DLBCL) and its biological impact on tumor microenvironment remains unclear. METHODS: MiR21 was assessed by quantitative RT-PCR in patients with newly diagnosed DLBCL. The mechanism of action of miR21 on lymphoma progression and tumor angiogenesis was examined in vitro in B-lymphoma cell lines and in vivo in a murine xenograft model. RESULTS: Serum miR21 was significantly elevated in patients and associated with advanced disease stage, International Prognostic Index indicating intermediate-high and high-risk, and increased tumor angiogenesis. When co-cultured with immune cells and endothelial cells, miR21-overexpressing B-lymphoma cells were resistant to chemotherapeutic agents, but sensitive to Bcl-2 inhibitor ABT-199, irrespective of Bcl-2 expression on lymphoma cells. In both co-culture systems of Bcl-2positive and Bcl-2negative B-lymphoma cells, miR21 induced inducible co-stimulator (ICOS) expression on regulatory T (Treg) cells. Through crosstalking with Treg cells by ICOS ligand (ICOSL), endothelial cells were activated, resulting in stimulation of Bcl-2 expression and vessel formation. ABT-199 directly targeted Bcl-2 on endothelial cells, induced endothelial cell apoptosis and inhibited tumor angiogenesis. In a murine xenograft model established with subcutaneous injection of B-lymphoma cells, ABT-199 particularly retarded the growth of miR21-overexpressing tumors, consistent with the induction of endothelial cell apoptosis and inhibition of tumor angiogenesis. CONCLUSIONS: As a serum oncogenic biomarker of B-cell lymphoma, miR21 indicated B-lymphoma cell sensitivity to ABT-199 via ICOS/ICOSL-mediated interaction of Treg cells with endothelial cells.


Assuntos
Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Endotélio Vascular/imunologia , Ligante Coestimulador de Linfócitos T Induzíveis/metabolismo , Proteína Coestimuladora de Linfócitos T Induzíveis/metabolismo , Linfoma Difuso de Grandes Células B/imunologia , MicroRNAs/genética , Sulfonamidas/farmacologia , Linfócitos T Reguladores/imunologia , Animais , Apoptose , Proliferação de Células , Células Cultivadas , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/metabolismo , Feminino , Humanos , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Linfoma Difuso de Grandes Células B/genética , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , MicroRNAs/sangue , Pessoa de Meia-Idade , Prognóstico , Linfócitos T Reguladores/efeitos dos fármacos , Linfócitos T Reguladores/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
18.
Zhongguo Shi Yan Xue Ye Xue Za Zhi ; 25(2): 426-430, 2017 Apr.
Artigo em Chinês | MEDLINE | ID: mdl-28446287

RESUMO

OBJECTIVE: To investigate the prognostic significance of Follicular Lymphoma International Prognostic Index 2 (FLIPI2) in FL patients treated with rituximab maintenance. METHODS: A tatol of 140 newly diagnosed FL patients who received Rituximab plus cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP) chemotherapy in our department were retrospectively analyzed from December 2002 to December 2014. Among 140 patients with FL 122 patients achieved response, from them 56 patients received R maintenance (RM) every 2 months for median 8 times (RM group) while the rest 66 patients did not receive further anti-lymphoma treatment (non-RM group). RESULTS: There was no statistical difference in age, sex, pathologic grading, staging, FLIPI or FLIPI2 between RM and non-RM groups. The 2-year progression-free survival (PFS) of RM and non-RM groups were 89.7% and 77.6% (P=0.043) while the 2-year overall survival were 100% and 98.6% (P=0.131). FLIPI2 is a significant prognostic model either in the total cohort, RM or non-RM groups (P<0.001 all). In subgroup analysis, RM was able to decrease disease progression in low and intermediate-risk group of FLIPI2, while the 2-year PFS of RM and non-RM groups in high-risk group were similar (55.6% vs 46.9%)(P=0.920). CONCLUSION: FLIPI2 presents robust prognostic significance either in RM or OBS patients, the patients in FLIPI2 low and intermediate-risk group may benefite from RM, but the role of RM in high-risk patients should be further to investigate.


Assuntos
Antineoplásicos Imunológicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Linfoma Folicular/tratamento farmacológico , Rituximab/uso terapêutico , Anticorpos Monoclonais Murinos/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Ciclofosfamida/administração & dosagem , Intervalo Livre de Doença , Doxorrubicina/administração & dosagem , Humanos , Prednisona/administração & dosagem , Prognóstico , Estudos Retrospectivos , Vincristina/administração & dosagem
19.
EBioMedicine ; 16: 106-114, 2017 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-28153771

RESUMO

Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous subtype of non-Hodgkin lymphoma. In addition to clinical and immunophenotypic characteristics, recurrent gene mutations have recently been identified in patients with DLBCL using next-generation sequencing technologies. The aim of this study is to investigate the clinical relevance of B-cell function gene mutations in DLBCL. Clinical analysis was performed on 680 Chinese DLBCL patients (146 non-CR and 534 CR cases) treated with six cycles of 21-day R-CHOP (Rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone), alone or followed by two additional doses of rituximab consolidation on patients' own intention. Somatic mutations of B-cell function genes were further screened on 275 (71 non-CR and 204 CR) cases with available tumor samples by targeted sequencing, including genes involved in B-cell receptors (BCRs) pathway (CARD11, LYN, CD79A, and CD79B), Toll-like receptors (TLRs) pathway (MYD88), and tumor necrotic factor receptor (TNFR) pathway (TRAF2 and TNFAIP3). B-cell function gene mutations occurred in 44.0% (121/275) of DLBCL patients. The TLRs and TNFR related gene mutations were more frequently observed in non-CR patients (p=0.019 and p=0.032, respectively). BCRs related gene mutations, as well as revised IPI (R-IPI) and double BCL-2/MYC expression, were independently related to short progression-free survival in DLBCL after CR. The adverse prognostic effect of BCRs related gene mutations could be overcome by two additional doses of rituximab consolidation. These results highlight the molecular heterogeneity of DLBCL and identify a significant role of B-cell function gene mutations on lymphoma progression and response to rituximab in DLBCL.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Linfócitos B/metabolismo , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Linfoma Difuso de Grandes Células B/genética , Mutação , Sequência de Aminoácidos , Ciclofosfamida/administração & dosagem , Intervalo Livre de Doença , Doxorrubicina/administração & dosagem , Esquema de Medicação , Feminino , Humanos , Linfoma Difuso de Grandes Células B/patologia , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Fator 88 de Diferenciação Mieloide/genética , Prednisona/administração & dosagem , Prognóstico , Indução de Remissão , Estudos Retrospectivos , Rituximab/administração & dosagem , Homologia de Sequência de Aminoácidos , Resultado do Tratamento , Proteína 3 Induzida por Fator de Necrose Tumoral alfa/genética , Vincristina/administração & dosagem
20.
Biomed Res Int ; 2015: 197241, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26436088

RESUMO

MicroRNAs (miRs) play an important role in tumorogenesis and chemoresistance in lymphoid malignancies. Comparing with reactive hyperplasia, miR181a was overexpressed in 130 patients with T-cell leukemia/lymphoma, including acute T-cell lymphoblastic leukemia (n = 32), T-cell lymphoblastic lymphoma (n = 16), peripheral T-cell lymphoma, not otherwise specified (n = 45), anaplastic large cell lymphoma (n = 15), and angioimmunoblastic T-cell lymphoma (n = 22). Irrespective to histological subtypes, miR181a overexpression was associated with increased AKT phosphorylation. In vitro, ectopic expression of miR181a in HEK-293T cells significantly enhanced cell proliferation, activated AKT, and conferred cell resistance to doxorubicin. Meanwhile, miR181a expression was upregulated in Jurkat cells, along with AKT activation, during exposure to chemotherapeutic agents regularly applied to T-cell leukemia/lymphoma treatment, such as doxorubicin, cyclophosphamide, cytarabine, and cisplatin. Isogenic doxorubicin-resistant Jurkat and H9 cells were subsequently developed, which also presented with miR181a overexpression and cross-resistance to cyclophosphamide and cisplatin. Meanwhile, specific inhibition of miR181a enhanced Jurkat and H9 cell sensitivity to chemotherapeutic agents, further indicating that miR181a was involved in acquired chemoresistance. Collectively, miR181a functioned as a biomarker of T-cell leukemia/lymphoma through modulation of AKT pathway. Related to tumor cell chemoresistance, miR181a could be a potential therapeutic target in treating T-cell malignancies.


Assuntos
Resistencia a Medicamentos Antineoplásicos , MicroRNAs/metabolismo , Leucemia-Linfoma Linfoblástico de Células T Precursoras/genética , Adulto , Antineoplásicos/farmacologia , Proliferação de Células/efeitos dos fármacos , Doxorrubicina/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/genética , Ativação Enzimática/efeitos dos fármacos , Feminino , Regulação Leucêmica da Expressão Gênica/efeitos dos fármacos , Células HEK293 , Humanos , Células Jurkat , Masculino , MicroRNAs/genética , Pessoa de Meia-Idade , Leucemia-Linfoma Linfoblástico de Células T Precursoras/enzimologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Regulação para Cima/efeitos dos fármacos , Regulação para Cima/genética
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