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1.
Clin Cancer Res ; 2020 Mar 31.
Artigo em Inglês | MEDLINE | ID: mdl-32234760

RESUMO

PURPOSE: Adults with T-cell lymphoblastic lymphoma (T-LBL) generally benefit from treatment with acute lymphoblastic leukemia (ALL)-like regimens, but approximately 40% will relapse after such treatment. We evaluated the value of CpG methylation in predicting relapse for adults with T-LBL treated with ALL-like regimens. EXPERIMENTAL DESIGN: A total of 549 adults with T-LBL from 27 medical centers were included in the analysis. Using the Illumina Methylation 850K Beadchip, 44 relapse-related CpGs were identified from 49 T-LBL samples by two algorithms: least absolute shrinkage and selector operation (LASSO) and support vector machine-recursive feature elimination (SVM-RFE). We built a four-CpG classifier using LASSO Cox regression based on association between the methylation level of CpGs and relapse-free survival in the training cohort (n = 160). The four-CpG classifier was validated in the internal testing cohort (n = 68) and independent validation cohort (n = 321). RESULTS: The four-CpG-based classifier discriminated patients with T-LBL at high risk of relapse in the training cohort from those at low risk (P < 0.001). This classifier also showed good predictive value in the internal testing cohort (P < 0.001) and the independent validation cohort (P < 0.001). A nomogram incorporating five independent prognostic factors including the CpG-based classifier, lactate dehydrogenase levels, Eastern Cooperative Oncology Group performance status, central nervous system involvement, and NOTCH1/FBXW7 status showed a significantly higher predictive accuracy than each single variable. Stratification into different subgroups by the nomogram helped identify the subset of patients who most benefited from more intensive chemotherapy and/or sequential hematopoietic stem cell transplantation. CONCLUSIONS: Our four-CpG-based classifier could predict disease relapse in patients with T-LBL, and could be used to guide treatment decision.

2.
Ann Hematol ; 99(6): 1311-1319, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32285160

RESUMO

To assess the survival outcomes and adverse events (AEs) of high-intermediate- or high-risk patients with diffuse large B cell lymphoma (DLBCL) who underwent conventional chemotherapy plus rituximab with or without first-line autologous stem cell transplantation (ASCT). Related studies published on Medline, Embase, Cochrane Library, and Web of science were searched, comprising both retrospective and randomized clinical trials (RCTs). The primary endpoints were overall survival (OS) and progression-free survival (PFS). The meta-analysis was performed using the software RevMan v5.3. Four RCTs and six retrospective trials with a total of 1811 patients were identified. Pooled data indicated that conventional chemotherapy plus rituximab followed by ASCT as the first-line therapy contributed to better PFS (HR = 0.73, 95% CI 0.62-0.86, p = 0.0002) but did not significantly improve OS (HR = 0.74, 95% CI 0.55-1.01, p = 0.06) of high-intermediate/high-risk patients. Subgroup analyses of patients with complete remission after induction chemotherapy may benefit from the upfront ASCT (OS, HR = 0.48, 95% CI 0.28-0.82, p = 0.008). The incidences of grade ≥ 3 hematological and non-hematological AEs occurred more frequently in the transplantation group. High-intermediate or high-risk untreated patients with DLBCL only achieved short-term survival benefit with the upfront ASCT.

3.
Leukemia ; 2020 Feb 20.
Artigo em Inglês | MEDLINE | ID: mdl-32080345

RESUMO

We aimed to establish a discriminative gene-expression-based classifier to predict survival outcomes of T-cell lymphoblastic lymphoma (T-LBL) patients. After exploring global gene-expression profiles of progressive (n = 22) vs. progression-free (n = 28) T-LBL patients, 43 differentially expressed mRNAs were identified. Then an eleven-gene-based classifier was established using LASSO Cox regression based on NanoString quantification. In the training cohort (n = 169), high-risk patients stratified using the classifier had significantly lower progression-free survival (PFS: hazards ratio 4.123, 95% CI 2.565-6.628; p < 0.001), disease-free survival (DFS: HR 3.148, 95% CI 1.857-5.339; p < 0.001), and overall survival (OS: HR 3.790, 95% CI 2.237-6.423; p < 0.001) compared with low-risk patients. The prognostic accuracy of the classifier was validated in the internal testing (n = 84) and independent validation cohorts (n = 360). A prognostic nomogram consisting of five independent variables including the classifier, lactate dehydrogenase levels, ECOG-PS, central nervous system involvement, and NOTCH1/FBXW7 status showed significantly greater prognostic accuracy than each single variable alone. The addition of a five-miRNA-based signature further enhanced the accuracy of this nomogram. Furthermore, patients with a nomogram score ≥154.2 significantly benefited from the BFM protocol. In conclusion, our nomogram comprising the 11-gene-based classifier may make contributions to individual prognosis prediction and treatment decision-making.

4.
Lancet Oncol ; 21(2): 306-316, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31879220

RESUMO

BACKGROUND: Extranodal natural killer T-cell lymphoma (NKTCL; nasal type) is an aggressive malignancy with a particularly high prevalence in Asian and Latin American populations. Epstein-Barr virus infection has a role in the pathogenesis of NKTCL, and HLA-DPB1 variants are risk factors for the disease. We aimed to identify additional novel genetic variants affecting risk of NKTCL. METHODS: We did a genome-wide association study of NKTCL in multiple populations from east Asia. We recruited a discovery cohort of 700 cases with NKTCL and 7752 controls without NKTCL of Han Chinese ancestry from 19 centres in southern, central, and northern regions of China, and four independent replication samples including 717 cases and 12 650 controls. Three of these independent samples (451 cases and 5301 controls) were from eight centres in the same regions of southern, central, and northern China, and the fourth (266 cases and 7349 controls) was from 11 centres in Hong Kong, Taiwan, Singapore, and South Korea. All cases had primary NKTCL that was confirmed histopathologically, and matching with controls was based on geographical region and self-reported ancestry. Logistic regression analysis was done independently by geographical regions, followed by fixed-effect meta-analyses, to identify susceptibility loci. Bioinformatic approaches, including expression quantitative trait loci, binding motif and transcriptome analyses, and biological experiments were done to fine-map and explore the functional relevance of genome-wide association loci to the development of NKTCL. FINDINGS: Genetic data were gathered between Jan 1, 2008, and Jan 23, 2019. Meta-analysis of all samples (a total of 1417 cases and 20 402 controls) identified two novel loci significantly associated with NKTCL: IL18RAP on 2q12.1 (rs13015714; p=2·83 × 10-16; odds ratio 1·39 [95% CI 1·28-1·50]) and HLA-DRB1 on 6p21.3 (rs9271588; 9·35 × 10-26 1·53 [1·41-1·65]). Fine-mapping and experimental analyses showed that rs1420106 at the promoter of IL18RAP was highly correlated with rs13015714, and the rs1420106-A risk variant had an upregulatory effect on IL18RAP expression. Cell growth assays in two NKTCL cell lines (YT and SNK-6 cells) showed that knockdown of IL18RAP inhibited cell proliferation by cell cycle arrest in NKTCL cells. Haplotype association analysis showed that haplotype 47F-67I was associated with reduced risk of NKTCL, whereas 47Y-67L was associated with increased risk of NKTCL. These two positions are component parts of the peptide-binding pocket 7 (P7) of the HLA-DR heterodimer, suggesting that these alterations might account for the association at HLA-DRB1, independent of the previously reported HLA-DPB1 variants. INTERPRETATION: Our findings provide new insights into the development of NKTCL by showing the importance of inflammation and immune regulation through the IL18-IL18RAP axis and antigen presentation involving HLA-DRB1, which might help to identify potential therapeutic targets. Taken in combination with additional genetic and other risk factors, our results could potentially be used to stratify people at high risk of NKTCL for targeted prevention. FUNDING: Guangdong Innovative and Entrepreneurial Research Team Program, National Natural Science Foundation of China, National Program for Support of Top-Notch Young Professionals, Chang Jiang Scholars Program, Singapore Ministry of Health's National Medical Research Council, Tanoto Foundation, National Research Foundation Singapore, Chang Gung Memorial Hospital, Recruitment Program for Young Professionals of China, First Affiliated Hospital and Army Medical University, US National Institutes of Health, and US National Cancer Institute.

5.
Leukemia ; 33(10): 2454-2465, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-30953029

RESUMO

New prognostic factors are needed to establish indications for haematopoietic stem cell transplantation (HSCT) in first complete remission (CR1) for T-cell lymphoblastic lymphoma (T-LBL) patients. We used microarray to compare T-LBL tissue samples (n = 75) and fetal thymus tissues (n = 20), and identified 35 differentially expressed miRNAs. Using 107 subjects as the training group, we developed a five-miRNA-based classifier to predict patient survival with LASSO Cox regression: lower risk was associated with better prognosis (disease-free survival (DFS): hazard ratio (HR) 4.548, 95% CI 2.433-8.499, p < 0.001; overall survival (OS): HR 5.030, 95% CI 2.407-10.513, p < 0.001). This classifier displayed good performance in the internal testing set (n = 106) and the independent external set (n = 304). High risk was associated with more favorable response to HSCT (DFS: HR 1.675, 95% CI 1.127-2.488, p = 0.011; OS: HR 1.602, 95% CI 1.055-2.433, p = 0.027). When combined with ECOG-PS and/or NOTCH1/FBXW7 status, this classifier had even better prognostic performance in patients receiving HSCT (DFS: HR 2.088, 95% CI 1.290-3.379, p = 0.003; OS: HR 1.996, 95% CI 1.203-3.311, p = 0.007). The five-miRNA classifier may be a useful prognostic biomarker for T-LBL adults, and could identify subjects who could benefit from HSCT.


Assuntos
MicroRNAs/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Linfócitos T/metabolismo , Linfócitos T/patologia , Intervalo Livre de Doença , Feminino , Transplante de Células-Tronco Hematopoéticas/métodos , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Prognóstico , Modelos de Riscos Proporcionais , Indução de Remissão/métodos
6.
Leuk Lymphoma ; 60(8): 1917-1925, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30646796

RESUMO

Circulating EBV-DNA is an accurate biomarker of tumor load in extranodal natural killer (NK)/T cell lymphoma (ENKTL); however, its role in patients treated with P-GEMOX has not been evaluated. In this study, we examined plasma EBV-DNA of 99 patients at different time points by real-time quantitative polymerase chain reaction. Multivariate analysis revealed that ECOG PS score, response rate, and post-treatment EBV-DNA level were independent predictors of progression-free survival (PFS) and overall survival (OS). Positive post-treatment plasma EBV-DNA was associated with poor OS in ENKTL patients. The 3-year OS for patients with positive pre-, interim-, post-treatment EBV-DNA was significantly lower than that for patients with negative EBV-DNA; the values were 70.2% vs. 93.9% (p = .022), 53.8% vs. 99.1% (p < .001), and 40.6% vs. 91.8% (p < .001), respectively. We conclude that monitoring dynamic changes in plasma EBV-DNA in ENKTL patients treated with P-GEMOX could predict important outcomes such as OS.

7.
Leukemia ; 33(6): 1451-1462, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30546078

RESUMO

Extranodal natural killer T-cell lymphoma (nasal type; NKTCL) is an aggressive malignancy strongly associated with Epstein-Barr virus (EBV) infection. However, the role of EBV in NKTCL development is unclear, largely due to the lack of information about EBV genome and transcriptome in NKTCL. Here, using high-throughput sequencing, we obtained whole genome (n = 27) and transcriptome datasets (n = 18) of EBV derived from NKTCL tumor biopsies. We assembled 27 EBV genomes and detected an average of 1,152 single nucleotide variants and 44.8 indels (<50 bp) of EBV per sample. We also identified frequent focal EBV genome deletions and integrated EBV fragments in the host genome. Moreover, Phylogenetic analysis revealed that NKTCL-derived EBVs are closely clustered; transcriptome analysis revealed less activation of both latent and lytic genes and larger amount of T-cell epitope alterations in NKTCL, as compared with other EBV-associated cancers. Furthermore, we observed transcriptional defects of the BARTs miRNA by deletion, and the disruption of host NHEJ1 by integrated EBV fragment, implying novel pathogenic mechanisms of EBV. Taken together, we reported for the first time global mutational and transcriptional profiles of EBV in NKTCL clinical samples, revealing important somatic events of EBV and providing insights to better understanding of EBV's contribution in tumorigenesis.


Assuntos
Infecções por Vírus Epstein-Barr/genética , Genoma Viral , Herpesvirus Humano 4/genética , Linfoma Extranodal de Células T-NK/genética , Células T Matadoras Naturais/metabolismo , Transcriptoma , Proteínas Virais/genética , Adulto , Infecções por Vírus Epstein-Barr/complicações , Infecções por Vírus Epstein-Barr/virologia , Feminino , Regulação Viral da Expressão Gênica , Genômica/métodos , Humanos , Linfoma Extranodal de Células T-NK/epidemiologia , Linfoma Extranodal de Células T-NK/virologia , Masculino , Mutação , Células T Matadoras Naturais/virologia , Sequenciamento Completo do Genoma
8.
BMC Cancer ; 20(1): 1, 2019 Dec 31.
Artigo em Inglês | MEDLINE | ID: mdl-31892356

RESUMO

BACKGROUND: Bcl-2 family members play an important role in the development of malignant lymphoma and can induce drug resistance in anticancer treatment. The development of small molecules targeting Bcl-2 family proteins may be a new strategy for the treatment of malignant lymphoma. In this study, we investigate the antitumor effect and cellular mechanism of a novel Bcl-2/Bcl-xL dual inhibitor, BM-1197, in DCBCL and Burkitt lymphoma cells. METHODS: The CCK-8 assay was used to detect cell viability. Apoptosis was determined by Hoechst 33258 staining and flow cytometry. The activity of caspase-3/caspase-9 was determined using a caspase-3/caspase-9 activity kit. Western blotting analysis was performed to evaluate the changes in protein expression. Functional analysis was performed via immunoprecipitation and siRNA interference. Human malignant lymphoma xenograft models in nude mice were established for in vivo efficacy detection. RESULTS: We find that BM-1197 exerts potent growth-inhibitory activity against lymphoma cells that harbor high expression of Bcl-2 and Bcl-xL in vitro and has a synergistic effect with chemotherapeutic drugs. Mechanistically, we see that the intrinsic apoptosis pathway is activated upon BM-1197 treatment. BM-1197 affects the protein interactions of Bak/Bcl-xl, Bim/Bcl-2, Bim/Bcl-xl, and PUMA/Bcl-2 and induces conformational changes in the Bax protein, which result in the activation of Bax and release of cytochrome c, activate caspase - 9, - 3, and - 7 and finally induce cell apoptosis. Furthermore, our data demonstrate that BM-1197 exhibits strong anti-tumor effects against established human malignant lymphoma xenograft models. CONCLUSIONS: Our study demonstrated BM-1197 exerts potent antitumor effects both in vitro and in vivo and provides promising preclinical data for the further development of BM-1197 in malignant lymphoma.


Assuntos
Compostos de Anilina/farmacologia , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Linfoma/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/antagonistas & inibidores , Sulfonamidas/farmacologia , Animais , Linhagem Celular Tumoral , Humanos , Células Jurkat , Masculino , Camundongos , Ensaios Antitumorais Modelo de Xenoenxerto
9.
Ann Hematol ; 97(12): 2381-2389, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30116872

RESUMO

Although gemcitabine, oxaliplatin and L-asparaginase/pegylated asparaginase (P-GEMOX) treatment for early-stage extranodal natural killer/T cell lymphoma (ENKTL) is effective, some patients die within 1 year of diagnosis. We attempted to determine an optimal biomarker for identifying such patients. We enrolled 71 patients with ENKTL who received P-GEMOX between January 2011 and January 2014. We classified the patients according to the outcome into worse (died within 1 year) or better groups (survival time ≥ 3, 4 or 5 years). The area under the curve (AUC) was determined to identify the optimal biomarker for differentiating the groups. The AUC was highest in patients who were plasma Epstein-Barr virus (EBV) DNA-positive post-treatment. The AUC was 0.82, 0.86 and 0.86 when the worse group was compared to the better group, respectively. Among the post-treatment EBV DNA-positive patients, as compared to EBV DNA-negative patients, pre-treatment EBV DNA-positive patients had a higher proportion of CD4 + CD25 + T cells. There was higher programmed cell death protein ligand-1(PD-L1) expression in post-treatment EBV DNA-positive patients. Post-treatment positive EBV DNA status maybe a useful biomarker of worse outcomes in early stage ENKTL.


Assuntos
Antígeno B7-H1/biossíntese , Biomarcadores Tumorais/sangue , DNA de Neoplasias/sangue , Regulação Neoplásica da Expressão Gênica , Herpesvirus Humano 4 , Subunidade alfa de Receptor de Interleucina-2/sangue , Linfoma Extranodal de Células T-NK , Proteínas de Neoplasias/sangue , Linfócitos T/metabolismo , Adolescente , Adulto , Idoso , Intervalo Livre de Doença , Feminino , Humanos , Contagem de Linfócitos , Linfoma Extranodal de Células T-NK/sangue , Linfoma Extranodal de Células T-NK/mortalidade , Linfoma Extranodal de Células T-NK/virologia , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Estudos Retrospectivos , Taxa de Sobrevida
10.
Lancet Oncol ; 19(9): 1239-1246, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-30082170

RESUMO

BACKGROUND: Anti-angiogenic therapy combined with chemotherapy could improve the outcomes of patients with platinum-resistant ovarian cancer. Apatinib is an oral tyrosine kinase inhibitor that selectively inhibits VEGF receptor 2. We assessed the efficacy and safety of the combination therapy of apatinib and oral etoposide, considering the potential advantage of home administration without hospital admission, in patients with platinum-resistant or platinum-refractory ovarian cancer. METHODS: In this phase 2, single-arm, prospective study, we recruited patients aged 18-70 years with platinum-resistant or platinum-refractory ovarian cancer at the Sun Yat-sen University Cancer Center (China). The treatment consisted of apatinib at an initial dose of 500 mg once daily on a continuous basis, and oral etoposide at a dose of 50 mg once daily on days 1-14 of a 21-day cycle. Oral etoposide was administered for a maximum of six cycles. Treatment was continued until disease progression, patient withdrawal, or unacceptable toxic effects. The primary endpoint was the proportion of patients achieving an objective response according to Response Evaluation Criteria in Solid Tumors, version 1.1. We used Simon's two-stage design, and analysed efficacy in the intention-to-treat and per-protocol populations. Safety analyses included enrolled patients who had received at least one dose of study medication, but excluded those without any safety data. This study is registered with ClinicalTrials.gov, number NCT02867956. FINDINGS: Between Aug 10, 2016, and Nov 9, 2017, we screened 38 and enrolled 35 patients. At the data cutoff date (Dec 31, 2017), 20 (57%) patients had discontinued the study, and 15 (43%) patients remained on treatment. Objective responses were achieved in 19 (54%; 95% CI 36·6-71·2) of 35 patients in the intention-to-treat population and in 19 (61%; 42·2-78·2) of 31 patients in the per-protocol population. The most common grade 3 or 4 adverse events were neutropenia (17 [50%]), fatigue (11 [32%]), anaemia (ten [29%]), and mucositis (eight [24%]). Serious adverse events were reported in two patients who were admitted to hospital (one patient had anaemia and anorexia; the other patient had increased ascites due to disease progression). No treatment-related deaths were recorded. INTERPRETATION: The combination of apatinib with oral etoposide shows promising efficacy and manageable toxicities in patients with platinum-resistant or platinum-refractory ovarian cancer, and further study in phase 3 trials is warranted. FUNDING: None.


Assuntos
Inibidores da Angiogênese/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Etoposídeo/administração & dosagem , Neoplasias Ovarianas/tratamento farmacológico , Compostos de Platina/administração & dosagem , Piridinas/administração & dosagem , Administração Oral , Adolescente , Adulto , Idoso , Inibidores da Angiogênese/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Progressão da Doença , Esquema de Medicação , Resistencia a Medicamentos Antineoplásicos , Etoposídeo/efeitos adversos , Feminino , Humanos , Pessoa de Meia-Idade , Neoplasias Ovarianas/mortalidade , Neoplasias Ovarianas/patologia , Compostos de Platina/efeitos adversos , Intervalo Livre de Progressão , Estudos Prospectivos , Piridinas/efeitos adversos , Fatores de Tempo , Adulto Jovem
11.
Chin J Cancer ; 36(1): 94, 2017 Dec 16.
Artigo em Inglês | MEDLINE | ID: mdl-29246182

RESUMO

BACKGROUND: The programmed cell death-1 (PD-1)/programmed cell death-ligand 1 (PD-L1) pathway inhibits the activation of T cells and plays a crucial role in the negative regulation of cellular and humoral immune responses. Diffuse large B-cell lymphoma (DLBCL) is the most common lymphoid malignancy in adults. In the present study, we aimed to detect the expression of PD-L1 in DLBCL and to analyze its relationship with prognosis. METHODS: We reviewed medical records of 204 newly diagnosed DLBCL patients in Sun Yat-sen University Cancer Center between October 2005 and August 2012. The expression of PD-L1 in tumor tissues from these 204 patients was detected using immunohistochemical (IHC) assay. The expression of anaplastic lymphoma kinase (ALK), CD5, CD30, and C-Myc in tumor specimens from 109 patients was detected using IHC, and Epstein-Barr virus (EBV)-encoded RNAs (EBERs) were detected using fluorescence in situ hybridization. The Spearman method was used for correlation analysis. The Kaplan-Meier method with log-rank test was used for univariate analysis. Cox proportional hazards model was used for multivariate analysis. RESULTS: Of the 204 patients, 100 (49.0%) were PD-L1-positive in tumor cells and 44 (21.6%) were PD-L1-positive in tumor microenvironment. PD-L1 expression in tumor cells and tumor microenvironment were more common in the non-germinal center B-cell-like (GCB) subtype than in the GCB subtype (P = 0.02 and P = 0.04). Patients with PD-L1 expression in tumor microenvironment were more likely to be resistant to first-line chemotherapy when compared with the patients without PD-L1 expression in tumor microenvironment (P = 0.03). PD-L1 expression in tumor microenvironment was negatively correlated with C-Myc expression (r = - 0.20, P = 0.04). No correlations were detected between PD-L1 expression and the expression of ALK, CD5, and CD30 as well as EBERs. The 5-year overall survival (OS) rates were 50.0% and 67.3% in patients with and without PD-L1 expression in tumor cells (P = 0.02). PD-L1 expression in tumor cells was an independent risk predictor for OS (P < 0.01). CONCLUSIONS: PD-L1 expression is more common in the non-GCB subtype than in the GCB subtype. PD-L1 expression in tumor microenvironment has a negative correlation with C-Myc. PD-L1 positivity predicts short survival in DLBCL patients. For patients with PD-L1 expression, more strategy such as anti-PD-L1 antibody treatment should be recommended.


Assuntos
Antígeno B7-H1/metabolismo , Biomarcadores Tumorais , Linfoma Difuso de Grandes Células B/metabolismo , Linfoma Difuso de Grandes Células B/mortalidade , Adulto , Idoso , Antígeno B7-H1/genética , Feminino , Seguimentos , Expressão Gênica , Humanos , Imuno-Histoquímica , Hibridização in Situ Fluorescente , Estimativa de Kaplan-Meier , Linfoma Difuso de Grandes Células B/genética , Linfoma Difuso de Grandes Células B/patologia , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Prognóstico , Modelos de Riscos Proporcionais , Estudos Retrospectivos
12.
J Cancer ; 8(5): 793-800, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28382141

RESUMO

Background: Recently double-hit lymphoma or double protein expressor lymphoma has been identified as a distinct group of diffuse large B cell lymphoma with poor prognosis. However, the expression status, clinical and prognostic effect of combined overexpression of MYC and BCL2 in extranodal NK/T-cell lymphoma, nasal type (ENKTL) are not known. Materials and methods: Paraffin-embedded lymphoma samples from 53 patients with newly diagnosed ENKTL were studied using immunohistochemistry for MYC and BCL2, and fluorescent in situ hybridization (FISH) for MYC and BCL2 were done on 5 tissue sections with highest percentages of both MYC and BCL2 positive lymphoma cells. Results: The median percentage of MYC-positive lymphoma cells and BCL2-positive lymphoma cells were 20% (range, 5%-45%) and 70% (10%-95%), respectively. Using median scores as cutoffs, we assigned each patient an IHC double-hit score (DHS) that ranged from 0 to 2. Using this DHS, 15 patients (28.3%) had a DHS of 0, 24 patients (45.3%) had a DHS of 1, and the remaining 14 patients (26.4%) had a DHS of 2. FISH analysis was performed on 5 tissue sections with DHS of 2, and none of them had MYC or BCL2 rearrangement. The DHS was not associated with patients' age, gender, disease stage, LDH level, B symptoms, performance status, or local tumor invasiveness. However, patients with tumor localized in extranasal sites seemed to have higher expression of BCL2 and higher DHS than nasal lesions (p=0.014 and 0.042, respectively). In univariate survival analysis, either high expression of MYC or BCL2 was significantly correlated with inferior PFS and OS (p<0.05). According to the DHS, patients with ENKTL could be divided into three significantly different risk groups for PFS and OS (3-year PFS rate for DHS of 0, 1, and 2 was 60%, 41%, and 21%, respectively, p=0.008; 3-year OS rate for DHS of 0, 1, and 2 was 79%, 49%, and 33%, respectively, p=0.015). In multivariate survival analysis, it was found that DHS was an independent prognostic factor for both PFS and OS (p=0.006 and 0.011, respectively). Conclusions: Our study demonstrated that DHS can help identify patients with newly diagnosed ENKTL who are at a high risk for a poor clinical outcome, which needs to be validated in prospective clinical trials with patients treated uniformly.

13.
Oncotarget ; 8(7): 11480-11488, 2017 Feb 14.
Artigo em Inglês | MEDLINE | ID: mdl-28002792

RESUMO

This study retrospectively investigated asparaginase-based chemotherapy treatment outcomes with or without radiotherapy in 143 patients with stage IE-IIE extranodal natural killer/T cell lymphoma (ENKTCL). All patients received a median of three cycles of asparaginase-based chemotherapy, while 121 patients received radiotherapy following the chemotherapy. The complete remission (CR) rate for all patients post-chemotherapy was 58.7%, and rose to 73.4% by the end of treatment. Patients who received radiotherapy achieved better survival outcomes than those who did not (89.7% vs. 49.0% for 2-year overall survival (OS), P<0.001; 86.8% vs. 37.4% for 2-year progression-free survival (PFS), P<0.001). Additionally, even patients who achieved CR post-chemotherapy exhibited differential survival rates with or without radiotherapy (90.8% vs. 60% for 2-year OS, P=0.006; 86.1% vs. 60% for 2-year PFS, P=0.044). Multivariate analysis revealed that radiotherapy was an independent factor favoring OS (HR=0.098, 95%CI=0.031-0.314, P=0.001) and PFS (HR=0.156, 95%CI=0.062-0.396, P=0.001). Thus, radiotherapy is recommended for stage IE-IIE ENKTCL patients treated with asparaginase-based chemotherapy, even in cases of CR following chemotherapy.


Assuntos
Quimiorradioterapia/métodos , Linfoma Extranodal de Células T-NK/mortalidade , Linfoma Extranodal de Células T-NK/terapia , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Asparaginase/uso terapêutico , Intervalo Livre de Doença , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Resultado do Tratamento
14.
J Hematol Oncol ; 9(1): 109, 2016 10 13.
Artigo em Inglês | MEDLINE | ID: mdl-27737703

RESUMO

BACKGROUND: Natural killer/T-cell lymphoma (NKTCL) is an Epstein-Barr virus (EBV)-associated, highly aggressive lymphoma. Treatment outcome remains sub-optimal, especially for advanced-stage or relapsed diseases. Programmed cell death receptor 1 (PD-1) and PD ligand 1 (PD-L1) have become promising therapeutic targets for various malignancies, but their role in the pathogenesis and their interactions with EBV in NKTCL remains to be investigated. METHODS: Expression of PD-L1 was measured in NK-92 (EBV-negative) and SNK-6 (EBV-positive) cells by western blot, quantitative real-time PCR and enzyme-linked immunosorbent assay, and flow cytometry, respectively. Latent membrane protein 1 (LMP1)-harboring lentiviral vectors were transfected into NK-92 cells to examine the correlation between LMP1 and PD-L1 expression. Proteins in the downstream pathways of LMP1 signaling were measured in NK-92 cells transfected with LMP1-harboring or negative control vectors as well as in SNK-6 cells. PD-L1 expression on tumor specimens and serum concentration of soluble PD-L1 were collected in a retrospective cohort of patients with Ann Arbor stage I~II NKTCL, and their prognostic significance were analyzed. RESULTS: Expression of PD-L1 was significantly higher in SNK-6 cells than in NK-92 cells, at both protein and mRNA levels. Expression of PD-L1 was remarkably upregulated in NK-92 cells transfected with LMP1-harboring lentiviral vectors compared with those transfected with negative control vectors. Proteins in the MAPK/NF-κB pathway were upregulated in LMP1-expressing NK-92 cells compared with the negative control. Selective inhibitors of those proteins induced significant downregulation of PD-L1 expression in LMP1-expressing NK-92 cells as well as in SNK-6 cells. Patients with a high concentration of serum soluble PD-L1 (≥3.4 ng/ml) or with a high percentage of PD-L1 expression in tumor specimens (≥38 %) exhibited significantly lower response rate to treatment and remarkably worse survival, compared with their counterparts. A high concentration of serum soluble PD-L1 and a high percentage of PD-L1 expression in tumor specimens were independent adverse prognostic factors among patients with stage I~II NKTCL. CONCLUSIONS: PD-L1 expression positively correlated LMP1 expression in NKTCL, which was probably mediated by the MAPK/NF-κB pathway. PD-L1 expression in serum and tumor tissues has significant prognostic value for early-stage NKTCL.


Assuntos
Antígeno B7-H1/análise , Linfoma Extranodal de Células T-NK/diagnóstico , NF-kappa B/metabolismo , Proteínas da Matriz Viral/fisiologia , Antígeno B7-H1/sangue , Biópsia , Células Cultivadas , Feminino , Regulação Neoplásica da Expressão Gênica , Herpesvirus Humano 4 , Interações Hospedeiro-Patógeno , Humanos , Linfoma Extranodal de Células T-NK/patologia , Linfoma Extranodal de Células T-NK/virologia , Masculino , Pessoa de Meia-Idade , Prognóstico , Transfecção , Proteínas da Matriz Viral/genética
15.
Onco Targets Ther ; 9: 5875-5881, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27713641

RESUMO

Previous studies have found that radiotherapy (RT) dose less than 50 Gy resulted in inferior outcomes for early stage extranodal NK/T-cell lymphoma (ENKTL). Nowadays, induction chemotherapy (CT) followed by RT consolidation is often used. For patients who get complete response (CR) after CT, whether RT dose can be safely reduced or not remains unknown. This retrospective study compared the survival outcomes between patients who received higher dose (>50 Gy) and lower dose (≤50 Gy) RT after CR was attained by CT. One hundred and forty four patients of early stage ENKTL got CR after induction CT and received RT consolidation. Thirty-one patients received lower dose RT (median 46 Gy, range, 36-50 Gy), and 113 patients received higher dose RT (median 56 Gy, range, 52-66 Gy). In univariate survival analysis, age >60, local tumor invasion, and non-asparaginase-based CT were associated with inferior progression-free survival (PFS) and overall survival (OS). However, there were no differences in PFS and OS between patients treated with higher and lower dose RT, which was confirmed in the multivariate survival analysis. Furthermore, reduced dose RT did not affect local control rate. Most common RT-related side effects were grade 1/2 mucositis and dermatitis, and the incidence rate of grade 3 mucositis or dermatitis was lower in patients treated with reduced dose RT (9.7% vs 15.0% for mucositis, and 6.5% vs 17.7% for dermatitis). In conclusion, this study found that RT dose could be safely reduced without compromising survival outcomes and further improved RT-related side effects. Prospective randomized controlled trials are warranted to validate our findings.

16.
Chin J Cancer ; 35(1): 87, 2016 09 13.
Artigo em Inglês | MEDLINE | ID: mdl-27624700

RESUMO

BACKGROUND: In patients with diffuse large B-cell lymphoma (DLBCL), central nervous system (CNS) relapse is uncommon but is nearly always fatal. This study aimed to determine the risk factors for CNS relapse in DLBCL patients and to evaluate the efficacy of rituximab and intrathecal chemotherapy prophylaxis for CNS relapse reduction. METHODS: A total of 511 patients with newly diagnosed DLBCL treated at the Sun Yat-sen University Cancer Center between January 2003 and December 2012 were included in the study. Among these patients, 376 received R-CHOP regimen (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) as primary treatment, and 135 received CHOP regimen (cyclophosphamide, doxorubicin, vincristine, and prednisone) as primary treatment. Intrathecal chemotherapy prophylaxis (methotrexate plus cytarabine) was administered to those who were deemed at high risk for CNS relapse. In the entire cohort and in the R-CHOP set in particular, the Kaplan-Meier method coupled with the log-rank test was used for univariate analysis, and the Cox proportional hazards model was used for multivariate analysis. Differences were evaluated using a two-tailed test, and P < 0.05 was considered significant. RESULTS: At a median follow-up of 46 months, 25 (4.9%) patients experienced CNS relapse. There was a trend of reduced occurrence of CNS relapse in patients treated with rituximab; the 3-year cumulative CNS relapse rates were 7.1% in CHOP group and 2.7% in R-CHOP group (P = 0.045). Intrathecal chemotherapy prophylaxis did not confer much benefit in terms of preventing CNS relapse. Bone involvement [hazard ratio (HR) = 4.21, 95% confidence interval (CI) 1.38-12.77], renal involvement (HR = 3.85, 95% CI 1.05-14.19), alkaline phosphatase (ALP) >110 U/L (HR = 3.59, 95% CI 1.25-10.34), serum albumin (ALB) <35 g/L (HR = 3.63, 95% CI 1.25-10.51), treatment with rituximab (HR = 0.34, 95% CI 0.12-0.96), and a time to complete remission ≤ 108 days (HR = 0.22, 95% CI 0.06-0.78) were independent predictive factors for CNS relapse in the entire cohort. Bone involvement (HR = 4.44, 95% CI 1.08-18.35), bone marrow involvement (HR = 11.70, 95% CI 2.24-60.99), and renal involvement (HR = 10.83, 95% CI 2.27-51.65) were independent risk factors for CNS relapse in the R-CHOP set. CONCLUSIONS: In the present study, rituximab decreased the CNS relapse rate of DLBCL, whereas intrathecal chemotherapy prophylaxis alone was not sufficient for preventing CNS relapse. Serum levels of ALB and ALP, and the time to complete remission were new independent predictive factors for CNS relapse in the patients with DLBCL. In the patients received R-CHOP regimen, a trend of increased CNS relapse was found to be associated with extranodal lesions.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias do Sistema Nervoso Central/patologia , Linfoma Difuso de Grandes Células B/patologia , Recidiva Local de Neoplasia/patologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias do Sistema Nervoso Central/tratamento farmacológico , Ciclofosfamida/administração & dosagem , Doxorrubicina/administração & dosagem , Feminino , Seguimentos , Humanos , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/tratamento farmacológico , Estadiamento de Neoplasias , Prednisona/administração & dosagem , Prognóstico , Estudos Retrospectivos , Fatores de Risco , Rituximab/administração & dosagem , Taxa de Sobrevida , Vincristina/administração & dosagem , Adulto Jovem
17.
Am J Ind Med ; 59(10): 832-40, 2016 10.
Artigo em Inglês | MEDLINE | ID: mdl-27373879

RESUMO

BACKGROUND: Acute occupational hand injuries are a common occurrence in China's metal manufacturing industries. This study aimed to explore the transient risk factors for acute occupational hand injuries among metal manufacturing workers. METHODS: A case-crossover study was conducted from October 2013 through December 2013 in Zhongshan city, southern China. Face-to-face interviews were used to collect information on the occurrence of 12 transient risk factors during the "hazard" period (a 60-min period prior to occupational hand injury) and a "control" period (the week before the injury). RESULTS: One hundred ninety-four qualified acute occupational hand injury cases (139 male, 55 female) were enrolled in this study, with a mean age of 35.5 (standard deviation [SD] 10.4) years. The most common (64.9%) type of work was punching, and the most common injures were crushes and fractures (28.8 and 23.7%, respectively). Of these cases, 62.9% were regarded as severe or major. Among the 12 transient risk factors, 11 ones were significantly associated with acute occupational hand injuries occurring during the hazard period: "replacing sharp knives" (IRR = 14.38, 95%CI 11.43-18.08), "using malfunctioning machinery" (IRR = 30.59, 95%CI 17.84-52.48), "using different tools" (IRR = 10.96, 95%CI 4.77-25.17), "using different machines" (IRR = 5.20, 95%CI 2.25-12.00), "performing unusual work tasks" (IRR = 24.38, 95%CI 14.11-42.15), "working overtime" (IRR = 13.40, 95%CI 7.70-23.29), "performing a task with a different method" (IRR = 56.41, 95%CI 23.61-134.81), "being in a bad mood" (IRR = 108.11, 95%CI 55.10-211.11), "feeling ill" (RR = 12.27, 95%CI 4.95-30.43), "rushing" (IRR = 5.16, 95%CI 2.49-10.70), and "not wearing gloves" (IRR = 1.63, 95%CI 1.23-2.15). CONCLUSIONS: Our study suggested that multiple transient risk factors were responsible for the acute occupational hand injuries in China's metal manufacturing industries. Am. J. Ind. Med. 59:832-840, 2016. © 2016 Wiley Periodicals, Inc.


Assuntos
Traumatismos da Mão/epidemiologia , Traumatismos da Mão/etiologia , Traumatismos Ocupacionais/epidemiologia , Traumatismos Ocupacionais/etiologia , Acidentes de Trabalho/estatística & dados numéricos , Adulto , China/epidemiologia , Estudos Cross-Over , Feminino , Hospitais , Humanos , Entrevistas como Assunto , Masculino , Instalações Industriais e de Manufatura , Metais , Pessoa de Meia-Idade , Reprodutibilidade dos Testes , Fatores de Risco
18.
Sci Rep ; 6: 23996, 2016 Apr 04.
Artigo em Inglês | MEDLINE | ID: mdl-27041507

RESUMO

The optimal treatment strategy for relapsed natural killer/T-cell lymphoma (NKTCL) remains largely unknown. We retrospectively reviewed the treatment modalities and prognosis of 56 relapsed NKTCL patients. Chemotherapy was the initial salvage treatment, followed by radiotherapy (RT) or autologous hematopoietic stem cell transplantation (AHSCT) as consolidative therapy, depending on the status of remission and the pattern of relapse. For patients with locoregional relapse alone, consolidative RT after salvage chemotherapy significantly improved prognosis compared with follow-up (5-year OS: 83.3 vs. 41.7%, P = 0.047). For patients with distant relapse, consolidative AHSCT after salvage chemotherapy significantly prolonged survival compared with follow-up (2-year OS: 100.0 vs. 20.0%, P = 0.004). Patients without consolidative treatment after response to salvage chemotherapy exhibited a comparable survival to those who experienced stable or progressive disease after chemotherapy. Asparaginase (ASP)-containing salvage chemotherapy failed to confer a survival advantage over ASP-absent chemotherapy (5-year OS: 44.2 vs. 39.3%, P = 0.369). In conclusion, consolidative RT or AHSCT improved prognosis in patients with relapsed NKTCL who responded to initial salvage chemotherapy, and the role of ASP in salvage chemotherapy requires further exploration in prospective studies.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Transplante de Células-Tronco Hematopoéticas/métodos , Linfoma Extranodal de Células T-NK/terapia , Recidiva Local de Neoplasia/terapia , Radioterapia/métodos , Adolescente , Adulto , Idoso , Criança , Terapia Combinada , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Terapia de Salvação , Análise de Sobrevida , Transplante Autólogo/métodos , Resultado do Tratamento , Adulto Jovem
19.
Oncotarget ; 7(23): 35412-22, 2016 Jun 07.
Artigo em Inglês | MEDLINE | ID: mdl-27072578

RESUMO

Extranodal natural killer/T-cell lymphoma (ENKTL) is an aggressive neoplasm with a poor outcome. Novel L-asparaginase-based treatment regimens, such as GELOX (gemcitabine, oxaliplatin, and L-asparaginase) and P-gemox (gemcitabine, oxaliplatin, and pegaspargase), have shown promising results against stage IE/IIE ENKTL. To define the general applicability of P-gemox, in a retrospective analysis we examined the efficacy and safety of P-gemox in a cohort of 117 patients with newly diagnosed or relapsed/refractory ENKTL. Treatment included 2 to 8 cycles of P-gemox: intravenous gemcitabine (1250 mg/m2) and oxaliplatin (85 mg/m2) and intramuscular pegaspargase (2500 IU/ m2) on day 1 and repeated every 2 weeks, or intravenous gemcitabine (1000 mg/m2) on days 1 and 8 and intravenous oxaliplatin (130 mg/m2) and intramuscular pegaspargase (2500 IU/m2) on day 1 and repeated every 3 weeks. Upon completion of treatment, the overall response rate was 88.8%, and responses were similar for newly diagnosed and relapsed/refractory patients. After a median follow-up of 17 months, the 3-year overall and progression-free survival rates were 72.7% and 57.8%, respectively. Multivariate analysis showed that CR after treatment was the most significant factor affecting survival. P-gemox thus appears to be an effective and well-tolerated treatment for patients with ENKTL.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Linfoma Extranodal de Células T-NK/tratamento farmacológico , Adolescente , Adulto , Idoso , Asparaginase/administração & dosagem , Asparaginase/efeitos adversos , Desoxicitidina/administração & dosagem , Desoxicitidina/efeitos adversos , Desoxicitidina/análogos & derivados , Intervalo Livre de Doença , Feminino , Humanos , Linfoma Extranodal de Células T-NK/mortalidade , Masculino , Pessoa de Meia-Idade , Compostos Organoplatínicos/administração & dosagem , Compostos Organoplatínicos/efeitos adversos , Oxaliplatina , Polietilenoglicóis/administração & dosagem , Polietilenoglicóis/efeitos adversos , Estudos Retrospectivos , Resultado do Tratamento , Adulto Jovem
20.
Oncotarget ; 7(20): 29092-101, 2016 May 17.
Artigo em Inglês | MEDLINE | ID: mdl-27093153

RESUMO

Extranodal natural killer/T-cell lymphoma (ENKTL) is an aggressive neoplasm with a poor outcome. Asparaginase-based regimens are recommended for patients with advanced-stage or relapsed/refractory ENKTL. We retrospectively investigated the efficacy and toxicity of combined gemcitabine, oxaliplatin, and pegaspargase (P-gemox) in these patients. A total of 35 patients with newly diagnosed stage III-IV, relapsed or refractory ENKTL were treated with 2 to 8 cycles of P-gemox: gemcitabine (1250 mg/m2) and oxaliplatin (85 mg/m2) injected intravenously and pegaspargase (2500 IU/m2) injected intramuscularly on day 1 and repeated every 2 weeks. Upon completion of treatment, the overall response rate was 80.0%, with a complete response in 51.4% of patients. The 1-, 2- and 3- year progression-free survival rates were 45.0%, 38.6% and 38.6%, and overall survival rates were 76.8%, 64.7% and 64.7%, respectively. Patients who attained a complete response showed better progression-free survival than those without a complete response (p = 0.01). The major adverse effects were hematologic toxicity and liver dysfunction. Grade 3/4 leucopenia and neutropenia occurred in 40.0% of patients. No treatment-related deaths occurred. These results indicate the P-gemox regimen is a safe and effective treatment for patients with newly diagnosed advanced-stage or relapsed/refractory ENKTL. We anticipate future prospective trials will confirm the efficacy.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Linfoma Extranodal de Células T-NK/tratamento farmacológico , Adolescente , Adulto , Idoso , Asparaginase/administração & dosagem , Asparaginase/efeitos adversos , Desoxicitidina/administração & dosagem , Desoxicitidina/efeitos adversos , Desoxicitidina/análogos & derivados , Intervalo Livre de Doença , Feminino , Humanos , Estimativa de Kaplan-Meier , Linfoma Extranodal de Células T-NK/mortalidade , Masculino , Pessoa de Meia-Idade , Compostos Organoplatínicos/administração & dosagem , Compostos Organoplatínicos/efeitos adversos , Oxaliplatina , Polietilenoglicóis/administração & dosagem , Polietilenoglicóis/efeitos adversos , Estudos Retrospectivos , Resultado do Tratamento , Adulto Jovem
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