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MYC , BCL2, and BCL6 rearrangements are clinically important events of diffuse large B-cell lymphoma (DLBCL). The ability and clinical value of targeted next-generation sequencing (NGS) in the detection of these rearrangements in DLBCL have not been fully determined. We performed targeted NGS (481-gene-panel) and break-apart FISH of MYC , BCL2, and BCL6 gene regions in 233 DLBCL cases. We identified 88 rearrangements (16 MYC ; 20 BCL2 ; 52 BCL6 ) using NGS and 96 rearrangements (28 MYC ; 20 BCL2 ; 65 BCL6 ) using FISH. The consistency rates between FISH and targeted NGS for the detection of MYC , BCL2, and BCL6 rearrangements were 93%, 97%, and 89%, respectively. FISH-cryptic rearrangements (NGS+/FISH-) were detected in 7 cases (1 MYC ; 3 BCL2 ; 2 BCL6 ; 1 MYC::BCL6 ), mainly caused by small chromosomal insertions and inversions. NGS-/FISH+ were detected in 38 cases (14 MYC ; 4 BCL2 ; 20 BCL6 ).To clarify the cause of the inconsistencies, we selected 17 from the NGS-/FISH+ rearrangements for further whole genome sequencing (WGS), and all 17 rearrangements were detected with break points by WGS. These break points were all located outside the region covered by the probe of targeted NGS, and most (16/17) were located in the intergenic region. These results indicated that targeted NGS is a powerful clinical diagnostics tool for comprehensive MYC , BCL2, and BCL6 rearrangement detection. Compared to FISH, it has advantages in describing the break point distribution, identifying uncharacterized partners, and detecting FISH-cryptic rearrangements. However, the lack of high-sensitivity caused by insufficient probe coverage is the main limitation of the current technology.
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Linfoma Difuso de Grandes Células B , Proteínas Proto-Oncogênicas c-bcl-2 , Proteínas Proto-Oncogênicas c-bcl-6 , Proteínas Proto-Oncogênicas c-myc , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Adulto Jovem , Biomarcadores Tumorais/genética , Rearranjo Gênico , Predisposição Genética para Doença , Sequenciamento de Nucleotídeos em Larga Escala , Hibridização in Situ Fluorescente , Linfoma Difuso de Grandes Células B/genética , Linfoma Difuso de Grandes Células B/patologia , Valor Preditivo dos Testes , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteínas Proto-Oncogênicas c-bcl-6/genética , Proteínas Proto-Oncogênicas c-myc/genética , Reprodutibilidade dos TestesRESUMO
A significant variation in chromatin accessibility is an epigenetic feature of leukemia. The cause of this variation in leukemia, however, remains elusive. Here, we identify SMARCA5, a core ATPase of the imitation switch (ISWI) chromatin remodeling complex, as being responsible for aberrant chromatin accessibility in leukemia cells. We find that SMARCA5 is required to maintain aberrant chromatin accessibility for leukemogenesis and then promotes transcriptional activation of AKR1B1, an aldo/keto reductase, by recruiting transcription co-activator DDX5 and transcription factor SP1. Higher levels of AKR1B1 are associated with a poor prognosis in leukemia patients and promote leukemogenesis by reprogramming fructose metabolism. Moreover, pharmacological inhibition of AKR1B1 has been shown to have significant therapeutic effects in leukemia mice and leukemia patient cells. Thus, our findings link the aberrant chromatin state mediated by SMARCA5 to AKR1B1-mediated endogenous fructose metabolism reprogramming and shed light on the essential role of AKR1B1 in leukemogenesis, which may provide therapeutic strategies for leukemia.
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Frutose , Humanos , Animais , Camundongos , Frutose/metabolismo , Cromatina/metabolismo , Aldeído Redutase/metabolismo , Aldeído Redutase/genética , Leucemia/metabolismo , Leucemia/patologia , Leucemia/genética , Proteínas Cromossômicas não Histona/metabolismo , Proteínas Cromossômicas não Histona/genética , Montagem e Desmontagem da Cromatina , Carcinogênese/metabolismo , Carcinogênese/patologia , Carcinogênese/genética , Linhagem Celular Tumoral , Fatores de Transcrição/metabolismo , Fatores de Transcrição/genética , Adenosina TrifosfatasesRESUMO
BACKGROUND: Pegylated liposomal doxorubicin (PLD) is a liposome-encapsulated form of doxorubicin with equivalent efficacy and less cardiotoxicity. This phase 2 study evaluated the efficacy and safety of the PLD-containing CHOP regimen in newly diagnosed patients with aggressive peripheral T-cell lymphomas (PTCL). METHODS: Patients received PLD, cyclophosphamide, vincristine/vindesine, plus prednisone every 3 weeks for up to 6 cycles. The primary endpoint was the objective response rate at the end of treatment (EOT). RESULTS: From September 2015 to January 2017, 40 patients were treated. At the EOT, objective response was achieved by 82.5% of patients, with 62.5% complete response. As of the cutoff date (September 26, 2023), median progression-free survival (mPFS) and overall survival (mOS) were not reached (NR). The 2-year, 5-year, and 8-year PFS rates were 55.1%, 52.0%, and 52.0%. OS rate was 80.0% at 2 years, 62.5% at 5 years, and 54.3% at 8 years. Patients with progression of disease within 24 months (POD24) had worse prognosis than those without POD24, regarding mOS (41.2 months vs NR), 5-year OS (33.3% vs 94.4%), and 8-year OS (13.3% vs 94.4%). Common grade 3-4 adverse events were neutropenia (87.5%), leukopenia (80.0%), anemia (17.5%), and pneumonitis (17.5%). CONCLUSION: This combination had long-term benefits and manageable tolerability, particularly with less cardiotoxicity, for aggressive PTCL, which might provide a favorable benefit-risk balance. CLINICALTRIALS.GOV IDENTIFIER: Chinese Clinical Trial Registry, ChiCTR2100054588; IRB Approved: Ethics committee of Fudan University Shanghai Cancer Center (Date 2015.8.31/No. 1508151-13.
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BACKGROUND: Left ventricular global longitudinal strain (LVGLS) has been recommended by current guidelines for diagnosing anthracycline-induced cardiotoxicity. However, little is known about the early changes in left atrial (LA) morphology and function in this population. Our study aimed to evaluate the potential usefulness of LA indices and their incremental value to LVGLS with three-dimensional echocardiography (3DE) in the early detection of subclinical cardiotoxicity in patients with lymphoma receiving anthracycline. METHODS: A total of 80 patients with diffuse large B-cell lymphoma who received six cycles of anthracycline-based treatment were enrolled. Echocardiography was performed at baseline (T0), after four cycles (T1), and after the completion of six cycles of chemotherapy (T2). Left ventricular ejection fraction (LVEF), LVGLS, LA volumes, LA emptying fraction (LAEF), LA active emptying fraction (LAAEF), and LA reservoir longitudinal strain (LASr) were quantified with 3DE. Left atrioventricular global longitudinal strain (LAVGLS) was calculated as the sum of peak LASr and the absolute value of peak LVGLS (LAVGLS = LASr+|LVGLS|). LV cardiotoxicity was defined as a new LVEF reduction by ≥10 percentage points to an LVEF of ≤50%. RESULTS: Fourteen (17.5%) patients developed LV cardiotoxicity at T2. LA volumes, LAEF, and LAAEF remained stable over time. Impairment of LASr (28.35 ± 5.03 vs. 25.04 ± 4.10, p < .001), LVGLS (-22.77 ± 2.45 vs. -20.44 ± 2.62, p < .001), and LAVGLS (51.12 ± 5.63 vs. 45.61 ± 5.22, p < .001) was observed by the end of the fourth cycle of chemotherapy (T1). Statistically significant declines in LVEF (61.30 ± 4.73 vs. 57.08 ± 5.83, p < .001) were only observed at T2. The relative decrease in LASr (ΔLASr), LVGLS (ΔLVGLS), and LAVGLS (ΔLAVGLS) from T0 to T1 were predictors of LV cardiotoxicity. A ΔLASr of >19.75% (sensitivity, 71.4%; specificity, 87.9%; area under the curve (AUC), .842; p < .001), a ΔLVGLS of >13.19% (sensitivity, 78.6%; specificity, 74.2%; AUC, .763; p < .001), and a ΔLAVGLS of >16.80% (sensitivity, 78.6%; specificity, 93.9%; AUC, .905; p < .001) predicted subsequent LV cardiotoxicity at T2, with the AUC of ΔLAVGLS significantly larger than that of ΔLVGLS (.905 vs. .763, p = .027). Compared to ΔLVGLS, ΔLAVGLS showed improved specificity (93.9% vs. 74.2%, p = .002) and maintained sensitivity in predicting LV cardiotoxicity. CONCLUSIONS: LASr could predict anthracycline-induced LV cardiotoxicity with excellent diagnostic performance. Incorporating LASr into LVGLS (LAVGLS) led to a significantly improved specificity and maintained sensitivity in predicting LV cardiotoxicity.
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Cardiotoxicidade , Disfunção Ventricular Esquerda , Humanos , Cardiotoxicidade/diagnóstico por imagem , Cardiotoxicidade/etiologia , Função Ventricular Esquerda , Antraciclinas/efeitos adversos , Deformação Longitudinal Global , Volume Sistólico , Antibióticos Antineoplásicos/efeitos adversos , Disfunção Ventricular Esquerda/induzido quimicamente , Disfunção Ventricular Esquerda/diagnóstico por imagem , Disfunção Ventricular Esquerda/tratamento farmacológicoRESUMO
Peripheral T cell lymphoma (PTCL) is a heterogeneous group of non-Hodgkin's lymphomas varying in clinical, phenotypic, and genetic features. The molecular pathogenesis and the role of the tumor microenvironment in PTCL are poorly understood, with limited biomarkers available for genetic subtyping and targeted therapies. Through an integrated genomic and transcriptomic study of 221 PTCL patients, we delineate the genetic landscape of PTCL, enabling molecular and microenvironment classification. According to the mutational status of RHOA, TET2, histone-modifying, and immune-related genes, PTCL is divided into 4 molecular subtypes with discrete patterns of gene expression, biological aberrations, and vulnerabilities to targeted agents. We also perform an unsupervised clustering on the microenvironment transcriptional signatures and categorize PTCL into 4 lymphoma microenvironment subtypes based on characteristic activation of oncogenic pathways and composition of immune communities. Our findings highlight the potential clinical rationale of future precision medicine strategies that target both molecular and microenvironment alterations in PTCL.
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Linfoma de Células T Periférico , Humanos , Linfoma de Células T Periférico/genética , Linfoma de Células T Periférico/metabolismo , Perfilação da Expressão Gênica , Genômica , Mutação , Microambiente Tumoral/genéticaRESUMO
The bone marrow microenvironment (BMM) can regulate leukemia stem cells (LSCs) via secreted factors. Increasing evidence suggests that dissecting the mechanisms by which the BMM maintains LSCs may lead to the development of effective therapies for the eradication of leukemia. Inhibitor of DNA binding 1 (ID1), a key transcriptional regulator in LSCs, previously identified by us, controls cytokine production in the BMM, but the role of ID1 in acute myeloid leukemia (AML) BMM remains obscure. Here, we report that ID1 is highly expressed in the BMM of patients with AML, especially in BM mesenchymal stem cells, and that the high expression of ID1 in the AML BMM is induced by BMP6, secreted from AML cells. Knocking out ID1 in mesenchymal cells significantly suppresses the proliferation of cocultured AML cells. Loss of Id1 in the BMM results in impaired AML progression in AML mouse models. Mechanistically, we found that Id1 deficiency significantly reduces SP1 protein levels in mesenchymal cells cocultured with AML cells. Using ID1-interactome analysis, we found that ID1 interacts with RNF4, an E3 ubiquitin ligase, and causes a decrease in SP1 ubiquitination. Disrupting the ID1-RNF4 interaction via truncation in mesenchymal cells significantly reduces SP1 protein levels and delays AML cell proliferation. We identify that the target of Sp1, Angptl7, is the primary differentially expression protein factor in Id1-deficient BM supernatant fluid to regulate AML progression in mice. Our study highlights the critical role of ID1 in the AML BMM and aids the development of therapeutic strategies for AML.
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Proteína 7 Semelhante a Angiopoietina , Proteína 1 Inibidora de Diferenciação , Leucemia Mieloide Aguda , Animais , Camundongos , Proteína 7 Semelhante a Angiopoietina/genética , Proteína 7 Semelhante a Angiopoietina/metabolismo , Medula Óssea/metabolismo , Modelos Animais de Doenças , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patologia , Microambiente Tumoral , Humanos , Proteína 1 Inibidora de Diferenciação/metabolismoRESUMO
Serologic biomarker to predict clinical outcome is needed for immune checkpoint inhibitors (ICIs). We evaluated soluble intercellular adhesion molecules-1 (sICAM-1) as a predictor of response to ICIs treatment. Ninety-five patients with cancer treated with ICI were studied. The serum sICAM-1 levels of baseline, post two cycle therapy and end of therapy (EOT) were measured by enzyme-linked immunoassay. We randomly assigned the patients into the primary cohort (n = 47) and validation cohort (n = 48). Serum sICAM-1 post two cycle (277.7 ± 181.6 ng/mL) and EOT (403.9 ± 218.9 ng/mL) were significantly elevated compared to baseline (244.8 ± 153.8 ng/mL, p = 0.008 and p = 0.004, respectively). Early changes of sICAM-1 (ΔsICAM-1), deemed as sICAM-1 after two cycles minus baseline, were assessed. Following ICI treatments, responders had significantly lower ΔsICAM-1 compared with nonresponders in the primary cohort (p = 0.040) and the validation cohort (p = 0.026). High ΔsICAM-1 was strongly associated with inferior progression-free survival (PFS; (primary cohort: p = 0.001 and validation cohort: p = 0.002) and overall survival (OS; (primary cohort: p < 0.001 and validation cohort: p = 0.007). The ΔsICAM-1 remained independently associated with worse PFS and OS in the primary cohort and the validation cohort. Subgroup analysis indicated patients whose sICAM-1 significantly elevated had shorter PFS and OS in both anti-PD-1 and anti-PD-L1 treatment groups. Early change of serum sICAM-1 could be used to monitor and predict clinical benefit of ICI therapy in patients with solid cancer.
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Inibidores de Checkpoint Imunológico , Humanos , Prognóstico , Inibidores de Checkpoint Imunológico/uso terapêutico , BiomarcadoresRESUMO
BACKGROUND: Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of non-Hodgkin lymphoma with heterogenicity in clinical manifestation and prognosis. Some microRNAs can influence the development of tumors and may be related to the response of therapy or prognosis. This study aims to explore the role of serum miR-146a in predicting the prognosis of DLBCL. METHODS: A total of 72 de novo DLBCL patients received 6 cycles of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) or rituximab combined CHOP (R-CHOP) regimen, and their serum samples were collected before treatment and after 4 cycles of chemotherapy. RESULTS: The results show that a high level of miR-146a is significantly associated with a good outcome in baseline and is more obvious in post-chemotherapy. In addition, a high level of miR-146a was associated with better progression-free survival and overall survival in patients treated with R-CHOP but has not been related to a superior outcome in patients treated with CHOP. Rituximab may improve the efficacy of therapy, especially in patients with high miR-146a levels. The level of miR-146a decreased in more patients after chemotherapy, and it seems patients with a decreased expression of miR-146a after chemotherapy tended a better outcome, but it is not statistically significant. CONCLUSION: Our results suggest that the level of serum miR-146a can serve as a potential prognostic biomarker for DLBCL patients.
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Linfoma Difuso de Grandes Células B , MicroRNAs , Humanos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Biomarcadores , Ciclofosfamida/uso terapêutico , Doxorrubicina/uso terapêutico , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Linfoma Difuso de Grandes Células B/genética , MicroRNAs/genética , MicroRNAs/metabolismo , Prognóstico , Rituximab/uso terapêutico , Resultado do Tratamento , Vincristina/uso terapêuticoRESUMO
The patients with relapsed and refractory diffuse large B-cell lymphoma (DLBCL) have poor prognosis, and a novel and effective therapeutic strategy for these patients is urgently needed. Although ubiquitin-specific protease 1 (USP1) plays a key role in cancer, the carcinogenic effect of USP1 in B-cell lymphoma remains elusive. Here we found that USP1 is highly expressed in DLBCL patients, and high expression of USP1 predicts poor prognosis. Knocking down USP1 or a specific inhibitor of USP1, pimozide, induced cell growth inhibition, cell cycle arrest and autophagy in DLBCL cells. Targeting USP1 by shRNA or pimozide significantly reduced tumor burden of a mouse model established with engraftment of rituximab/chemotherapy resistant DLBCL cells. Pimozide significantly retarded the growth of lymphoma in a DLBCL patient-derived xenograft (PDX) model. USP1 directly interacted with MAX, a MYC binding protein, and maintained the stability of MAX through deubiquitination, which promoted the transcription of MYC target genes. Moreover, pimozide showed a synergetic effect with etoposide, a chemotherapy drug, in cell and mouse models of rituximab/chemotherapy resistant DLBCL. Our study highlights the critical role of USP1 in the rituximab/chemotherapy resistance of DLBCL through deubiquitylating MAX, and provides a novel therapeutic strategy for rituximab/chemotherapy resistant DLBCL.
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Linfoma Difuso de Grandes Células B , Linfoma não Hodgkin , Animais , Camundongos , Humanos , Rituximab/uso terapêutico , Pimozida/uso terapêutico , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Linfoma Difuso de Grandes Células B/genética , Linfoma Difuso de Grandes Células B/patologia , Linfoma não Hodgkin/tratamento farmacológico , Proteases Específicas de Ubiquitina/genética , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêuticoRESUMO
BACKGROUND: Plasmablastic lymphoma (PBL) is a rare but aggressive B-cell lymphoma subtype with poor prognosis. Knowledge about the etiology, clinicopathologic and molecular features, and outcomes of PBL is limited. This study aimed to examine the clinicopathologic characteristics, therapeutic approaches, and clinical outcomes of PBL patients in a Chinese population. METHODS: A total of 102 PBL patients were recruited from three cancer centers. The pathologic features and clinical outcomes of 56 patients with available treatment details and follow-up data were reviewed and analyzed. RNA sequencing was performed in 6 PBL and 11 diffuse large B-cell lymphoma (DLBCL) patients. RESULTS: Most patients in our cohort were male (n = 36, 64.3%), and 35 patients presented with Ann Arbor stage I/II disease at diagnosis. All these patients showed negative findings for human immunodeficiency virus, and the vast majority of patients in our cohort were immunocompetent. Lymph nodes (n = 13, 23.2%) and gastrointestinal tract (n = 10, 17.9%) were the most commonly involved site at presentation. Post-treatment complete remission (CR) was the only prognostic factor affecting overall survival (OS) and progression-free survival (PFS) in the multivariate analysis. RNA-seq demonstrated that B-cell receptor (BCR), T-cell receptor (TCR), P53, calcium signaling, and Wnt signaling pathways were significantly downregulated in PBLs compared with GCB (or non-GCB) DLBCLs. CONCLUSIONS: In this multicenter study in the Chinese population, PBL mainly occurred in immunocompetent individuals and most patients present with early-stage disease at diagnosis. Post-treatment CR was an important prognostic factor affecting OS and PFS. RNA-seq showed that the B-cell receptor (BCR), P53, calcium signaling, cell adhesion molecules, and Wnt signaling pathways significantly differed between PBL and GCB (or non-GCB) DLBCL, which provided theoretical basis for its pathogenesis and future treatment.
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Linfoma Plasmablástico , Humanos , Masculino , Feminino , Linfoma Plasmablástico/diagnóstico , Linfoma Plasmablástico/genética , Linfoma Plasmablástico/patologia , Prognóstico , Proteína Supressora de Tumor p53 , Transdução de Sinais/genética , Receptores de Antígenos de Linfócitos BRESUMO
Aberrant self-renewal of leukemia initiation cells (LICs) drives aggressive acute myeloid leukemia (AML). Here, we report that UHRF1, an epigenetic regulator that recruits DNMT1 to methylate DNA, is highly expressed in AML and predicts poor prognosis. UHRF1 is required for myeloid leukemogenesis by maintaining self-renewal of LICs. Mechanistically, UHRF1 directly interacts with Sin3A-associated protein 30 (SAP30) through two critical amino acids, G572 and F573 in its SRA domain, to repress gene expression. Depletion of UHRF1 or SAP30 derepresses an important target gene, MXD4, which encodes a MYC antagonist, and leads to suppression of leukemogenesis. Further knockdown of MXD4 can rescue the leukemogenesis by activating the MYC pathway. Lastly, we identified a UHRF1 inhibitor, UF146, and demonstrated its significant therapeutic efficacy in the myeloid leukemia PDX model. Taken together, our study reveals the mechanisms for altered epigenetic programs in AML and provides a promising targeted therapeutic strategy against AML.
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Leucemia Mieloide Aguda , Humanos , Carcinogênese , Proteínas Estimuladoras de Ligação a CCAAT/genética , Proteínas Estimuladoras de Ligação a CCAAT/metabolismo , Histona Desacetilases , Leucemia Mieloide Aguda/genética , Ubiquitina-Proteína Ligases/genética , Ubiquitina-Proteína Ligases/metabolismoRESUMO
Background: Primary breast diffuse large B-cell lymphoma (PB-DLBCL) is a rare subtype of non-Hodgkin lymphoma (NHL) with limited data on the clinical features and prognostic factors. Patients and Methods: A consecutive cohort of patients with PB-DLBCL was retrospectively analyzed in our hospital from February 1997 through July 2018. The primary endpoint is overall survival (OS) contributing to any cause. Results: A total of 76 patients were diagnosed with PB-DLBCL. The median age at diagnosis was 51 years (range: 25-80 years), with female prevalence (98.7%). Forty (52.6%) patients had right-sided breast involvement but no bilateral breast involvement at diagnosis. Overall, disease stages IE and IIE were seen in 55 (72.4%) and 21 (27.6%) patients, respectively. According to the stage-modified International Prognostic Index (IPI), 37 (48.7%) patients were classified in the very good risk group (IPI 0). Of the 72 patients available, the non-germinal center B-cell (non-GCB) subtype of DLBCL was observed in 66 (91.6%) patients. All patients received anthracycline-based chemotherapy, 56 (73.7%) with rituximab, 31 (40.8%) also with additional radiation therapy, and 14 (18.4%) patients received a prophylactic intrathecal injection. Seven (9.2%) patients had refractory disease. With a median follow-up of 6.8 years (range 0.4-25.0 years), 10 (13.2%) patients had a relapse in the central nervous system (CNS) site. The 5-year and 10-year OS of all the patients was 97.2% (95% CI: 99.3-89.5) and 84.8% (95% CI: 70.0-93.5), respectively. The median OS was not reached. The median progression-free survival (PFS) was 10.3 years for patients with PB-DLBCL. The 5-year PFS of all the patients was 76.3% (95% CI: 64.6-84.6). Univariate analysis revealed several prognostic factors, including stage-modified IPI, breast surgery, refractory disease, and CNS relapse. Multivariate analyses produced two independent prognostic factors for patients with PB-DLBCL, including stage-modified IPI score (2-3 versus 0) (hazard ratio: 19.114, 95% CI 1.841 to 198.451, p=0.013) and CNS relapse (hazard ratio: 5.522, 95% CI 1.059 to 28.788, p=0.043). Conclusion: In our cohort, PB-DLBCL clinical features are similar to prior literature reports. Stage-modified IPI score and CNS relapse were associated with overall survival.
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BACKGROUND: There is limited evidence supporting the use of taxane-based chemotherapy combined with cetuximab to treat recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC). This retrospective study aimed to explore treatment efficacy and safety in a first-line setting. METHODS: Fifty-nine patients received ≤6 cycles of combined cetuximab, platinum compounds, and taxane (median follow-up, 352 days). Kaplan-Meier survival curves were constructed. RESULTS: The median patient age was 54 years (23-75 years; 50 males and 9 females). The most common distant metastatic site was the lung. Patients received ≥2 cycles chemotherapy (33 [55.9%] received cetuximab, paclitaxel, and carboplatin; 21 [35.5%] received cetuximab maintenance; median progression-free survival, 7 months; overall survival, 12 months). The most common hematological toxicity was Grade 3 or 4 neutropenia, which was successfully managed through growth-stimulating factors and dose modifications. No treatment-associated deaths occurred. CONCLUSIONS: Combined cetuximab, platinum, and taxane is effective and tolerable in R/M HNSCC.
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Carcinoma de Células Escamosas , Neoplasias de Cabeça e Pescoço , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma de Células Escamosas/patologia , Cetuximab/uso terapêutico , Feminino , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Neoplasias de Cabeça e Pescoço/etiologia , Humanos , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/etiologia , Platina/uso terapêutico , Estudos Retrospectivos , Carcinoma de Células Escamosas de Cabeça e Pescoço/tratamento farmacológico , Carcinoma de Células Escamosas de Cabeça e Pescoço/etiologia , Taxoides/uso terapêuticoRESUMO
Background: Peripheral T-cell lymphomas (PTCL) are aggressive lymphomas with poor prognosis, and therefore, there is a pressing need to explore new targets or compounds. Mitochondria may serve as a potential therapeutic target for PTCL. A designed positively-charged segment (pKV) is anchored to the specific 15 amino acid sequence (MIASHLLAYFFTELN) to yield a cell-penetrating peptide (pHK-pKV) and a lipid chain (Pal) is conjugated to the N-terminus of pHK-pKV (Pal-pHK-pKV) are bioactive amphiphilic peptide assemblies targeting the interaction between mitochondrial voltage dependent anion channel 1 (VDAC1) and hexokinase II (HKII). Methods: PTCL cell line H9 was treated with Pal-pHK-pKV and pHK-pKV, respectively. Cell proliferation in each group was measured by detecting cell viability and the corresponding marker Ki-67. Apoptosis was detected by immunofluorescence, flow cytometry and western blot. We also measured mitochondrial membrane potential, adenosine triphosphate (ATP) production, the cytochrome c distribution and the expression levels of B cell lymphoma 2 (BCL-2) and BCL-2 associated X protein (BAX). Western blot was used to detect the activation of the extracellular regulated protein kinases (ERK) signaling pathway. Results: Pal-pHK-pKV and pHK-pKV with 20 µM blocked the interaction between VDAC1 and HKII, and detached HKII from mitochondria, which depolarized the mitochondrial membrane potential, induced mitochondria dysfunction, and decreased ATP production. The decreased ATP subsequently inhibited the activation of the ERK/BCL-2 pathway and increased the BAX/BCL-2 ratio. Cytochrome c was then released from the mitochondria and induced capase-3 activation and subsequently apoptosis. Additionally, decreased ATP induced the expression of FAS and then apoptosis. Conclusions: Mitochondria specific peptide amphiphiles induce mitochondrial dysfunction and provide a new approach for the treatment of PTCL.
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We aimed to assess HKII expression and its prognostic significance in diffuse large B-cell lymphoma (DLBCL) patients. The HKII protein level was determined by immunohistochemistry in 159 newly diagnosed DLBCL patients, and its relationship with overall response rate, progression-free survival (PFS), and overall survival (OS) was analyzed. HKII was expressed in 95 DLBCL patients (59.7%). HKII-positive patients had poorer outcomes than negative patients for 5-y PFS (68% vs. 84%, p = 0.029) and 5-y OS (78% vs. 94%, p = 0.05). When only patients without no bulky disease, B symptoms, or extranodal involvement who had low IPI scores were considered, those with positive HKII had worse 5y-PFS and 5y-OS (p < 0.05). Multivariate analysis indicated that HKII status was an independent prognostic factor of OS. In subgroup analysis, HKII expression was associated with inferior OS in the CHOP group (p = 0.017). In CHOP group patients without bulky disease or extranodal involvement who had low LDH and low IPI scores (p < 0.05), positive HKII was associated with worse PFS and OS. No differences in PFS and OS, or any independent prognostic factors, were found in the RCHOP group. In DLBCL, HKII is valuable as a prognostic biomarker and may be useful as a tool for assessing disease risk.
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Hexoquinase , Linfoma Difuso de Grandes Células B , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Ciclofosfamida/uso terapêutico , Doxorrubicina/uso terapêutico , Hexoquinase/uso terapêutico , Humanos , Linfoma Difuso de Grandes Células B/diagnóstico , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Linfoma Difuso de Grandes Células B/patologia , Prednisona/uso terapêutico , Prognóstico , Estudos Retrospectivos , Rituximab/uso terapêutico , Vincristina/uso terapêuticoRESUMO
Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of non-Hodgkin's lymphoma, with the combination of rituximab and chemotherapy being the standard treatment for it. Although rituximab monotherapy has a remarkable response rate, drug resistance with unclear mechanisms and lack of effective second-line therapy limit the survival benefits of patients with lymphoma. Here, we report that MORTALIN is highly expressed and correlates with resistance to rituximab-based therapy and poor survival in patients with DLBCL. Mechanistically, gain- and loss-of-function experiments revealed that the voltage-dependent anion channel 1-binding protein, MORTALIN, regulated Ca2+ release from the endoplasmic reticulum through mitochondria-associated membrane, facilitating AP1-mediated cell proliferation and YY-1-mediated downregulation of FAS in DLBCL cells. These dual mechanisms contribute to rituximab resistance. In mouse models, genetic depletion of MORTALIN markedly increased the antitumor activity of rituximab. We shed mechanistic light on MORTALIN-Ca2+-CaMKII-AP1-mediated proliferation and MORTALIN-Ca2+-CaMKII-inhibited death receptor in DLBCL, leading to rituximab resistance, and propose MORTALIN as a novel target for the treatment of DLBCL.
Assuntos
Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina , Linfoma Difuso de Grandes Células B , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Proteínas de Choque Térmico HSP70 , Humanos , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Linfoma Difuso de Grandes Células B/genética , Linfoma Difuso de Grandes Células B/patologia , Camundongos , Rituximab/farmacologiaRESUMO
T cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological malignancy of T cell progenitors, known to be a heterogeneous disease in pediatric and adult patients. Here we attempted to better understand the disease at the molecular level based on the transcriptomic landscape of 707 T-ALL patients (510 pediatric, 190 adult patients, and 7 with unknown age; 599 from published cohorts and 108 newly investigated). Leveraging the information of gene expression enabled us to identify 10 subtypes (G1G10), including the previously undescribed one characterized by GATA3 mutations, with GATA3R276Q capable of affecting lymphocyte development in zebrafish. Through associating with T cell differentiation stages, we found that high expression of LYL1/LMO2/SPI1/HOXA (G1G6) might represent the early T cell progenitor, pro/precortical/cortical stage with a relatively high age of disease onset, and lymphoblasts with TLX3/TLX1 high expression (G7G8) could be blocked at the cortical/postcortical stage, while those with high expression of NKX2-1/TAL1/LMO1 (G9G10) might correspond to cortical/postcortical/mature stages of T cell development. Notably, adult patients harbored more cooperative mutations among epigenetic regulators, and genes involved in JAK-STAT and RAS signaling pathways, with 44% of patients aged 40 y or above in G1 bearing DNMT3A/IDH2 mutations usually seen in acute myeloid leukemia, suggesting the nature of mixed phenotype acute leukemia.
Assuntos
Leucemia-Linfoma Linfoblástico de Células T Precursoras , Transcriptoma , Criança , Humanos , Mutação , Leucemia-Linfoma Linfoblástico de Células T Precursoras/genéticaRESUMO
BACKGROUND: R-CHOP with or without radiotherapy is the standard treatment for limited-stage diffuse large B-cell lymphoma (DLBCL). To prevent overtreatment, we assessed whether four cycles of CHOP plus six applications of rituximab was adequate with negative interim PET/CT and the role of consolidation radiotherapy specifically for patients with Waldeyer's ring DLBCL. One hundred and twenty-nine patients with limited-stage DLBCL were enrolled in this open-label, nonrandomized, single-arm, phase 2 clinical trial (NCT01804127). METHODS: All patients were initially treated with 4 cycles of R-CHOP and underwent interim PET/CT. Patients with negative PET/CT (Deauville scores 1-2) received 2 additional cycles of rituximab monotherapy, unless they had any risk factors (primary mediastinal large B-cell lymphoma, extranodal primary or bulky disease). Otherwise, patients received another 2 cycles of R-CHOP. Patients with partial response on interim PET/CT received another 4 cycles of R-CHOP. No radiotherapy was conducted in Waldeyer's ring DLBCL patients with negative PET/CT. The primary endpoint was 3-year progression-free survival (PFS). Overall survival (OS) in this study was compared with those from a historical study (NCT 00854568159). RESULTS: One hundred fifteen interim PET/CT scans (89.1%) were negative after 4 cycles of R-CHOP. An elevated lactate dehydrogenase level was significantly associated with positive interim PET/CT (P < 0.05). A trend of inferior outcome was observed in patients with positive interim PET/CT in terms of 3-year PFS (78.6% vs. 91.9%, P = 0.24) and 3-year OS (85.7% vs. 95.6%, P = 0.16). There were no PFS or OS differences found between patients treated with 4R-CHOP+2R and those treated with 6R-CHOP from a historical control study. Patients with Waldeyer's ring DLBCL and negative interim PET/CT achieved a 3-year PFS of 87.2% and a 3-year OS of 89.7%. CONCLUSIONS: Our results suggested that for interim PET/CT-negative patients without risk factors, the extra 2 cycles of CHOP might be omitted, and radiotherapy might also be omitted in patients with Waldeyer's ring DLBCL without compromising the efficacy. These results need to be confirmed in a randomized study. TRIAL REGISTRATION: clinicaltrials.gov , NCT01804127 . Date of first registration: 05/03/2013.
Assuntos
Linfoma Difuso de Grandes Células B , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Ciclofosfamida/uso terapêutico , Doxorrubicina/uso terapêutico , Fluordesoxiglucose F18/uso terapêutico , Humanos , Linfoma Difuso de Grandes Células B/diagnóstico por imagem , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Linfoma Difuso de Grandes Células B/radioterapia , Prednisona/uso terapêutico , Estudos Prospectivos , Rituximab , Vincristina/uso terapêuticoRESUMO
OTUD7B is a deubiquitinase and has been reported as a prognostic factor in various solid tumors. However, its prognostic value in lymphoma patients remains unclear. We detected OTUD7B expression levels in 160 diffuse large B-cell lymphoma (DLBCL) tissue samples by immunohistochemistry, and analyzed correlations between its expression and clinic-pathologic parameters as well as clinical outcomes. We also investigated association between OTUD7B expression and chemotherapeutic drugs anti-tumor activity in vitro. We found that OTUD7B overexpressed in 129 (80.6%) cases, and patients with overexpression of OTUD7B experienced better overall survival comparing to those with OTUD7B low expression (P=0.021). Multivariate Cox regression analysis illustrated that OTUD7B was an independent prognostic indicator. In DLBCL cell lines, we found that Chidamide could up-regulate OTUD7B in several DLBCL cell lines, and also had synergistic effect with doxorubicin at low concentration. Our data illustrated that OTUD7B deficiency is a negative predictor of clinical outcome, and might be a potential therapeutic target in the treatment of diffuse large B-cell lymphoma.
RESUMO
OBJECTIVE: Primary mediastinal B-cell lymphoma (PMBCL) lacks standard treatment regimens. This study aimed to identify the disease's clinical features and prognostic factors. METHODS: This retrospective study included 56 patients with PMBCL. Patient demographic details and clinicopathological characteristics were summarized, and their effects on progression-free survival (PFS) and overall survival (OS) were analyzed. RESULTS: The median patient age was 29 years (range, 14-56). Twenty-two patients received DA-EPOCH-R (dose-adjusted etoposide, vincristine, and doxorubicin for 96 hours with bolus doses of cyclophosphamide and oral prednisone, as well as rituximab), and 34 patients received R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone). Clinical/laboratory parameters, overall response rates, and 5-year PFS and OS rates did not differ between the treatment groups. Kaplan-Meier analysis indicated that late-stage disease and a higher International Prognostic Index (IPI) were associated with shorter PFS and OS. Furthermore, patients with B symptoms and first-line treatment non-responders exhibited worse OS. 18Fluorodeoxyglucose-positron emission tomography/computed tomography quantitative parameters, such as higher metabolic tumor volume (MTV) and total lesion glycolysis (TLG), were corrected with shorter PFS. CONCLUSIONS: This study revealed that stage IV disease, higher IPI, and B symptoms were poor prognostic factors in patients with PMBCL. Significantly, higher MTV and TLG portended worse PFS.