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Histone methyltransferase KMT2D is one of the most frequently mutated genes in diffuse large B-cell lymphoma (DLBCL) and has been identified as an important pathogenic factor and prognostic marker. However, the biological relevance of KMT2D mutations on tumor microenvironment remains to be determined. KMT2D mutations were assessed by whole-genome/exome sequencing (WGS/WES) in 334 patients and by targeted sequencing in 427 patients with newly diagnosed DLBCL. Among all 761 DLBCL patients, somatic mutations in KMT2D were observed in 143 (18.79%) patients and significantly associated with advanced Ann Arbor stage and MYC expression ≥ 40%, as well as inferior progression-free survival and overall survival. In B-lymphoma cells, the mutation or knockdown of KMT2D inhibited methylation of lysine 4 on histone H3 (H3K4), downregulated FBXW7 expression, activated NOTCH signaling pathway and downstream MYC/TGF-ß1, resulting in alterations of tumor-induced regulatory T cell trafficking. In B-lymphoma murine models established with subcutaneous injection of SU-DHL-4 cells, xenografted tumors bearing KMT2D mutation presented lower H3K4 methylation, higher regulatory T cell recruitment, thereby provoking rapid tumor growth compared with wild-type KMT2D via FBXW7-NOTCH-MYC/TGF-ß1 axis.
Assuntos
Proteína 7 com Repetições F-Box-WD , Linfoma Difuso de Grandes Células B , Mutação , Proteínas Proto-Oncogênicas c-myc , Linfócitos T Reguladores , Humanos , Proteína 7 com Repetições F-Box-WD/metabolismo , Proteína 7 com Repetições F-Box-WD/genética , Linfoma Difuso de Grandes Células B/genética , Linfoma Difuso de Grandes Células B/metabolismo , Linfoma Difuso de Grandes Células B/patologia , Animais , Camundongos , Feminino , Proteínas Proto-Oncogênicas c-myc/metabolismo , Proteínas Proto-Oncogênicas c-myc/genética , Masculino , Linfócitos T Reguladores/metabolismo , Proteínas de Ligação a DNA/metabolismo , Proteínas de Ligação a DNA/genética , Receptores Notch/metabolismo , Pessoa de Meia-Idade , Linhagem Celular Tumoral , Proteínas de Neoplasias/metabolismo , Proteínas de Neoplasias/genética , Transdução de Sinais , Adulto , Progressão da Doença , IdosoRESUMO
Chimeric antigen receptor T (CAR-T) cell therapy has demonstrated promising efficacy in early trials for relapsed/refractory diffuse large B cell lymphoma (DLBCL). However, its efficacy in treating primary refractory DLBCL has not been comprehensively investigated, and the underlying resistance mechanisms remain unclear. Here, we report the outcomes of a phase I, open-label, single-arm clinical trial of relmacabtagene autoleucel (relma-cel), a CD19-targeted CAR-T cell product, with safety and efficacy as primary endpoints. Among the 12 enrolled patients, 8 experienced grade 4 hematologic toxicity of treatment-emergent adverse event. No grade ≥3 cytokine release syndrome or neurotoxicity occurred. Single-cell RNA sequencing revealed an increase proportion of C1QB-expressing macrophages in patients with progressive disease before CAR-T cell therapy. Cholesterol efflux from M2 macrophages was found to inhibit CAR-T cells cytotoxicity by inducing an immunosuppressive state in CD8+ T cells, leading to their exhaustion. Possible interactions between macrophages and CD8+ T cells, mediating lipid metabolism (AFR1-FAS), immune checkpoint activation, and T cell exhaustion (LGALS9-HAVCR2, CD86-CTLA4, and NECTIN2-TIGIT) were enhanced during disease progression. These findings suggest that cholesterol efflux from macrophages may trigger CD8+ T cell exhaustion, providing a rationale for metabolic reprogramming to counteract CAR-T treatment failure. Chinadrugtrials.org.cn identifier: CTR20200376.
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Colesterol , Imunoterapia Adotiva , Linfoma Difuso de Grandes Células B , Macrófagos , Receptores de Antígenos Quiméricos , Humanos , Linfoma Difuso de Grandes Células B/terapia , Linfoma Difuso de Grandes Células B/imunologia , Linfoma Difuso de Grandes Células B/metabolismo , Linfoma Difuso de Grandes Células B/genética , Macrófagos/metabolismo , Macrófagos/imunologia , Imunoterapia Adotiva/métodos , Pessoa de Meia-Idade , Feminino , Masculino , Colesterol/metabolismo , Receptores de Antígenos Quiméricos/metabolismo , Receptores de Antígenos Quiméricos/imunologia , Receptores de Antígenos Quiméricos/genética , Idoso , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Adulto , Resistencia a Medicamentos AntineoplásicosAssuntos
Inibidores de Histona Desacetilases , Proteínas Proto-Oncogênicas c-bcl-2 , Inibidores de Histona Desacetilases/farmacologia , Inibidores de Histona Desacetilases/uso terapêutico , Humanos , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Proteínas Proto-Oncogênicas c-myc/genética , Proteínas Proto-Oncogênicas c-myc/metabolismo , Linfoma/tratamento farmacológico , Linfoma/genética , Linfoma/metabolismoRESUMO
Natural killer T cell lymphoma (NKTCL) is highly aggressive, with advanced stage patients poorly responding to intensive chemotherapy. To explore effective and safe treatment for newly diagnosed advanced stage NKTCL, we conducted a phase II study of anti-metabolic agent pegaspargase plus PD-1 antibody sintilimab (NCT04096690). Twenty-two patients with a median age of 51 years (range, 24-74) were enrolled and treated with induction treatment of pegaspargase 2500 IU/m2 intramuscularly on day 1 and sintilimab 200 mg intravenously on day 2 for 6 cycles of 21 days, followed by maintenance treatment of sintilimab 200 mg for 28 cycles of 21 days. The complete response and overall response rate after induction treatment were 59% (95%CI, 43-79%) and 68% (95%CI, 47-84%), respectively. With a median follow-up of 30 months, the 2 year progression-free and overall survival rates were 68% (95%CI, 45-83%) and 86% (95%CI, 63-95%), respectively. The most frequently grade 3/4 adverse events were neutropenia (32%, n = 7) and hypofibrinogenemia (18%, n = 4), which were manageable and led to no discontinuation of treatment. Tumor proportion score of PD-L1, peripheral blood high-density lipoprotein cholesterol, and apolipoprotein A-I correlated with good response, while PD-1 on tumor infiltrating lymphocytes and peripheral Treg cells with poor response to pegaspargase plus sintilimab treatment. In conclusion, the chemo-free regimen pegaspargase plus sintilimab was effective and safe in newly diagnosed, advanced stage NKTCL. Dysregulated lipid profile and immunosuppressive signature contributed to treatment resistance, providing an alternative therapeutic approach dual targeting fatty acid metabolism and CTLA-4 in NKTCL.
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Anticorpos Monoclonais Humanizados , Asparaginase , Linfoma , Células T Matadoras Naturais , Polietilenoglicóis , Humanos , Receptor de Morte Celular Programada 1 , Adulto , Pessoa de Meia-Idade , Idoso , Adulto JovemRESUMO
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
ABSTRACT: Diffuse large B-cell lymphoma (DLBCL) is a highly aggressive subtype of lymphoma with clinical and biological heterogeneity. The International Prognostic Index (IPI) shows great prognostic capability in the era of rituximab, but the biological signatures of IPI remain to be discovered. In this study, we analyzed the clinical data in a large cohort of 2592 patients with newly diagnosed DLBCL. Among them, 1233 underwent DNA sequencing for oncogenic mutations, and 487 patients underwent RNA sequencing for lymphoma microenvironment (LME) alterations. Based on IPI scores, patients were categorized into 4 distinct groups, with 5-year overall survival of 41.6%, 55.3%, 71.7%, and 89.7%, respectively. MCD-like subtype was associated with age of >60 years, multiple extranodal involvement, elevated serum lactate dehydrogenase (LDH), and IPI scores ranging from 2 to 5, whereas ST2-like subtype showed an opposite trend. Patients with EZB-like MYC+ and TP53Mut subtypes exhibited poor clinical outcome independent of the IPI; integrating TP53Mut into IPI could better distinguish patients with dismal survival. The EZB-like MYC-, BN2-like, N1-like, and MCD-like subtypes had inferior prognosis in patients with IPI scores of ≥2, indicating necessity for enhanced treatment. Regarding LME categories, the germinal center-like LME was more prevalent in patients with normal LDH and IPI scores of 0 to 1. The mesenchymal LME served as an independent protective factor, whereas the germinal center-like, inflammatory, and depleted LME categories correlated with inferior prognosis for IPI scores of 2 to 5. In summary, our work explored the biological signatures of IPI, thus providing useful rationale for future optimization of the IPI-based treatment strategies with multi-omics information in DLBCL.
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Linfoma Difuso de Grandes Células B , Humanos , Pessoa de Meia-Idade , Prognóstico , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Rituximab/uso terapêutico , Centro Germinativo/patologia , Microambiente TumoralRESUMO
Gastric cancer (GC) is a gastric epithelium-derived malignancy insensitive to post-surgical radiotherapy. Paclitaxel, an anti-microtubule drug, has been proven to induce apoptosis of GC cells; however, its exact mechanism of action is unclear. Therefore, the molecular mechanism by which paclitaxel inhibits the proliferation, migration and invasion of GC cells was investigated in this study. First off, SNU-719 cells were co-cultured with paclitaxel and/or Caspase1 inhibitor VX765. Then the proliferation ability of the cells was detected by MTT after paclitaxel treatment (0, 10, 20, 40, and 80 nM), the migration ability by scratch assay, and the invasion ability by Transwell assay. Next, the levels of interleukin (IL)-1ß and IL-18 in cell culture supernatant were detected by the enzyme linked immunosorbent assay (ELISA). And the level of lactate dehydrogenase (LDH) in the supernatant was measured by a corresponding kit. Finally, western blot was performed to detect the concentrations of Gasdermin E (GSDME), GSDME-N, nod-like receptor family pyrin domain-containing 3 (NLRP3), caspase-1, cleaved caspase-1 protein in GC cells. As a result, paclitaxel inhibited the proliferation, migration, and invasion of SNU-719 cells in a concentration-dependent manner. Moreover, it induced the pyroptosis of SNU-719 cells. After cell co-culture with VX765 paclitaxel showed decreased inhibitory effect on the migration and invasion of SNU-719 cells. VX765, additionally, suppressed the NLRP3/caspase-1/GSDME mediated pyroptosis pathway activated by paclitaxel. In a nutshell, paclitaxel may inhibit the migration and invasion of GC cells SNU-719 through the NLRP3/caspase-1/GSDME mediated pyroptosis pathway.
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Proteína 3 que Contém Domínio de Pirina da Família NLR , Neoplasias Gástricas , Humanos , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Piroptose , Proteínas NLR/metabolismo , Caspase 1/metabolismo , Caspase 1/farmacologia , Paclitaxel/farmacologia , Gasderminas , Neoplasias Gástricas/tratamento farmacológico , Domínio PirinaRESUMO
Epstein-Barr virus (EBV) is the oncogenic driver of multiple cancers. However, the underlying mechanism of virus-cancer immunological interaction during disease pathogenesis remains largely elusive. Here we reported the first comprehensive proteogenomic characterization of natural killer/T-cell lymphoma (NKTCL), a representative disease model to study EBV-induced lymphomagenesis, incorporating genomic, transcriptomic, and in-depth proteomic data. Our multi-omics analysis of NKTCL revealed that EBV gene pattern correlated with immune-related oncogenic signaling. Single-cell transcriptome further delineated the tumor microenvironment as immune-inflamed, -deficient, and -desert phenotypes, in association with different setpoints of cancer-immunity cycle. EBV interacted with transcriptional factors to provoke GPCR interactome (GPCRome) reprogramming. Enhanced expression of chemokine receptor-1 (CCR1) on malignant and immunosuppressive cells modulated virus-cancer interaction on microenvironment. Therapeutic targeting CCR1 showed promising efficacy with EBV eradication, T-cell activation, and lymphoma cell killing in NKTCL organoid. Collectively, our study identified a previously unknown GPCR-mediated malignant progression and translated sensors of viral molecules into EBV-specific anti-cancer therapeutics.
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Infecções por Vírus Epstein-Barr , Linfoma , Células T Matadoras Naturais , Humanos , Herpesvirus Humano 4/genética , Infecções por Vírus Epstein-Barr/complicações , Proteômica , Linfoma/complicações , Células T Matadoras Naturais/patologia , Microambiente Tumoral/genéticaRESUMO
TP53 mutation (TP53mut) occurs in 10-20% of diffuse large B-cell lymphoma (DLBCL) cases and serves as an unfavorable biomarker of DLBCL progression. It confers resistance to immunochemotherapy, high-dose chemotherapy, autologous stem cell transplantation, and anti-CD19 chimeric antigen receptor T-cell therapy. Therapeutic targeting of TP53mut remains a significant challenge in DLBCL treatment. Here we assessed TP53mut in 667 patients with newly diagnosed DLBCL, including 576 patients treated with immunochemotherapy rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) and 91 patients with decitabine plus R-CHOP (DR-CHOP, NCT02951728 and NCT04025593). TP53mut independently predicted an inferior prognosis in R-CHOP-treated DLBCL, although this could be mitigated by DR-CHOP treatment. In TP53mut patients, multiple viral regulation pathways were repressed, resulting in the inhibition of immune modulation, as revealed by gene set enrichment analysis. TP53mut DLBCL exhibited increased methyltransferase SUV39H1 expression and H3K9 trimethylation (H3K9me3), contributing to repression of endogenous retroviruses (ERVs) and immunosuppressive tumor microenvironment. In TP53mut DLBCL cell lines, decitabine down-regulated SUV39H1, inhibited H3K9me3 occupancy on ERVs, and triggered ERV expression, thereby unleashing interferons program and CD4+T/CD8+T cell activation. Molecular silencing of SUV39H1 significantly abrogated decitabine-induced H3K9me3 inhibition and ERV expression. In TP53mut patient-derived xenograft models and TP53mut patients, the anti-tumor effect was improved upon the use of combined treatment of decitabine and doxorubicin via SUV39H1-H3K9me3-ERVs axis. Collectively, our findings highlight an ERV regulatory circuitry in TP53mut DLBCL and the crucial roles ERVs for epigenetically reprogramming tumor microenvironment for treating TP53mut-driven cancers.
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Retrovirus Endógenos , Transplante de Células-Tronco Hematopoéticas , Linfoma Difuso de Grandes Células B , Humanos , Decitabina/farmacologia , Decitabina/uso terapêutico , Transplante Autólogo , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Linfoma Difuso de Grandes Células B/genética , Linfoma Difuso de Grandes Células B/patologia , Rituximab/farmacologia , Rituximab/genética , Doxorrubicina/farmacologia , Epigênese Genética/genética , Microambiente Tumoral/genética , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismoRESUMO
We report the results of GUIDANCE-01 (NCT04025593), a randomized, phase II trial of R-CHOP alone or combined with targeted agents (R-CHOP-X) guided by genetic subtyping of newly diagnosed, intermediate-risk, or high-risk diffuse large B cell lymphoma (DLBCL). A total of 128 patients were randomized 1:1 to receive R-CHOP-X or R-CHOP. The study achieved the primary endpoint, showing significantly higher complete response rate with R-CHOP-X than R-CHOP (88% vs. 66%, p = 0.003), with overall response rate of 92% vs. 73% (p = 0.005). Two-year progression-free survival rates were 88% vs. 63% (p < 0.001), and 2-year overall survival rates were 94% vs. 77% (p = 0.001). Meanwhile, post hoc RNA-sequencing validated our simplified genetic subtyping algorithm and previously established lymphoma microenvironment subtypes. Our findings highlight the efficacy and safety of R-CHOP-X, a mechanism-based tailored therapy, which dually targeted genetic and microenvironmental alterations in patients with newly diagnosed DLBCL.
RESUMO
BACKGROUND: The current standard of care for non-bulky diffuse large B-cell lymphoma (DLBCL) patients with an International Prognostic Index (IPI) of 0 is four cycles of rituximab plus cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP) but whether the same efficacy can be achieved with reduced chemotherapy regimen of four cycles for non-bulky DLBCL patients with an IPI of 1 remains unclear. This study compared four cycles versus six cycles of chemotherapy in non-bulky low-risk DLBCL patients with negative interim positron emission tomography with computed tomography (PET-CT, Deauville 1-3), irrespective of age and other IPI risk factors (IPI 0-1). METHODS: This was an open-label, randomized, phase III, non-inferiority trial. Patients aged 14-75 years with newly diagnosed low-risk DLBCL, according to IPI, achieving PET-CT confirmed complete response (CR) after four cycles of R-CHOP were randomized (1:1) between four cycles of rituximab (4R-CHOP+4R arm) or two cycles of R-CHOP plus two cycles of rituximab (6R-CHOP+2R arm). The primary endpoint was 2-year progression-free survival (PFS), conducted in the intention-to-treat population. Safety was assessed in patients with at least one cycle of assigned treatment. The non-inferiority margin was -8%. RESULTS: A total of 287 patients were included in the intention-to-treat analysis, the median follow-up was 47.3 months, and the 2-year PFS rate was 95% (95% confidence interval [CI], 92% to 99%) and 94% (95% CI, 91% to 98%) for the 4R-CHOP+4R and 6R-CHOP+2R arm. The absolute difference in 2-year PFS between the two arms was 1% (95% CI, -5% to 7%), supporting the non-inferiority of 4R-CHOP+4R. Grade 3-4 neutropenia was lower in the last four cycles of rituximab alone in the 4R-CHOP+4R arm (16.7% versus 76.9%), with decreased risk of febrile neutropenia (0.0% versus 8.4%) and infection (2.1% versus 14.0%). CONCLUSIONS: For newly diagnosed low-risk DLBCL patients, interim PET-CT after four cycles of R-CHOP was effective in identifying patients with Deauville 1-3 who would have a good response and Deauville 4-5 patients who might have high-risk biological features or develop resistance. Reducing the standard six cycles to four cycles of chemotherapy had comparable clinical efficacy and fewer adverse events in low-risk, non-bulky DLBCL with interim PET-CT confirmed CR.
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Linfoma Difuso de Grandes Células B , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Humanos , Rituximab , Anticorpos Monoclonais Murinos/uso terapêutico , Intervalo Livre de Doença , Linfoma Difuso de Grandes Células B/diagnóstico por imagem , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Vincristina/efeitos adversos , Ciclofosfamida/efeitos adversos , Doxorrubicina/efeitos adversos , Prednisona/efeitos adversos , Tomografia por Emissão de Pósitrons/métodos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêuticoRESUMO
Genetic classification helps to disclose molecular heterogeneity and therapeutic implications in diffuse large B-cell lymphoma (DLBCL). Using whole exome/genome sequencing, RNA-sequencing, and fluorescence in situ hybridization in 337 newly diagnosed DLBCL patients, we established a simplified 38-gene algorithm (termed 'LymphPlex') based on the information on mutations of 35 genes and rearrangements of three genes (BCL2, BCL6, and MYC), identifying seven distinct genetic subtypes: TP53Mut (TP53 mutations), MCD-like (MYD88, CD79B, PIM1, MPEG1, BTG1, TBL1XR1, PRDM1, IRF4 mutations), BN2-like (BCL6 fusion, NOTCH2, CD70, DTX1, BTG2, TNFAIP3, CCND3 mutations), N1-like (NOTCH1 mutations), EZB-like (BCL2 fusion, EZH2, TNFRSF14, KMT2D, B2M, FAS, CREBBP, ARID1A, EP300, CIITA, STAT6, GNA13 mutations, with or without MYC rearrangement), and ST2-like (SGK1, TET2, SOCS1, DDX3X, ZFP36L1, DUSP2, STAT3, IRF8 mutations). Extended validation of 1001 DLBCL patients revealed clinical relevance and biological signature of each genetic subtype. TP53Mut subtype showed poor prognosis, characterized by p53 signaling dysregulation, immune deficiency, and PI3K activation. MCD-like subtype was associated with poor prognosis, activated B-cell (ABC) origin, BCL2/MYC double-expression, and NF-κB activation. BN2-like subtype showed favorable outcome within ABC-DLBCL and featured with NF-κB activation. N1-like and EZB-like subtypes were predominated by ABC-DLBCL and germinal center B-cell (GCB)-DLBCL, respectively. EZB-like-MYC+ subtype was characterized by an immunosuppressive tumor microenvironment, while EZB-like-MYC- subtype by NOTCH activation. ST2-like subtype showed favorable outcome within GCB-DLBCL and featured with stromal-1 modulation. Genetic subtype-guided targeted agents achieved encouraging clinical response when combined with immunochemotherapy. Collectively, LymphPlex provided high efficacy and feasibility, representing a step forward to the mechanism-based targeted therapy in DLBCL.
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Proteínas Imediatamente Precoces , Linfoma Difuso de Grandes Células B , Humanos , NF-kappa B/genética , Hibridização in Situ Fluorescente , Proteína 1 Semelhante a Receptor de Interleucina-1/genética , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Proteínas Proto-Oncogênicas c-bcl-2/genética , Microambiente Tumoral , Fator 1 de Resposta a Butirato/genética , Proteínas Imediatamente Precoces/genética , Proteínas Imediatamente Precoces/uso terapêutico , Proteínas Supressoras de Tumor/genéticaAssuntos
Doença da Artéria Coronariana , Estenose Coronária , Reserva Fracionada de Fluxo Miocárdico , Humanos , Prognóstico , Valor Preditivo dos Testes , Doença da Artéria Coronariana/diagnóstico por imagem , Doença da Artéria Coronariana/terapia , Tomografia Computadorizada por Raios X , Angiografia Coronária , Angiografia por Tomografia Computadorizada , Índice de Gravidade de DoençaRESUMO
Background A noninvasive coronary CT angiography (CCTA)-based radiomics technique may facilitate the identification of vulnerable plaques and patients at risk for future adverse events. Purpose To assess whether a CCTA-based radiomic signature (RS) of vulnerable plaques defined with intravascular US was associated with increased risk for future major adverse cardiac events (MACE). Materials and Methods In a retrospective study, an RS of vulnerable plaques was developed and validated using intravascular US as the reference standard. The RS development data set included patients first undergoing CCTA and then intravascular US within 3 months between June 2013 and December 2020 at one tertiary hospital. The development set was randomly assigned to training and validation sets at a 7:3 ratio. Diagnostic performance was assessed internally and externally from three tertiary hospitals using the area under the curve (AUC). The prognostic value of the RS for predicting MACE was evaluated in a prospective cohort with suspected coronary artery disease between April 2018 and March 2019. Multivariable Cox regression analysis was used to evaluate the RS and conventional anatomic plaque features (eg, segment involvement score) for predicting MACE. Results The RS development data set included 419 lesions from 225 patients (mean age, 64 years ± 10 [SD]; 68 men), while the prognostic cohort included 1020 lesions from 708 patients (mean age, 62 years ± 11; 498 men). Sixteen radiomic features, including two shape features and 14 textural features, were selected to build the RS. The RS yielded a moderate to good AUC in the training, validation, internal, and external test sets (AUC = 0.81, 0.75, 0.80, and 0.77, respectively). A high RS (≥1.07) was independently associated with MACE over a median 3-year follow-up (hazard ratio, 2.01; P = .005). Conclusion A coronary CT angiography-derived radiomic signature of coronary plaque enabled the detection of vulnerable plaques that were associated with increased risk for future adverse cardiac outcomes. © RSNA, 2023 Supplemental material is available for this article. See also the editorial by De Cecco and van Assen in this issue.
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Doença da Artéria Coronariana , Placa Aterosclerótica , Masculino , Humanos , Pessoa de Meia-Idade , Angiografia por Tomografia Computadorizada/métodos , Estudos Retrospectivos , Estudos Prospectivos , Doença da Artéria Coronariana/complicações , Placa Aterosclerótica/diagnóstico por imagem , Placa Aterosclerótica/complicações , Angiografia Coronária/métodos , Prognóstico , Valor Preditivo dos TestesRESUMO
OBJECTIVES: To investigate the predictive value of CT-derived fractional flow reserve (FFRCT) in anastomosis occlusion after coronary artery bypass graft (CABG) surgery. METHODS: Patients undergoing CABG with both pre- and post-operative coronary computed tomographic angiography (CCTA) were retrospectively included. Preoperative CCTA studies were used to evaluate anatomical and FFRCT information of target vessels. A diameter stenosis (DS) ≥ 70% or left main > 50% was considered to be anatomically severe, while FFRCT value ≤ 0.80 be functionally significant. The primary endpoint was anastomosis occlusion evaluated on post-operative CCTA during follow-up. Predictors of anastomosis occlusion were assessed by the multivariate binary logistic regression with generalized estimating equations. RESULTS: A total of 270 anastomoses were identified in 88 enrolled patients. Forty-one anastomoses from 30 patients exhibited occlusion during a follow-up of 15.3 months after CABG. The occluded group had significantly increased prevalence of non-severe DS (58.5% vs. 40.2%; p = 0.023) and non-significant FFRCT (48.8% vs. 10.0%; p < 0.001). Multivariable analysis indicated FFRCT ≤ 0.80 (odds ratio [OR]: 0.10, 95% CI: 0.03-0.33; p < 0.001) and older age (OR: 0.92, 95% CI: 0.87-0.97; p = 0.001) were predictors for bypass patency during follow-up, while myocardial infarction history and anastomosis to a local lesion or bifurcation (all p value < 0.05) were predictors of occlusion. Adding FFRCT into the model based on the clinical and anatomical predictors had an improved AUC of 0.848 (p = 0.005). CONCLUSIONS: FFRCT ≤ 0.80 was associated with a significant risk reduction of anastomosis occlusion after CABG. Preoperative judgment of the hemodynamic significance may improve the CABG surgery strategy and reduce graft failure. KEY POINTS: ⢠FFRCT ≤ 0.80 was associated with a significant risk reduction of anastomosis occlusion after CABG. ⢠The addition of FFRCT into the integrated model including clinical (age and history of myocardial infarction) and anatomical CCTA indicators (local lesion and bifurcation) significantly improved the model performance with an AUC of 0.848 (p = 0.005). ⢠Preoperative judgment of the hemodynamic significance may help improve the decision-making and surgery planning in patients indicated for CABG and significantly reduce graft failure, without an extra radiation exposure and risk of invasive procedure.
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Doença da Artéria Coronariana , Estenose Coronária , Reserva Fracionada de Fluxo Miocárdico , Infarto do Miocárdio , Doenças Vasculares , Humanos , Doença da Artéria Coronariana/diagnóstico por imagem , Doença da Artéria Coronariana/cirurgia , Estudos Retrospectivos , Angiografia Coronária/métodos , Prognóstico , Valor Preditivo dos Testes , Vasos Coronários/diagnóstico por imagem , Vasos Coronários/cirurgia , Tomografia Computadorizada por Raios X , Ponte de Artéria Coronária , Angiografia por Tomografia Computadorizada/métodosRESUMO
OBJECTIVES: To investigate the optimal measurement site of coronary-computed tomography angiography-derived fractional flow reserve (FFR CT ) for the assessment of coronary artery disease (CAD) in the whole clinical routine practice. MATERIALS AND METHODS: This retrospective multicenter study included 396 CAD patients who underwent coronary-computed tomography angiography, FFR CT , and invasive FFR. FFR CT was measured at 1 cm (FFR CT -1 cm), 2 cm (FFR CT -2 cm), 3 cm (FFR CT -3 cm), and 4 cm (FFR CT -4 cm) distal to coronary stenosis, respectively. FFR CT and invasive FFR ≤0.80 were defined as lesion-specific ischemia. The diagnostic performance of FFR CT to detect ischemia was obtained using invasive FFR as the reference standard. Reduced invasive coronary angiography rate and revascularization efficiency were calculated. After a median follow-up of 35 months in 267 patients for major adverse cardiovascular events (MACE), Cox hazard proportional models were performed with FFR CT values at each measurement site. RESULTS: For discriminating lesion-specific ischemia, the areas under the curve of FFR CT -1 cm (0.91) as well as FFR CT -2 cm (0.91) were higher than those of FFR CT -3 cm (0.89) and FFR CT -4 cm (0.88), respectively (all P <0.05). The higher reduced invasive coronary angiography rate (81.6%) was found at FFR CT -1 cm than FFR CT -2 cm (81.6% vs. 62.6%, P <0.05). Revascularization efficiency did not differ between FFR CT -1 cm and FFR CT -2 cm (80.8% vs. 65.5%, P =0.019). In 12.4% (33/267) MACE occurred and only values of FFR CT -2 cm were independently predictive of MACE (hazard ratio: 0.957 [95% CI: 0.925-0.989]; P =0.010). CONCLUSIONS: This study indicates FFR CT -2 cm is the optimal measurement site with superior diagnostic performance and independent prognostic role.
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Doença da Artéria Coronariana , Estenose Coronária , Reserva Fracionada de Fluxo Miocárdico , Humanos , Angiografia por Tomografia Computadorizada/métodos , Doença da Artéria Coronariana/diagnóstico por imagem , Estenose Coronária/diagnóstico por imagem , Tomografia Computadorizada por Raios X , Angiografia Coronária/métodos , Estudos Retrospectivos , Valor Preditivo dos TestesRESUMO
Lymphoma cells expressing CD5 (CD5+) confer inferior outcome of diffuse large B-cell lymphoma (DLBCL), especially in non-MYC/BCL2 double expressor (non-DE) patients. In tumor microenvironment, CD5+ non-DE tumor revealed increased proportion of immunosuppressive M2 macrophages and enhanced pathways related to macrophage activation and migration. In accordance to M2 activation, lipid metabolism was upregulated, including fatty acid uptake and fatty acid oxidation, which supplied energy for M2 macrophage polarization and activation. Meanwhile, CD36 expression was upregulated and strongly correlated to the proportion of M2 macrophages in CD5+ non-DE DLBCL. In vitro, a DLBCL cell line (LY10) overexpressing CD5 significantly increased M2 proportion in comparison with control when cocultured with peripheral blood mononuclear cells (PBMCs). The addition of metformin significantly decreased the M2 proportion and the CD36 expression level in the coculture systems, indicating that metformin could target altered lipid metabolism and decrease M2 macrophages in DLBCL, especially in CD5+ non-DE lymphoma. In conclusion, enhanced lipid metabolism and M2 macrophage activation contributed to the immunosuppressive tumor microenvironment and could be potential therapeutic targets in CD5+ non-DE DLBCL.
RESUMO
INTRODUCTION: Previous studies have shown that diffuse large B-cell lymphoma (DLBCL) subtype with both B-cell antigen receptor complex-associated protein beta chain (CD79B) and myeloid differentiation primary response 88 mutations (MYD88) had inferior outcome under standard immunochemotherapy. However, the prognostic significance of CD79B alone in DLBCL has not been fully elucidated. We conducted a meta-analysis to investigate the role of CD79B mutation on overall survival (OS) in patients with DLBCL. METHODS: We performed literature search in PubMed and Embase databases and followed PRISMA guidelines to select publications for analysis. The primary and secondary outcome was OS and progression-free survival (PFS) respectively. Hazard ratio (HR) for OS/PFS in CD79B mutant group with that in wild-type group in R-chemotherapy patients was either estimated using Cox proportional hazard model from the studies with individual participant level data or extracted from the original publication with aggregated results. RESULTS: Nine eligible studies with survival information according to CD79B mutation status were included in this meta-analysis. The pooled hazard ratio for OS was 1.38 (95% CI, 1.13-1.70; p = 0.0021) for CD79B mutation, providing evidence that CD79B mutation was unfavorable prognostic factor for survival in DLBCL patients treated with immunochemotherapy. We identified the inferior prognostic impact of CD79B mutation was independent from well-established prognostic model in DLBCL, International Prognostic Index. The predictive power of CD79B mutation was stronger than that of MYD88 mutation. CONCLUSION: This meta-analysis revealed that CD79B mutation could be a key biomarker for DLBCL disease progression and future mechanism-based target therapy in DLBCL needs to be studied.
Assuntos
Linfoma Difuso de Grandes Células B , Fator 88 de Diferenciação Mieloide , Humanos , Prognóstico , Fator 88 de Diferenciação Mieloide/genética , Linfoma Difuso de Grandes Células B/diagnóstico , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Linfoma Difuso de Grandes Células B/genética , Mutação , Imunoterapia , Antígenos CD79/genética , Antígenos CD79/metabolismoRESUMO
BACKGROUND: The optimal treatment for older adults with diffuse large B-cell lymphoma (DLBCL) needs to be further explored due to patient comorbidities, standard immunochemotherapy intolerance, and unfavourable genetic features. We did a phase 2 trial of ibrutinib, rituximab, and lenalidomide (iR2) to evaluate the efficacy and safety in older adult patients with de novo DLBCL. METHODS: In this phase 2, single-arm study, unfit or frail patients with de novo DLBCL aged 75 years or older were enrolled at Shanghai Ruijin Hospital, Shanghai, China. During the induction phase from cycle 1 to 6, 560 mg ibrutinib was given orally daily throughout each 21-day treatment cycle, 375 mg/m2 rituximab was given intravenously on day 1, and 25 mg lenalidomide was given orally daily from day 1 to 10 in each cycle. Patients who had a complete response after induction were given another 6 cycles of lenalidomide maintenance (25 mg orally daily from day 1 to 10 every 21 days from cycle 7 to 12). The primary endpoint was complete response rate after 6 cycles or at the end of the induction treatment. This trial is registered with ClinicalTrials.gov, NCT03949062. FINDINGS: Between May 15, 2019, and May 8, 2020, a total of 30 patients were enrolled. The end of induction complete response rate was 56·7% (95% CI 37·4-74·5), and overall response rate was 66·7% (95% CI 47·2-82·7). With a median follow-up of 27·6 months (IQR 23·9-29·6), the 2-year progression-free survival rate was 53·3% (95% CI 34·3-69·1) and the 2-year overall survival rate was 66·7% (95% CI 46·9-80·5). The main grade 3-4 haematological adverse events were neutropenia (seven patients [23%]), thrombocytopenia (three patients [10%]), and anaemia (two patients [7%]). The most common grade 3-4 non-haematological adverse event was pulmonary infection (seven patients [23%]). Atrial fibrillation was observed in three (10%) patients, including one grade 2 and two grade 3. INTERPRETATION: A chemotherapy-free iR2 regimen is clinically effective and safe and warrants further investigation in phase 3 trials as first-line treatment in older adult patients with DLBCL. FUNDING: National Natural Science Foundation of China, Shanghai Municipal Education Commission Gaofeng Clinical Medicine Grant Support, Clinical Research Plan of Shanghai Hospital Development Center, and Multicenter Clinical Research Project by Shanghai Jiao Tong University School of Medicine.