RESUMEN
BACKGROUND: Patients with mantle cell lymphoma (MCL) follow a heterogeneous clinical course. While they generally require treatment initiation shortly after diagnosis, it is unclear whether deferring treatment in selected patients with an indolent clinical behavior affects their overall outcome. PATIENTS AND METHODS: In this population-based study, all patients diagnosed with MCL during 1998-2014 were identified in the British Columbia Cancer Agency Lymphoid Cancer Database. The associations between clinico-pathologic characteristics, including the expression of Ki67, SOX11, and TP53, and time to treatment (TtT) and OS were analyzed. RESULTS: A total of 440 patients with MCL were evaluated: 365 (83%) received early treatment and 75 (17%) were observed ≥3 months. In the observation group, 54 (72%) patients had a nodal presentation, 16 (21%) a non-nodal presentation, and 5 (7%) had only gastrointestinal involvement. Characteristics associated with deferred treatment included good performance status, no B symptoms, low LDH, non-bulky disease, non-blastoid morphology, and lower Ki67 values. The median TtT in the observation group was 35 months (range 5-79), and 60 (80%) patients were observed beyond 12 months. The median OS was significantly longer in the observation group than in the early treatment group (72 versus 52.5 months, respectively, P = 0.041). In multivariable analysis, treatment decision was not associated with OS [HR 0.804 (95% CI 0.529-1.221), P = 0.306]. CONCLUSIONS: A subgroup of patients with MCL may be safely observed from diagnosis without negatively impacting their outcomes, including patients with non-nodal presentation as well as asymptomatic patients with low burden nodal presentation and a low proliferative rate.
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Linfoma de Células del Manto/diagnóstico , Linfoma de Células del Manto/terapia , Espera Vigilante/métodos , Adulto , Anciano , Anciano de 80 o más Años , Colombia Británica/epidemiología , Estudios de Cohortes , Femenino , Humanos , Linfoma de Células del Manto/mortalidad , Linfoma de Células del Manto/patología , Masculino , Persona de Mediana Edad , Estudios RetrospectivosRESUMEN
Follicular lymphoma (FL) is typically an indolent disease, but 30-40% of FL cases transform into an aggressive lymphoma (tFL) with a poor prognosis. To identify the genetic changes that drive this transformation, we sequenced the exomes of 12 cases with paired FL and tFL biopsies and identified 45 recurrently mutated genes in the FL-tFL data set and 39 in the tFL cases. We selected 496 genes of potential importance in transformation and sequenced them in 23 additional tFL cases. Integration of the mutation data with copy-number abnormality (CNA) data provided complementary information. We found recurrent mutations of miR-142, which has not been previously been reported to be mutated in FL/tFL. The genes most frequently mutated in tFL included KMT2D (MLL2), CREBBP, EZH2, BCL2 and MEF2B. Many recurrently mutated genes are involved in epigenetic regulation, the Janus-activated kinase-signal transducer and activator of transcription (STAT) or the nuclear factor-κB pathways, immune surveillance and cell cycle regulation or are TFs involved in B-cell development. Of particular interest are mutations and CNAs affecting S1P-activated pathways through S1PR1 or S1PR2, which likely regulate lymphoma cell migration and survival outside of follicles. Our custom gene enrichment panel provides high depth of coverage for the study of clonal evolution or divergence.
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Carcinogénesis/genética , Transformación Celular Neoplásica/genética , Dosificación de Gen , Linfoma Folicular/genética , Evolución Clonal/genética , Análisis Mutacional de ADN , Epigénesis Genética/genética , Exoma/genética , Humanos , OncogenesAsunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Linfoma de Células del Manto/tratamiento farmacológico , Anticuerpos Monoclonales/uso terapéutico , Anticuerpos Monoclonales de Origen Murino/uso terapéutico , Ciclofosfamida/uso terapéutico , Doxorrubicina/uso terapéutico , Estudios de Seguimiento , Humanos , Linfoma de Células del Manto/radioterapia , Prednisona/uso terapéutico , Radioinmunoterapia/métodos , Rituximab , Vincristina/uso terapéuticoRESUMEN
BACKGROUND: The added diagnostic and prognostic value of routine bone marrow biopsy (BMB) in patients with diffuse large B-cell lymphoma (DLBCL) undergoing positron emission tomography combined with computed tomography (PET/CT) staging is controversial. PATIENTS AND METHODS: Patients with newly diagnosed DLBCL who underwent both staging PET/CT and BMB were retrospectively identified in British Columbia, Aalborg, and Copenhagen. Original written PET/CT and pathology reports were retrospectively reviewed to determine Ann Arbor stage and outcomes, with and without the contribution of BMB. RESULTS: A total of 530 patients were identified: 146 (28%) had focal bone marrow (BM) lesions on PET/CT and 87 (16%) had positive BMB. Fifty-two of 146 patients (36%) with positive PET/CT had a positive BMB [39 DLBCL, 13 indolent non-Hodgkin lymphoma (iNHL)], while 35 of 384 patients (9%) with negative PET/CT had positive BMB (12 DLBCL, 23 iNHL). BMB upstaged 12/209 (6%) of stage I/II patients to stage IV, although this was the case for only 3 (1%) patients with DLBCL in the BMB. PET/CT identified BM involvement by BMB with sensitivity 60%, specificity 79%, positive predictive value 36%, and negative predictive value 91%. Concordant histological involvement of the BM by DLBCL was associated with worse overall survival and progression-free survival than discordant or no involvement in univariate and multivariate analyses. CONCLUSIONS: In patients with DLBCL, staging PET/CT can miss BM involvement with concordant DLBCL (less common) or discordant iNHL (more common). Routine BMB does not add relevant diagnostic or prognostic value over PET/CT alone in the majority of patients with DLBCL.
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Médula Ósea/diagnóstico por imagen , Linfoma de Células B Grandes Difuso/diagnóstico por imagen , Tomografía Computarizada por Tomografía de Emisión de Positrones , Pronóstico , Adulto , Anciano , Biopsia , Médula Ósea/patología , Canadá , Dinamarca , Supervivencia sin Enfermedad , Femenino , Fluorodesoxiglucosa F18/uso terapéutico , Humanos , Linfoma de Células B Grandes Difuso/diagnóstico , Linfoma de Células B Grandes Difuso/epidemiología , Linfoma de Células B Grandes Difuso/patología , Masculino , Persona de Mediana EdadRESUMEN
Primary refractory diffuse large B cell lymphoma (DLBCL) following R-CHOP chemotherapy is a major concern. We identified 1126 patients with DLBCL treated with R-CHOP from 2000 to 2009, of whom 166 (15 %) had primary refractory disease. Of the 75/166 (45 %) who were age <70 years and had been planned for stage-directed curative therapy, 43 (57 %) were primary nonresponders and 32 (43 %) relapsed within 3 months of completing R-CHOP. Thirty of 75 (40 %) patients had serious comorbidity and organ dysfunction precluding intensive treatment and had palliative treatment only. Twelve of 45 (27 %) patients responded to second-line treatment and underwent ASCT. The median overall survival for the 75 patients was 10 months with only seven patients alive without evidence of disease at follow-up ranging from 14 to 106 months. Primary refractory DLBCL after R-CHOP has a very poor outcome with only anecdotal survivors independent of the intended treatment approach.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Resistencia a Antineoplásicos , Linfoma de Células B Grandes Difuso/diagnóstico , Linfoma de Células B Grandes Difuso/tratamiento farmacológico , Adulto , Anciano , Anticuerpos Monoclonales de Origen Murino/uso terapéutico , Colombia Británica/epidemiología , Ciclofosfamida/uso terapéutico , Doxorrubicina/uso terapéutico , Femenino , Humanos , Linfoma de Células B Grandes Difuso/mortalidad , Linfoma de Células B Grandes Difuso/patología , Masculino , Persona de Mediana Edad , Prednisona/uso terapéutico , Pronóstico , Sistema de Registros , Rituximab , Análisis de Supervivencia , Insuficiencia del Tratamiento , Vincristina/uso terapéutico , Adulto JovenRESUMEN
Diffuse large B-cell lymphoma (DLBCL) is a biologically and clinically heterogeneous disease with marked genomic instability and variable response to conventional R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone) chemotherapy. More clinically aggressive cases of DLBCLs have high level of circulating interleukin 10 (IL10) cytokine and evidence of activated intracellular STAT3 (signal transducer and activator of transcription 3) signaling. We investigated the role of IL10 and its surface receptor in supporting the neoplastic phenotype of DLBCLs. We determined that IL10RA gene is amplified in 21% and IL10RB gene in 10% of primary DLBCLs. Gene expression of IL10, IL10RA and IL10RB was markedly elevated in DLBCLs. We hypothesized that DLBCLs depend for their proliferation and survival on IL10-STAT3 signaling and that blocking the IL10 receptor (IL10R) would induce cell death. We used anti-IL10R blocking antibody, which resulted in a dose-dependent cell death in all tested activated B-cell-like subtype of DLBCL cell lines and primary DLBCLs. Response of germinal center B-cell-like subtype of DLBCL cell lines to anti-IL10R antibody varied from sensitive to resistant. Cells underwent cell cycle arrest, followed by induction of apoptosis. Cell death depended on inhibition of STAT3 and, to a lesser extent, STAT1 signaling. Anti-IL10R treatment resulted in interruption of IL10-IL10R autostimulatory loop. We thus propose that IL10R is a novel therapeutic target in DLBCLs.
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Biomarcadores de Tumor/metabolismo , Interleucina-10/metabolismo , Linfoma de Células B Grandes Difuso/metabolismo , Linfoma de Células B Grandes Difuso/patología , Receptores de Interleucina-10/metabolismo , Apoptosis , Biomarcadores de Tumor/genética , Western Blotting , Ciclo Celular , Proliferación Celular , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Técnicas para Inmunoenzimas , Interleucina-10/genética , Linfoma de Células B Grandes Difuso/mortalidad , Estadificación de Neoplasias , Pronóstico , ARN Mensajero/genética , Reacción en Cadena en Tiempo Real de la Polimerasa , Receptores de Interleucina-10/genética , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Tasa de Supervivencia , Análisis de Matrices Tisulares , Células Tumorales CultivadasRESUMEN
Sex determining region Y-box 11 (SOX11) expression is specific for mantle cell lymphoma (MCL) as compared with other non-Hodgkin's lymphomas. However, the function and direct-binding targets of SOX11 in MCL are largely unknown. We used high-resolution chromatin immunoprecipitation sequencing to identify the direct target genes of SOX11 in a genome-wide, unbiased manner and elucidate its functional significance. Pathway analysis identified WNT, PKA and TGF-beta signaling pathways as significantly enriched by SOX11-target genes. Quantitative chromatin immunoprecipitation sequencing and promoter reporter assays confirmed that SOX11 directly binds to individual genes and modulates their transcription activities in these pathways in MCL. Functional studies using RNA interference demonstrate that SOX11 directly regulates WNT in MCL. We analyzed SOX11 expression in three independent well-annotated tissue microarrays from the University of Wisconsin (UW), Karolinska Institute and British Columbia Cancer Agency. Our findings suggest that high SOX11 expression is associated with improved survival in a subset of MCL patients, particularly those treated with intensive chemotherapy. Transcriptional regulation of WNT and other biological pathways affected by SOX11-target genes may help explain the impact of SOX11 expression on patient outcomes.
Asunto(s)
Linfoma de Células del Manto/genética , Linfoma de Células del Manto/metabolismo , Factores de Transcripción SOXC/metabolismo , Protocolos de Quimioterapia Combinada Antineoplásica , Sitios de Unión , Puntos de Control del Ciclo Celular , Línea Celular Tumoral , Proliferación Celular , Supervivencia Celular/efectos de los fármacos , Inmunoprecipitación de Cromatina , Expresión Génica , Regulación Neoplásica de la Expresión Génica , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Linfoma de Células del Manto/tratamiento farmacológico , Linfoma de Células del Manto/mortalidad , Motivos de Nucleótidos , Pronóstico , Unión Proteica , Factores de Transcripción SOXC/genética , Transducción de Señal , Transcripción Genética , Proteínas Wnt/metabolismo , Vía de Señalización Wnt , beta Catenina/metabolismoRESUMEN
BACKGROUND: The role of body mass index (BMI) in survival outcomes is controversial among lymphoma patients. We evaluated the association between BMI at study entry and failure-free survival (FFS) and overall survival (OS) in three phase III clinical trials, among patients with diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL) and Hodgkin's lymphoma (HL). PATIENTS AND METHODS: A total of 537, 730 and 282 patients with DLBCL, HL and FL were included in the analysis. Baseline patient and clinical characteristics, treatment received and clinical outcomes were compared across BMI categories. RESULTS: Among patients with DLBCL, HL and FL, the median age was 70, 33 and 56; 29%, 29% and 37% were obese and 38%, 27% and 37% were overweight, respectively. Age was significantly different among BMI groups in all three studies. Higher BMI groups tended to have more favorable prognosis factors at study entry among DLBCL and HL patients. BMI was not associated with clinical outcome with P-values of 0.89, 0.30 and 0.40 for FFS, and 0.64, 0.67 and 0.09 for OS, for patients with DLBCL, HL and FL, respectively. The association remains non-significant after adjusting for other clinical factors in the Cox model. A subset analysis of males with DLBCL treated on R-CHOP revealed no differences in FFS (P = 0.48) or OS (P = 0.58). CONCLUSION: BMI was not significantly associated with clinical outcomes among patients with DLBCL, HD or FL, in three prospective phase III clinical trials. The findings contradict some previous reports of similar investigations. Further work is required to understand the observed discrepancies.
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Índice de Masa Corporal , Enfermedad de Hodgkin/mortalidad , Linfoma Folicular/mortalidad , Linfoma de Células B Grandes Difuso/mortalidad , Obesidad/mortalidad , Anticuerpos Monoclonales de Origen Murino/uso terapéutico , Antineoplásicos/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Ciclofosfamida/uso terapéutico , Supervivencia sin Enfermedad , Doxorrubicina/uso terapéutico , Femenino , Enfermedad de Hodgkin/tratamiento farmacológico , Humanos , Linfoma Folicular/tratamiento farmacológico , Linfoma de Células B Grandes Difuso/tratamiento farmacológico , Masculino , Persona de Mediana Edad , Prednisona/uso terapéutico , Estudios Prospectivos , Rituximab , Resultado del Tratamiento , Estados Unidos , Vincristina/uso terapéuticoRESUMEN
We previously identified autoantibodies to the endocytic-associated protein Huntingtin-interacting protein 1-related (HIP1R) in diffuse large B-cell lymphoma (DLBCL) patients. HIP1R regulates internalization of cell surface receptors via endocytosis, a process relevant to many therapeutic strategies including CD20 targeting with rituximab. In this study, we characterized HIP1R expression patterns, investigated a mechanism of transcriptional regulation and its clinical relevance in DLBCL patients treated with immunochemotherapy (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone, R-CHOP). HIP1R was preferentially expressed in germinal center B-cell-like DLBCL (P<0.0001) and inversely correlated with the activated B-cell-like DLBCL (ABC-DLBCL) associated transcription factor, Forkhead box P1 (FOXP1). HIP1R was confirmed as a direct FOXP1 target gene in ABC-DLBCL by FOXP1-targeted silencing and chromatin immunoprecipitation. Lower HIP1R protein expression (≤ 10% tumoral positivity) significantly correlated with inferior overall survival (OS, P=0.0003) and progression-free survival (PFS, P=0.0148) in R-CHOP-treated DLBCL patients (n=157). Reciprocal expression with ≥ 70% FOXP1 positivity defined FOXP1(hi)/HIP1R(lo) patients with particularly poor outcome (OS, P=0.0001; PFS, P=0.0016). In an independent R-CHOP-treated DLBCL (n=233) microarray data set, patients with transcript expression in lower quartile HIP1R and FOXP1(hi)/HIP1R(lo) subgroups exhibited worse OS, P=0.0044 and P=0.0004, respectively. HIP1R repression by FOXP1 is strongly associated with poor outcome, thus further understanding of FOXP1-HIP1R and/or endocytic signaling pathways might give rise to novel therapeutic options for DLBCL.
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Factores de Transcripción Forkhead/genética , Regulación Neoplásica de la Expresión Génica , Linfoma de Células B Grandes Difuso/genética , Linfoma de Células B Grandes Difuso/mortalidad , Proteínas Represoras/genética , Proteínas de Transporte Vesicular/genética , Proteínas Adaptadoras Transductoras de Señales , Adulto , Anciano , Anciano de 80 o más Años , Anticuerpos Monoclonales de Origen Murino/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Linfocitos B/metabolismo , Ciclofosfamida/uso terapéutico , Doxorrubicina/uso terapéutico , Femenino , Factores de Transcripción Forkhead/metabolismo , Humanos , Linfoma de Células B Grandes Difuso/tratamiento farmacológico , Linfoma de Células B Grandes Difuso/patología , Masculino , Proteínas de Microfilamentos , Persona de Mediana Edad , Estadificación de Neoplasias , Prednisona/uso terapéutico , Pronóstico , Unión Proteica , Proteínas Represoras/metabolismo , Rituximab , Resultado del Tratamiento , Proteínas de Transporte Vesicular/metabolismo , Vincristina/uso terapéutico , Adulto JovenRESUMEN
BACKGROUND: The established treatment of limited-stage follicular lymphoma is radiotherapy (RT). There is an inherent risk of transformation of follicular lymphoma to aggressive lymphoma; however, the frequency and impact on the outcome are unknown in limited-stage patients. MATERIALS AND METHODS: We identified 237 patients with limited-stage follicular lymphoma treated with curative intent RT. Cases were reviewed to determine the frequency of transformation and subsequent survival. RESULTS: With a median follow-up of 7.4 years, the 10-year risk of transformation was 18.5%. With a median follow-up after transformation of 4.7 years, the 3-year post-transformation progression-free survival (PFS) and overall survival (OS) were 42% and 44%, respectively. The addition of rituximab improved the 3-year post-transformation PFS and OS compared with combination chemotherapy alone (78% versus 15%, P < 0.00001) and (87% versus 38.5%, P < 0.00001), respectively. In multivariate analysis, only rituximab was associated with OS [HR 0.07 (95% CI 0.015-0.312, P = 0.001)] and PFS [HR 0.19 (95% CI 0.55-0.626, P = 0.007)] following transformation. CONCLUSIONS: There is a moderate risk of transformation in limited-stage follicular lymphoma treated with curative intent RT, and it substantially impacts outcome in these patients. Treatment with rituximab at the time of transformation appears to improve survival in this otherwise poor-risk population.
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Transformación Celular Neoplásica , Linfoma Folicular/patología , Linfoma Folicular/radioterapia , Anciano , Anciano de 80 o más Años , Anticuerpos Monoclonales de Origen Murino/efectos adversos , Anticuerpos Monoclonales de Origen Murino/uso terapéutico , Terapia Combinada , Supervivencia sin Enfermedad , Femenino , Humanos , Linfoma Folicular/tratamiento farmacológico , Linfoma Folicular/mortalidad , Masculino , Persona de Mediana Edad , Rituximab , Sobrevida , Resultado del TratamientoRESUMEN
BCL2 is deregulated in diffuse large B-cell lymphoma (DLBCL) by the t(14;18) translocation, gene amplification and/or nuclear factor-κB signaling. RNA-seq data have recently shown that BCL2 is the most highly mutated gene in germinal center B-cell (GCB) DLBCL. We have sequenced BCL2 in 298 primary DLBCL biopsies, 131 additional non-Hodgkin lymphoma biopsies, 24 DLBCL cell lines and 51 germline DNAs. We found frequent BCL2 mutations in follicular lymphoma (FL) and GCB DLBCL, but low levels of BCL2 mutations in activated B-cell DLBCL, mantle cell lymphoma, small lymphocytic leukemia and peripheral T-cell lymphoma. We found no BCL2 mutations in GC centroblasts. Many mutations were non-synonymous; they were preferentially located in the flexible loop domain, with few in BCL2-homology domains. An elevated transition/transversions ratio supports that the mutations result from somatic hypermutation. BCL2 translocations correlate with, and are likely important in acquisition of, additional BCL2 mutations in GCB DLBCL and FL. DLBCL mutations were not independently associated with survival. Although previous studies of BCL2 mutations in FL have reported mutations to result in pseudo-negative BCL2 protein expression, we find this rare in de-novo DLBCL.
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Leucemia Linfocítica Crónica de Células B/genética , Linfoma de Células B Grandes Difuso/genética , Linfoma de Células del Manto/genética , Linfoma de Células T Periférico/genética , Neoplasias del Mediastino/genética , Mutación/genética , Proteínas Proto-Oncogénicas c-bcl-2/genética , Análisis Citogenético , Humanos , Técnicas para Inmunoenzimas , Leucemia Linfocítica Crónica de Células B/metabolismo , Linfoma de Células B Grandes Difuso/metabolismo , Linfoma de Células del Manto/metabolismo , Linfoma de Células T Periférico/metabolismo , Neoplasias del Mediastino/metabolismo , Transporte de Proteínas , Proteínas Proto-Oncogénicas c-bcl-2/metabolismoRESUMEN
Follicular lymphoma (FL) cases with a t(14;18)(q32;q21) and minimal or no additional karyotypic alterations, such as copy number gains and losses and/or chromosomal rearrangements, may exhibit pathologic features and a clinical behavior similar to those with more complex karyotypes. This study sought to investigate whether the copy-neutral loss of heterozygosity (cnLOH) profiles of these minimally evolved t(14;18)(q32;q21)-positive follicular lymphoma (MEV-FL) cases are similar to or different from the majority of FL cases with more karyotypic alterations. Affymetrix SNP 6.0 array analysis was applied to the tumor genomes of 23 MEV-FL biopsy samples to assess for the presence of cnLOH. These cases carried either a single or no chromosomal abnormality in addition to t(14;18)(q32;q21) as determined by karyotyping. We found that, although these MEV-FL cases had simple karyotypes, they showed very similar cnLOH profiles as compared to cytogenetically complex cases. The most frequent regions affected by cnLOH were 1p (17%), 6p (17%), 12q (13%) and 16p (13%). Our study suggests that cnLOH alterations may serve as important contributors to the pathological and clinical manifestations of FL.
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Cromosomas Humanos Par 14 , Cromosomas Humanos Par 18 , Pérdida de Heterocigocidad , Linfoma Folicular/genética , Aberraciones Cromosómicas , Variaciones en el Número de Copia de ADN , Femenino , Reordenamiento Génico , Humanos , Cariotipo , Cariotipificación/métodos , Masculino , Análisis por Micromatrices/métodos , Persona de Mediana Edad , Polimorfismo de Nucleótido SimpleRESUMEN
BACKGROUND: The revised World Health Organization (WHO) classification maintains a histological grading system (grades 1-3) for follicular lymphoma (FL) and subdivides grade 3 into 3A (FL3A) and 3B (FL3B) subtypes. Optimal therapy of FL grade 3 and its potential curability with anthracycline-based chemotherapy remain uncertain. PATIENTS AND METHODS: We carried out a retrospective population-based analysis evaluating the clinical characteristics and outcome of FL3A and FL3B as strictly defined by WHO diagnostic criteria. Using the BC Cancer Agency Lymphoid Cancer Database, 161 patients with FL grade 3 were identified and, following detailed pathology review, composed of 139 with FL3A and 22 with FL3B. RESULTS: Patients with FL3B had a higher overall International Prognostic Index (IPI) score than FL3A patients (P = 0.03), though no significant difference in individual IPI risk factor frequencies was noted. More patients with FL3B received front-line anthracycline-containing chemotherapy (82% versus 36%, P ≤ 0.001). With median follow-up of 45 months, no difference in disease-specific survival (P = 0.74) or overall survival (OS) (P = 0.87) was found between FL3A and FL3B and no survival curve plateau was observed. Analysis limited to FL3A patients showed no OS advantage with front-line anthracycline use (P = 0.33). CONCLUSION: Using strict diagnostic criteria, there appears to be no difference in outcome between patients with FL3A and FL3B and no evidence of curability with anthracycline-based therapy.
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Antraciclinas/uso terapéutico , Antineoplásicos/uso terapéutico , Linfoma Folicular/tratamiento farmacológico , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Supervivencia sin Enfermedad , Femenino , Humanos , Estimación de Kaplan-Meier , Linfoma Folicular/mortalidad , Linfoma Folicular/patología , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Insuficiencia del Tratamiento , Adulto JovenRESUMEN
Tumor progression is a multiple step process in which, in addition to oncogenic mutation, other supporting factors can contribute to transformation. The role these factors have in cancer is an open question. Using the Emicro-myc model of B-cell transformation, we evaluated the contribution of the cytokine interleukin-7 (IL-7) in supporting lymphomagenesis. We have previously shown that disruption of the Y449xxM motif of the IL-7 receptor alpha (IL-7Ralpha) in a knock-in mouse model (IL-7Ralpha(449F)) has minor effects on lymphocyte production, but interferes with the activation of survival effectors. To address the hypothesis that targeted signal ablation would selectively affect lymphocyte transformation, IL-7Ralpha(449F) mice were crossed with two lymphomagenesis models, transgenic (Tg) IL-7 and Emicro-myc mice. We found that the loss of IL-7Ralpha Y449 signaling prevented Tg IL-7-mediated T- and B-lymphocyte transformation and decreased the development of Emicro-myc-induced B-cell tumors. We showed that the IL-7Ralpha(449F) mutation prevented increased survival of Tg IL-7 CD8 T cells, and decreased viability of bone marrow progenitor B cells, as well as Emicro-myc-induced proliferation. This study shows that IL-7Ralpha Y449 is important for lymphocyte transformation, and that unlike deficiencies in pre-B cell receptor signaling, Myc overexpression cannot compensate for the loss of IL-7Ralpha signals in early B-cell development.
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Secuencias de Aminoácidos , Linfocitos/citología , Linfoma/patología , Receptores de Interleucina-7/fisiología , Animales , Citometría de Flujo , Genes myc , Ratones , Ratones Transgénicos , Receptores de Interleucina-7/química , Receptores de Interleucina-7/genéticaRESUMEN
BACKGROUND: The addition of rituximab to CHOP (R-CHOP; CHOP, cyclophosphamide, doxorubicin, vincristine, and prednisone) chemotherapy improves outcome in patients with diffuse large B-cell lymphoma (DLBCL). We evaluated the risk of central nervous system (CNS) relapse in the R-CHOP in a population-based cohort of patients with DLBCL. METHODS: Patients with DLBCL diagnosed from 1 September 1999 to 14 January 2005 at the British Columbia Cancer Agency (BCCA) were identified. Patients were included if they were > or =16 years old with advanced stage or any stage with testicular involvement and were treated with CHOP (1999-2001) or R-CHOP (2001-2005) with curative intent. RESULTS: Four hundred and thirty-five patients were identified; 126 (29%) were treated with CHOP and 309 (71%) with R-CHOP. With a median follow-up of 5.7 years, there were 31 CNS relapses in total with a trend to a reduced likelihood of CNS relapse in R-CHOP-treated patients (3-year risk 9.7% versus 6.4, P = 0.085). In multivariate analysis, the use of rituximab significantly reduced the risk of CNS relapse [hazard ratio (HR) 0.45, P = 0.034]; this benefit was more striking in patients who achieved a complete response (HR 0.18, P = 0.005). CONCLUSION: The use of R-CHOP appears to reduce the overall risk of CNS relapse in patients with DLBCL particularly in patients who achieve a complete response.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias del Sistema Nervioso Central/tratamiento farmacológico , Neoplasias del Sistema Nervioso Central/secundario , Linfoma de Células B Grandes Difuso/tratamiento farmacológico , Neoplasias del Mediastino/tratamiento farmacológico , Recurrencia Local de Neoplasia/diagnóstico , Anciano , Anticuerpos Monoclonales/administración & dosificación , Anticuerpos Monoclonales de Origen Murino , Estudios de Cohortes , Ciclofosfamida/administración & dosificación , Doxorrubicina/administración & dosificación , Femenino , Estudios de Seguimiento , Humanos , Incidencia , Linfoma de Células B Grandes Difuso/patología , Masculino , Neoplasias del Mediastino/patología , Persona de Mediana Edad , Prednisona/administración & dosificación , Pronóstico , Factores de Riesgo , Rituximab , Tasa de Supervivencia , Vincristina/administración & dosificaciónRESUMEN
Quantitative methylation profiling was performed using the Illumina GoldenGate Assay in untreated follicular lymphoma (FL) (164), paired pre- and post-transformation FL (20), benign haematopoietic (24) samples and purified B and T cells from two FL cases. Methylation values allowed separation of untreated FL samples from controls with one exception, based primarily on tumour-specific gains of methylation typically occurring within CpG islands. Genes that are targets for epigenetic repression in stem cells by Polycomb Repressor Complex 2 were significantly over-represented among hypermethylated genes. Methylation profiles were conserved in sequential FL and t-FL biopsies, suggesting that widespread methylation represents an early event in lymphomagenesis and may not contribute substantially to transformation. A significant (P<0.05) correlation between FL methylation values and reduced gene expression was shown for up to 28% of loci. Methylation changes occurred predominantly in B cells with variability in the amount of non-malignant tissue between samples preventing conclusive correlation with survival. This represents an important caveat in attributing prognostic relevance to methylation and future studies in cancer will optimally require purified tumour populations to address the impact of methylation on clinical outcome.
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Metilación de ADN , Perfilación de la Expresión Génica , Ganglios Linfáticos/patología , Linfoma Folicular/genética , Análisis de Secuencia por Matrices de Oligonucleótidos , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Niño , Preescolar , Islas de CpG , Epigénesis Genética , Regulación Neoplásica de la Expresión Génica , Humanos , Persona de Mediana Edad , Adulto JovenRESUMEN
BACKGROUND: The International Peripheral T-cell Lymphoma Project was organized to better understand the T-cell and natural killer (NK) cell lymphomas, and our task is to present the clinicopathologic correlations and therapeutic results for adult T-cell leukemia/lymphoma (ATL). PATIENTS AND METHODS: Among 1153 patients with T-cell or NK cell lymphomas, 126 patients (9.6%) with ATL were represented in this project. All were categorized as aggressive ATL, i.e. acute or lymphoma type, and 87% fell into the lymphoma type. RESULTS: The median age was 62 years and the male to female ratio was 1.2 : 1. Significant prognostic factors for overall survival (OS) by univariate analysis were the presence of B symptoms (P = 0.018), platelet count <150 x 10(9)/l (P = 0.065), and the International Prognostic Index (IPI; P = 0.019). However, multivariate analysis indicated that only the IPI was an independent predictor of OS. Combination chemotherapy including anthracyclines was given as the initial therapy in 109 of the 116 patients (94%) who received treatment, and the overall and complete response rates were 70% and 34%, respectively. However, there was no survival benefit for those receiving an anthracycline-containing regimen. CONCLUSION: Patients with aggressive ATL have a poor clinical outcome and the IPI is a useful model for predicting outcome in ATL of the lymphoma type.
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Leucemia-Linfoma de Células T del Adulto/patología , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Masculino , Persona de Mediana Edad , PronósticoRESUMEN
BACKGROUND AND AIMS: The results of class prediction and the determination of prognostic markers in diffuse large B-cell lymphoma (DLBCL) have been variably reported. Apart from biological variations, this may be caused by differences in laboratory techniques, scoring definitions and inter- and intra-observer variation. In this study, an international collaboration of clinical lymphoma research groups has concentrated on validation and standardisation of immunohistochemistry of the currently potentially interesting prognostic markers in DLBCL. METHODS: Sections of a tissue microarray with 36 cases of DLBCL were stained in eight laboratories with antibodies to CD20, CD5, bcl-2, bcl-6, CD10, HLA-DR, MUM-1 and Ki-67 according to local methods. The study was performed in two rounds, firstly focused on the evaluation of laboratory staining variation, and secondly on the scoring variation. RESULTS: Different techniques resulted in highly variable results and poor reproducibility for almost all markers. Reproducibility of the nuclear markers was highly sensitive to technical variations, including immunological enhancement techniques (agreements 34%). With elimination of variation due to staining and uniformly agreed on scoring criteria, significant improvement was seen; however less so for bcl-6 and Ki-67 (agreement 53-58%). Absence of internal controls that preclude scoring, significantly influenced the results for CD10 and bcl-6. CONCLUSION: Semi-quantitative immunohistochemistry for subclassification of DLBCL is feasible, but with varying rates of concordance for different markers and only using optimised techniques and strict scoring criteria. These findings may explain the wide variation in prognostic impact reported in the literature. Harmonisation of techniques and centralised consensus review appears mandatory when using immunohistochemical biomarkers for treatment stratification.
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Biomarcadores de Tumor/metabolismo , Linfoma de Células B Grandes Difuso/diagnóstico , Antígenos CD/metabolismo , Proteínas de Unión al ADN/metabolismo , Antígenos HLA-DR/metabolismo , Humanos , Antígeno Ki-67/metabolismo , Linfoma de Células B Grandes Difuso/clasificación , Proteínas de Neoplasias/metabolismo , Variaciones Dependientes del Observador , Pronóstico , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Proteínas Proto-Oncogénicas c-bcl-6 , Reproducibilidad de los Resultados , Análisis de Matrices Tisulares/métodosRESUMEN
BACKGROUND: The addition of rituximab to combination chemotherapy with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP), or R-CHOP, has significantly improved the survival of patients with diffuse large-B-cell lymphoma. Whether gene-expression signatures correlate with survival after treatment of diffuse large-B-cell lymphoma is unclear. METHODS: We profiled gene expression in pretreatment biopsy specimens from 181 patients with diffuse large-B-cell lymphoma who received CHOP and 233 patients with this disease who received R-CHOP. A multivariate gene-expression-based survival-predictor model derived from a training group was tested in a validation group. RESULTS: A multivariate model created from three gene-expression signatures--termed "germinal-center B-cell," "stromal-1," and "stromal-2"--predicted survival both in patients who received CHOP and patients who received R-CHOP. The prognostically favorable stromal-1 signature reflected extracellular-matrix deposition and histiocytic infiltration. By contrast, the prognostically unfavorable stromal-2 signature reflected tumor blood-vessel density. CONCLUSIONS: Survival after treatment of diffuse large-B-cell lymphoma is influenced by differences in immune cells, fibrosis, and angiogenesis in the tumor microenvironment.
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Perfilación de la Expresión Génica , Expresión Génica , Linfoma de Células B Grandes Difuso/genética , Células del Estroma/metabolismo , Anticuerpos Monoclonales/administración & dosificación , Anticuerpos Monoclonales de Origen Murino , Protocolos de Quimioterapia Combinada Antineoplásica , Ciclofosfamida , Progresión de la Enfermedad , Doxorrubicina , Matriz Extracelular/genética , Regulación Neoplásica de la Expresión Génica , Genes MHC Clase II , Centro Germinal , Humanos , Factores Inmunológicos/administración & dosificación , Estimación de Kaplan-Meier , Linfoma de Células B Grandes Difuso/tratamiento farmacológico , Linfoma de Células B Grandes Difuso/mortalidad , Linfoma de Células B Grandes Difuso/patología , Persona de Mediana Edad , Análisis Multivariante , Neovascularización Patológica/genética , Prednisona , Pronóstico , Rituximab , Células del Estroma/patología , VincristinaRESUMEN
Outcome is poor with conventional therapy for relapsed transformed non-Hodgkin's lymphoma (NHL). Autologous SCT has been successfully employed; however the impact of allogeneic SCT has not been well defined. We therefore studied 40 consecutive patients who received allogeneic SCT for relapsed composite and transformed NHL (25 transformed, 8 composite (same site) and 7 discordant (different sites)) with related (n=25) and unrelated donors (n=15) to evaluate long-term outcome. Conditioning was myeloablative in the majority (39 of 40). Of 40 patients, 11 survive with median follow-up of 25 months. Death occurred in similar proportions due to relapsed NHL (n=14) or treatment-related complications (transplant-related mortality, TRM; n=15). The cumulative incidence of TRM was 36% at 3 years and disease relapse was 42% at 5 years. Probability of 2- and 5-year event-free survival is 36 and 23% with overall survival 39 and 23%. Performance of SCT within 1 year of NHL diagnosis predicted improved outcome. Relapse and TRM remain significant problems in this setting, indicating the need for strategies whereby patients at high risk of transformation should be selected for early SCT, ideally before their actual transformation.