RESUMO
BACKGROUND: Diffuse low-grade and intermediate-grade gliomas (which together make up the lower-grade gliomas, World Health Organization grades II and III) have highly variable clinical behavior that is not adequately predicted on the basis of histologic class. Some are indolent; others quickly progress to glioblastoma. The uncertainty is compounded by interobserver variability in histologic diagnosis. Mutations in IDH, TP53, and ATRX and codeletion of chromosome arms 1p and 19q (1p/19q codeletion) have been implicated as clinically relevant markers of lower-grade gliomas. METHODS: We performed genomewide analyses of 293 lower-grade gliomas from adults, incorporating exome sequence, DNA copy number, DNA methylation, messenger RNA expression, microRNA expression, and targeted protein expression. These data were integrated and tested for correlation with clinical outcomes. RESULTS: Unsupervised clustering of mutations and data from RNA, DNA-copy-number, and DNA-methylation platforms uncovered concordant classification of three robust, nonoverlapping, prognostically significant subtypes of lower-grade glioma that were captured more accurately by IDH, 1p/19q, and TP53 status than by histologic class. Patients who had lower-grade gliomas with an IDH mutation and 1p/19q codeletion had the most favorable clinical outcomes. Their gliomas harbored mutations in CIC, FUBP1, NOTCH1, and the TERT promoter. Nearly all lower-grade gliomas with IDH mutations and no 1p/19q codeletion had mutations in TP53 (94%) and ATRX inactivation (86%). The large majority of lower-grade gliomas without an IDH mutation had genomic aberrations and clinical behavior strikingly similar to those found in primary glioblastoma. CONCLUSIONS: The integration of genomewide data from multiple platforms delineated three molecular classes of lower-grade gliomas that were more concordant with IDH, 1p/19q, and TP53 status than with histologic class. Lower-grade gliomas with an IDH mutation either had 1p/19q codeletion or carried a TP53 mutation. Most lower-grade gliomas without an IDH mutation were molecularly and clinically similar to glioblastoma. (Funded by the National Institutes of Health.).
Assuntos
DNA de Neoplasias/análise , Genes p53 , Glioma/genética , Mutação , Adolescente , Adulto , Idoso , Cromossomos Humanos Par 1 , Cromossomos Humanos Par 19 , Análise por Conglomerados , Feminino , Glioblastoma/genética , Glioma/metabolismo , Glioma/mortalidade , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Modelos de Riscos Proporcionais , Análise de Sequência de DNA , Transdução de SinaisRESUMO
PURPOSE: Primary central nervous system lymphoma (PCNSL) is an aggressive non-Hodgkin lymphoma confined to the central nervous system. Whether there is a PCNSL-specific genomic signature and, if so, how it differs from systemic diffuse large B-cell lymphoma (DLBCL) is uncertain. EXPERIMENTAL DESIGN: We performed a comprehensive genomic study of tumor samples from 19 immunocompetent PCNSL patients. Testing comprised array-comparative genomic hybridization and whole exome sequencing. RESULTS: Biallelic inactivation of TOX and PRKCD was recurrently found in PCNSL but not in systemic DLBCL, suggesting a specific role in PCNSL pathogenesis. In addition, we found a high prevalence of MYD88 mutations (79%) and CDKN2A biallelic loss (60%). Several genes recurrently affected in PCNSL were common with systemic DLBCL, including loss of TNFAIP3, PRDM1, GNA13, TMEM30A, TBL1XR1, B2M, CD58, activating mutations of CD79B, CARD11, and translocations IgH-BCL6. Overall, B-cell receptor/Toll-like receptor/NF-κB pathways were altered in >90% of PNCSL, highlighting its value for targeted therapeutic approaches. Furthermore, integrated analysis showed enrichment of pathways associated with immune response, proliferation, apoptosis, and lymphocyte differentiation. CONCLUSIONS: In summary, genome-wide analysis uncovered novel recurrent alterations, including TOX and PRKCD, helping to differentiate PCNSL from systemic DLBCL and related lymphomas.
Assuntos
Neoplasias do Sistema Nervoso Central/genética , Variação Genética , Estudo de Associação Genômica Ampla , Linfoma não Hodgkin/genética , Neoplasias do Sistema Nervoso Central/metabolismo , Neoplasias do Sistema Nervoso Central/mortalidade , Aberrações Cromossômicas , Cromossomos Humanos Par 6 , Hibridização Genômica Comparativa , Variações do Número de Cópias de DNA , Exoma , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Cariótipo , Linfoma não Hodgkin/metabolismo , Linfoma não Hodgkin/mortalidade , Mutação , PrognósticoRESUMO
BACKGROUND: Primary central nervous system lymphoma (PCNSL) is a rare extranodal lymphoma with distinctive biological behaviors. The evolving treatment of PCNSL has greatly improved the outcome for patients with this disease and has stimulated interest in second malignancies (SMs) in patients diagnosed with PCNSL. METHODS: The records of 129 cases of PCNSL at Mayo Clinic, diagnosed between January 1, 1988, and November 26, 2012, were reviewed. Data on clinical characteristics, laboratory parameters, treatments, outcomes, and SMs were collected. The mean follow-up time was 44.8 months (range, 0.5-240 months; median, 28.0 months). RESULTS: Altogether, 28 cases with 30 (23.26%) SMs were identified. Twenty (15.50%) patients had prior or synchronous SM. Ten (7.76%) patients developed a subsequent primary cancer after PCNSL. The most common sites of prior or synchronous SMs were prostate (4/20), skin (4/20), and gastrointestinal (3/20). The most common site of the subsequent SM was skin (4/10). Two cases were identified with both prior SM and subsequent SM. CONCLUSIONS: Second malignancies in cases with PCNSL were not uncommon and occurred in nearly a quarter of our cohort. Nonmelanoma skin cancers were frequently seen. Therefore, screening for SMs should also be considered in long-term follow-up of patients with PCNSL. In addition, the high incidence of subsequent cancer, synchronous cancer, and frequently seen nonmelanoma skin cancers may all indicate an immunosuppressed state in patients with PCNSL.
Assuntos
Neoplasias do Sistema Nervoso Central/epidemiologia , Linfoma/epidemiologia , Segunda Neoplasia Primária/epidemiologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Adulto JovemRESUMO
Glioma, the most common central nervous system cancer in adults, has poor prognosis. Here we identify a new SNP associated with glioma risk, rs1920116 (near TERC), that reached genome-wide significance (Pcombined = 8.3 × 10(-9)) in a meta-analysis of genome-wide association studies (GWAS) of high-grade glioma and replication data (1,644 cases and 7,736 controls). This region has previously been associated with mean leukocyte telomere length (LTL). We therefore examined the relationship between LTL and both this new risk locus and other previously established risk loci for glioma using data from a recent GWAS of LTL (n = 37,684 individuals). Alleles associated with glioma risk near TERC and TERT were strongly associated with longer LTL (P = 5.5 × 10(-20) and 4.4 × 10(-19), respectively). In contrast, risk-associated alleles near RTEL1 were inconsistently associated with LTL, suggesting the presence of distinct causal alleles. No other risk loci for glioma were associated with LTL. The identification of risk alleles for glioma near TERC and TERT that also associate with telomere length implicates telomerase in gliomagenesis.
Assuntos
Glioma/genética , Polimorfismo de Nucleotídeo Único/genética , RNA/genética , Telomerase/genética , Telômero/genética , Adulto , Estudos de Casos e Controles , Estudo de Associação Genômica Ampla , Genótipo , Glioma/patologia , Humanos , Leucócitos/metabolismo , Leucócitos/patologia , Gradação de Tumores , Prognóstico , Fatores de RiscoRESUMO
BACKGROUND: Gliomas are the most common primary malignant brain tumors in adults with great heterogeneity in histopathology and clinical course. The intent was to evaluate the relevance of known glioblastoma (GBM) expression and methylation based subtypes to grade II and III gliomas (ie. lower grade gliomas). METHODS: Gene expression array, single nucleotide polymorphism (SNP) array and clinical data were obtained for 228 GBMs and 176 grade II/II gliomas (GII/III) from the publically available Rembrandt dataset. Two additional datasets with IDH1 mutation status were utilized as validation datasets (one publicly available dataset and one newly generated dataset from MD Anderson). Unsupervised clustering was performed and compared to gene expression subtypes assigned using the Verhaak et al 840-gene classifier. The glioma-CpG Island Methylator Phenotype (G-CIMP) was assigned using prediction models by Fine et al. RESULTS: Unsupervised clustering by gene expression aligned with the Verhaak 840-gene subtype group assignments. GII/IIIs were preferentially assigned to the proneural subtype with IDH1 mutation and G-CIMP. GBMs were evenly distributed among the four subtypes. Proneural, IDH1 mutant, G-CIMP GII/III s had significantly better survival than other molecular subtypes. Only 6% of GBMs were proneural and had either IDH1 mutation or G-CIMP but these tumors had significantly better survival than other GBMs. Copy number changes in chromosomes 1p and 19q were associated with GII/IIIs, while these changes in CDKN2A, PTEN and EGFR were more commonly associated with GBMs. CONCLUSIONS: GBM gene-expression and methylation based subtypes are relevant for GII/III s and associate with overall survival differences. A better understanding of the association between these subtypes and GII/IIIs could further knowledge regarding prognosis and mechanisms of glioma progression.
Assuntos
Neoplasias Encefálicas/classificação , Neoplasias Encefálicas/genética , Glioblastoma/classificação , Glioblastoma/genética , Glioma/classificação , Glioma/genética , Neoplasias Encefálicas/patologia , Ilhas de CpG/genética , Variações do Número de Cópias de DNA/genética , Metilação de DNA/genética , Feminino , Regulação Neoplásica da Expressão Gênica , Glioblastoma/patologia , Glioma/patologia , Humanos , Isocitrato Desidrogenase/genética , Masculino , Pessoa de Meia-Idade , Mutação/genética , Gradação de Tumores , Análise de SobrevidaRESUMO
Glioblastoma multiforme (GBM) accounts for about 38% of primary brain tumors in the United States. GBM is characterized by extensive angiogenesis induced by vascular growth factors and cytokines. The transcription of these growth factors and cytokines is regulated by the Hypoxia-Inducible-Factor-1(HIF-1), which is a key regulator mediating the cellular response to hypoxia. It is known that Factor Inhibiting HIF-1, or FIH-1, is also involved in the cellular response to hypoxia and has the capability to physically interact with HIF-1 and block its transcriptional activity under normoxic conditions. Delineation of the regulatory role of FIH-1 will help us to better understand the molecular mechanism responsible for tumor growth and progression and may lead to the design of new therapies targeting cellular pathways in response to hypoxia. Previous studies have shown that the chromosomal region of 10q24 containing the FIH-1 gene is often deleted in GBM, suggesting a role for the FIH-1 in GBM tumorigenesis and progression. In the current study, we found that FIH-1 is able to inhibit HIF-mediated transcription of GLUT1 and VEGF-A, even under hypoxic conditions in human glioblastoma cells. FIH-1 has been found to be more potent in inhibiting HIF function than PTEN. This observation points to the possibility that deletion of 10q23-24 and loss or decreased expression of FIH-1 gene may lead to a constitutive activation of HIF-1 activity, an alteration of HIF-1 targets such as GLUT-1 and VEGF-A, and may contribute to the survival of cancer cells in hypoxia and the development of hypervascularization observed in GBM. Therefore FIH-1 can be potential therapeutic target for the treatment of GBM patients with poor prognosis.
Assuntos
Neoplasias Encefálicas/metabolismo , Regulação Neoplásica da Expressão Gênica , Glioblastoma/metabolismo , Subunidade alfa do Fator 1 Induzível por Hipóxia/fisiologia , Oxigenases de Função Mista/fisiologia , Proteínas Repressoras/fisiologia , Transcrição Gênica , Animais , Neoplasias Encefálicas/genética , Hipóxia Celular , Linhagem Celular Tumoral , Proteína p300 Associada a E1A/metabolismo , Glioblastoma/genética , Transportador de Glucose Tipo 1/genética , Transportador de Glucose Tipo 1/metabolismo , Humanos , Camundongos , Camundongos Nus , Transplante de Neoplasias , Fator A de Crescimento do Endotélio Vascular/genética , Fator A de Crescimento do Endotélio Vascular/metabolismoRESUMO
OBJECTIVE: To report and compare spinal cord [(18)F]-fluorodeoxyglucose-positron emission tomography (FDG-PET) metabolism in 51 patients with active myelopathy. PATIENTS AND METHODS: We retrospectively identified patients from January 1, 2001, through December 31, 2011, with active myelopathy in whom FDG-PET was performed. Inclusion criteria were (1) intramedullary myelopathy, (2) neoplastic/inflammatory etiology, and (3) FDG-PET performed after myelopathy onset. Exclusion criteria were (1) extramedullary myelopathy, (2) radiation-associated myelopathy, (3) no pathological confirmation of neoplasm, and (4) inactive myelopathy. Diagnostic categories of nonsarcoid inflammatory, neoplastic, and neurosarcoid were based on their final myelopathic diagnosis. Two radiologists who independently assessed FDG-PET for spinal cord hypermetabolism and maximum standardized uptake value (SUVmax) were blinded to the underlying etiology. RESULTS: Fifty-one patients (53% women) with a median age of 60 years (range, 20-82 years) were included. Inflammatory myelopathic diagnoses (n=24) were as follows: paraneoplastic (n=13), autoimmune/other (n=5), inflammatory demyelinating (n=4), and transverse myelitis (n=2). Neoplastic diagnoses (n=21) were as follows: intramedullary metastases (n=12), intramedullary lymphoma/leukemia (n=7), and primary intramedullary neoplasm (n=2). Six patients had neurosarcoid myelopathy. Spinal cord hypermetabolism was more common with neoplastic myelopathy than with nonsarcoid inflammatory myelopathy (17 of 21 [81%] vs 6 of 24 [25%]; P<.001). Agreement between radiologist's assessments was excellent (κ=0.88). Median SUVmax was greater in neoplastic than in nonsarcoid inflammatory causes of myelopathy (3.3 g/mL vs 1.9 g/mL; P<.001). The FDG-PET hypermetabolism was seen in 3 of the 6 patients (50%) with neurosarcoid myelopathy (median SUVmax, 2.6 g/mL; range, 1.8-12.2 g/mL). CONCLUSION: Spinal cord FDG-PET hypermetabolism in patients with active myelopathy may be reliably detected and was more common in neoplastic than in inflammatory myelopathies in this study. Future investigation of spinal cord FDG-PET is indicated to assess its potential contributions in evaluating active myelopathies.
Assuntos
Fluordesoxiglucose F18 , Tomografia por Emissão de Pósitrons/métodos , Doenças da Medula Espinal/diagnóstico por imagem , Medula Espinal/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Fluordesoxiglucose F18/farmacocinética , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Medula Espinal/diagnóstico por imagem , Adulto JovemRESUMO
There has been an overall decline in the United States incidence of Primary CNS Lymphoma (PCNSL) from 1998 to 2008. This study's intent was to characterize the cohorts contributing to it. First, calculated the PCNSL incidence rates from nine Surveillance, Epidemiology, and End Results (SEER) registries for time period 1973 to 2008. Second, examined the time trends overall and by age and gender. Third, used 1992-2008 SEER data from the same registries to obtain overall trends for diffuse large B-cell lymphoma (DLBCL). Last, rates were age-adjusted to the 2000 US standard population and reported per 100,000 person-years. Rates continued to increase in women at all ages and men aged 65 and older. In men aged 20-39 and 40-64 years incidence rates peaked in 1995 and then declined dramatically, stabilizing after 1998. The trends in the incidence of PCNSL over this time frame were significantly different from DLBCL for ages 20-39 (P < 0.001) and 40-64 (P < 0.001) years but were not different for the 65 years and older age group (P = 0.99). The overall PCNSL incidence rate declined since 1995 and was driven primarily by the changing incidence in young and middle-aged men. The rate has continued to increase in men aged 65 years and older and in women. The trends in incidence in the younger age groups over this time period did not parallel those observed for DLBCL.
Assuntos
Neoplasias do Sistema Nervoso Central/epidemiologia , Linfoma não Hodgkin/epidemiologia , Adulto , Distribuição por Idade , Idoso , Feminino , Humanos , Incidência , Linfoma Relacionado a AIDS/epidemiologia , Linfoma Difuso de Grandes Células B/epidemiologia , Masculino , Pessoa de Meia-Idade , Morbidade/tendências , Sistema de Registros , Programa de SEER/estatística & dados numéricos , Sarcoma de Kaposi/epidemiologia , Distribuição por Sexo , Neoplasias Cutâneas/epidemiologia , Estados Unidos/epidemiologiaRESUMO
INTRODUCTION: Recent discoveries of inherited glioma risk loci and acquired IDH mutations are providing new insights into glioma etiology. IDH mutations are common in lower grade gliomas and secondary glioblastomas and uncommon in primary glioblastomas. Because the inherited variant in 11q23 has been associated with risk of lower grade glioma and not with glioblastomas, we hypothesized that this variant increases susceptibility to IDH-mutated gliomas, but not to IDH-wild-type gliomas. METHODS: We tested this hypothesis in patients with glioma and controls from the San Francisco Adult Glioma Study, the Mayo Clinic, and Illumina controls (1102 total patients, 5299 total controls). Case-control additive associations of 11q23 risk alleles (rs498872, T allele) were calculated using logistic regression, stratified by tumor IDH status (mutated or wild-type) and by histology and grade. We also adjusted for the recently discovered 8q24 glioma risk locus rs55705857 G allele. RESULTS: The 11q23 glioma risk locus was associated with increased risk of IDH-mutated gliomas of all histologies and grades (odds ratio [OR] = 1.50; 95% confidence interval [CI] = 1.29-1.74; P = 1.3X10(-7)) but not with IDH-wild-type gliomas of any histology or grade (OR = 0.91; 95% CI = 0.81-1.03; P = 0.14). The associations were independent of the rs55705857 G allele. CONCLUSION: A variant at the 11q23 locus increases risk for IDH-mutated but not IDH-wild-type gliomas, regardless of grade or histology.
Assuntos
Neoplasias Encefálicas/genética , Cromossomos Humanos Par 11/genética , Predisposição Genética para Doença , Glioma/genética , Isocitrato Desidrogenase/genética , Mutação/genética , Adulto , Biomarcadores Tumorais/genética , Neoplasias Encefálicas/patologia , Estudos de Casos e Controles , Cromossomos Humanos Par 8/genética , Feminino , Glioma/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Estadiamento de Neoplasias , Polimorfismo de Nucleotídeo Único/genética , PrognósticoRESUMO
Cognitive dysfunction is a common manifestation of primary brain tumors. We evaluated the association between early cognitive dysfunction and prognosis in a cohort of patients with newly diagnosed glioblastoma. Ninety-one patients who completed neuropsychological assessment after tumor resection but before further treatment were identified in the MD Anderson Neuropsychology database. The relationship between performance on cognitive testing and survival was evaluated using not only Cox proportional hazards models that included clinical factors such as age and KPS but also the Kaplan-Meier method. Median survival time from surgery was 20.7 months. Rates of impairment on cognitive testing ranged from 7.1% for Similarities, to 60.0% for Hopkins Verbal Learning Test-Revised Total Recall. As continuous variables, the Clinical Trial Battery Composite, Trail Making Test Part B, and Controlled Oral Word Association test were associated with survival. Impairment on the Trail Making Test Part B, Controlled Oral Word Association, Similarities, and Digit Span were associated with mortality. Kaplan-Meier analysis demonstrated the survival impact of these tests on the group as a whole and in select patient subgroups defined by classification by the Radiation Therapy Oncology Group (RTOG) Recursive Partitioning Analysis (RPA). Cognitive impairment as measured by specific neuropsychological tests is independently associated with poor prognosis in patients with newly diagnosed glioblastoma, and this effect remains significant even within patient subgroups defined by RTOG RPA class. Executive function and attention are the cognitive domains most closely associated with prognosis in this analysis.
Assuntos
Neoplasias Encefálicas/mortalidade , Neoplasias Encefálicas/psicologia , Transtornos Cognitivos/mortalidade , Glioblastoma/mortalidade , Glioblastoma/psicologia , Adulto , Neoplasias Encefálicas/diagnóstico , Feminino , Seguimentos , Glioblastoma/diagnóstico , Humanos , Estimativa de Kaplan-Meier , Avaliação de Estado de Karnofsky , Masculino , Pessoa de Meia-Idade , Testes Neuropsicológicos , Prognóstico , Taxa de SobrevidaRESUMO
PURPOSE: Glioblastoma is a devastating, incurable disease with few known prognostic factors. Here, we present the first genome-wide survival and validation study for glioblastoma. EXPERIMENTAL DESIGN: Cox regressions for survival with 314,635 inherited autosomal single-nucleotide polymorphisms (SNP) among 315 San Francisco Adult Glioma Study patients for discovery and three independent validation data sets [87 Mayo Clinic, 232 glioma patients recruited from several medical centers in Southeastern United States (GliomaSE), and 115 The Cancer Genome Atlas patients] were used to identify SNPs associated with overall survival for Caucasian glioblastoma patients treated with the current standard of care, resection, radiation, and temozolomide (total n = 749). Tumor expression of the gene that contained the identified prognostic SNP was examined in three separate data sets (total n = 619). Genotype imputation was used to estimate hazard ratios (HR) for SNPs that had not been directly genotyped. RESULTS: From the discovery and validation analyses, we identified a variant in single-stranded DNA-binding protein 2 (SSBP2) on 5q14.1 associated with overall survival in combined analyses (HR, 1.64; P = 1.3 × 10(-6)). Expression of SSBP2 in tumors from three independent data sets also was significantly related to patient survival (P = 5.3 × 10(-4)). Using genotype imputation, the SSBP2 SNP rs17296479 had the strongest statistically significant genome-wide association with poorer overall patient survival (HR, 1.79; 95% CI, 1.45-2.22; P = 1.0 × 10(-7)). CONCLUSION: The minor allele of SSBP2 SNP rs17296479 and the increased tumor expression of SSBP2 were statistically significantly associated with poorer overall survival among glioblastoma patients. With further confirmation, previously unrecognized inherited variations influencing survival may warrant inclusion in clinical trials to improve randomization. Unaccounted for genetic influence on survival could produce unwanted bias in such studies.
Assuntos
Neoplasias Encefálicas/genética , Proteínas de Ligação a DNA/genética , Glioblastoma/genética , Polimorfismo de Nucleotídeo Único , Neoplasias Encefálicas/mortalidade , Neoplasias Encefálicas/terapia , Dacarbazina/análogos & derivados , Dacarbazina/uso terapêutico , Feminino , Estudo de Associação Genômica Ampla , Glioblastoma/mortalidade , Glioblastoma/terapia , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , TemozolomidaRESUMO
Intramedullary spinal cord metastases of solid neoplasms are associated with poor long-term survival. As the characteristics of secondary intramedullary spinal cord non-Hodgkin's lymphoma (NHL) are not well understood, we sought to describe its clinical features and outcome. We retrospectively reviewed the Mayo Clinic patient database, lymphoma database, and pathology records from 1996 to 2010 and identified patients with clinical myelopathy and neuroimaging evidence of secondary intramedullary spinal cord involvement from pathologically confirmed systemic NHL. Seven patients were included in this study. The median age was 61 years (range, 41-81). Symptom onset was subacute (≤8 weeks) in six. Four patients were wheelchair-dependent at diagnosis. Spinal cord NHL was diagnosed by cerebrospinal fluid cytology in four; Positron emission tomography hypermetabolism in two; or MRI features alone. Myelopathy developed in five patients at a median 8 months (range, 1-58) following systemic NHL diagnosis, while myelopathy was the heralding symptom of NHL in two patients. Spinal cord MRI lesions were characteristically gadolinium enhancing and expansile. Four patients had co-existing MRI brain lesions. Six patients had B-cell NHL and one patient T-cell NHL. Six of the seven were treated (high dose intravenous methotrexate in three; radiation therapy in two; and R-CHOP in one). Median survival was 11.5 months (range, 1-28) with a 33% 2-year survival compared to historical median survival estimates of spinal cord metastases due to solid tumors of 3 months. In secondary intramedullary spinal cord involvement of NHL early neurological morbidity is common, but overall survival compares favorably to previously reported survival in spinal cord metastases from solid tumors.
Assuntos
Linfoma não Hodgkin/diagnóstico , Neoplasias da Medula Espinal/diagnóstico , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Estimativa de Kaplan-Meier , Linfoma não Hodgkin/mortalidade , Linfoma não Hodgkin/terapia , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Neoplasias da Medula Espinal/mortalidade , Neoplasias da Medula Espinal/secundário , Neoplasias da Medula Espinal/terapiaRESUMO
The standard-of-care treatment for newly diagnosed glioblastoma changed in 2005, when radiation therapy plus temozolomide chemotherapy replaced radiation therapy alone. It is not yet clear how this change in treatment has influenced patient survival in routine clinical practice, or if a survival benefit extends to patients older than those enrolled in the trial. Data from the Surveillance, Epidemiology, and End Results (SEER) Program was analyzed to compare survival of adult glioblastoma patients diagnosed from 2000-2003 to patients diagnosed from 2005-2008, in order to evaluate pre-temozolomide and post-temozolomide periods. The Kaplan-Meier method and Cox proportional hazards models were used. 6,673 patients with glioblastoma diagnosed from 2000-2003 and 7,259 patients diagnosed from 2005-2008 were identified. Median survival times of all patients diagnosed in the 2000-2003 and 2005-2008 periods were 8.1 and 9.7 months, respectively. Amongst patients treated with surgery and a radiation-containing regimen, median survival was 12.0 months in 2000-2003 and 14.2 months in 2005-2008. In the temozolomide era, median survival times ranged from a high of 31.9 months in patients age 20-29 to a low of 5.6 months in patients age 80 and older. The survival of patients with newly diagnosed glioblastoma improved from 2000-2003 to 2005-2008, likely due to temozolomide use. However, median survival time after glioblastoma diagnosis in the SEER population remains well under one year, largely driven by poor prognosis in elderly patients.
Assuntos
Antineoplásicos Alquilantes/uso terapêutico , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/epidemiologia , Dacarbazina/análogos & derivados , Glioblastoma/tratamento farmacológico , Glioblastoma/epidemiologia , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Neoplasias Encefálicas/mortalidade , Dacarbazina/uso terapêutico , Feminino , Glioblastoma/mortalidade , Humanos , Estimativa de Kaplan-Meier , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Temozolomida , Resultado do Tratamento , Estados Unidos/epidemiologia , Adulto JovemRESUMO
Glioma risk has consistently been inversely associated with allergy history but not with smoking history despite putative biologic plausibility. Data from 855 high-grade glioma cases and 1,160 controls from 4 geographic regions of the United States during 1997-2008 were analyzed for interactions between allergy and smoking histories and inherited variants in 5 established glioma risk regions: 5p15.3 (TERT), 8q24.21 (CCDC26/MLZE), 9p21.3 (CDKN2B), 11q23.3 (PHLDB1/DDX6), and 20q13.3 (RTEL1). The inverse relation between allergy and glioma was stronger among those who did not (odds ratio(allergy-glioma) = 0.40, 95% confidence interval: 0.28, 0.58) versus those who did (odds ratio(allergy-glioma) = 0.76, 95% confidence interval: 0.59, 0.97; P(interaction) = 0.02) carry the 9p21.3 risk allele. However, the inverse association with allergy was stronger among those who carried (odds ratio(allergy-glioma) = 0.44, 95% confidence interval: 0.29, 0.68) versus those who did not carry (odds ratio(allergy-glioma) = 0.68, 95% confidence interval: 0.54, 0.86) the 20q13.3 glioma risk allele, but this interaction was not statistically significant (P = 0.14). No relation was observed between glioma risk and smoking (odds ratio = 0.92, 95% confidence interval: 0.77, 1.10; P = 0.37), and there were no interactions for glioma risk of smoking history with any of the risk alleles. The authors' observations are consistent with a recent report that the inherited glioma risk variants in chromosome regions 9p21.3 and 20q13.3 may modify the inverse association of allergy and glioma.
Assuntos
Alelos , Astrocitoma/genética , Neoplasias Encefálicas/genética , Predisposição Genética para Doença/genética , Glioblastoma/genética , Hipersensibilidade/complicações , Polimorfismo de Nucleotídeo Único , Fumar/efeitos adversos , Astrocitoma/etiologia , Neoplasias Encefálicas/etiologia , Estudos de Casos e Controles , Feminino , Glioblastoma/etiologia , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de RiscoRESUMO
PURPOSE: Only a limited number of genetic studies have been conducted in primary central nervous system lymphomas (PCNSL), partly due to the rarity of the tumors and the very limited amount of available tissue. In this report, we present the first molecular characterization of copy number abnormalities (CNA) of newly diagnosed PCNSL by array-based comparative genomic hybridization (aCGH) in formalin-fixed paraffin-embedded (FFPE) specimens and compare the results with matched, frozen tumor specimens. EXPERIMENTAL DESIGN: We conducted aCGH in FFPE tissues from PCNSL. Results were compared with matched, paired, frozen tumors. RESULTS: Our analysis confirmed the good to fair quality and reliability of the data generated from limited amounts of tumoral FFPE tissue. Overall, all PCNSL cases were characterized by highly complex karyotypes, with a median of 23 CNAs per patient (range, 17-47). Overall, 20 chromosomal regions were recurrently found in more than 40% of cases. Deletions of 6p21, 6q, and 9p21.3 and gain of 12q12-q24.33 were the commonest CNAs. Other minimal affected regions were defined, and novel recurrent CNAs affecting single genes were identified in 3q26.32 (TBL1XR1) and 8q12.1 (TOX). CONCLUSIONS: The results obtained are encouraging. Larger archival tissue collections can now be analyzed to complement the still fragmented knowledge we have of the genetic basis of the PCNSL.
Assuntos
Neoplasias do Sistema Nervoso Central/genética , Hibridização Genômica Comparativa , Linfoma/genética , Idoso , Neoplasias do Sistema Nervoso Central/patologia , Aberrações Cromossômicas , Hibridização Genômica Comparativa/normas , Variações do Número de Cópias de DNA/genética , Feminino , Fixadores , Formaldeído , Regulação Neoplásica da Expressão Gênica , Humanos , Linfoma/patologia , Masculino , Pessoa de Meia-Idade , Inclusão em ParafinaRESUMO
PURPOSE: To describe the demographic and clinical features and outcomes for children and adolescents with primary CNS lymphoma (PCNSL). EXPERIMENTAL DESIGN: A retrospective series of children and adolescents with PCNSL was assembled from 10 cancer centers in 3 countries. RESULTS: Twenty-nine patients with a median age of 14 years were identified. Sixteen (55%) had Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 1 or greater. Frontline therapy consisted of chemotherapy only in 20 patients (69%), while 9 (31%) had chemotherapy plus cranial radiotherapy. Most patients received methotrexate (MTX)-based regimens. Overall response rate was 86% (complete remission 69%, partial remission 17%). The 2-year progression-free survival (PFS) and overall survival (OS) rates were 61% and 86%, respectively; the 3-year OS was 82%. Univariate analyses were conducted for age (≤ 14 vs. >14 years), PS (0 or 1 vs. >1), deep brain lesions, MTX dose, primary treatment with chemotherapy alone, intrathecal chemotherapy, and high-dose therapy. Primary treatment with chemotherapy alone was associated with better overall response rates with an odds ratio (OR) of 0.125 (P = 0.02). There was a marginally significant relationship between higher doses of MTX and response (OR = 1.5, P = 0.06). ECOG-PS of 0 to 1 was the only factor associated with better outcome with hazard ratios of 0.136 (P = 0.017) and 0.073 (P = 0.033) for PFS and OS, respectively. CONCLUSION: This is the largest series collected of pediatric PCNSL. The outcome of children and adolescents seems to be better than in adults. PS of 0 to 1 is associated with better survival.
Assuntos
Neoplasias do Sistema Nervoso Central/diagnóstico , Linfoma/diagnóstico , Adolescente , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias do Sistema Nervoso Central/mortalidade , Neoplasias do Sistema Nervoso Central/terapia , Criança , Pré-Escolar , Feminino , Humanos , Linfoma/mortalidade , Linfoma/terapia , Masculino , Estudos Retrospectivos , Resultado do Tratamento , Adulto JovemRESUMO
PURPOSE: To assess the efficacy and toxicity of chemotherapy consisting of cyclophosphamide, doxorubicin (Adriamycin), vincristine, and dexamethasone (CHOD) plus bis-chloronitrosourea (BCNU), cytosine arabinoside, and methotrexate (BVAM) followed by whole-brain irradiation (WBRT) for patients with primary central nervous system lymphoma (PCNSL). METHODS AND MATERIALS: Patients 70 years old and younger with newly diagnosed, biopsy-proven PCNSL received one cycle of CHOD followed by two cycles of BVAM. Patients then received WBRT, 30.6 Gy, if a complete response was evoked, or 50.4 Gy if the response was less than complete; both doses were given in 1.8-Gy daily fractions. The primary efficacy endpoint was 1-year survival. RESULTS: Thirty-six patients (19 men, 17 women) enrolled between 1995 and 2000. Median age was 60.5 years (range, 34 to 69 years). Thirty (83%) patients had baseline Eastern Cooperative Oncology Group performance scores of 0 to 1. All 36 patients were eligible for survival and response evaluations. Median time to progression was 12.3 months, and median survival was 18.5 months. The percentages of patients alive at 1, 2, and 3 years were 64%, 36%, and 33%, respectively. The best response was complete response in 10 patients and immediate progression in 7 patients. Ten (28%) patients had at least one grade 3 or higher neurologic toxicity. CONCLUSIONS: This regimen did improve the survival of PCNSL patients but also caused substantial toxicity. The improvement in survival is less than that reported with high-dose methotrexate-based therapies.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias do Sistema Nervoso Central/tratamento farmacológico , Neoplasias do Sistema Nervoso Central/radioterapia , Irradiação Craniana/métodos , Linfoma não Hodgkin/tratamento farmacológico , Linfoma não Hodgkin/radioterapia , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Carmustina/administração & dosagem , Carmustina/efeitos adversos , Neoplasias do Sistema Nervoso Central/mortalidade , Terapia Combinada/métodos , Irradiação Craniana/efeitos adversos , Ciclofosfamida/administração & dosagem , Ciclofosfamida/efeitos adversos , Citarabina/administração & dosagem , Citarabina/efeitos adversos , Dexametasona/administração & dosagem , Dexametasona/efeitos adversos , Progressão da Doença , Doxorrubicina/administração & dosagem , Doxorrubicina/efeitos adversos , Feminino , Humanos , Linfoma não Hodgkin/mortalidade , Masculino , Metotrexato/administração & dosagem , Metotrexato/efeitos adversos , Pessoa de Meia-Idade , Dosagem Radioterapêutica , Indução de Remissão , Vincristina/administração & dosagem , Vincristina/efeitos adversosRESUMO
Patients with glioblastoma (GBM) exhibit profound systemic immune defects that affect the success of conventional and immune-based treatments. A better understanding of the contribution of the tumor and/or therapy on systemic immune suppression is necessary for improved therapies, to monitor negative effects of novel treatments, to improve patient outcomes, and to increase understanding of this complex system. To characterize the immune profile of GBM patients, we phenotyped peripheral blood and compared these to normal donors. In doing so, we identified changes in systemic immunity associated with both the tumor and dexamethasone treated tumor bearing patients. In particular, dexamethasone exacerbated tumor associated lymphopenia primarily in the T cell compartment. We have also identified unique tumor and dexamethasone dependent altered monocyte phenotypes. The major population of altered monocytes (CD14(+)HLA-DR(lo/neg)) had a phenotype distinct from classical myeloid suppressor cells. These cells inhibited T cell proliferation, were unable to fully differentiate into mature dendritic cells, were associated with dexamethasone-mediated changes in CCL2 levels, and could be re-created in vitro using tumor supernatants. We provide evidence that tumors express high levels of CCL2, can contain high numbers of CD14(+) cells, that tumor supernatants can transform CD14(+)HLA-DR(+) cells into CD14(+)HLA-DR(lo/neg) immune suppressors, and that dexamethasone reduces CCL2 in vitro and is correlated with reduction of CCL2 in vivo. Consequently, we have developed a model for tumor mediated systemic immune suppression via recruitment and transformation of CD14(+) cells.
Assuntos
Comunicação Celular/imunologia , Dexametasona/metabolismo , Glioblastoma/imunologia , Antígenos HLA-DR/metabolismo , Tolerância Imunológica , Receptores de Lipopolissacarídeos/biossíntese , Monócitos/imunologia , Biomarcadores Tumorais/imunologia , Biomarcadores Tumorais/metabolismo , Comunicação Celular/genética , Células Cultivadas , Dexametasona/farmacologia , Glioblastoma/tratamento farmacológico , Glioblastoma/genética , Humanos , Tolerância Imunológica/efeitos dos fármacos , Tolerância Imunológica/imunologia , Receptores de Lipopolissacarídeos/genética , Monócitos/efeitos dos fármacos , Monócitos/patologiaRESUMO
To determine racial and ethnic differences in incidence and survival in patients with primary central nervous system lymphoma (PCNSL), NCI Surveillance, Epidemiology, and End Results (SEER) program data from 1992 to 2002 were queried. Data were substratified by age (20-49 years vs. 50 or above) and race (White, Black, Asian/Pacific Islander [A/PI], American Indian/Alaskan Native [AI/AN]). Incidence of PCNSL and survival were calculated by SEER(*)Stat software. The incidence rates were 0.94 per 100,000 per year (95% confidence interval [CI] 0.90-0.98) for Whites, 1.10 (95% CI 0.98-1.22) for Blacks, 0.51 (95% CI 0.28-0.74) for AI/AN, and 0.64 (95% CI 0.56-0.72) for A/PI. In patients aged 20-49 years the rates were 0.72 (95% CI 0.68-0.76) for Whites, 1.43 (95% CI 1.27-1.59) for Blacks, 0.58 (95% CI 0.30-0.86) for AI/AN, and 0.21 (CI 0.15-0.27) for A/PI. In patients over 49 years, the rates were 1.30 (95% CI 1.22-1.38) for Whites, 0.56 (95% CI 0.40-0.72) for Blacks, 0.34 (95% CI 0-0.70) for AI/AN, and 1.31 (95% CI 1.00-1.53) for A/PI. PCNSL incidence for ages 20-49 years for Black patients was twice that for Whites. Incidence for ages over 49 years for Whites was twice that for Blacks. Survival at 12 months, 24 months, and 60 months was higher among Whites than Blacks. Research is needed to determine the origin of these differences.
Assuntos
Neoplasias do Sistema Nervoso Central/epidemiologia , Linfoma/epidemiologia , Adulto , Negro ou Afro-Americano , Povo Asiático , População Negra , Feminino , Humanos , Incidência , Indígenas Norte-Americanos , Inuíte , Masculino , Pessoa de Meia-Idade , Grupos Raciais , Programa de SEER , Taxa de Sobrevida , População BrancaRESUMO
The purpose of this study was to evaluate long-term survival in patients with nonpilocytic low-grade gliomas (LGGs). Records of 314 adult patients with nonpilocytic LGGs diagnosed between 1960 and 1992 at the Mayo Clinic, Rochester, Minnesota, were retrospectively reviewed. The Kaplan-Meier method estimated progression-free survival (PFS) and overall survival (OS). Median age at diagnosis was 36 years. Median follow-up was 13.6 years. Operative pathology revealed pure astrocytoma in 181 patients (58%), oligoastrocytoma in 99 (31%), and oligodendroglioma in 34 (11%). Gross total resection (GTR) was achieved in 41 patients (13%), radical subtotal resection (rSTR) in 33 (11%), subtotal resection in 130 (41%), and biopsy only in 110 (35%). Median OS was 6.9 years (range, 1 month-38.5 years). Adverse prognostic factors for OS identified by multivariate analysis were tumor size 5 cm or larger, pure astrocytoma histology, Kernohan grade 2, undergoing less than rSTR, and presentation with sensory motor symptoms. Statistically significant adverse prognostic factors for PFS by multivariate analysis were only tumor size 5 cm or larger and undergoing less than rSTR. In patients who underwent less than rSTR, radiotherapy (RT) was associated with improved OS and PFS. A substantial proportion of patients have a good long-term prognosis after GTR and rSTR, with nearly half of patients free of recurrence 10 years after diagnosis. Postoperative RT was associated with improved OS and PFS and is recommended for patients after subtotal resection or biopsy.