Survival by Race and Ethnicity in Pediatric and Adolescent Patients With Hodgkin Lymphoma: A Children's Oncology Group Study.

PURPOSE: Population-based studies of children and adolescents with Hodgkin lymphoma (HL) report a survival disadvantage in nonwhite-non-Hispanic black (NHB) and Hispanic-patients. Whether disparities persist after adjustment for clinical and treatment-related variables is unknown. We examined survival by race/ethnicity in children receiving risk-based, response-adapted, combined-modality therapy for HL in contemporary Children's Oncology Group trials. PATIENTS AND METHODS: This pooled analysis used individual-level data from 1,605 patients (younger than age 1 to 21 years) enrolled in phase III trials for low-risk (AHOD0431), intermediate-risk (AHOD0031), and high-risk (AHOD0831) HL from 2002 to 2012. Event-free survival (EFS) and overall survival (OS) were compared between non-Hispanic white (NHW) and nonwhite patients. Cox proportional hazards for survival were estimated for both de novo and relapsed HL, adjusting for demographics, disease characteristics, and therapy. RESULTS: At median follow up of 6.9 years, cumulative incidence of relapse was 17%. Unadjusted 5-year EFS and OS were 83% (SE, 1.2%) and 97% (SE, < 1%), respectively. Neither differed by race/ethnicity. In multivariable analyses for OS, nonwhite patients had a 1.88× higher hazard of death (95% CI, 1.1 to 3.3). Five-year postrelapse survival probabilities by race were as follows: NHW, 90%; NHB, 66%; and Hispanic, 80% (P < .01). Compared with NHW, Hispanic and NHB children had 2.7-fold (95% CI, 1.2 to 6.2) and 3.5-fold (95% CI, 1.5 to 8.2) higher hazard of postrelapse mortality, respectively. CONCLUSION: In patients who were treated for de novo HL in contemporary Children's Oncology Group trials, EFS did not differ by race/ethnicity; however, adjusted OS was significantly worse in nonwhite patients, a finding driven by increased postrelapse mortality in this population. Additional studies examining treatment and survival disparities after relapse are warranted.

Racial disparities in the survival of American children, adolescents, and young adults with acute lymphoblastic leukemia, acute myelogenous leukemia, and Hodgkin lymphoma.

BACKGROUND: Race-based survival in children and adolescents with hematologic malignancies has been a national challenge for decades. Large-scale investigations of age- and race-based survival trends over time in these patients have not previously been reported. The objective of this study was to investigate whether race- and age-related differences in pediatric and adolescent and young adult (AYA) leukemia and lymphoma survival persist and to what extent these differences have changed over time. METHODS: Using the Surveillance, Epidemiology, and End Results program, this study investigated the outcomes of black and white (1975-2012; n = 27,369) and white and Hispanic (1992-2012; n = 20,574) children (0-14 years old) and AYAs (15-39 years old) with acute lymphoblastic leukemia (ALL), acute myelogenous leukemia (AML), and Hodgkin lymphoma (HL). Estimates of 5- and 10-year relative survival were compared over time. RESULTS: Trends showed a convergence of survival for white and black children with ALL but a divergence in survival for AYA patients. Hispanic children and AYAs both suffered inferior outcomes. Trends for AML revealed persistent survival differences between black and white children and suggested worsening disparities for AYAs. Survival trends in HL revealed sustained survival differences between black and white AYA patients, whereas no differences were found in Hispanic and white patient outcomes for AML or HL. CONCLUSIONS: Although survival for children and AYAs with ALL, AML, and HL has improved over the past 4 decades, differences persist between black, white, and Hispanic children and AYAs; survival disparities between black and white children with ALL have been nearly eliminated. Strategies aimed at identifying causality and reducing disparities are warranted. Cancer 2016. © 2016 American Cancer Society. Cancer 2016;122:2723-2730. © 2016 American Cancer Society.

Pretreatment whole blood Epstein-Barr virus-DNA is a significant prognostic marker in patients with Hodgkin lymphoma.

Epstein-Barr virus (EBV) in the peripheral blood has become a significant predictor of clinical outcomes in EBV-associated Hodgkin lymphoma (HL). However, due to its relative rarity, prevalence and prognostic role of circulating EBV-DNA has not been well established in Asian patients. Seventy patients with newly diagnosed HL were prospectively registered between October 2007 and January 2013, and underwent pretreatment whole blood (WB) EBV-DNA quantitation using real-time polymerase chain reaction (RT-PCR). WB EBV-DNA in baseline and serial RT-PCR within 1 year were investigated. Clinicopathologic parameters of the patients according to pretreatment WB EBV-DNA were also explored. Twelve patients (17.1 %) demonstrated WB EBV-DNA(+), which was significantly associated to older age, advanced stages, frequent involvements of extranodal sites, low serum albumin and hemoglobin levels, and high international prognostic scores ≥2. Three-year event-free survival (EFS) and overall survival (OS) were significantly inferior in patients with pretreatment WB EBV-DNA(+) (53.5 vs 67.0 and 65.6 vs 90.2 %) (p < 0.032 and <0.01). Negatively conversed EBV-DNA within 1 year after chemotherapy also significantly affected favorable EFS (p < 0.01). Taken together, pretreatment WB EBV-DNA(+) may be a significant predictor of inferior EFS and OS over EBV-encoded RNA in situ hybridization (EBER-ISH)(+) in Korean patients with HL. Serial EBV-DNA monitoring following chemotherapy also seems helpful to predict survival outcomes.

HLA Polymorphism in Algerian Children With Lymphomas.

BACKGROUND: Non-Hodgkin lymphoma (NHL) and Hodgkin lymphoma (HL) are the 2 types of lymphoma that represent the third most common childhood malignancy. Multiple etiological factors are involved in lymphoma pathogenesis, including viral infection, immune deficiencies, environmental agents, and genetic factors. Strong arguments supporting a genetic linkage between the susceptibility to lymphomas and human leukocyte antigens (HLA) are reported and give an idea about susceptibility or protection from the disease. METHODS: Seventy-one cases were included in this study: 36 cases of non-Hodgkin lymphoma and 35 patients with Hodgkin lymphoma. Their ages ranged from 4 to 18 years. The control group consisted of 70 unrelated healthy individuals, with a mean age of 5 to 17 years. The genotype of HLA-A, HLA-B, HLA-DR, and HLA-DQ alleles was typed by means of PCR sequence-specific priming. RESULTS: HLA-B*18, HLA-DRB1*03, *07, and HLA-DQB1*02 were significantly increased in patients with lymphomas when compared with controls, whereas HLA-DRB1*13 and DQB1*03 were significantly decreased when compared with controls. CONCLUSIONS: These results indicate that HLA-B*18, DRB1*03, *07, and DQB1*02 may contribute to lymphoma susceptibility, whereas HLA-DRB1*13 and DQB1*03 may confer protection to lymphoma in the Algerian population.

Hodgkin lymphoma incidence in California Hispanics: influence of nativity and tumor Epstein-Barr virus.

PURPOSE: For classical Hodgkin lymphoma (HL), migrant studies could elucidate contributions of environmental factors (including Epstein-Barr virus (EBV)) to the lower rates in non-whites. Given the well-described etiologic complexity of HL, this research requires a large, immigrant population, such as California Hispanics. METHODS: With 1988-2004 California Cancer Registry data (2,595 Hispanic, 8,637 white HL cases) and tumor cell EBV status on a subset (218 Hispanics, 656 whites), we calculated ethnicity- and nativity-specific HL incidence rates simultaneously by age, sex, and histologic subtype, and tumor cell EBV prevalence. RESULTS: Compared with white rates, Hispanic HL rates were lower overall (70 %) and for nodular sclerosis HL, particularly among young adults (60-65 % for females). However, they were higher among children (200 %) and older adults, and for mixed cellularity HL. Compared with rates in foreign-born Hispanics, rates in US-born Hispanics were higher among young adults (>threefold in females), lower for children and adults over age 70, and consistently intermediate compared with rates in whites. EBV tumor prevalence was 67, 32, and 23 % among foreign-born Hispanics, US-born Hispanics, and whites, respectively, although with variation by age, sex, and histology. CONCLUSIONS: Findings strongly implicate environmental influences, such as nativity-related sociodemographic differences, on HL occurrence. In addition, lower young adult rates and higher EBV prevalence in US-born Hispanics than in whites raise questions about the duration/extent of environmental change for affecting HL rates and also point to ethnic differences in genetic susceptibility. Lesser variation in mixed cellularity HL rates and greater variation in rates for females across groups suggest less modifiable factors interacting with environmental influences.

Aurora B kinase in Hodgkin lymphoma: immunohistochemical pattern of expression in neoplastic Hodgkin and Reed-Sternberg cells.

Aurora B is a member of the chromosomal passenger complex, which is essential for proper completion of mitosis and cell division (cytokinesis). Inappropriate chromosomal segregation and cytokinesis due to deregulated expression of chromosome passenger proteins may lead to aneuploidy and cancer including lymphomas. According to our knowledge there are extremely limited studies investigating the immunohistochemical expression of Aurora B in tumor specimens of Hodgkin lymphoma. Our purpose was to characterize the expression of Aurora B in biopsies of Hodgkin lymphomas, and to evaluate the pattern of immunoreactivity in neoplastic Hodgkin and Reed-Sternberg cells (RS cells). We examined Aurora B immunoreactivity in paraffin sections of 15 samples of Hodgkin lymphomas, obtained from 15 patients, 8 men and 7 women. Ten were of nodular sclerosis type and five were of mixed cellularity. Our results showed immunoexpression of Aurora B in mononuclear lymphoid cells as well as in bi- and multinucleated RS cells. In addition, positive neoplastic cells in mitosis were observed, whereas a subpopulation without evidence of immunoreaction was also detected in each case. Taken together our results point to a possible association between Aurora B expression and mitotic deregulation in Hodgkin lymphoma, which may provide novel targets for treatment.

Variation at 3p24.1 and 6q23.3 influences the risk of Hodgkin's lymphoma.

In addition to HLA, recent genome-wide association studies (GWASs) of Hodgkin's lymphoma (HL) have identified susceptibility loci for HL at 2p16.1, 8q24.21 and 10p14. In this study, we perform a GWAS meta-analysis with published GWAS (totalling 1,465 cases and 6,417 controls of European background), and follow-up the most significant association signals in 2,024 cases and 1,853 controls. A combined analysis identifies new HL susceptibility loci mapping to 3p24.1 (rs3806624; P=1.14 × 10(-12), odds ratio (OR)=1.26) and 6q23.3 (rs7745098; P=3.42 × 10(-9), OR=1.21). rs3806624 localizes 5' to the EOMES (eomesodermin) gene within a p53 response element affecting p53 binding. rs7745098 maps intergenic to HBS1L and MYB, a region previously associated with haematopoiesis. These findings provide further insight into the genetic and biological basis of inherited susceptibility to HL.

On the aetiology of Hodgkin lymphoma.

The thesis is based on seven publications in English and a review of the literature. The studies were carried out to contribute to the understanding of Hodgkin lymphoma epidemiology through descriptions of its occurrence and its association with Epstein-Barr virus (EBV) infection presenting as infectious mononucleosis. The investigations were supported by the Danish Cancer Society, the Swedish Cancer Society, the Danish Cancer Research Foundation, the Nordic Cancer Union, the Lundbeck Foundation, Plan Danmark, Danish National Research Foundation, Lily Benthine Lund's Foundation, Aase og Ejnar Danielsen's Foundation, Grosserer L. F. Foght's Foundation, the Leukaemia Reseach Fund, the Kay Kendall Leukaemia Fund, and the U.S. National Institutes of Health. The work was carried out in the period 1999-2010 during my employment at the Department of Epidemiology Research at Statens Serum Institut. The employed study designs included population-based incidence surveys of Hodgkin lymphoma in the Nordic countries and in Singapore, register-based cohort studies to characterise the pattern of cancer occurrence in patients with infectious mononucleosis and their first degree relatives, a register-based cohort and a population-based case-control study to characterise the association between infectious mononucleosis and Hodgkin lymphoma taking tumour EBV-status into consideration, and a case-series analysis to assess the association between HLA class I alleles and EBV-positive and EBV-negative Hodgkin lymphomas. Analyses of Nordic incidence data demonstrated that the occurrence of Hodgkin lymphoma had increased markedly younger adults in the period 1978-97, whereas it had decreased among older adults. In combination, these developments led to an accentuation of the younger adult Hodgkin lymphoma incidence peak, which has been a hallmark of Hodgkin lymphoma epidemiology in the Western hemisphere for more than a half century. The opposing incidence trends in younger and older adults are consistent with the prevailing hypothesis of aetiological heterogeneity between Hodgkin lymphomas in different age groups. In contrast to Western industrialised countries, absence of a younger adult incidence peak has been a characteristic of Hodgkin lymphoma epidemiology in developing and Asian populations. A survey of Hodgkin lymphoma occurrence in Singapore 1968-2002 revealed increasing incidence rates and the emergence of an incidence peak in younger adults. The appearance of a younger adult incidence peak in conjunction to socio-economic transition towards Western world lifestyle in Singapore is compatible with the suspicion that Hodgkin lymphoma in younger adults is associated with correlates of socioeconomic affluence in childhood, such as delayed exposure to childhood infectious agents. EBV can be demonstrated in the malignant cells in a subset of Hodgkin lymphomas and it has been speculated that the virus' presence and absence may distinguish between aetiologically separate Hodgkin lymphoma entities. This possibility was explored in five investigations characterising the association between infectious mononucleosis and Hodgkin lymphoma. In these studies, infectious mononucleosis was not accompanied by an increased risk of cancer in general, but specifically with an increased risk of Hodgkin lymphoma. The increased risk of Hodgkin lymphoma decreased with time since infectious mononucleosis and because of the typical adolescent age at infectious mononucleosis it was most prominent for Hodgkin lymphoma in younger adults. Supplementing studies provided little support for the notion that the observed association between Hodgkin lymphoma and infectious mononucleosis was explained by confounding or biases. Analyses stratified by Hodgkin lymphoma EBV status indicated that the increased risk after infectious mononucleosis was confined to the subset of Hodgkin lymphomas that harbour the virus in the malignant cells. The genetic analyses pointed to increased and decreased risk of EBV-positive Hodgkin lymphoma associated with HLA-A*01 and HLA-A*02 alleles, respectively. The increased risk of EBV-positive Hodgkin lymphoma after infectious mononucleosis was not explained by the two HLA class I alleles, but HLA-A*02 abrogated its effect. This led to an immunological model for EBV-positive Hodgkin lymphoma according to which the level of circulating EBV infected lymphocyte regulated by cytotoxic T-cell responses is a critical determinant of disease risk. Overall, the studies included in the thesis favour that EBV infection is causally associated with development of EBV-positive Hodgkin lymphoma. The circumstances under which the ubiquitous infection leads to lymphoma development must be explored in future studies, which should include analyses of gene-environment interactions. Meanwhile, the aetiology of EBV-negative Hodgkin lymphoma remains elusive. Possible clinical implications of the aetiological heterogeneity should also be considered and assessed.

Racial, socioeconomic, and demographic disparities in access to fertility preservation in young women diagnosed with cancer.

BACKGROUND: This study seeks to examine the relation between sociodemographic characteristics and the utilization of fertility preservation services in reproductive age women diagnosed with cancer. METHODS: A total of 1041 women diagnosed with cancer between the ages of 18 and 40 years responded to a retrospective survey on demographic information and reproductive health history. Five cancer types were included: leukemia, Hodgkin disease, non-Hodgkin lymphoma, breast cancer, and gastrointestinal cancer. Nine hundred eighteen women reported treatment with potential to affect fertility (chemotherapy, pelvic radiation, pelvic surgery, or bone marrow transplant). Student t test, linear regression, and multivariate logistic regression were used where appropriate to determine the relation between sociodemographic characteristics and the odds of using fertility preservation services. RESULTS: Sixty-one percent of women were counseled on the risk of cancer treatment to fertility by the oncology team. Overall, 4% of women pursued fertility preservation. In multivariate analysis, women who had not attained a bachelor's degree (odds ratio [OR], 0.7; 95% confidence interval [CI], 0.5-0.9) were less likely to be counseled. Trends also suggested possible disparities in access to fertility preservation with age older than 35 years (OR, 0.1; 95% CI, 0.0-1.4) or previous children (OR, 0.3; 95% CI, 0.1-1.1) at diagnosis. Disparities in access to fertility preservation based on ethnicity and sexual orientation were also observed. CONCLUSIONS: Sociodemographic health disparities likely affect access to fertility preservation services. Although awareness of fertility preservation has improved in the past decade, an unmet need remains for reproductive health counseling and fertility preservation in reproductive age women diagnosed with cancer.

Predictive factors for inadequate stem cell mobilization in Chinese patients with NHL and HL: 14-year experience of a single-center study.

BACKGROUND: Factors affecting progenitor cell mobilization in patients with non-Hodgkin's lymphoma (NHL) and Hodgkin's lymphoma (HL) are incompletely understood. The aim of this retrospective study was to determine which factors are crucial for effective mobilization and collection of autologous peripheral blood stem cells (PBSC) prior to transplantation in Chinese patients. PATIENTS AND METHODS: A total of 239 patients with lymphoma (198 NHL and 41 HL patients) underwent PBSC collection after mobilization with granulocyte-colony-stimulating factor (G-CSF) or G-CSF plus chemotherapy priming. RESULTS: Patient characteristics at diagnosis and transplant, including low Eastern Cooperative Oncology Group score (P = 0.013), lack of extranodal invasion (P = 0.034), previously administered radiotherapy regimens (P = 0.040), treatment with platinum prior to mobilization (P = 0.042), previous chemotherapy regimens (P = 0.001) and cycles (P < 0.001), and chemotherapy regimens (P < 0.001) were statistically significant for successful mobilization in multivariate analysis. Premobilization factors, including previous radiotherapy (P = 0.009), previous chemotherapy regimens (P = 0.043) and cycles (P = 0.039), low platelet count prior to mobilization (P = 0.042), and lower CD34+ cells in peripheral blood (PB) (P = 0.050) or bone marrow (BM) (P = 0.007) were considered possibly predictive of poor mobilization. We found the patients who had chemosensitive lymphoma had worse progress-free survival (PFS) than the patients with initial treatment and high risks (P = 0.017). CONCLUSION: Our analysis showed that high amounts of chemotherapy, radiotherapy, low platelet count, chemosensitive recurrent patients, combination chemotherapy plus G-CSF and low CD34+ cells in BM prior to mobilization could emerged as important predictive factors for mobilization failure in Chinese patients with NHL and HL.

Racial disparities in Hodgkin's lymphoma: a comprehensive population-based analysis.

BACKGROUND: Racial disparity has been investigated in a number of cancers; however, there remains a comparative paucity of data in Hodgkin's lymphoma (HL). PATIENTS AND METHODS: We examined time-, age-, and gender-specific incidence, disease characteristics, and survival across and within races for adolescent/adult HL (age 10-79 years) diagnosed during 1992-2007 in the SEER 13 registries. RESULTS: A total of 15 662 HL cases were identified [11,211 non-Hispanic whites, 2067 Hispanics, 1662 blacks, and 722 Asian/Pacific Islanders (A/PI)]. Similar to whites, A/PIs had bimodal age-specific incidence, while blacks and Hispanics did not. Further, HL was significantly more common in Hispanics versus whites age>65 years (7.0/1×10(6) versus 4.5/1×10(6), respectively, P<0.01). By place of birth, US-born Hispanics and A/PIs age 20-39 years had higher incidence of HL versus their foreign-born counterparts (P<0.05), however, rates converged age>40 years. Interestingly, from 1992-1997 to 2003-2007, A/PI incidence rates increased >50% (P<0.001). Moreover, this increase was restricted to US-born A/PI. We also identified a number of disease-related differences based on race. Finally, 5-, 10-, and 15-year overall survival rates were inferior for blacks and Hispanics compared with whites (P<0.005 and P<0.001, respectively) and A/PI (P<0.018 and P<0.001, respectively). These differences persisted on multivariate analysis. CONCLUSION: Collectively, we identified multiple racial disparities, including survival, in adolescent/adult HL.

CD68 and CD163 as prognostic factors for Korean patients with Hodgkin lymphoma.

BACKGROUND: Limited progress had been made in prognostic stratification of patients with Hodgkin lymphoma (HL) until recent studies suggested that the number of CD68-expressing macrophages is prognostic in classical HL. However, its significance in Asian patients with HL has not been explored yet perhaps because of its low incidence in Asia. METHODS: In this work, we performed immunohistochemical analysis of CD163, as well as CD68, in 144 Korean patients with HL treated between November 1990 and December 2009 in a single center. The relative percentages of CD68+ and CD163+ cells with respect to the overall cellularity (CD68 index and CD163 index, respectively) were correlated with clinical outcomes. RESULTS: Both high CD68 and CD163 indices (>20%) were associated with a rise in treatment-related deaths and poorer event-free survival (P = 0.009 and P = 0.0023, respectively), disease-specific survival (P = 0.011 and P = 0.001), and overall survival (P = 0.023 and P = 0.001). In particular, a high CD163 index was related to lower complete response (CR) rate (P = 0.022) and shorter duration of CR (P = 0.030). CONCLUSIONS: High index of either CD68 or CD163 (>20%) is significantly correlated with poor prognosis in Korean patients with HL. CD163, a specific marker of macrophages, seems to be another prognostic factor for classical HL.

Disparities in cancer outcomes: lessons learned from children with cancer.

Disparities in cancer burden by race/ethnicity have been reported, primarily in adults with cancer. However, there appear to be gaps in the pediatric oncology literature with regards to a comprehensive overview on this topic. Extant literature is used to highlight the results of studies focusing on racial and ethnic disparities in outcome observed in selected childhood cancers. A comprehensive approach is utilized to understand possible underlying causes of disparities in cancer outcomes, and to highlight the gaps that currently exist. This review helps define areas of future research that could help develop targeted, disease-specific approaches to eliminate the disparities.

Fatores genéticos e ambientais na patogênese, constituição do microambiente tumoral e prognóstico clínico do linfoma de hodgkin pediátrico

O linfoma de Hodgkin classico (LHc) é caracterizado pelo pequeno número de células de Hodgkin e Reed-Sternberg (H-RS) em meio a um fundo de células não neoplásicas, principalmente T e B. Este microambiente tumoral tem sido considerado uma manifestação imune do hospedeiro contra as células H-RS. Uma vez que crianças e adultos apresentam diferenças quanto a constituição e funcionalidade do sistema imune, além de eventos patogênicos distintos, é de se esperar que o microambiente tumoral no LHc exiba diferenças entre crianças e adultos. Neste estudo, nós analisamos uma série de casos de LHc (100 casos) em relação as características clínico-histológicas, composição do microambiente tumoral através da imunomarcação para CD3, CD4, C-maf, T-bet, FoxP3, CD8, Tia-1, Granzima B (GrB) e CD20, além do impacto prognóstico destas características. O índice de proliferação celular (IPC) das células neoplásicas e benignas foi determinado a partir da imunoexpressão de Ki67. Os polimorfismos de base única (SNPs) da IL10 -1082A/G, -819C/T e -592C/A foram determinados através de PCR alelo-específica. Os SNPs de CTLA4 -1722 A/G, +49 A/G e CT60 A/G foram determinados por descriminação alélica. O vírus Epstein-Barr (EBV) foi determinado por hibridização in situ (EBER-ISH) e imunomarcação para LMP1. A idade ao diagnóstico variou de 3 a 18 anos (mediana 14 anos) com 27% dos casos 10 anos ao diagnóstico. A esclerose nodular (EN) foi o subtipo mais freqüente (69%), sendo comum nas crianças >10 anos, seguida da celularidade mista (CM, 23%), distribuída igualmente entre os grupos etários. 44,8% dos casos foram EBV+, sem associação com os grupos etários (10 anos). Os casos de CM estavam independentemente associados ao EBV (p= 0,045) e à relação CD4/CD20 4/mm2 (p= 0,045) estiveram independentemente associados a pior sobrevida livre de eventos (SLE). Um escore prognóstico foi construído e permitiu a separação dos casos em 3 grupos com diferenças na SLE (p= 0,005). Os genótipos da IL10 -1082GG e -592CC e o haplótipo GCC estiveram associados a características histológicas, baixo número de linfócitos Th2 e alto número de células T reguladoras (Tregs). O genótipo do CTLA4 CT60GG foi associado ao maior IPC das células H-RS. O SNP CT60A e o haplótipo +49A/CT60A estiveram relacionados ao maior número de linfócitos CD4+, enquanto o SNP CT60G e o genótipo cT60GG estiverem associados ao maior número de linfócitos CD8+ e Tregs. O haplótipo CTLA4 +49G/CT0G foi independentemente associado a pior SLE (p= 0,036). Em conclusão: 1) O LHc pediátrico no sudeste do Brasil deve ter um padrão epidemiológico intermediário entre o LHc pediátrico visto nas regiões menos e mais desenvolvidas. A histopatogênese da CM deve ser resultante de uma exposição precoce ao EBV num contexto de déficit imune, refletido pela razão CD4/CD20 <1 no microambiente tumoral; 2) Este é o 1º estudo a descrever a composição do microambiente tumoral no LHc pediátrico e a determinar que os SNPs da IL10 e CTLA4 são capazes de influenciar a composição do microambiente tumoral no LHc; e 3) O EBV tem uma influência significante na composição do microambiente tumoral e na modulação da resposta imune contra o tumor

Classical Hodgkin lymphoma (cHL) is characterized by a small number of neoplastic, Hodgkin and Reed-Sternberg (H-RS) cells in a background of non-neoplastic, mainly B and T cells. This tumor microenvironment has been considered to be a manifestation of host immune reactions to malignant cells. Since children and adults have difference in the constitution and functionality of the immune system, and pathogenic events differ in pediatric and adult cHL, it is likely that the tumor microenvironment in cHL may be distinct in the pediatric setting. In this study, we analyzed a series of pediatric cHL (100 cases) regarding the clinical and histological characteristics, as well as composition of the tumor microenvironment by CD3, CD4, C-maf, T-bet, FoxP3, CD8, Tia-1, Granzyme B (GrB) and CD20 immunostain and its prognostic impact. Proliferation index of neoplastic and benign infiltrating cells was determined by Ki67 immunostain. We determined also the IL10 -1082A/G, -819C/T and -592C/A genotype of single nucleotide polymorphisms (SNPs) and haplotypes by Allele-specific (AS) PCR and CTLA4 -1722 A/G, +49 A/G and CT60 A/G SNPs by allele discrimination with fluorogenic hydrolysis probes (Taqman® Applied Biosystems). Epstein-Barr virus (EBV) was determined by in situ hybridization (EBERs-ISH) and LMP1 immunostain. Age at diagnosis ranged from 3 to 18 years (median 14) with 27% of cases 10 years age group. Nodular sclerosis (NS) was the most frequent subtype (69%) and was more frequent in the >10 years age group, followed by mixed cellularity (MC, 23%) which was distributed equally between age groups. EBV was identified in 44.8% of cases, without preferential association with age groups (10 years). MC cases were independently associated with EBV (P= 0.045) and with a CD4/CD20 ratio 10) exhibiting a shift from more cytotoxic to more suppressive profile along with age. EBV influenced the lymphocyte composition with more CD8+, Tia-1+, GrB+, and T-bet+ (Th1) cells. Extranodal disease (P=0.016) and GrB+ lymphocytes >4 cells/mm2 (P= 0.045) were independently associated with worst event-free survival (EFS). A prognostic score was constructed and allowed to segregate the children in 3 groups with differences in EFS (P= 0.005). IL10 genotypes -1082GG and -592CC and haplotype GCC associated with histological characteristics, low number of Th2 and high number of regulatory T (Treg) cells. CTLA4 CT60GG genotype was associated with high H-RS proliferative index (Ki67>50%). The SNP CT60A and haplotype +49A/CT60A were related with high number of CD4+ T cells, while the SNP CT60G and the genotype CT60GG were associated with high number of CD8+ and Treg cells. The CTLA4 haplotype +49G/CT60G was independently associated with worst EFS (p= 0.036). In conclusion: 1) Pediatric cHL in Southeastern Brazil may have an intermediate epidemiological situation between childhood cHL in underdeveloped and developed regions. Histopathogenesis of MC subtype may result from early exposure to EBV in the context of an impaired immune system reflected by a CD4/CD20 ratio <1; 2) This the 1st study to describe the specific characteristics of tumor microenvironment composition in pediatric cHL and to determine that IL10 and CTLA4 SNPs are able to influence the tumor microenvironment composition in cHL; and 3) EBV-status has a significant influence in the tumor microenvironment composition and likely in the modulation of the imune response against the tumor

A sharp rise in the incidence of Hodgkin's lymphoma in young adults in Israel.

BACKGROUND: Hodgkin's lymphoma is a distinct primary solid tumor of the immune system that shows wide variation in incidence among different geographic regions and among various races. It was previously suggested that susceptible people living in certain parts of Israel had a higher risk of HL because of exposure to unidentified environmental factors in these regions. Compared with other parts of Israel, these regions were characterized by a higher proportion of Israeli-born Jews. OBJECTIVES: To study time trends in the incidence rate of HL in Israeli-born Jews of all age groups during the years 1960-2005. RESULTS: A total of 4812 Jewish cases of HL were reported to the Israel Cancer Registry during the study period 1960-2005. There has been a persistent increase in the age-standardized incidence rate of HL, all subtypes pooled, in Israeli-born Jews in both men and women. The age distribution pattern in both genders was bimodal in all periods. The highest incidence was observed in the 20-24 year age group: for women (9.13 per 100,000 per year) during the period 1988-1996, and for men (6.60 per 100,000 per year) during the period 1997-2005. CONCLUSIONS: The reported incidence level of HL in Israeli-born young adult Jews in Israel has increased in recent years to high levels compared with other western countries. Our findings suggest a cohort effect to unidentified factors affecting Israeli-born young adult Jews in Israel.

Disparities in survival after Hodgkin lymphoma: a population-based study.

Survival after Hodgkin lymphoma (HL) is generally favorable, but may vary by patient demographic characteristics. The authors examined HL survival according to race/ethnicity and neighborhood socioeconomic status (SES), determined from residential census-block group at diagnosis. For 12,492 classical HL patients ≥ 15 years diagnosed in California during 1988-2006 and followed through 2007, we determined risk of overall and HL-specific death using Cox proportional hazards regression; analyses were stratified by age and Ann Arbor stage. Irrespective of disease stage, patients with lower neighborhood SES had worse overall and HL-specific survival than patients with higher SES. Patients with the lowest quintile of neighborhood SES had a 64% (patients aged 15-44 years) and 36% (≥ 45 years) increased risk of HL-death compared to patients with the highest quintile of SES; SES results were similar for overall survival. Even after adjustment for neighborhood SES, blacks and Hispanics had increased risks of HL-death 74% and 43% (15-44 years) and 40% and 17% (≥ 45 years), respectively, higher than white patients. The racial/ethnic differences in survival were evident for all stages of disease. These data provide evidence for substantial, and probably remediable, racial/ethnic and neighborhood SES disparities in HL outcomes.

Ethnicity and incidence of Hodgkin lymphoma in Canadian population.

BACKGROUND: Research has shown that ethnicity is a significant predictor of Hodgkin lymphoma (HL). Variations in cancer incidence among ethnic groups in the same country can lead to important information in the search for etiological factors. Other risk factors important in the etiology of HL are medical history and exposure to pesticides. In this report we investigated the association between ethnicity and HL in the presence of medical history, and exposure to pesticides. METHODS: The data resulting from a matched population-based case-control study conducted in six provinces of Canada (Ontario, Quebec, Manitoba, Saskatchewan, Alberta, and British Columbia) was analyzed to determine whether or not there was any association between ethnicity and incidence of HL when adjusted for personal medical history and pesticide exposure. Information on ethnicity, personal medical history, and pesticide exposure was collected by questionnaires via mail on 316 men diagnosed with HL; and on 1506 controls. A conditional logistic regression was utilized and results were presented as odds ratios and 95% confidence intervals. RESULTS: In our study population, the distribution of ethnic groups was: 38.5% North American, 15% British, 8.4% Western European, 8.2% Eastern European, 1.7% Asian, 1.4% Scandinavian and 27% of other ethnic origin. Compared to North Americans (i) the risk of HL was greater among the Eastern European descendents (Odds Ratio (ORadj): 1.82; 95% confidence interval (CI): 1.02, 3.25) and Western European (ORadj: 1.62; 95% CI: 0.95-2.76) descent population (borderline significance at 5% level); and (ii) the risk of HL was lower in Asian descents. Diagnosis with measles (ORadj: 0.72, 95% C.I.: 0.53-0.98) and/or positive history of allergy desensitization shots (ORadj: 0.55, 95% C.I.: 0.30-0.99) were negatively associated with the incidence of HL, while diagnosis with acne (ORadj: 2.12, 95% C.I.: 1.19-3.78), shingles (ORadj: 2.41, 95% C.I.: 1.38-4.22) and positive family history of cancer (ORadj: 1.93, 95% C.I.: 1.40-2.65) increased the risk of HL. Exposure to individual herbicide dichlorprop showed an increased risk of HL (ORadj: 6.35, 95% C.I.: 1.56-25.92). CONCLUSION: In Canada, compared to North Americans descendents, the risk of HL was significantly greater among the Eastern European and Western European descent population. Our results related to association between ethnicity and HL support the findings reported by other researchers. Our data showed that subjects who were diagnosed with measles or had allergy desensitization shots negatively associated with the incidence of HL; and other medical conditions, ever diagnosed with acne, and positive family history of cancer were positively associated with the incidence of HL.

Ethnicity and characteristics of Hodgkin lymphoma in children.

AIM: To identify ethnic group differences in the prognostic of Hodgkin lymphoma (HL) in South African children. PATIENTS AND METHODS: In order to create a larger database, cases were pooled from two South African hospitals: Tygerberg in the Western Cape and Bloemfontein Academic Complex in Free State. Self-assigned ethnicity was used to allocate the children to the following groups: black, white, and colored (historical descendants of couples of distinct ethnicity, the "Cape colored" are the largest population group in Western Cape). Retrospective data over 21 years were obtained from the tumor registry. Age at presentation, sex, ethnic group, stage, histological type, treatment protocol, event-free survival interval, and mortality were analyzed. The statistical significance of the findings was tested using the chi-square, Mann-Whitney U, and Kruskal-Wallis tests, as indicated. RESULTS: The study population of 138 comprised 78 black (56.5%), 38 colored (27.5%), and 22 white (16%) children under 15 years of age. There was a 3:1 predominance of the male gender. The median age at diagnosis was 8 years 11 months. Black patients presented at the youngest age (median 103 months), whereas white patients were the oldest at presentation (median age 133 months; P = 0.04).Forty-five percent of all patients were seen in stage 2. Black and colored patients presented with significantly more advanced stage disease (P = 0.04) than whites. B symptoms were evenly distributed among ethnic groups; they increased the mortality ratio from 10% to 33% (P = 0.0019). Histologically, mixed cellularity was seen in 50% of the black children, while nodular sclerosis was found in 50% of whites. The overall survival rate is 79%, with 68% in whites, 84% in patients of mixed ethnicity, and 79% in blacks (P = 0.35). CONCLUSIONS: White children had the worst HL prognosis in this series, in spite of a less advanced stage at presentation.

Racial/ethnic variation in EBV-positive classical Hodgkin lymphoma in California populations.

Epstein-Barr virus (EBV) is detected in the tumor cells of some but not all Hodgkin lymphoma (HL) patients, and evidence indicates that EBV-positive and -negative HL are distinct entities. Racial/ethnic variation in EBV-positive HL in international comparisons suggests etiologic roles for environmental and genetic factors, but these studies used clinical series and evaluated EBV presence by differing protocols. Therefore, we evaluated EBV presence in the tumors of a large (n = 1,032), racially and sociodemographically diverse series of California incident classical HL cases with uniform pathology re-review and EBV detection methods. Tumor EBV-positivity was associated with Hispanic and Asian/Pacific Islander (API) but not black race/ethnicity, irrespective of demographic and clinical factors. Complex race-specific associations were observed between EBV-positive HL and age, sex, histology, stage, neighborhood socioeconomic status (SES), and birth place. In Hispanics, EBV-positive HL was associated not only with young and older age, male sex, and mixed cellularity histology, but also with foreign birth and lower SES in females, suggesting immune function responses to correlates of early childhood experience and later environmental exposures, respectively, as well as of pregnancy. For APIs, a lack of association with birth place may reflect the higher SES of API than Hispanic immigrants. In blacks, EBV-positive HL was associated with later-stage disease, consistent with racial/ethnic variation in certain cytokine polymorphisms. The racial/ethnic variation in our findings suggests that EBV-positive HL results from an intricate interplay of early- and later-life environmental, hormonal, and genetic factors leading to depressed immune function and poorly controlled EBV infection.