Plasma metabolites in childhood Burkitt lymphoma cases and cancer-free controls in Uganda.

INTRODUCTION: Burkitt lymphoma (BL) is an aggressive non-Hodgkin lymphoma associated with Plasmodium falciparum and Epstein-Barr virus, both of which affect metabolic pathways. The metabolomic patterns of BL is unknown. MATERIALS AND METHODS: We measured 627 metabolites in pre-chemotherapy treatment plasma samples from 25 male children (6-11 years) with BL and 25 cancer-free area- and age-frequency-matched male controls from the Epidemiology of Burkitt Lymphoma in East African Children and Minors study in Uganda using liquid chromatography-tandem mass spectrometry. Unconditional, age-adjusted logistic regression analysis was used to estimate odds ratios (ORs) and their 95% confidence intervals (CIs) for the BL association with 1-standard deviation increase in the log-metabolite concentration, adjusting for multiple comparisons using false discovery rate (FDR) thresholds and Bonferroni correction. RESULTS: Compared to controls, levels for 42 metabolite concentrations differed in BL cases (FDR < 0.001), including triacylglyceride (18:0_38:6), alpha-aminobutyric acid (AABA), ceramide (d18:1/20:0), phosphatidylcholine ae C40:6 and phosphatidylcholine C38:6 as the top signals associated with BL (ORs = 6.9 to 14.7, P < 2.4✕10- 4). Two metabolites (triacylglyceride (18:0_38:6) and AABA) selected using stepwise logistic regression discriminated BL cases from controls with an area under the curve of 0.97 (95% CI: 0.94, 1.00). CONCLUSION: Our findings warrant further examination of plasma metabolites as potential biomarkers for BL risk/diagnosis.

A novel prognostic index for sporadic Burkitt lymphoma in adult patients: a real-word multicenter study.

BACKGROUND: Adult sporadic Burkitt lymphoma (BL) is a rare but highly aggressive subtype of lymphoma which lacks its own unique prognostic model. Systemic inflammatory biomarkers have been confirmed as prognostic markers in several types of malignancy. Our objective was to explore the predictive value of pretreatment inflammatory biomarkers and establish a novel, clinically applicable prognostic index for adult patients with sporadic BL. METHODS: We surveyed retrospectively 336 adult patients with newly diagnosed sporadic BL at 8 Chinese medical centers and divided into training cohort (n = 229) and validation cohort (n = 107). The pretreatment inflammatory biomarkers were calculated for optimal cut-off value. The association between serum biomarkers and overall survival (OS) was analyzed by Kaplan-Meier curves and Cox proportional models. The risk stratification was defined based on normal LDH level, Ann Arbor stage of I and completely resected abdominal lesion or single extra-abdominal mass < 10 cm. RESULTS AND CONCLUSIONS: Univariate and multivariate analyses revealed that platelets< 254 × 109/L, albumin< 40 g/L, lactate dehydrogenase≥334 U/L independently predicted unfavorable OS. We used these data as the basis for the prognostic index, in which patients were stratified into Group 1 (no or one risk factor), Group 2 (two risk factors), or Group 3 (three risk factors), which were associated with 5-year OS rates of 88.1, 72.4, and 45%, respectively. In the subgroup analysis for high-risk patients, our prognostic model results showed that high-risk patients with no more than one adverse factor presented a 5-year survival rate of 85.9%, but patients with three adverse factors had a 5-year survival rate of 43.0%. Harrell's concordance index (C-index) of the risk group score was 0.768. Therefore, the new prognostic model could be used to develop risk-adapted treatment approaches for adult sporadic BL.

Real-world outcomes of AIDS-related Burkitt lymphoma: a retrospective study of 78 cases over a 10-year period.

We investigated the clinical characteristics and outcomes of acquired immunodeficiency syndrome-related Burkitt lymphoma (AIDS-BL). A single-center retrospective study was performed of 78 cases over a 10-year period. The baseline characteristics of enrolled patients included the following: median age, 46 years; median CD4+ T lymphocyte count, 156 cells/µL; advanced stage, 74.3%; > 1 extranodal site, 55.1%; international prognostic index (IPI) > 1, 85.9%; and elevated serum lactate dehydrogenase, 82.1%. The 1-year and 2-year overall survival (OS) rates were 52.2 ± 5.9% and 42.7 ± 6.2%, respectively. A prognostic analysis of 65 patients who had undergone chemotherapy showed that B symptoms (with vs. without fever, night sweat or weight loss), number of extranodal sites (0, 1 vs. > 1), level of serum albumin (≥ 35 g/L vs. < 35 g/L), hemoglobin (≥ 110 g/L vs. < 110 g/L), and IPI score (≤ 2 vs. > 1) were all associated with OS. However, only B symptoms (HR = 4.036, 95% CI 1.821-8.948, p = 0.001), serum albumin level < 35 g/L (HR = 2.131, 95% CI 1.013-4.483, p = 0.046), and chemotherapy without rituximab (HR = 2.286, 95% CI 1.108-4.714, p = 0.025) were independent predictors of OS after multivariate adjustment. Patients with AIDS-BL were likely to present with high-risk features, and their clinical outcomes were relatively poor, especially those with B symptoms and lower serum albumin levels.

Prognostic Stratification of Patients with Burkitt Lymphoma Using Serum ß2-microglobulin Levels.

PURPOSE: We aimed to investigate the prognostic value of serum ß2-microglobulin for patients with Burkitt lymphoma (BL) and to propose a risk-stratifying classification system. MATERIALS AND METHODS: A prospective registry-based cohort study of BL patients treated with dose-intensive or effective dose-adjusted chemotherapies (n=81) was conducted. Survival outcomes were compared based on previously reported risk groups and/or serum ß2-microglobulin levels. A risk-stratifying classification system incorporating serum ß2-microglobulin levels was proposed and validated in an independent validation cohort (n=60). RESULTS: The median age was 47 years, and 57 patients (70.4%) were male. Patients with high serum ß2-microglobulin levels (> 2 mg/L) had significantly worse progression-free survival (PFS) and overall survival (OS) (p < 0.01 for both). Serum ß2-microglobulin levels further stratified patients in the low-risk and high-risk groups in terms of PFS (p=0.010 and p=0.044, respectively) and OS (p=0.014 and p=0.026, respectively). Multivariate analyses revealed that a high serum ß2-microglobulin level (> 2 mg/L) was independently associated with a shorter PFS (hazards ratio [HR], 3.56; p=0.047) and OS (HR, 4.66; p=0.043). The new classification system incorporating the serum ß2-microglobulin level allowed the stratification of patients into three distinct risk subgroups with 5-year OS rates of 100%, 89.5%, and 62.5%. In an independent cohort of BL, the system was validated by stratifying patients with different survival outcomes. CONCLUSION: Serum ß2-microglobulin level is an independent prognostic factor for BL patients. The proposed ß2-microglobulin-based classification system could stratify patients with distinct survival outcomes, which may help define appropriate treatment approaches for individual patients.

Burkitt lymphoma in the modern era: real-world outcomes and prognostication across 30 US cancer centers.

We examined adults with untreated Burkitt lymphoma (BL) from 2009 to 2018 across 30 US cancer centers. Factors associated with progression-free survival (PFS) and overall survival (OS) were evaluated in univariate and multivariate Cox models. Among 641 BL patients, baseline features included the following: median age, 47 years; HIV+, 22%; Eastern Cooperative Oncology Group (ECOG) performance status (PS) 2 to 4, 23%; >1 extranodal site, 43%; advanced stage, 78%; and central nervous system (CNS) involvement, 19%. Treatment-related mortality was 10%, with most common causes being sepsis, gastrointestinal bleed/perforation, and respiratory failure. With 45-month median follow-up, 3-year PFS and OS rates were 64% and 70%, respectively, without differences by HIV status. Survival was better for patients who received rituximab vs not (3-year PFS, 67% vs 38%; OS, 72% vs 44%; P < .001) and without difference based on setting of administration (ie, inpatient vs outpatient). Outcomes were also improved at an academic vs community cancer center (3-year PFS, 67% vs 46%, P = .006; OS, 72% vs 53%, P = .01). In multivariate models, age ≥ 40 years (PFS, hazard ratio [HR] = 1.70, P = .001; OS, HR = 2.09, P < .001), ECOG PS 2 to 4 (PFS, HR = 1.60, P < .001; OS, HR = 1.74, P = .003), lactate dehydrogenase > 3× normal (PFS, HR = 1.83, P < .001; OS, HR = 1.63, P = .009), and CNS involvement (PFS, HR = 1.52, P = .017; OS, HR = 1.67, P = .014) predicted inferior survival. Furthermore, survival varied based on number of factors present (0, 1, 2 to 4 factors) yielding 3-year PFS rates of 91%, 73%, and 50%, respectively; and 3-year OS rates of 95%, 77%, and 56%, respectively. Collectively, outcomes for adult BL in this real-world analysis appeared more modest compared with results of clinical trials and smaller series. In addition, clinical prognostic factors at diagnosis identified patients with divergent survival rates.

Mean platelet counts are relatively decreased with malaria but relatively increased with endemic Burkitt Lymphoma in Uganda, Tanzania, and Kenya.

Platelet counts are decreased in Plasmodium falciparum malaria, which is aetiologically linked with endemic Burkitt lymphoma (eBL). However, the pattern of platelet counts in eBL cases is unknown. We studied platelet counts in 582 eBL cases and 2 248 controls enrolled in a case-control study in Uganda, Tanzania and Kenya (2010-2016). Mean platelet counts in controls or eBL cases with or without malaria-infection in controls versus eBLcases were compared using Student's t-test. Odds ratios (ORs) and two-sided 95% confidence intervals (95% CIs) were estimated using multiple logistic regression, controlling for age, sex, haemoglobin and white blood cell counts. Platelets were decreased with malaria infection in the controls [263 vs. 339 × 109 platelets/l, P < 0·0001; adjusted OR (aOR) = 3·42, 95% CI: 2·79-4·18] and eBL cases (314 vs. 367 × 109 platelets/l, P-value = 0·002; aOR = 2·36, 95% CI: 1·49-3·73). Unexpectedly, platelets were elevated in eBL cases versus  controls in overall analyses (mean: 353 vs. 307 × 109 platelets/l, P < 0·0001; aOR = 1·41; 95% CI: 1·12-1·77), and when restricted to malaria-positive (mean 314 vs. 263 × 109 platelets/l, P < 0·0001; OR = 2·26; 95% CI: 1·56-3·27) or malaria-negative (mean 367 vs. 339 × 109 platelets/l, P < 0·001; OR = 1·46; 95% CI: 1·17-1·83) subjects. Platelets were decreased with malaria infection in controls and eBL cases but elevated with eBL.

Variation in the Human Leukocyte Antigen system and risk for endemic Burkitt lymphoma in northern Uganda.

Endemic Burkitt lymphoma (eBL) is an aggressive childhood B-cell lymphoma associated with Plasmodium falciparum (Pf) malaria and Epstein-Barr virus (EBV) infections. Variation in the Human Leukocyte Antigen (HLA) system is suspected to play a role, but assessments using less accurate serology-based HLA typing techniques in small studies yielded conflicting results. We studied 200 eBL cases and 400 controls aged 0-15 years enrolled in northern Uganda and typed by accurate high-resolution HLA sequencing methods. HLA results were analyzed at one- or two-field resolution. Odds ratios and 95% confidence intervals (aOR, 95% CI) for eBL risk associated with common HLA alleles versus alleles that were rare (<1%) or differed by <2% between the cases and controls as the reference category, were estimated using multiple logistic regression adjusting for age, sex, microgeography, region, malaria positivity and treatment history, and genetic variants associated with eBL. Compared to the controls, eBL cases had a lower frequency of HLA-A*02 (aOR = 0·59, 95% CI 0·38-0·91), HLA-B*41 (aOR = 0·36, 95% CI 0·13-1·00), and HLA-B*58 alleles (aOR = 0·59, 95% CI 0·36-0·97). eBL cases had a lower frequency of HLA-DPB1 homozygosity (aOR = 0·57, 95% CI 0·40-0·82) but a higher frequency of HLA-DQA1 homozygosity (aOR = 2·19, 95% CI 1·42-3·37). Our results suggest that variation in HLA may be associated with eBL risk.

Burkitt Leukemia With Precursor B-Cell Immunophenotype and Dual Translocation of t(14;18) and t(8;14) in a Child: Case Report and Review of the Literature.

BACKGROUND: Burkitt leukemia (BL) with the precursor B-cell immunophenotype is a rarely reported condition. The prognosis of such patients is similar to that of classic BL. However, the combination of chromosomal translocations associated with bcl-2 and c-myc rearrangement has a poor prognosis. OBSERVATIONS: An 11-year-old child presented with fever and weakness. Bone marrow aspiration showed morphologically L1 type blasts and flow cytometry analysis was compatible with precursor B-cell immunophenotype. Cytogenetic analysis revealed a combination of t(8;14) and t(14;l8). CONCLUSIONS: The combination of t(8;14) and t(14;l8) can exhibit different immunophenotypical and morphologic features in leukemias.

The Association between the Comprehensive Epstein-Barr Virus Serologic Profile and Endemic Burkitt Lymphoma.

BACKGROUND: The discovery of Epstein-Barr virus (EBV) in Burkitt lymphoma tumors represented the first link between a virus and cancer in humans, but the underlying role of this virus in endemic Burkitt lymphoma remains unclear. Nearly all children in Burkitt lymphoma-endemic areas are seropositive for EBV, but only a small percentage develop disease. Variation in EBV-directed immunity could be an explanatory cofactor. METHODS: We examined serum from 150 Burkitt lymphoma cases and 150 controls using a protein microarray that measured IgG and IgA antibodies against 202 sequences across the entire EBV proteome. Variation in the EBV-directed antibody repertoire between Burkitt lymphoma cases and controls was assessed using unpaired t tests. ORs quantifying the association between anti-EBV IgG response tertiles and Burkitt lymphoma status were adjusted for age, sex, and study year. RESULTS: Thirty-three anti-EBV IgG responses were elevated in Burkitt lymphoma cases compared with controls (P ≤ 0.0003). Burkitt lymphoma-associated IgG elevations were strongest for EBV proteins involved in viral replication and antiapoptotic signaling. Specifically, we observed ORs ≥4 for BMRF1 (early antigen), BBLF1 (tegument protein), BHRF1 (Bcl-2 homolog), BZLF1 (Zebra), BILF2 (glycoprotein), BLRF2 [viral capsid antigen (VCA)p23], BDLF4, and BFRF3 (VCAp18). Adjustment for malaria exposure and inheritance of the sickle cell variant did not alter associations. CONCLUSIONS: Our data suggest that the anti-EBV serologic profile in patients with Burkitt lymphoma is altered, with strong elevations in 33 of the measured anti-EBV IgG antibodies relative to disease-free children. IMPACT: The Burkitt lymphoma-specific signature included EBV-based markers relevant for viral replication and antiapoptotic activity, providing clues for future Burkitt lymphoma pathogenesis research.

Posttransplant monomorphic Burkitt's lymphoma: clinical characteristics and outcome of a multicenter series.

Burkitt's monomorphic posttransplant lymphoproliferative disorder (B-PTLD) is an uncommon subtype of PTLD. Owing to the paucity of this complication, clinical characteristics and outcome has not been fully described. Clinical characteristics and outcomes of 20 patients diagnosed with B-PTLD from 10 transplant centers belonging to the GEL/TAMO group were reviewed. Median time from transplant to B-PTLD was 7.2 years. All the cases fulfill the morphologic and genetic criteria of B-PTLD, whereas Epstein-Barr virus (EBV) was detected in 70% of cases. Patients were treated with different chemotherapy combinations, and three patients received upfront rituximab monotherapy. The great majority of patients receiving CHOP-like regimens attained a complete response (CR) (73%), similar to that obtained with dose-intensive chemotherapy (83% CR). In contrast, patients receiving upfront rituximab monotherapy required subsequent chemotherapy. Two patients (10%) died during treatment due to infection. The median progression-free survival and overall survival (OS) were 16 months and 139 months, respectively. When analyzing variables predicting for OS, we found that patients with bone marrow involvement had an adverse prognosis, with a median OS of 6 months (p = 0.008). In conclusion, B-PTLD is an uncommon complication usually associated with EBV infection and with an aggressive clinical course, particularly in patients with bone marrow involvement. High-dose chemoimmunotherapy obtained similar responses to R-CHOP, suggesting that R-CHOP could be an adequate alternative for these patients. In contrast, rituximab monotherapy does not seem to be effective enough to control the disease.

Plasma magnesium is inversely associated with Epstein-Barr virus load in peripheral blood and Burkitt lymphoma in Uganda.

BACKGROUND: Epstein-Barr virus (EBV) causes endemic Burkitt lymphoma (eBL). EBV control was improved by magnesium (Mg2+) supplementation in XMEN, an X-linked genetic disease associated with Mg2+ deficiency, high circulating EBV levels (viral loads), and EBV-related lymphomas. We, therefore, investigated the relationship between Mg2+ levels and EBV levels and eBL in Uganda. METHODS: Plasma Mg2+ was measured in 45 women with low or high circulating EBV levels, 40 pediatric eBL cases, and 79 healthy children. Mg2+ uptake by T-lymphocytes was evaluated in samples from healthy donors. RESULTS: Plasma Mg2+ deficiency (plasma level <1.8 mg/dl) was more likely in women with high- vs. low-EBV levels (76.0% vs. 35%; odds ratio [OR] 11.3, 95% CI 2.14-60.2), controlling for age, and in eBL cases than controls (42.0% vs. 13.9%; OR 3.61, 95% CI 1.32-9.88), controlling for sex, age group, and malaria status. Mg2+ uptake by T-lymphocytes was related to extracellular Mg2+ concentration. INTERPRETATION: Plasma Mg2+ deficiency is associated with high EBV levels and eBL.

Longitudinal Monitoring of Antibody Responses against Tumor Cells Using Magneto-nanosensors with a Nanoliter of Blood.

Each immunoglobulin isotype has unique immune effector functions. The contribution of these functions in the elimination of pathogens and tumors can be determined by monitoring quantitative temporal changes in isotype levels. Here, we developed a novel technique using magneto-nanosensors based on the effect of giant magnetoresistance (GMR) for longitudinal monitoring of total and antigen-specific isotype levels with high precision, using as little as 1 nL of serum. Combining in vitro serologic measurements with in vivo imaging techniques, we investigated the role of the antibody response in the regression of firefly luciferase (FL)-labeled lymphoma cells in spleen, kidney, and lymph nodes in a syngeneic Burkitt's lymphoma mouse model. Regression status was determined by whole body bioluminescent imaging (BLI). The magneto-nanosensors revealed that anti-FL IgG2a and total IgG2a were elevated and sustained in regression mice compared to non-regression mice (p < 0.05). This platform shows promise for monitoring immunotherapy, vaccination, and autoimmunity.

Primary Central Nervous System Lymphomas of the Brain: A Retrospective Analysis in a Single Institution.

BACKGROUND: Primary central nervous system lymphomas (PCNSLs) are relatively rare brain tumors. Accurate diagnosis is usually made by surgical biopsy. In addition to surgical biopsy and decompression, treatment options include high-dose methotrexate and chemotherapy, radiation therapy, and stem cell therapy. Because of the rarity of this disease, guidelines for PCNSL diagnosis and treatment usually are formed from a large series of experiences. METHODS: We retrospectively reviewed 79 patients in our tertiary referral center during a 13-year period. All patients with PCNSL underwent surgical or bone marrow biopsy procedures, and diagnoses were confirmed by hematologists or neuropathologists. At the time of diagnosis, 44 patients presented with a single lesion. Human immunodeficiency virus was confirmed positive in 1 patient. The standard therapy protocol included high-dose methotrexate (intravenous and intrathecal) and chemotherapy with cytosine arabinoside, followed by external irradiation of the brain. RESULTS: Significant prognostic factors in these patients were low serum lactate dehydrogenase levels and radiation therapy. Multiplicity of lesions at time of diagnosis did not imply a worse outcome, and surgical resection and debulking did not show a significant survival benefit. CONCLUSIONS: PCNSL has a poor prognosis. Further clinical trials and diagnostic tools are needed to reveal the complexity of this disease.

Serum Metabolomics of Burkitt Lymphoma Mouse Models.

Burkitt lymphoma (BL) is a rare and highly aggressive type of non-Hodgkin lymphoma. The mortality rate of BL patients is very high due to the rapid growth rate and frequent systemic spread of the disease. A better understanding of the pathogenesis, more sensitive diagnostic tools and effective treatment methods for BL are essential. Metabolomics, an important aspect of systems biology, allows the comprehensive analysis of global, dynamic and endogenous biological metabolites based on their nuclear magnetic resonance (NMR) and mass spectrometry (MS). It has already been used to investigate the pathogenesis and discover new biomarkers for disease diagnosis and prognosis. In this study, we analyzed differences of serum metabolites in BL mice and normal mice by NMR-based metabolomics. We found that metabolites associated with energy metabolism, amino acid metabolism, fatty acid metabolism and choline phospholipid metabolism were altered in BL mice. The diagnostic potential of the metabolite differences was investigated in this study. Glutamate, glycerol and choline had a high diagnostic accuracy; in contrast, isoleucine, leucine, pyruvate, lysine, α-ketoglutarate, betaine, glycine, creatine, serine, lactate, tyrosine, phenylalanine, histidine and formate enabled the accurate differentiation of BL mice from normal mice. The discovery of abnormal metabolism and relevant differential metabolites may provide useful clues for developing novel, noninvasive approaches for the diagnosis and prognosis of BL based on these potential biomarkers.

Screening of renal dysfunction among Burkitt lymphoma survivors by novel markers.

BACKGROUND: Burkitt lymphoma (BL) represents the most common pathological type of non-Hodgkin lymphoma in our region. Recently, high success rates have been achieved in BL treatment. Little is known about long-term renal dysfunction in this vulnerable group. In the present study, we tried to detect early chronic kidney diseases (CKD) among BL survivors by using novel screening modalities. PATIENTS AND METHODS: we investigated 53 children (aged 10 ± 2.8 years, 34 boys) who successfully treated for Burkitt lymphoma, based on LMB96 protocol, as "patient group" and 30 children as control. All eligible participants were subjected to history taking, physical assessment, and routine laboratory investigations including urine analysis, serum creatinine. Estimated glomerular filtration rates using new Schwartz formula (GFRCKD) were calculated and chronic kidney disease prevalence was diagnosed accordingly. Also, serum Cystatin-C (Cys-C) and neutrophil-gelatinase-associated Lipocalin (NGAL) were determined as novel markers aiming at early and accurate detection of CKD in BL survivors. RESULTS: After 18.3 ± 5.2 months of BL cytotoxic therapy completion, almost one fifth of asymptomatic BL survivors showed evidence of subclinical CKD when estimated GFRCKD (16.9%), serum Cystatin-C (15%) and serum neutrophil-gelatinase-associated Lipocalin (18.8%) were used for kidney function monitoring. This prevalence was four to fivefolds higher than that detected by routine serum creatinine screening (3.7%). Significant persistent albuminuria was diagnosed at 4/53 (7.5.3%) of BL survivors and asymptomatic hypertension was reported in 1/53 (1.9%) of them compared to none of the controls. Positive correlation could be displayed between serum Cys-C and serum NGAL. Conversely, negative correlations between both of them and estimated GFRCKD were documented. CONCLUSION: Novel modalities such new Schwartz formula (GFRCKD) estimation, serum Cys-C, and serum NGAL assessment should be incorporated in the routine follow-up screening for CKD among BL survivors for accurate diagnosis of such detrimental morbidity.

Risk-adapted stratification for optimally intensive treatment assignment of pediatric patients with non-Hodgkin lymphoma is an effective strategy in developing countries.

BACKGROUND: Pediatric patients with non-Hodgkin lymphoma (NHL) in developing countries (DCs) present with greater tumor load even at lower stages and with comorbidities that impact therapy delivery. This causes toxic mortality with "standard" intensive protocols or recurrences with "gentler" treatment. OBJECTIVES: We developed and evaluated a risk stratification schema that guides intensity of therapy. DESIGN/METHODS: Sixty-nine patients were prospectively assigned to five risk groups (A-E; n = 6, 15, 16, 15, and 17) following staging and treated with protocols of risk-stratified intensity. Risk stratification utilized St. Jude stage, disease bulk, and sites involved. RESULTS: Between 2006 and 2011, 69 patients with B-cell NHL were enrolled. Among these, 72.5% were boys with mean age of 6.9 years (±3.33 [SD]; range 2.4-14.2 years). Eighty-seven percent had Burkitt lymphoma, 82.6% had advanced stage (25 [36.2%] stage III; 32 [46.4%] stage IV), and 24.6% were central nervous system positive. Mean lactate dehydrogenase increased progressively across the risk strata. Among these, 0/6, 1/15, 3/16, 2/15, and 7/17 patients relapsed/progressed within each risk stratum. Fifteen patients died; three from treatment-related toxicity. At a median follow-up of 6.2 years, the overall and event-free survival (EFS) for all patients was 78.1 and 75.4%, respectively; EFS was related to risk assignment. The frequency of documented infectious and noninfectious toxicities increased with higher risk group assignment causing prolongation of admissions and potential treatment delays. CONCLUSIONS: Reduction in treatment intensity for an identified subset of patients with NHL is feasible, while high-intensity therapy is required for high-risk groups. This risk stratification system may be a first step toward improving the outcomes in some DCs.

Circulating MicroRNA-21, MicroRNA-23a, and MicroRNA-125b as Biomarkers for Diagnosis and Prognosis of Burkitt Lymphoma in Children.

BACKGROUND The aim of this study was to investigate the diagnostic and prognostic value of microRNA (miRNA)-21, miRNA-23a, and miRNA-125b in Burkitt lymphoma (BL) in children. MATERIAL AND METHODS We recruited 41 children with BL for the case group, 56 children with lymph node inflammation for the positive control group, and 60 healthy children for the negative control group. Real-time fluorescent quantitative polymerase chain reaction (RT-qPCR) was conducted for detection of circulating miRNA-21, miRNA-23a, and miRNA-125b. A receiver operating characteristic (ROC) curve was drawn to compare the diagnostic value of miRNA-21, miRNA-23a, and miRNA-125b. Kaplan-Meier method and log-rank test were used for prognostic analyses. RESULTS MiRNA-21 and miRNA-23a had significantly higher expression in cases than in positive and negative controls (all P<0.05). Overexpression of miRNA-21 and miRNA-23a were associated with staging, WBC, upregulated serum lactate dehydrogenase (LDH) level, presence of lymphoma size ≥6 cm, and cluster of differentiation 10 (CD10) expression, while miRNA-125b expression had an association with staging and upregulated serum LDH level (both P<0.05). ROC curves of miRNA-21, miRNA-23a, and miRNA-125b presented an area under curve (AUC) of 0.759, 0.853 and 0.615, respectively. MiRNA-21 and miRNA-23a in combination had an AUC of 0.869. After treatment, both miRNA-21 and miRNA-23a expression were significantly decreased (both P<0.05). Advanced clinical stage, upregulated LDH, and lymphoma size of ³6 cm were related to low complete remission rate (all P<0.05). CONCLUSIONS Patients with high expression of miRNA-21 and miRNA-23a had significantly lower complete remission rates and survival rates than those with low expression. Expression of miRNA-21 and miRNA-23a may serve as useful diagnostic and prognostic biomarkers in children with BL.

Burkitt cells on a peripheral blood smear: how to deal with?

The diagnosis of double hit lymphoma remains a challenge for the biologist for a good management of the patient. This new category of lymphoma "double hit" (DH) is part of a new entity of the WHO classification 2008: « Unclassifiable B lymphoma with features intermediate between diffuse large cell B lymphoma and Burkitt's lymphoma ¼. It is defined by the presence of a breakpoint at the locus 8q24 of the c-MYC gene associated with a recurrent translocation involving BCL2 genes primarily BCL6 or more rarely CCDN1 or BCL3 genes. These chromosomal alterations are not systematically screened at diagnosis, which can cause misdiagnosis and poor therapy management. These lymphomas DH have variable cytology and may be confused with Burkitt lymphoma (BL) or with diffuse large B-cell lymphoma (DLBCL). They have a very poor prognosis and are often resistant to chemotherapy. Their therapy and their prognosis are different from those of the BL or the DLBCL. This entity and its morphology as well as histology either immunophenotypic or cytogenetic characteristics must therefore be known to biologists, pathologists, and clinicians. Cooperation between the various actors in these disciplines is essential in case of atypical BL or DLBCL to lead to a precise classification of the pathology.

Burkitt Lymphoma Preceded by Autoimmune Hemolytic Anemia due to Anti-D Antibody.

We herein report a rare case of Burkitt lymphoma (BL) preceded by autoimmune hemolytic anemia (AIHA) caused by autoantibodies against D antigen. After a partial response to AIHA with prednisolone (PSL) treatment for 7 months, the patient developed BL with a t(8;22)(q24;q11.2) chromosomal translocation. Intensive immunochemotherapy, including rituximab, led to a complete response (CR) of BL; however, anti-D antibody remained detectable in the plasma and antibody-dissociated solution from erythrocytes, thus continuous therapy with PSL was necessary even after achievement of the CR. BL with AIHA is extremely rare, with only one previously reported case in the literature.