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Blinatumomab, a bispecific T cell engager that binds CD19 in leukemic cells and CD3 in cytotoxic T cells and leads to leukemic blast lysis, is often used in pediatric patients with relapsed/refractory (R/R) B cell acute lymphoblastic leukemia (B-ALL) prior to allogeneic hematopoietic cell transplantation (allo-HCT). Concerns about the potential risk of blinatumomab-related immune-mediated toxicities after allo-HCT have not been adequately addressed. These include graft-versus-host disease (GVHD), delayed engraftment, and graft failure or rejection. Pediatric-specific data reporting post-HCT outcomes of patients treated with blinatumomab are scarce and limited to small cohorts. We sought to investigate the clinical outcomes of pediatric patients with R/R B-ALL who received blinatumomab therapy pre-HCT, focusing on overall survival (OS), leukemia-free survival (LFS), cumulative incidence of relapse (CIR), and nonrelapse mortality (NRM), as well as the incidence of immune-mediated post-HCT complications including GVHD, delayed neutrophil or platelet engraftment, graft failure, and graft rejection. We also investigated blinatumomab's effects on B cell reconstitution based on achievement of i.v. immunoglobulin (IVIG) independence post-HCT. This single-center, retrospective study included patients with B-ALL receiving blinatumomab therapy before undergoing allo-HCT, with transplantation performed between 2016 and 2021 at our institution. Patients receiving blinatumomab for relapse after allo-HCT were excluded. Patients receiving chemotherapy alone before allo-HCT during the same period composed the control group. Seventy-two patients were included, 31 of whom received blinatumomab before allo-HCT. Survival estimates were obtained using the Kaplan-Meier method, and the log-rank test was used to analyze differences between groups. Categorical variables were compared between groups using the chi-square test or Fisher exact test, and continuous variables were compared using the Wilcoxon rank-sum test. Cumulative incidences were estimated using the competing risks method, and Gray's test was used to analyze differences between groups. A Cox proportional hazards regression model was used for univariate and multivariable analyses for OS. Landmark analysis was performed at the set time points of 30 days and 100 days post-allo-HCT. Most patients in the study cohort had high-risk relapsed B-ALL. Blinatumomab therapy induced minimal residual disease (MRD)-negative remissions in all patients, whereas 5 patients (12.2%) receiving chemotherapy alone had persistent MRD pre-allo-HCT. Time from the start of therapy to the date of allo-HCT was shorter for patients who received blinatumomab compared with those who received chemotherapy (P < .0001). Blinatumomab therapy was associated with greater LFS compared to chemotherapy alone (P = .049), but when limited to 1 year, LFS was not significantly different from control (P = .066). There appeared to be higher OS, lower CIR, and lower NRM in patients receiving blinatumomab compared to the control group; however, the differences were not significant. None of the variables assessed in multivariable analysis was associated with differences in OS. When compared to the controls, blinatumomab therapy did not result in a higher incidence of acute or chronic GVHD, delayed neutrophil or platelet engraftment, or graft failure or rejection. The time to IVIG infusion independence post-allo-HCT was similar in the 2 groups. This study supports the use of blinatumomab salvage therapy for R/R B-ALL before allo-HCT given its efficacy in inducing MRD-negative remissions and optimizing LFS, as well as its lack of association with an increased incidence of post-allo-HCT adverse immune-mediated toxicities. Larger, prospective studies are needed to confirm these findings and to investigate blinatumomab's effects in long-term post-allo-HCT events., (Copyright © 2023 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

Background: The 2 cofactors in the etiology of Burkitt lymphoma (BL) are Epstein-Barr virus (EBV) and repeated Plasmodium falciparum malaria infections. This study evaluated EBV loads in mucosal and systemic compartments of children with malaria and controls. Age was analyzed as a covariate because immunity to malaria in endemic regions is age dependent., Methods: Children (2-10 years) with clinical malaria from Western Kenya and community controls without malaria were enrolled. Saliva and blood samples were collected, EBV viral load was assessed by quantitative polymerase chain reaction, and EpiTYPER MassARRAY was used to assess methylation of 3 different EBV genes., Results: Regardless of the compartment, we detected EBV more frequently in malaria cases compared to controls, although the difference was not significant. When EBV was detected, there were no differences in viral load between cases and controls. However, EBV methylation was significantly lower in the malaria group compared to controls in both plasma and saliva (P < .05), indicating increased EBV lytic replication. In younger children before development of immunity to malaria, there was a significant effect of malaria on EBV load in peripheral blood mononuclear cells (P = .04)., Conclusions: These data suggest that malaria can directly modulate EBV persistence in children, increasing their risk for BL., Competing Interests: Potential conflicts of interest. All authors: No reported conflicts of interest., (© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

The approval of tisagenlecleucel (tisa-cel) for use in children with B cell acute lymphoblastic leukemia (B-ALL) was based on the phase 2 ELIANA trial, a global registration study. However, the ELIANA trial excluded specific subsets of patients facing unique challenges and did not include a sufficient number of patients to adequately evaluate outcomes in rare subpopulations. Since the commercialization of tisa-cel, data have become available that support therapeutic indications beyond the specific cohorts previously eligible for chimeric antigen receptor (CAR) T cells targeted to CD19 (CD19 CAR-T) therapy on the registration clinical trial. Substantial real-world data and aggregate clinical trial data have addressed gaps in our understanding of response rates, longer-term efficacy, and toxicities associated with CD19 CAR-T in special populations and rare clinical scenarios. These include patients with central nervous system relapsed disease, who were excluded from ELIANA and other early CAR-T trials owing to concerns about risk of neurotoxicity that have not been born out. There is also interest in the use of CD19 CAR-T for very-high-risk patients earlier in the course of therapy, such as patients with persistent minimal residual disease after 2 cycles of upfront chemotherapy and patients with first relapse of B-ALL. However, these indications are not specified on the label for tisa-cel and historically were not included in eligibility criteria for most clinical trials; data addressing these populations are needed. Populations at high risk of relapse, including patients with high-risk cytogenetic lesions, infants with B-ALL, patients with trisomy 21, and young adults with B-ALL, also may benefit from earlier treatment with CD19 CAR-T. It is important to prospectively study patient-reported outcomes given the differential toxicity expected between CD19 CAR-T and the historic standard of care, hematopoietic cell transplantation. Now that CD19 CAR-T therapy is commercially available, studies evaluating potential access disparities created by this very expensive novel therapy are increasingly pressing., (Copyright © 2023 The American Society for Transplantation and Cellular Therapy. All rights reserved.)

Objectives: Studies on the prognosis and risk stratification of patients with acquired immune deficiency syndrome (AIDS) - related Burkitt lymphoma (AR-BL) are rare. We aim to construct a novel model to improve the risk assessment of these patients. Methods: We retrospectively analyzed the clinical data of 34 patients over the past 10 years and the factors associated with progression-free survival (PFS) and overall survival (OS) were evaluated in univariate and multivariate Cox models. Then, the novel model consisting of screened factors was compared with the existing models. Results: With a 37-month median follow-up, the overall 2-year PFS and OS rates were 40.50% and 36.18%, respectively. The OS of patients who received chemotherapy was better compared with those without chemotherapy ( P =  .0012). Treatment with an etoposide, prednisone, oncovin, cyclophosphamide, and hydroxydaunorubicin-based regimen was associated with longer OS and PFS compared with a cyclophosphamide, doxorubicin, vincristine, and prednisone-based regimen (OS, P =  .0002; PFS, P =  .0158). Chemotherapy (hazard ratio [ HR ] = 0.075; 95% confidence interval [CI], 0.009-0.614) and Eastern Cooperative Oncology Group Performance Status (ECOG PS) 2 to 4 ( HR =  4.738; 95% CI, 1.178-19.061) were independent prognostic factors of OS in multivariate analysis and we established a novel prognostic risk stratification model named GZ8H model with chemotherapy and ECOG PS. Conclusion: GZ8H showed better stratification ability than the international prognostic index (IPI) or Burkitt lymphoma IPI (BL-IPI). Furthermore, the C-index of the nomogram used to predict OS was 0.884 in the entire cohort and the calibration curve showed excellent agreement between the predicted and actual results of OS. No human immunodeficiency virus-related factors were found to be associated with OS and PFS of AR-BL patients in our study. Overall, the clinical characteristics and outcomes in AR-BL were shown and prognostic factors for OS and PFS were identified in this study., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Donor-derived hematological malignancies have been recognized as rare but serious late complications in allogeneic hematopoietic stem cell transplantation (allo-HSCT) recipients. Most cases in the literature were diagnosed as myelodysplastic syndrome or acute leukemia, with very few malignant lymphoma reported. We herein present another case of donor-derived Burkitt lymphoma that occurred 9 years after allo-HSCT under continued administration of immunosuppressants for chronic graft-versus-host disease (GVHD). The patient achieved a partial response after rituximab-combined intensive chemotherapy. To reduce the risk of relapse and to avoid organ toxicities due to repeated chemotherapies, we performed upfront high-dose chemotherapy followed by stem cell rescue using donor-derived CD34 + cells, called pseudo-autologous HSCT (pASCT), and adjusted immunosuppressants appropriately. The patient remained disease-free for 23 months after pASCT without exacerbation of cGVHD. Although the observation period has been relatively short and longer follow-up is needed, pASCT may be a feasible option for donor-derived lymphoma even in patients with active cGVHD., (© 2022. Japanese Society of Hematology.)

Clinical outcomes of hematopoietic stem cell transplantation (HSCT) using a haploidentical stem cell graft and an unrelated umbilical cord blood unit (haplo-cord HSCT) for the treatment of B cell acute lymphoblastic leukemia (B-ALL) remain unclear. This study was conducted to explore the clinical outcomes of haplo-cord HSCT in patients with B-ALL. A total of 112 B-ALL patients who underwent haplo-cord HSCT and 64 B-ALL patients who underwent haploidentical HSCT (haplo-HSCT) at our center between 2010 and 2020 were retrospectively included in this study, and clinical outcomes and prognostic factors were further analyzed. Of the 112 haplo-cord HSCT recipients, 106 (94.6%) achieved complete haploidentical chimerism and 6 (5.4%) had mixed cord blood chimerism. No differences in neutrophil and platelet recovery or in the incidences of graft-versus-host disease, cytomegalovirus/Epstein-Barr virus viremia, bloodstream infection, or hemorrhagic cystitis were observed between the haplo-cord HSCT and haplo-HSCT groups. Compared with the haplo-HSCT group, the haplo-cord HSCT group had a higher absolute number of CD3 + cells (P = .029) and a lower ratio of CD3 + CD4 + /CD3 + CD8 + cells (P = .049) at 1 month post-transplantation. Moreover, the haplo-cord HSCT group had lower minimal residual disease (MRD) levels at 1 month (P = .020) and 100 days (P = .038) post-transplantation and a better 3-year prognosis (overall survival, P = .016; disease-free survival, P = .041; cumulative incidence of relapse [CIR], P = .016). The CIRs in patients with adverse genomic features (P = .040) or flow cytometry-based MRD (FCM-MRD) ≥1 × 10 -4 (P = .033) were improved by haplo-cord HSCT. Multivariate analysis revealed that haplo-cord HSCT could independently improve the 3-year OS, DFS, and CIR of B-ALL patients (OS, P = .029; DFS, P = .024; CIR, P = .024). In addition, allo-HSCT at first complete remission was an independent parameter associated with 3-year OS for B-ALL patients (P = .014). An FCM-MRD ≥1 × 10 -4 pre-HSCT could independently predict unfavorable 3-year DFS and CIR (DFS, P = .020; CIR, P = .036) in B-ALL patients. Our data suggest that the use of haplo-cord HSCT can independently improve survival in patients with B-ALL., (Copyright © 2021 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

Sporadic Burkitt lymphoma (BL) is the most frequent tumour of children and adolescents but a rare subtype of lymphomas in adults. To date most molecular data have been obtained from lymphomas arising in the young. Recently, Epstein-Barr virus (EBV) positive and negative BL in young patients was shown to differ in molecular features. In the present study, we present a large age-overarching cohort of sporadic BL (n = 162) analysed by immunohistochemistry, translocations of MYC proto-oncogene, basic helix-loop-helix transcription factor (MYC), B-cell leukaemia/lymphoma 2 (BCL2) and B-cell leukaemia/lymphoma 6 (BCL6) and by targeted sequencing. We illustrate an age-associated inter-tumoral molecular heterogeneity in this disease. Mutations affecting inhibitor of DNA binding 3, HLH protein (ID3), transcription factor 3 (TCF3) and cyclin D3 (CCND3), which are highly recurrent in paediatric BL, and expression of sex determining region Y-box transcription factor 11 (SOX11) declined with patient age at diagnosis (P = 0·0204 and P = 0·0197 respectively). In contrast, EBV was more frequently detected in adult patients (P = 0·0262). Irrespective of age, EBV-positive sporadic BL showed significantly less frequent mutations in ID3/TCF3/CCND3 (P = 0·0088) but more often mutations of G protein subunit alpha 13 (GNA13; P = 0·0368) and forkhead box O1 (FOXO1; P = 0·0044) compared to EBV-negative tumours. Our findings suggest that among sporadic BL an EBV-positive subgroup of lymphomas increases with patient age that shows distinct pathogenic features reminiscent of EBV-positive endemic BL., (© 2021 The Authors. British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd.)

A 62-year-old woman, who had a 16-year history of JAK2 V617F -mutated myeloproliferative neoplasm (MPN), developed Burkitt leukemia (BL) 16 months after treatment with ruxolitinib to control hydroxyurea-refractory conditions. BL cells were CD10 + , CD19 + , CD20 - , CD34 - , cytoplasmic CD79a + , and TdT + , and lacked surface immunoglobulins but expressed the cytoplasmic μ heavy chain. In the bone marrow, nuclear MYC + BL cells displaced the MPN tissues. t(8;14)(q24;q32) occurred at a CG dinucleotide within MYC exon 1 and at the IGHJ3 segment, and an N-like segment was inserted at the junction. The V-D-J sequence of the non-translocated IGH allele had the unmutated configuration. DNA from peripheral blood at a time of the course of MPN exhibited homozygous JAK2 V617F mutation, while that at BL development included both JAK2 V617F and wild-type DNAs. Although the association between JAK1/2 inhibitor therapy for MPN and secondary development of aggressive B-cell neoplasm remains controversial, this report suggests that, in selected patients, close monitoring of clonal B-cells in the BM is required before and during treatment with JAK1/2 inhibitors.

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.

In the immunocompromised setting, recipients of solid-organ or hematopoietic stem-cell transplants carry an increased risk of post-transplant lymphoproliferative disorder (PTLD). Burkitt lymphoma (BL) PTLD is a rare form of monomorphic B-cell PTLD, which lacks a standard best treatment. Here, we report the successful treatment of refractory BL-PTLD with autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy. A male patient was diagnosed with BL-PTLD, with an increasing Epstein-Barr virus (EBV) viral load, at 21 months after undergoing living liver transplantation from his mother due to neonatal biliary atresia. After 10 cycles rituximab +/- intensive chemotherapy and surgical tumor resection, the tumors significantly advanced. Next-generation sequencing (NGS) was performed on formalin-fixed paraffin-embedded tumor tissue, revealing one mutation in exon 5, TP53: p.A159 V, which may be associated with chemo-resistance. Thus, treatment was started with autologous anti-CD19 CAR T-cell therapy. We administered 9.0 × 10 6 /kg autologous anti-CD19 CAR T-cells, after conditioning with cyclophosphamide and fludarabine. Unexpectedly, the patient experienced only mild (Grade II) cytokine release syndrome (CRS) without neurotoxicity. Finally, he went into complete remission (CR), and has achieved 16-month event-free survival to date. In addition, liver function has remained stably within the normal range without any immunosuppressive therapy. The literature includes only five previously reported BL cases treated with CAR T-cell therapy. In conclusion, the present case suggests that autologous anti-CD19 CAR T-cell therapy may represent a new therapeutic option for some cases of refractory BL-PTLD.Clinical trial number: ChiCTR2000032211.

Burkitt lymphoma is a rare and aggressive non-Hodgkin lymphoma with three classifications: endemic, sporadic, and immunodeficiency-related. High-intensity chemotherapeutic regimens have considerably improved overall survival for patients with Burkitt lymphoma. In this Review of HIV-associated Burkitt lymphoma, we summarise expert opinion and provide general recommendations for the treatment of Burkitt lymphoma in patients with HIV on the basis of retrospective and prospective studies, taking into consideration immune status, CD4 cell counts, the presence of systemic disease, and the risk of CNS involvement or relapse. We also discuss the role of rituximab and antiretroviral therapy. We highlight the reasons behind the possible different mechanisms of lymphomagenesis in HIV-associated Burkitt lymphoma and endemic Burkitt lymphoma, which indicate that HIV might have either a direct or indirect oncogenic role in Burkitt lymphoma. We discuss the possible mechanisms by which HIV and HIV proteins could directly contribute to lymphomagenesis. Identifying these mechanisms might lead to the development of therapies that have fewer toxic effects than high-intensity chemotherapeutic regimens., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

"Burkitt-like lymphoma with 11q aberration" is a new provisional entity in the latest revision of lymphoma's World Health Organization classification described as carrying the specific 11q-gain/loss aberration and lacking MYC rearrangement. Morphologically, phenotypically and by gene and microRNA expression profiling these lymphomas resemble Burkitt lymphoma. The 11q-gain/loss was also found in post-transplant patients with molecular Burkitt lymphoma signature without MYC rearrangement. Recent reports describe aggressive lymphomas with coexistence of 11q-gain/loss and MYC rearrangement. In this report we describe post-transplant Burkitt-like lymphoma with 11q aberration and MYC amplification. Genetic studies were conducted at two time points: before therapy and during progression. In both cytogenetic examinations, peculiar 11q-gain/loss was detected. Percentage of cells carrying MYC amplification increased from 2% at initial diagnosis to 97% during progression. The MYC amplification can functionally correspond to MYC translocation and to MYC overexpression. The presence of MYC amplification seems to increase the aggressiveness of the reported disease course, so even a small clone with this change should be indicated in cytogenetic result., (Copyright © 2020. Published by Elsevier Inc.)

Background: Endemic Burkitt lymphoma (eBL) is associated with Epstein-Barr virus (EBV) and Plasmodium falciparum malaria coinfections. However, the role of Kaposi sarcoma-associated herpesvirus (KSHV), also endemic in Africa, has not been evaluated as a cofactor in eBL pathogenesis., Methods: Multiplexed seroprofiles for EBV, malaria, and KSHV were generated for 266 eBL patients, 78 non-eBL cancers, and 202 healthy children. KSHV and EBV loads were quantified by PCR., Results: KSHV seroprevalence did not differ by study group but was associated with age. Seropositivity, defined by K8.1/LANA or in combination with 5 other KSHV antigens (ORF59, ORF65, ORF61, ORF38, and K5) was associated with antimalarial antibody levels to AMA1 (odds ratio [OR], 2.41, P < .001; OR, 2.07, P < .001) and MSP1 (OR, 2.41, P = .0006; OR, 5.78, P < .001), respectively. KSHV loads did not correlate with antibody levels nor differ across groups but were significantly lower in children with detectable EBV viremia (P = .014)., Conclusions: Although KSHV-EBV dual infection does not increase eBL risk, EBV appears to suppress reactivation of KSHV while malaria exposure is associated with KSHV infection and/or reactivation. Both EBV and malaria should, therefore, be considered as potential effect modifiers for KSHV-associated cancers in sub-Saharan Africa., (© The Author(s) 2020. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

South Africa (SA) has a high prevalence of human immunodeficiency virus (HIV) infection. People living with HIV are at markedly increased risk of developing Burkitt lymphoma (BL), which is characterized by the MYC translocation. There is a paucity of survival data of HIV-associated Burkitt lymphoma/leukaemia (HIV-BL) cases from SA, and the relationship between karyotype and outcomes has not been widely reported. Here we report the clinico-pathological characteristics of a cohort of cytogenetically confirmed HIV-BL cases. A retrospective, descriptive review was conducted of clinico-pathological features of HIV-BL patients newly diagnosed and treated between 2005 and 2014 at our tertiary academic institution in Cape Town. Only HIV-BL patients with cytogenetic evidence of a MYC translocation were included for analysis. A multivariable Cox proportional hazards model assessed the impact of variables on overall survival (OS). Forty-nine patients met inclusion criteria. Their median age was 37 years (IQR 30-43 years) and 57% (n = 28) were females. Their median CD4 count was 240 cells/μl (IQR 103-423 cells/μl). The majority, 61% (n = 30), had leukaemic presentation, and 20% (n = 10) had a complex karyotype on conventional karyotyping. Seventy-seven percent (n = 36) received various protocols of combination intensive chemotherapy, excluding rituximab. Their OS was 64% (95% CI 45-77%) at 6 months, and 34% (95% CI 17-51%) at 5 years. Leukaemic presentation and a complex karyotype gave a 2.7-fold (95% CI 1.0-6.7) and 2.6-fold (95% CI 1.1-6.6) increased risk of mortality respectively, which were statistical significant (p < 0.05). We report 49 newly diagnosed, cytogenetically confirmed HIV-BL patients at our institution over a 10-year period. There was a high proportion of complex karyotypes and leukaemic presentation, which both independently adversely affected survival. This may be due to differences in the pathobiology of HIV-BL that requires further study and could lead to therapeutic advances in this patient group.

Endemic Burkitt lymphoma (eBL) is the most common childhood cancer in sub-Saharan African countries, however, few epidemiologic studies have been undertaken and none attempted enrolling cases from multiple countries. We therefore conducted a population-based case-control study of eBL in children aged 0-15 years old in six regions in Northern Uganda, Northern Tanzania and Western Kenya, enrolling 862 suspected cases and 2,934 population controls (response rates 98.5-100%), and processing ~40,000 vials of samples using standardized protocols. Risk factor questionnaires were administered, and malaria period prevalence was measured using rapid diagnostic tests (RDTs). A total of 80.9% of the recruited cases were diagnosed as eBL; 61.4% confirmed by histology. Associations with eBL risk were computed using logistic regression models adjusted for relevant confounders. Associations common in at least two countries were emphasized. eBL risk was decreased with higher maternal income and paternal education and elevated with history of inpatient malaria treatment >12 months before enrollment. Reporting malaria-attributed fever up to 6 months before enrollment and malaria-RDT positivity at enrollment were associated with decreased eBL risk. Conversely, reporting exposure to mass malaria suppression programs (e.g., indoor residual insecticide) was associated with elevated risk. HIV seropositivity was associated with elevated eBL risk, but the relative impact was small. The study shows that it is feasible to conduct networked, multisite population-based studies of eBL in Africa. eBL was inversely associated with socioeconomic status, positively associated with inpatient malaria treatment 12 months ago and with living in areas targeted for malaria suppression, which support a role of malaria in eBL., (© 2019 UICC.)

Burkitt lymphoma (BL) is an aggressive non-Hodgkin lymphoma. The prevalence of BL is ten-fold higher in areas with stable transmission of Plasmodium falciparum malaria, where it is the most common childhood cancer, and is referred to as endemic BL (eBL). In addition to its association with exposure to P. falciparum infection, eBL is strongly associated with Epstein-Barr virus (EBV) infection (>90%). This is in contrast to BL as it occurs outside P. falciparum-endemic areas (sporadic BL), where only a minority of the tumours are EBV-positive. Although the striking geographical overlap in the distribution of eBL and P. falciparum was noted shortly after the first detailed description of eBL in 1958, the molecular details of the interaction between malaria and eBL remain unresolved. It is furthermore unexplained why exposure to P. falciparum appears to be essentially a prerequisite to the development of eBL, whereas other types of malaria parasites that infect humans have no impact. In this brief review, we summarize how malaria exposure may precipitate the malignant transformation of a B-cell clone that leads to eBL, and propose an explanation for why P. falciparum uniquely has this capacity., (© 2020 APMIS. Published by John Wiley & Sons Ltd.)

Background: Although the increased use of combined antiretroviral therapy (cART) has decreased the incidence of lymphomas HIV-associated, Burkitt lymphoma (BL) incidence remains stable. Reported outcomes on HIV-associated BL from developed countries seem to corroborate that the regimens do not need to be tailored to the HIV-positive population., Materials and Methods: This is a retrospective multicenter cohort study from Brazil, including HIV-positive patients aged 15 years and above diagnosed with BL., Results: A total of 54 patients were included. Median age was 39 years (range, 15-64). At diagnosis, advanced disease was found in 86% and 52% had a CD4+ count lower than 200 cells/mm 3 . Five patients died before starting any regimen. Among the remaining 49 patients, most were treated with Hyper-CVAD (53%) and CODOX-M IVAC (18%). Rituximab was used in frontline in only 16% of the patients. Primary refractory disease was found in 14%. A treatment-related mortality of 38.7% and a complete response rate of 44.9% were found. At 4 years, estimated overall survival (OS) was 39.8%. All relapsed and primary refractory patients eventually died. Remaining patients died from infections (24/34), despite antimicrobial prophylaxis and associated cART., Conclusion: Early mortality and toxicity were higher in our cohort than in developed countries. A faster diagnosis, better understanding of the biology of the disease, establishment of low toxicity regimens, inclusion of rituximab and improvement of supportive care may decrease the mortality of HIV-associated BL in developing countries., Competing Interests: Declarations of Competing Interest None., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Immunotherapy has been showed as a promisor treatment, in special for hematological diseases. Chimeric antigen receptor T cells (CARs) which are showing satisfactory results in early-phase cancer clinical trials can be highlighted. However, preclinical models are critical steps prior to clinical trial. In this way, a well-established preclinical model is an important key in order to confirm the proof of principle. For this purpose, in this chapter will be pointed the methods to generate tumor cells expressing firefly Luciferase. In turn, these modified cells will be used to create a subcutaneous and a systemic murine model of Burkitt's lymphoma in order to evaluate the effectiveness of CAR-T.

Introduction: Chronic infections and infestations represent one of the leading causes of cancer. Eleven agents have been categorized by the International Agency for Research on Cancer (IARC) in Group 1, 3 in Group 2A and 4 in Group 2B. We previously estimated that the incidence of cancers associated with infectious agents accounted for the 8.5% of new cancer cases diagnosed in Italy in 2014., Methods: In the present study we evaluated the incidence of cancer in Italy and in the 20 Italian regions in 2018, based on the data of Cancer Registries, and calculated the fraction attributable to infectious agents., Results: Cancers of infectious origin contributed to the overall burden of cancer in Italy with more than 27,000 yearly cases, the 92% of which was attributable to Helicobacter pylori, human papillomaviruses, and hepatitis B and C viruses. With the exception of papillomavirus-related cancers, the incidence of cancers of infectious origin was higher in males (16,000 cases) than in females (11,000 cases). There were regional and geographical variations of cancers depending on the type of cancer and on the gender. Nevertheless, the overall figures were rather similar, the infection-related cancers accounting for the 7.2, 7.6, and 7.1% of all cancers in Northern, Central, and Southern Italy, respectively., Conclusions: The estimate of the incidence of cancers attributable to infectious agents in Italy in 2018 (7.3% of all cancer cases) is approximately half of the worldwide burden, which has been estimated by IARC to be the 15.4% of all cancer cases in 2012., (©2019 Pacini Editore SRL, Pisa, Italy.)

Platelet activation and functional changes in some haematological malignancies have been investigated with little or no known documentation on Burkitt lymphoma (BL). Abnormalities of platelets contribute to either haemorrhage or thrombotic episodes which are life-threatening in patients with BL. Thus, the study aimed at investigating the various platelet indices and platelet membrane glycoproteins in childhood Burkitt lymphoma. Platelet surface membrane glycoproteins (GPIIb/IIIa, P-selectin and GPIV using PAC 1, CD62p and CD36 monoclonal antibodies respectively) and platelet indices (Platelet Count [PLT], Plateletcrite [PCT], Mean Platelet Volume [MPV], Platelet Distribution Width [PDW] and Platelet Large Cell Ratio [P-LCR]) were determined in children with Burkitt lymphoma and healthy children (normal controls) based on flow cytometry and automated blood cell analysis techniques. PLT and PCT were higher in BL cases than in the normal controls with a significant difference in the PLT (P = 0.02). On the contrary, we observed a significant (p < 0.05) lower levels in the other platelet indices (MPV, PDW and P-LCR) in children with BL than the controls. With the exception of CD62 P, the other platelet membrane glycoproteins examined showed a decreased level of expression before and after the addition of an Adenosine -5- diphosphate (ADP) in cases of BL. In addition, PAC-1 was probably known to be associated with Burkitt Lymphoma (Odds Ratio [OR] 6.67, Relative Risk [RR] 3.13, 95% CI 1.06-9.21; p = 0.02). Finally, oral bleeding was observed to be the commonest bleeding episodes associated with childhood BL. Flow cytometry analysis and cell counting techniques of platelet assessment has described the expression of the platelet membrane glycoproteins and parameters in children with Burkitt lymphoma. Thus, children with Burkitt lymphoma tend to show normal to increased level of circulatory platelets but decreased platelet membrane glycoprotein expressions and platelet dysfunction., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

BACKGROUND Hepatitis E virus (HEV) is a common cause of acute hepatitis in developing regions. In high-income countries, hepatitis E is an emergent zoonotic disease of increasing concern. Clinically, the infection is usually acute and self-limited in immunocompetent individuals, although rare chronic cases in immunocompromised patients have been reported. Both acute and chronic infections have been recently associated with several extrahepatic manifestations, including neurological and hematological disorders. CASE REPORT A case of autochthonous chronic HEV infection in a liver-transplanted man from a non-endemic country is presented. Phylogenetic analysis revealed a swine origin of the HEV human infection. Chronic hepatitis E was treated with a 9-week course of ribavirin, after which viral clearance was achieved. Subsequently, the patient developed a post-transplant lymphoproliferative disorder (PTLD) in the form of Burkitt lymphoma. At the time of lymphoma diagnosis, the patient had shown a strong reactivation of Epstein-Barr virus (EBV) infection. After additional antiviral ganciclovir therapy and chemotherapy, the patient had a complete recovery with no sequelae. CONCLUSIONS The differential diagnosis of persistently elevated transaminases in transplanted and/or immunocompromised patients should include testing for HEV by appropriate nucleic acid techniques (NATs). Cases of HEV infection with an atypical clinical outcome, such as the one presented herein, highlights the need for increased awareness of chronic hepatitis E and its association with a wide range of extrahepatic manifestations.

Background: General practitioners encounter the vast majority of patients with Epstein-Barr virus-related disease, i.e. infectious mononucleosis in children and adolescents. With the expanding knowledge regarding the multifaceted role of Epstein-Barr virus in both benign and malignant disease we chose to focus this review on Epstein-Barr virus-related conditions with relevance to the general practitioners. A PubMed and Google Scholar literature search was performed using PubMed's MeSH terms of relevance to Epstein-Barr virus/infectious mononucleosis in regard to complications and associated conditions., Main Text: In the present review, these included three early complications; hepatitis, splenic rupture and airway compromise, as well as possible late conditions; lymphoproliferative cancers, multiple sclerosis, rheumatoid arthritis, and chronic active Epstein-Barr virus infection. This review thus highlights recent advances in the understanding of Epstein-Barr virus pathogenesis, focusing on management, acute complications, referral indications and potentially associated conditions., Conclusions: Hepatitis is a common and self-limiting early complication to infectious mononucleosis and should be monitored with liver tests in more symptomatic cases. Splenic rupture is rare. Most cases are seen within 3 weeks after diagnosis of infectious mononucleosis and may occur spontaneously. There is no consensus on the safe return to physical activities, and ultrasonic assessment of spleen size may provide the best estimate of risk. Airway compromise due to tonsil enlargement is encountered in a minority of patients and should be treated with systemic corticosteroids during hospitalization. Association between lymphoproliferative cancers, especially Hodgkin lymphoma and Burkitt lymphoma, and infectious mononucleosis are well-established. Epstein-Barr virus infection/infectious mononucleosis as a risk factor for multiple sclerosis has been documented and may be linked to genetic susceptibility. Chronic active Epstein-Barr virus infection is rare. However, a general practitioner should be aware of this as a differential diagnosis in patients with persisting symptoms of infectious mononucleosis for more than 3 months.

Burkitt lymphoma (BL) is a highly aggressive B-cell non-Hodgkin lymphoma characterized by marked tumor proliferation resulting from translocation of the MYC oncogene. Distinct clinical variants include endemic, sporadic, and immunodeficiency-associated cases. All variants are characterized by rapidly dividing tumor masses that quickly disseminate to extranodal sites, including the bone marrow and central nervous system (CNS). Although common in children, BL is rare in adults, mandating a high index of clinical suspicion for timely diagnosis. Prompt recognition and initiation of comprehensive supportive care are essential for prevention of early complications, such as tumor lysis syndrome and multisystem organ dysfunction. BL is highly sensitive to chemotherapy, and patients who tolerate highly intensive combination chemotherapy regimens are frequently cured. Most regimens were developed in children and young adults, however, and the treatment-related toxicities remain a major barrier for those with advanced age and/or comorbid conditions. Younger patients are less susceptible to acute toxicities but are more likely to experience long-term sequelae of treatment, including infertility and secondary malignancies. The infusional regimen of dose-adjusted etoposide, prednisolone, vincristine, cyclophosphamide, doxorubicin, and regular- or double-dose rituximab (DA-EPOCH-R or -RR) is less toxic than standard BL regimens, yet maintains high rates of cure across a diverse range of patients, including those with disseminated disease, advanced age, and HIV infection. Patients with low-risk BL can be cured with just 3 cycles of DA-EPOCH-RR. Still, patients with CNS involvement remain at high risk for early death, and prevention of late CNS relapses remains a priority. Future studies combining rational targeted agents with DA-EPOCH-R or -RR may further improve the cure rate.

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.

Background: The incidence of AIDS-defining cancers (ADCs) has decreased markedly in the era of highly active antiretroviral therapy (HAART). The occurrence of two ADCs is rare in people living with HIV or AIDS (PWHA) who are severely immunosuppressed or have incomplete virologic suppression., Case Presentation: We report a case of dual primary ADCs, especially NHL followed by KS, in a 70-year-old HIV-infected man who was on antiretroviral therapy and had successful virologic suppression. During HAART, he presented with generalized myalgia and abdominal pain. Multiple liver masses were detected and a biopsy revealed Burkitt's lymphoma. After three cycles of anticancer chemotherapy with a favorable response, he was diagnosed with cytomegalovirus retinitis and the anti-cancer chemotherapy was discontinued. Despite successful virologic suppression with HAART, human herpes virus-8 associated Kaposi's sarcoma was diagnosed in his right thigh. He underwent radiation therapy., Conclusion: These findings suggest that multiple ADCs can occur in PWHA who are receiving HAART and have successful virologic suppression. Healthcare providers caring for PWHA should maintain vigilance for the development of a broad spectrum of cancers.

Burkitt's lymphoma is a rarely encountered, aggressive B-cell lymphoma that is highly curable in children and young adults. In middle-aged and older adults, however, administering curative therapy may be challenging because standard Burkitt's lymphoma platforms are associated with high treatment-related toxicity in these age groups. Because of its high curability, the testing of alternative, less toxic approaches in Burkitt's lymphoma has been challenging. Although the critical role of MYC in Burkitt's lymphoma has been well described, recent biologic insights have identified several new mutations that cooperate with MYC in driving lymphomagenesis, paving the way for novel drug testing in this disease. Recently, intermediate-intensity approaches have been tested in Burkitt's lymphoma. Early multicenter results demonstrate good tolerability while maintaining high cure rates in all patient and age groups.

Background: Previous research strongly suggest that malaria is an important factor in the pathogenesis of endemic Burkitt's lymphoma (eBL). Therefore, genetic factors such as sickle cell trait (SCT) and blood group-O that offer protection against severe malaria would be expected to reduce the risks of eBL. However, previous reports on the protective roles of SCT and blood group-O against the risks of eBL were inconclusive. Hence, the need for further studies on the protective roles of SCT and blood group-O separately, and also to investigate whether or not the combined anti-severe malaria protective roles of SCT and blood group-O have synergistic effects in reducing the risks of eBL. We therefore hypothesize that SCT and blood group-O are independently associated with reduced risks of eBL, and the co-inheritance of both factors (SCT and group-O) would provide greater protection against eBL. If our hypothesis is correct, children who inherited both SCT and blood group-O would have lower risks of eBL than their counterparts who inherited SCT or blood group-O separately. To the best of our knowledge, the possible synergistic relationship between SCT and blood group-O with regards to the risk of eBL has not been previously studied., Patients and Methods: We conducted a retrospective logistic regression analysis of the frequencies of Hb phenotypes and ABO blood groups among patients with eBL in order to determine the separate and synergistic protective effects of SCT and blood group-O on the risk of eBL in Nigeria where eBL is among the most common malignant childhood cancers., Results: The Odd Ratios (OR) for the risk of eBL were 0.52 for 'SCT irrespective of ABO blood group'; 0.49 for 'blood group-O irrespective of Hb phenotype'; and 0.23 for 'SCT with blood group-O'., Discussion: These values suggest that both SCT and blood group-O are independently associated with modest reduction in the risk of eBL. However, when SCT with blood group-O was assessed for the risk factor for eBL, we obtained an Odds ratio of 0.23, which was significantly lower than the OR values for SCT (0.52) and blood group-O (0.49) separately. These figures suggest that coinheritance of SCT and blood group-O offers greater reduction in the risk of eBL than that provided by either SCT or blood group-O separately. The greater protection against eBL provided by the coinheritance of SCT and blood group-O is interpreted to be the resultant synergistic effect of the combined anti-malarial attributes of SCT and blood group-O., Conclusion: These findings suggest that the combined anti-malarial protective roles of SCT and blood group-O have synergistic effects in reducing the risks of eBL. This study has provided further evidence on the association between malaria-protective genetic polymorphisms and eBL, which is consistent with the aetiologic role of malaria in the pathogenesis of the tumour. Hence, the need for malaria endemic countries to intensify malaria control programs in order to curtail the incidence of eBL.

The care of patients with HIV and Burkitt lymphoma poses a challenge to clinicians. Due to the limited treatment options that exist for relapsed/refractory Burkitt lymphoma, there is a need for the development of new therapies. This review aims to discuss evidence for current management strategies including chemotherapy and stem cell transplant, and highlight gaps in knowledge that will need to be addressed in the future.

Background: Most children with cancer live in resource-limited countries where malnutrition is often prevalent. We identified the relationship between malnutrition and treatment-related morbidity (TRM), abandonment of therapy, and survival of children with cancer in Nicaragua to better inform targeted nutritional interventions., Procedure: We conducted a retrospective review of patients aged 6 months to 18 years with newly diagnosed acute lymphoblastic leukemia, acute myeloid leukemia (AML), Wilms tumor, Hodgkin lymphoma, or Burkitt lymphoma (BL) who were treated between January 1, 2004, and December 31, 2007 at Children's Hospital Manuel de Jesus Rivera in Managua, Nicaragua. Statistical analysis examined the relations among nutritional status and cancer type, risk category, TRM, and event-free survival (EFS)., Results: Sixty-seven percent of patients (189/282) were malnourished at diagnosis. Malnutrition was highest among patients with Wilms tumor (85.7%), BL (75%), and AML (74.3%). A total of 92.2% of patients (225/244) experienced morbidity during the first 90 days. Malnutrition was associated with severe infection (P = 0.033). Severely malnourished patients had ≥grade 3 TRM on more days (P = 0.023) and were more likely to experience severe TRM on >50% of days (P = 0.032; OR, 3.27 [95% CI, 1.05-10.16]). Malnourished patients had inferior median EFS (2.25 vs. 5.58 years; P = 0.049), and abandoned therapy more frequently (P = 0.015)., Conclusions: In Nicaragua, pediatric oncology patients with malnutrition at diagnosis experienced increased TRM, abandoned therapy more frequently, and had inferior EFS. Standardized nutritional evaluation of patients with newly diagnosed cancer and targeted provision of nutritional support are essential to decrease TRM and improve outcomes., (© 2017 Wiley Periodicals, Inc.)

We evaluated the efficacy and tolerability of chemotherapy in HIV-infected patients with diffuse large B-cell lymphoma (DLBCL) receiving CHOP ± R (n = 17) or Burkitt lymphoma (BL) receiving CODOX-M/IVAC ± R (n = 15). The study was conducted in Beijing Ditan Hospital from January 2009 to August 2015. The following grade 4 adverse effects were observed in BL and DLBCL patients, respectively: neutropenia (80% versus 47.1%), anaemia (46.7% versus 5.9%), thrombocytopenia (53.3% versus 11.8%), bacterial pneumonia (33.3% versus 5.9%), and sepsis (20% versus 5.9%) (p < 0.05). In the BL group, 10 (66.7%) patients died from treatment-related or tumour-related causes, 5 (33.3%) achieved complete response, 1 achieved partial response (6.7%), and 7 developed progressive disease. The 1-year overall survival and progression-free survival rates were 33.3%. Of the DLBCL patients, 3 (17.6%) died from treatment-related causes, 14 (82.4%) achieved complete response, and 3 had progressive disease. The 1-year overall survival and progression-free survival rates were 82.4%. The strongest risk factor for death was relapse between chemotherapy cycles (adjusted hazard ratio = 47.3; 95%CI, 4.2-528.6, p = 0.002). Initiating antiretroviral therapy before chemotherapy failed to improve overall survival. DLBCL patients demonstrated good responses and survival outcomes, while BL patients could not tolerate chemotherapy due to more severe toxicity, and showed poor responses and survival outcomes.

Epstein-Barr virus (EBV) infection is associated with several distinct hematological and epithelial malignancies, e.g., Burkitt lymphoma, Hodgkin lymphoma, nasopharyngeal carcinoma, gastric carcinoma, and others. The association with several malignant tumors of local and worldwide distribution makes EBV one of the most important tumor viruses. Furthermore, because EBV can cause posttransplant lymphoproliferative disease, transplant medicine has to deal with EBV as a major pathogenic virus second only to cytomegalovirus. In this review, we summarize briefly the natural history of EBV infection and outline some of the recent advances in the pathogenesis of the major EBV-associated neoplasms. We present alternative scenarios and discuss them in the light of most recent experimental data. Emerging research areas including EBV-induced patho-epigenetic alterations in host cells and the putative role of exosome-mediated information transfer in disease development are also within the scope of this review. This book contains an in-depth description of a series of modern methodologies used in EBV research. In this introductory chapter, we thoroughly refer to the applications of these methods and demonstrate how they contributed to the understanding of EBV-host cell interactions. The data gathered using recent technological advancements in molecular biology and immunology as well as the application of sophisticated in vitro and in vivo experimental models certainly provided deep and novel insights into the pathogenetic mechanisms of EBV infection and EBV-associated tumorigenesis. Furthermore, the development of adoptive T cell immunotherapy has provided a novel approach to the therapy of viral disease in transplant medicine and hematology.

Scientific evidence strongly suggests that parasites are directly or indirectly associated with carcinogenesis in humans. However, studies have also indicated that parasites or their products might confer resistance to tumour growth. Plasmodium protozoa, the causative agents of malaria, exemplify the ambivalent link between parasites and cancer. Positive relationships between malaria and virus-associated cancers are relatively well-documented; for example, malaria can reactivate the Epstein-Barr Virus, which is the known cause of endemic Burkitt lymphoma. Nevertheless, possible anti-tumour properties of malaria have also been reported and, interestingly, this disease has long been thought to be beneficial to patients suffering from cancers. Current knowledge of the potential pro- and anti-cancer roles of malaria suggests that, contrary to other eukaryotic parasites affecting humans, Plasmodium-related cancers are principally lymphoproliferative disorders and attributable to virus reactivation, whereas, similar to other eukaryotic parasites, the anti-tumour effects of malaria are primarily associated with carcinomas and certain sarcomas. Moreover, malarial infection significantly suppresses murine cancer growth by inducing both innate and specific adaptive anti-tumour responses. This review aims to present an update regarding the ambivalent association between malaria and cancer, and further studies may open future pathways to develop novel strategies for anti-cancer therapies.

Objectives: Liver transplant may complicated by various hematologic conditions, resulting in indication for bone marrow biopsy. Immunosuppressive therapies, specific infections, and secondary neoplasms affect bone marrow. In the present study, we evaluated the histologic spectrum of bone marrow findings in liver allograft recipients., Materials and Methods: Of 338 patients who received liver transplants and were followed at the Başkent University, Faculty of Medicine, 44 patients underwent bone marrow biopsy. The medical and pathologic information about these patients were evaluated, including age at liver transplant, age at bone marrow biopsy, sex, primary disease, bone marrow histology, and indication for bone marrow biopsy., Results: Of 44 patients who required bone marrow sampling, 30 were male (68.2%), and 14 were female (31.8%). Fifteen patients (34.1%) were in pediatric age group at the time of transplant. The most common cause of liver insufficiency leading to liver transplant was viral hepatitis in 11 patients (25%), followed by cryptogenic cirrhosis in 10 patients (22.8%). The source of the graft liver was a living donor in 40 patients (90.9%). The average age at transplant was 28.8 years, and the mean age at bone marrow sampling was 29.9 years. Nineteen patients (43.2%) required bone marrow sampling within the first year after transplant. The most common histologic findings were hypocellular, and normocellular bone marrow, observed in 18 patients (40.9%) each. Six patients (13.6%) had bone marrow biopsies for staging of posttransplant lymphoproliferative disorder. Only 1 patient of the 6 with this disease (16.7%) had malignant infiltration of the bone marrow, which was a case of Burkitt lymphoma developed as posttransplant lymphoproliferative disorder, and this was the only malignant infiltration in this patient group (2.3%). Neither specific infections nor granulomatous inflammation was detected., Conclusions: Bone marrow morphology has a major role in the follow-up of liver transplant patients, who may present with peripheral blood cytopenias. The present study represents the first systematic evaluation of bone marrow findings in liver allograft recipients.

The combination of Epstein-Barr virus (EBV) infection and high malaria exposure are risk factors for endemic Burkitt lymphoma, and evidence suggests that infants in regions of high malaria exposure have earlier EBV infection and increased EBV reactivation. In this study we analyzed the longitudinal antibody response to EBV in Kenyan infants with different levels of malaria exposure. We found that high malaria exposure was associated with a faster decline of maternally derived immunoglobulin G antibody to both the EBV viral capsid antigen and EBV nuclear antigen, followed by a more rapid rise in antibody response to EBV antigens in children from the high-malaria-transmission region. We also observed the long-term persistence of anti-viral capsid antigen immunoglobulin M responses in children from the high-malaria region. More rapid decay of maternal antibodies was a major predictor of EBV infection outcome, because decay predicted time to EBV DNA detection, independent of high or low malaria exposure., (© The Author 2016. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail journals.permissions@oup.com.)

Background: Bloom syndrome is a rare disease characterized by chromosomal instability and increased risk of developing lymphoma., Observation: We report on a case of Bloom syndrome in a 5-year-old boy with Burkitt lymphoma. The diagnosis was suspected by growth retardation, repeated respiratory infections, facial telangiectasia, and a low immunoglobulin level, then confirmed cytogenetically by sister chromatid exchanges. Chemotherapy was poorly tolerated, which required reducing the doses. Unfortunately, it was not sufficient to control the neoplasm and the patient died 14 months after diagnosis., Conclusions: Cancers in Bloom syndrome are a challenge since the potentially life-threatening side effects of the chemotherapy may require modifications in standard treatment such as dose reduction, which can compromise the tumor prognosis., (Copyright © 2015 Elsevier Masson SAS. All rights reserved.)

The diagnosis of lymphoproliferative disorders associated with immunodeficiency can be challenging because many of these conditions have overlapping clinical and pathologic features and share similarities with their counterparts in the immunocompetent setting. There are subtle but important differences between these conditions that are important to recognize for prognostic and therapeutic purposes. This article provides a clinicopathologic update on how understanding of these B-cell lymphoproliferations in immunodeficiency has evolved over the past decade., (Published by Elsevier Inc.)

Purpose: Clinical outcomes for lymphoma in people living with HIV (PLWH) are similar to those in the general public. However, a number of concerns remain including pharmacological interactions between cytotoxic chemotherapy and antiretroviral therapy (ARVs). Much attention has focussed on pharmacokinetic interactions attributable to effects on hepatic microsomal enzymes, but not on competition for the renal organic anion transport system. High-dose (3 g/m(2)) intravenous methotrexate (MTX) is part a of (R)-CODOX-M/IVAC chemotherapy regimen for HIV-associated Burkitt/Burkitt-like lymphoma (BL/BLL). We investigated MTX pharmacokinetics and evaluated the effects of renal function (eGFR), age and use of different classes of ARVs., Methods: Forty-three PLWH treated with ARVs and (R)-CODOX-M/IVAC are included in the analysis. Plasma MTX concentration was measured (ARK TM MTX assay, VITROS(®) 5600) daily after administration until levels were <0.04/mmol/L. MTX elimination half-life was correlated with age, renal function and antiretroviral regimen., Results: One hundred and fifty timed plasma MTX levels were collected. The median MTX elimination half-life was 21.7 h (range 9.4-204.4). MTX elimination half-life was not influenced by age (p = 0.71), eGFR (p = 0.67) or use of non-nucleoside reverse transcriptase inhibitors (NNRTIs) or integrase inhibitors (p = 0.15). Similarly, different NRTI backbones did not affect MTX elimination kinetics (p = 0.68), despite the potential overlapping competition for active renal tubular transporters between MTX and tenofovir., Conclusion: Although there is potential competition for active renal tubular transporters between MTX and tenofovir, no prolongation of MTX half-life was observed. These findings are reassuring to clinicians managing patients with dual diagnoses.

This study retrospectively investigated 54 cases of sporadic Burkitt lymphoma in Taiwan with histopathology review, immunohistochemistry, Epstein-Barr virus (EBV) in situ hybridization (EBER) and fluorescence in situ hybridization (FISH). The great majority revealed typical immunophenotype and 89% (47/53) cases expressed myc protein. EBER was positive in 20% (11/54) of cases, more frequently with nodal presentation, but not significantly associated with age (pediatric vs. adult), abdominal vs. extra-abdominal presentation or overall survival (OS). MYC and IGH were rearranged in 94% (46/49) and 85% (41/48) of cases, respectively. The concordance rate between myc expression and MYC translocation was 83% (40/48). By univariate analysis, OS was statistically associated with age, with or without chemotherapy, central nervous system (CNS) involvement, CNS prophylaxis and leukemic transformation, but not gender, nodal vs. extranodal involvement, stage, immunohistochemistry, EBER, myc expression, MYC translocation or radiotherapy. By multivariate analysis, CNS involvement at presentation and administration of chemotherapy were statistically associated with OS.

Background: Burkitt lymphoma has a low incidence, is highly aggressive, may be endemic, sporadic or associated with immunodeficiency and it has a high frequency of extranodal involvement. Overall and relapse free survival in HIV patients is 72 and 71% respectively. However, the current protocol in Chile considers a positive HIV serology as an exclusion criterion for intensive chemotherapy., Aim: To analyze the response to Burkitt lymphoma treatment among HIV positive patients., Material and Methods: All HIV positive patients with a Burkitt lymphoma treated using PANDA protocol in a public hospital were analyzed., Results: Eight male patients aged between 25 and 43 years, 63% in stage IV, were analyzed. All patients received an intensified chemotherapy regime, three of them without Rituximab. Complete remission was achieved in 87%. One patient was refractory to treatment and one patient relapsed at 5 months and died. Overall and relapse free survival were 58 and 60% respectively. All patients had episodes of high risk febrile neutropenia, but it did not cause deaths., Conclusions: In this group of HIV patients, intensive chemotherapy for Burkitt lymphoma had a high degree of effectiveness with a low relapse rate and high cure rate.

Epstein Barr virus (EBV) sequence variation is thought to contribute to Burkitt lymphoma (BL), but lack of data from primary BL tumors hampers efforts to test this hypothesis. We directly sequenced EBV from 12 BL biopsies from Ghana, Brazil, and Argentina, aligned the obtained reads to the wild-type (WT) EBV reference sequence, and compared them with 100 published EBV genomes from normal and diseased people from around the world. The 12 BL EBVs were Type 1. Eleven clustered close to each other and to EBV from Raji BL cell line, but away from 12 EBVs reported from other BL-derived cell lines and away from EBV from NPC and healthy people from Asia. We discovered 23 shared novel nucleotide-base changes in the latent membrane protein (LMP)-1 promoter and gene (associated with 9 novel amino acid changes in the LMP-1 protein) of the 11 BL EBVs. Alignment of this region for the 112 EBV genomes revealed four distinct patterns, tentatively termed patterns A to D. The distribution of BL EBVs was 48%, 8%, 24% and 20% for patterns A to D, respectively; the NPC EBV's were Pattern B, and EBV-WT was pattern D. Further work is needed to investigate the association between EBV LMP-1 patterns with BL.

Posttransplant lymphoproliferative disorder (PTLD) is a potentially fatal disorder arising after solid organ transplant (SOT) or hematopoietic stem cell transplant (HSCT). Iatrogenically impaired immune surveillance and Epstein-Barr virus (EBV) primary infection/reactivation are key factors in the pathogenesis. However, current knowledge on all aspects of PTLD is limited due to its rarity, morphologic heterogeneity, and the lack of prospective trials. Furthermore, the broad spectrum of underlying immune disorders and the type of graft represent important confounding factors. Despite these limitations, several reviews have been written aimed at offering a guide for pathologists and clinicians in diagnosing and treating PTLD. Rather than providing another classical review on PTLD, this "How I Treat" article, based on 2 case reports, focuses on specific challenges, different perspectives, and novel insights regarding the pathogenesis, diagnosis, and treatment of PTLD. These challenges include the wide variety of PTLD presentation (making treatment optimization difficult), the impact of EBV on pathogenesis and clinical behavior, and the controversial treatment of Burkitt lymphoma (BL)-PTLD., (© 2015 by The American Society of Hematology.)

Burkitt lymphoma is an uncommon form of aggressive lymphoma affecting approximately 1200 patients per year in the USA. It is characterized by a translocation involving the MYC oncogene. Three subtypes of Burkitt lymphoma are recognized: the endemic form, occurring primarily in Africa and associated with the Epstein-Barr virus (EBV); the sporadic form, representing less than 3 % of all non-Hodgkin lymphomas (NHL); and the immunodeficiency-associated form, occurring primarily in HIV-infected patients. Burkitt lymphoma appears histologically with a diffuse pattern of intermediate-sized monomorphic B cells, multiple nucleoli, a very high proliferative rate, and frequent mitotic figures. Recent advances in transcriptional profiling have improved the current molecular understanding of Burkitt lymphoma and have better characterized its mutational landscape. Most Burkitt lymphoma patients are cured with intensive treatment; however, prognosis is poor in elderly patients and those with relapsed disease.