儿童肠道息肉样淋巴瘤15例临床病理分析

目的 观察儿童肠道息肉样淋巴瘤(PL)的临床病理学特征.方法 收集江西省儿童医院诊治的15例儿童肠道PL的临床病理资料并进行随访,免疫组织化学法检测CD10、bcl-6、bcl-2、MUM-1和ERCC1表达,原位杂交检测EB病毒编码的RNA(EBER).结果 15例肠道PL中伯基特淋巴瘤(BL)13例,患者CD10、bcl-6、bcl-2、MUM-1和ERCC1阳性率分别为100.0%(13/13)、92.3%(12/13)、0、7.7%(1/13)和15.4%(2/13),EBER阳性7例(53.8%);弥漫大B细胞淋巴瘤(DLBCL)和介于BL和DLBCL之间的未分类B细胞淋巴瘤(BL/DLBCL)各1例.13例BL患儿临床分期:Ⅱ期11例(84.6%),Ⅲ期和Ⅳ期各1例(7.7%);DLBCL和BL/DLBCL患者临床分期均为Ⅱ期.术后化疗的14例PL患儿均无瘤生存,随访时间24~120个月,1例术后未化疗的Ⅳ期BL患儿于术后2个月死亡.结论 儿童肠道PL以BL多见,临床分期较低,术后积极化疗预后好.     

Expression of cyclin D2 and D3 in lymphoid lesions

The D-type cyclins, involved in the regulation of G1 progression of the cell cycle, are expressed in a lineage-specific manner. Normal hematopoietic cells express cyclin D2 and/or D3. In order to determine whether their expression pattern changes in lymphoid tumors, we examined cyclin D2 and D3 expression in non-neoplastic and neoplastic lymphoid lesions, using a sensitive immunohistochemical amplification method. Centroblasts in lymphoid follicles of reactive lymph nodes expressed exclusively cyclin D3 and no D2. Interfollicular areas contained scattered cyclin D3 and D2 positive cells. By double staining, cyclin D3 was detected in CD79a positive B cells, CD3 positive T cells and CD68 positive macrophages. Cyclin D2 was present only in CD3 positive T cells. Neoplastic lymphoid lesions included 33 B cell lymphomas, 9 T cell lymphomas and 12 Hodgkin's lymphomas. The B cell lymphomas comprised 9 follicular lymphomas (FL), 1 Burkitt lymphoma (BL), 22 diffuse large cell lymphomas (DL) and 1 chronic lymphocytic leukemia (CLL). All 9 FLs and the single BL expressed exclusively cyclin D3, similarly to germinal center B cells, that represent their cells of origin. Six DLs expressed both cyclin D2 and D3, while 6 expressed only D3. Among the 9 pleomorphic T cell lymphomas, medium and large cell type, 5 expressed cyclin D2. Cyclin D3 was also detected in scattered cells in 4 of 9 cases and was highly expressed in 2 of 9 T cell lymphomas. The majority of Hodgkin's lymphomas expressed both cyclin D2 and D3 in Hodgkin/Reed-Sternberg (HRS) cells. The high frequency of positive cells indicates that both cyclins were expressed in the same cells.     

A new variant 15; 16 translocation in mouse plasmacytoma leads to the juxtaposition of c-myc and immunoglobulin lambda.

Mouse plasmacytomas (MPCs) induced by pristane oil, or by a combination of pristane oil and Abelson virus, carry one of two chromosomal translocations. The typical 12; 15 translocation leads to the juxtaposition of c-myc and immunoglobulin heavy-chain sequences, whereas the 6; 15 translocation links the kappa light-chain locus with the pvt-1 (plasmacytoma variant translocation) locus, located at least 75kb 3' of c-myc [Cory, S., Graham, M., Webb, E., Corcoran, L. & Adams, J. (1985). EMBO J., 4, 675-681]. Unlike the human Burkitt's lymphoma-associated translocation, the lambda/myc juxtaposed variant translocation has not been found previously in MPCs. Using unconventional MPC induction systems in which the tumor precursor cell was induced to proliferate in a secondary host, we have recently identified a 15; 16 translocation in six of the derived MPCs [Wiener, F., Silva, S., Sugiyama, H., Babonits, M. & Klein, G. (1990). Genes Chromosomes Cancer, 2, 36-43]. Chromosome 16 harbors the lambda light-chain gene. To explore whether the 15; 16 translocation represents the lambda/myc juxtaposition, we have mapped the breakpoints on chromosomes 15 and 16 by pulsed-field gel electrophoresis (PFGE). The pvt-1 region was mapped to approximately 220 kb 3' of c-myc. The breakpoint on chromosome 15 in ABPC-Ch-163-10, one of the six 15; 16 translocation-carrying MPCs, was situated approximately 80 kb 3' of c-myc and 140 kb 5' of pvt-1b, the major breakpoint cluster region of the previously analysed 6; 15 variant MPCs. The breakpoint on chromosome 16 was found to cut between the V1 and C3 regions of the lambda locus. Co-migration experiments showed that the C3 and the myc gene were juxtaposed head to tail on the 15; 16 translocation chromosome. On the reciprocal product V1 was juxtaposed to pvt-1.     

Expression of cannabinoid receptors type 1 and type 2 in non-Hodgkin lymphoma: growth inhibition by receptor activation

Endogenous and synthetic cannabinoids exert antiproliferative and proapoptotic effects in various types of cancer and in mantle cell lymphoma (MCL). In this study, we evaluated the expression of cannabinoid receptors type 1 and type 2 (CB1 and CB2) in non-Hodgkin lymphomas of B cell type (n = 62). A majority of the lymphomas expressed higher mRNA levels of CB1 and/or CB2 as compared to reactive lymphoid tissue. With the exception of MCL, which uniformly overexpresses both CB1 and CB2, the levels of cannabinoid receptors within other lymphoma entities were highly variable, ranging from 0.1 to 224 times the expression in reactive lymph nodes. Low levels of the splice variant CB1a, previously shown to have a different affinity for cannabinoids than CB1, were detected in 44% of the lymphomas, while CB1b expression was not detected. In functional studies using MCL, Burkitt lymphoma (BL), chronic lymphatic leukemia (CLL) and plasma cell leukemia cell lines, the stable anandamide analog R(+)-methanandamide (R(+)-MA) induced cell death only in MCL and CLL cells, which overexpressed both cannabinoid receptors, but not in BL. In vivo treatment with R(+)-MA caused a significant reduction of tumor size and mitotic index in mice xenografted with human MCL. Together, our results suggest that therapies using cannabinoid receptor ligands will have efficiency in reducing tumor burden in malignant lymphoma overexpressing CB1 and CB2.     

Synergy between PI3K Signaling and MYC in Burkitt Lymphomagenesis

In Burkitt lymphoma (BL), a germinal center B-cell-derived tumor, the pro-apoptotic properties of c-MYC must be counterbalanced. Predicting that survival signals would be delivered by phosphoinositide-3-kinase (PI3K), a major survival determinant in mature B cells, we indeed found that combining constitutive c-MYC expression and PI3K activity in germinal center B cells of the mouse led to BL-like tumors, which fully phenocopy human BL with regard to histology, surface and other markers, and gene expression profile. The tumors also accumulate tertiary mutational events, some of which are recurrent in the human disease. These results and our finding of recurrent PI3K pathway activation in human BL indicate that deregulated c-MYC and PI3K activity cooperate in BL pathogenesis.     

The role of chromosome 15 in murine leukemogenesis. II. Relationship between tumorigenicity and the dosage of lymphoma vs. normal-parent-derived chromosomes 15 in somatic cell hybrids

Somatic cell hybrids were generated between an MCF-virus-induced 15-trisomic T-cell lymphoma of AKR origin with a proviral insertion near the c-myc locus, and normal diploid fibroblasts or lymphocytes of CBAT6T6 origin. Three lymphoma/fibroblast fusions were performed. Six independently-derived clones from 2 fusions were tested for tumorigenicity. Three of the 6 clones were weakly malignant (take incidence 20% below), and 3 were strongly malignant (take incidence over 80%). All 3 lymphoma/lymphocyte hybrids and 6 derived clones were strongly malignant. All hybrids contained a nearly complete chromosomal complement of both parental cells. This was confirmed at the molecular level by determining the ratio of germ-line (G) vs. rearranged (R) myc-carrying Eco RI fragments that showed the expected 1.9-2.7:1 proportion. Malignant segregants selected from the weakly malignant lymphoma/fibroblast hybrids by in vivo inoculation showed changed 15-chromosome ratios. Four out of the 6 clones showed amplification of the lymphoma-derived 15-chromosome that carries the R-myc fragment and a concomitant decrease in the average number of the G-myc-carrying chromosomes. This was deduced from the fact that the G:R ratio was between 2 and 3:1 in the in vitro hybrids but became inverted (1:2-3) in the tumors. Two tumors showed no amplification of R-myc. G-myc was decreased. One of these tumors showed a change in the G:R ratio from 2.5:1.0 to 1.2:1.0, while the other was essentially unchanged (1.9:1.0 in the in vitro clone and 2.2:1.0 in the derived tumor). These findings support the notion that both the amplification of the lymphoma-derived 15-chromosome with the retrovirally rearranged c-myc carrying fragment and/or the loss of the G-myc-carrying 15-chr can contribute to the tumorigenic potential of the hybrids.     

E2F3a在U251胶质瘤细胞中的功能研究

背景与目的：E2F3a是一种重要的转录激活因子，在多种肿瘤组织中均呈现表达上调。E2F3a在恶性化程度较高的神经胶质瘤中表达较高，目前它在胶质瘤细胞中的功能尚不清楚。本文的目的是研究E2F3。对U251胶质瘤细胞周期和凋亡的影响。方法：通过脂质体介导质粒转染在U251细胞中过表达E2F3a：用Western blotting检测细胞内E2F3a蛋白质的表达水平：用PT-核DNA染色结合流式细胞术分析细胞周期分布：用Annexin V—PE和7-AAD染色结合流式细胞术分析细胞凋亡比例；用实时荧光定量PCR方法测定细胞内A2、B1、D1和E细胞周期素mRNA的相对表达水平。结果：与空载体转染对照组相比．E2F3a过表达可将位于S期的细胞比例提高28％（P〈0．01），将位于G0/G1期和G2/M的细胞比例分别降低15％和13％（P〈0．01）。E2F3a过表达对细胞凋亡无明显影响。进一步研究发现，E2F3a可显著上调细胞周期素D1和E的mRNA表达．而不影响周期素A2和B1的mRNA表达。结论：E2F3a是胶质瘤细胞增殖的促进因子，它可通过上调细胞周期素D1和E的表达加速细胞由G，期进入S期。     

The gene from the short arm of chromosome 3, at D3F15S2, frequently deleted in renal cell carcinoma, encodes acylpeptide hydrolase

Loss or inactivation of a gene on the short arm of chromosome 3 may contribute to the genesis of renal cell carcinoma. A gene that corresponds to the most frequently lost RFLP site (D3F15S2) is expressed in a variety of human tissues, and at a particularly high level in the kidney. Its expression is markedly reduced in renal cell carcinoma. A database search showed that the gene product is closely related to or identical with acylpeptide hydrolase. The nucleotide identity between the rat acylpeptide hydrolase and the human gene at D3F15S2 is 88%, compatible with normal species differences. It is therefore likely that the human gene product is acylpeptide hydrolase. The renal cell carcinoma is then associated with a decrease of acylpeptide hydrolase activity. The gene may represent a tumor suppressor gene, whose loss contributes to the development of renal cell carcinoma. It might be speculated that it could act e.g. by affecting the activity of a small acetylated growth factor. Alternatively, its decreased expression may merely reflect the impairment of differentiation in RCC, compared to normal kidney. Loss of a linked but irrelevant gene by the 3p deletion is another possibility.     

Antiviral agent cidofovir decreases Epstein-Barr virus (EBV) oncoproteins and enhances the radiosensitivity in EBV-related malignancies

The Epstein-Barr virus (EBV) is involved in the carcinogenesis of several human cancers such as nasopharyngeal carcinoma (NPC) and Burkitt lymphoma (BL). Given the consistent role of EBV in transformation and maintenance of malignant phenotype, antiviral strategies provide an attractive approach to target EBV-expressing cells. In that aim, we have tested the Cidofovir, which is an acyclic nucleoside phosphonate analog known to exert an antiproliferative activity in some human virus-related tumors. Here, we show that Cidofovir induces a downregulation of the EBV oncoprotein LMP1 associated with a decrease of the antiapoptotic Bcl-2 and an increase of the proapoptotic Bax protein in Raji (BL) and C15 (NPC) cells. Using BL cell line BL2 B95-8 (BL2 infected with the B95.8 strain of EBV), we addressed the relation between EBV genome expression and modulation of viral oncoproteins by Cidofovir and/or ionizing radiation (IR). Cidofovir was able to significantly reduce LMP1 and EBNA2 mRNA and protein expression. This effect was associated with inhibition of proliferation, stimulation of apoptosis, and decrease of Bcl-2 expression in BL2 B95.8 cells. In addition, Cidofovir enhanced the radiation-induced apoptosis and the radiosensitivity through the proteolytic cleavage of death effectors caspase-9 and -3, which was specifically induced by combined treatment in EBV-positive cells compared to their negative counterparts. Furthermore, the combined treatment in nude mice led to a complete tumor remission without increasing toxicity in two human EBV-related cancer xenografts (Raji and C15). These results provide the basis for a novel anticancer strategy to enhance the therapeutic ratio of IR in EBV-related cancers.     

高度侵袭性非霍奇金淋巴瘤的规范化治疗

 经典CHOP方案不是所有非霍奇金淋巴瘤（NHL）的最佳治疗方案,特别是对于高度侵袭性NHL。Burkitt淋巴瘤的标准治疗为高剂量、短疗程的多药联合化疗（如CODOX-M／IVAC±R、R-HyperCVAD／MA）及中枢神经系统白血病（CNSL）的预防。淋巴母细胞淋巴瘤应采取同急性淋巴细胞白血病（ALL）的治疗策略。而对于套细胞淋巴瘤（MCL）,利妥昔单抗联合含大剂量阿糖胞苷方案化疗缓解后,巩固以自体细胞移植（ASCT）是目前对能耐受患者的一线治疗共识。     

SH2D1A and SLAM protein expression in human lymphocytes and derived cell lines

The gene defect responsible for the X-linked lymphoproliferative disease (XLP) is associated with an impaired control of Epstein-Barr virus (EBV) infection. The gene has been recently identified and the encoded protein (designated SH2D1A, DSHP or SAP) was characterized. It is a 128 amino acid (aa) protein, containing a single Src homology 2 (SH2) domain. It interacts with signaling lymphocytic activation molecule (SLAM) expressed on the surface of activated T and B cells. We show that activated T, but not activated B, cells express the SH2D1A protein. NK cells express the protein as well. Tumor lines originating from B, T or NK cells exhibited similar SH2D1A protein expression as the corresponding normal cells, with some notable exceptions. EBV-carrying, tumor phenotype representative (type I), but not EBV-carrying lymphoblastoid cell line (LCL)-like (type III) or EBV-negative Burkitt lymphoma (BL) lines expressed SH2D1A. The phenotypic switch from type I to type III in the EBV-carrying BL line Mutu was associated with a down-regulation of SH2D1A and up-regulation of SLAM. In contrast to normal ex vivo and long-term activated NK cells, 2 of 3 NK leukemia lines expressed SLAM. All 3 lines expressed SH2D1A, like their normal counterparts.     

Treatment outcomes of adult Burkitt lymphoma: results with a modified LMB protocol in Brazil and feasibility of outpatient administration

While Burkitt lymphoma (BL) is an aggressive subtype of non-Hodgkin lymphoma more prevalent in tropical areas, few studies on BL have been conducted in Latin America. Here, we evaluate the clinical presentation and outcomes of an adapted LMB regimen for adults with sporadic BL. We retrospectively evaluated hospital records from University of São Paulo (USP) between 1999 and 2017. Thirty-six patients were included, the median age was 33.5 years and 69% (25) were male. Most patients presented advanced stage disease (81%), 8% had CNS disease, and the majority belonged to LMB group B (75% (27)). Three patients died during the induction phase, and the remaining patients (33) achieved complete response. There was one relapse over a median follow-up of 6 years. Overall survival estimated at 5 years was 89%. We conclude that an adapted LMB protocol is safe and feasible in Brazil.     

Identification of susceptibility loci in a mouse model of KRASG12D-driven pancreatic cancer

Genetic background affects susceptibility to pancreatic ductal adenocarcinoma in the Ela-KRAS(G12D) mouse model. In this model, KRAS oncogene expression is driven by an elastase promoter in acinar cells of the pancreas on an FVB/NTac (FVB) background [FVB-Tg(Ela-KRAS(G12D))] with the transgene carried on the Y chromosome. Through linkage analysis of crosses between the C57BL/6J (B6), BALB/cJ (BALB), and DBA/2J (D2) inbred strains of mice and resistant FVB-Tg(Ela-KRAS(G12D)), we have identified six susceptibility loci that affect mean preinvasive lesion multiplicity. Markers on chromosome 2 segregated with high tumor multiplicity in all three strains; these loci were designated Prsq1-3 (pancreatic ras susceptibility quantitative trait loci 1-3; combined F2 and N2 LOD(W), 6.0, 4.1, and 2.7, respectively). Susceptibility loci on chromosome 4, designated Prsq4 and Prsq5, were identified in crosses between FVB transgenic mice and B6 or BALB mice (combined F2 and N2 LOD(W), 3.6 and 2.9, respectively). A marker on chromosome 12 segregated with tumor multiplicity in a BALB × FVB-Tg(Ela-KRAS(G12D)) cross and was designated Prsq6 (LOD(W), ～2.5). B6-Chr Y(FVB-Tg(Ela-KRASG12D)) and BALB-Chr Y(FVB-Tg(Ela-KRASG12D)) consomics, which carry the KRAS transgene on the FVB Y chromosome on an otherwise inbred B6 or BALB background, developed ～4-fold (B6) and ～10-fold (BALB) more lesions than FVB-Tg(Ela-KRAS(G12D)) mice. By 12 months of age, 10% of BALB-Chr Y(FVB-Tg(Ela-KRASG12D)) mice developed invasive carcinomas. Our findings provide evidence that regions of chromosomes 2, 4, and 12 influence the development and progression of pancreatic neoplasms initiated by an oncogenic allele of KRAS in mice.     

Functional homology between N-myc and c-myc in murine plasmacytomagenesis: plasmacytoma development in N-myc transgenic mice.

Mouse plasmacytomas induced by pristane oil alone, or in combination with Abelson murine leukemia virus (A-MuLV), regularly carry one of three alternative chromosomal translocations that juxtapose c-myc to immunoglobulin heavy- or light-chain loci. E mu-c-myc transgenic mice develop translocation-free plasmacytomas after induction by pristane oil and/or A-MuLV [Sugiyama, H., Silva, S., Wang, Y., Weber, G., Babonits, M., Rosen, A., Wiener, F. & Klein, G. (1990). Int. J. Cancer, 46, 845-852]. In order to test whether another member of the myc family, N-myc, could play a similar role as c-myc, we treated E mu-N-myc transgenic mice with pristane and helper-free A-MuLV. Of 20 mice that received a single pristane injection followed by A-MuLV, 17 developed plasmacytomas with a mean latency period of 54 +/- 20 days. In a corresponding group that only received a single pristane injection, five out of six transgenic mice developed plasmacytomas with a mean latency period of 142 +/- 32 days. However, after three monthly injections of pristane, all 15 transgenic mice developed plasmacytomas with a mean latency period of 128 +/- 20 days. All plasmacytomas expressed the N-myc transgene, while none of them expressed either c-myc or endogenous N-myc. None of the tumors carried the usual plasmacytoma-associated translocations.     

Partial trisomy 11, dup(11)(q23q13), as a defect characterizing lymphomas with Burkitt pathomorphology without MYC gene rearrangement

Burkitt lymphoma (BL) is an aggressive non-Hodgkin lymphoma characterized by specific morphological and immunophenotypic features. The basic genetic feature of BL is the rearrangement of MYC gene, visible as t(8;14)(q24;q32) translocation or its variant. However, some lymphomas with characteristic BL morphology are nowadays diagnosed as B-cell lymphoma unclassifiable with features intermediate between DLBCL and BL (Inter-DLBCL/BL) for biological or clinical reasons. We present four lymphomas without the MYC rearrangement presented typical Burkitt morphology, FCM immunophenotype with some deviations when compared to a typical BL. The cases were finally diagnosed as Inter-DLBCL/BL. All of them presented a recurrent abnormality within the chromosome 11: dup(11)(q23q13). We suppose that the dup(11)(q23q13), in absence of the MYC gene rearrangement, is connected with borderline lymphomas with a morphology similar or identical to that of the Burkitt lymphoma. Identifying such an aberration may be helpful in the diagnostics of Inter-DLBCL/BL eventually forming a distinct subgroup of lymphomas.     

不同类型淋巴瘤Survivin的表达及其意义

目的淋巴瘤的诊断与分型是临床病理诊断的难点。本研究检测抗凋亡基因survivin在不同类型淋巴瘤中的表达,并探讨其对淋巴瘤分型的意义。方法用免疫组化法检测中山大学附属一院及肿瘤医院2001年1月-2003年6月219例淋巴瘤、13例淋巴结反应性增生石蜡标本中survivin基因的表达;同时用RT-PCR检测K562、HL60、Raji、Jurkat细胞系和以上病例中18例淋巴瘤及2例淋巴结反应性增生新鲜标本中survivinmRNA的表达;对不同类型的淋巴瘤survivin蛋白及mRNA表达的结果进行半定量分析。结果Survivin蛋自在非霍奇金淋巴瘤(NHL)的弥漫性大B细胞性淋巴瘤(DLBL)(88.6%,70/79)、伯基特淋巴瘤(BL)(100%,2/2)、淋巴母细胞淋巴瘤(LBL)(92.3%,12/13)中有较高的表达,而在滤泡性淋巴瘤(FL)(18.2%),粘膜相关性结外边缘带B细胞淋巴瘤(MAL-oma)(40.9%)和MZL(marginalzonelymphoma)(33.3%)中表达较低,且多为弱阳性。高表达组(DLBL、BL、LBL)与低表达组(FL、MZL、MALT)之间差异有统计学意义,χ2检验,P<0.01。霍奇金淋巴瘤(HL)中大部分R-S(Reed-Sternberg)细胞表达survivin蛋白。NHL中survivinmRNA的检测结果与其蛋白水平的表达呈正相关(相关系数r=0.6270,P<0.01)。结论survivin蛋白及mRNA表达水平在不同类型淋巴瘤存在着明显的差异,survivin可能作为一个分子标记对淋巴瘤分型具有一定的价值。     

Cyclin D3 is a predictive and prognostic factor in diffuse large B-cell lymphoma.

Cyclin D3 is an important regulator for transition from G(1) to the S phase of the cell cycle. Cyclin D3 expression is associated with cell proliferation in lymphoid tissues, but its impact on clinical outcome in non-Hodgkin's lymphomas has not been studied. Therefore, we determined the clinical relevance of cyclin D3 expression in patients with diffuse large B-cell lymphoma. We examined the relation between cyclin D3 expression at diagnosis and response to conventional polychemotherapy and overall survival in 81 previously untreated patients with diffuse large B-cell lymphoma. Cyclin D3 expression was assessed by immunohistochemistry. Cyclin D3 immunostaining ranged from 0-100% (median, 30%) of the lymphoma cells. Patients with high (>or=50% cyclin D3-positive lymphoma cells) cyclin D3 expression had a more advanced clinical stage (P = 0.003) and more often had extranodal disease in more than one site (P = 0.007) than patients with low cyclin D3 expression. Patients with high cyclin D3 expression had a significantly lower complete response rate (17% versus 74%; P < 0.001) and a shorter overall survival (3-year survival rate, 18% versus 74%; P < 0.001) than those with low cyclin D3 expression. Multivariate analyses that included cyclin D3 and the International Prognostic Index demonstrated that cyclin D3 expression had independent effects on the complete response rates and overall survival of the patients. In conclusion, high cyclin D3 expression is an independent predictive and prognostic factor associated with poor clinical outcome in patients with diffuse large B-cell lymphoma.     

Tumor necrosis factor and lymphotoxin alfa genetic polymorphisms and outcome in pediatric patients with non-Hodgkin's lymphoma: results from Berlin-Frankfurt-Münster Trial NHL-BFM 95.

PURPOSE: To analyze the association of genetic variation within the tumor necrosis factor (TNF -308 [G-->A]) and lymphotoxin alfa (LT-a +252 [A-->G]) genes with outcome in non-Hodgkin's lymphoma of childhood and adolescence. PATIENTS AND METHODS: Genotyping of the TNF -308 (G-->A) and LT-a +252 (A-->G) polymorphisms in patients (n = 488) enrolled onto the German-Austrian-Swiss multicenter trial NHL-BFM 95 from April 1996 to January 2000 was performed by polymerase chain reaction with subsequent restriction fragment length polymorphism analysis on DNA from tumor-free specimen. RESULTS: In patients with Burkitt's lymphoma (BL) and B-cell acute lymphoblastic leukemia (B-ALL; n = 219, 211 eligible patients), patients carrying at least two variant alleles (high-producer haplotypes) had an increased risk of events: probability of event-free survival (pEFS) at 3 years was 81% (SE = 5%), compared with 91% (SE = 2%) in low-producer haplotypes (P = .018). In BL/B-ALL with high tumor load (lactate dehydrogenase [LDH] > or = 500 U/L; n = 104), pEFS was 69% (SE = 8%) in high-producer versus 85% (SE = 4%) in low-producer haplotypes (P = .05). In multivariate analysis including risk factors for events (LDH > or = 500 U/L, CNS involvement, methotrexate infusion regimen), TNF -308/LT-alpha +252 haplotype kept prognostic relevance: patients with high-producer haplotypes had a 2.34-fold increase in risk of events (P = .048). The TNF -308 (G-->A) and LT-alpha +252 (A-->G) polymorphisms were not associated with pEFS in lymphoblastic lymphoma (n = 101), anaplastic large-cell lymphoma (n = 67), or diffuse large B-cell lymphoma (n = 65), nor with therapy-related toxicity. CONCLUSION: The TNF -308 (G-->A) and LT-a +252 (A-->G) polymorphisms were negative prognostic factors in pediatric BL/B-ALL. Among patients with serum LDH > or = 500 U/L, haplotype analysis further determined patients at risk for events.