EBNA-1 sequences in endemic and sporadic Burkitt's lymphoma.
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Burkitt Lymphoma↗
Biomedical subjects
I Magrath
Publications and source records attributed to I Magrath.
Comparative incidence of the rearrangements of TEL/AML1 and ALL1 genes in pediatric precursor B acute lymphoblastic leukemias in India.
The TEL/AML1 translocation, which is specific for pre B-cell leukemias is predictive of a favorable treatment outcome. In contrast, translocations involving the ALL1 locus which are associated with both B and non B leukemias predict a poor outcome. To determine the relative distribution of high and low risk molecular subtypes of ALL in India, we analyzed the relative frequencies of these two translocations. The study included a random selection of 46 newly diagnosed patients of childhood ALL from the Tata Memorial Hospital, Bombay, India. Similar to the frequency observed in other world regions, we found an All1 rearrangement in less than 7% (3/46) of pre B-ALL patients. In contrast to the 25% frequency reported for other regions the low risk molecular subtype characterized by the TEL/AML1 translocation represented a comparatively smaller fraction (4/46) in this study. These results provide a preliminary support for a lower frequency of molecular subgroup of leukemias with a potential for favorable clinical outcome in precursor B-ALL from India.
Adolescent↗
Additional chemotherapy agents improve treatment outcome for children and adults with advanced B-cell lymphomas.
We report the updated results of an intensive treatment protocol for children (< 18 years) and adults (> or = 18 years) with advanced B-cell lymphomas. The protocol consists of two chemotherapy regimens: A, consisting of cyclophosphamide, doxorubicin, vincristine and high-dose methotrexate (CODOX-M), and B, consisting of ifosfamide, etoposide, and high-dose cytarabine (IVAC). Both cycles included intrathecal chemotherapy (cytarabine or methotrexate). Patients received a total of four cycles in the following sequence: A, B, A, B. Sixty-six previously untreated patients, enrolled before October 1996, were included in the present analysis. Of these, 55 had Burkitt's or Burkitt's-like lymphoma and 11 had diffuse large B-cell lymphoma. There were 53 males ad 13 females; 40 were children and 26 were adults (age range, 3 to 57 years). To date, 61 patients have achieved a complete response to therapy. Two patients subsequently relapsed, but one of these is a long-term survivor after further therapy and a bone marrow transplant. The event-free survival rate is 85% at I year and beyond. The median potential follow-up period is 48 months (range, 12 to 96 months) for patients remaining in complete remission. Neutropenia occurred in 98% of cycles and infection in 46% of A cycles and 50% of B cycles, but the duration was shortened in B cycles by the administration of granulocyte colony-stimulating factor. Positive blood cultures were observed in 21% of A cycles and 28% of B cycles, and there have been three toxic deaths. These results are better than those achieved with an earlier version of CODOX-M, suggesting that the addition of the IVAC regimen is responsible for the improved results. The similarity of the outcome in children and adults, however, confirms our previous observation that, at least in adults younger than 60 years with Burkitt's or Burkitt's-like lymphomas, treatment with regimens similar to those used in children is warranted.
Adolescent↗
Limiting therapy for limited childhood non-Hodgkin's lymphoma.
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Adult↗
Non-Hodgkin's lymphoma.
Pediatric lymphomas are the third most common group of malignancies in children and adolescents. Unlike lymphomas in adults, pediatric lymphomas are diffuse, aggressive neoplasms with a propensity for widespread dissemination. Intensification of conventional treatment approaches along with improvements in supportive care have resulted in dramatic improvement in event-free survival rates of close to 90% in patients with B-cell lymphomas and only slightly lower in patients with T-cell lymphomas. Lymphoid neoplasms arise because of genetic changes that result in altered growth and differential patterns of lymphoid cells. The characterization of these molecular abnormalities and an understanding of their consequences has led to new approaches to diagnosis and the detection of minimal residual disease and also provides the basis for the future development of novel treatment approaches targeted specifically to the neoplastic cells.
Adolescent↗
Preliminary report of an intensified, short duration chemotherapy protocol for the treatment of pediatric non-Hodgkin's lymphoma in India.
BACKGROUND: In the past, the results of the treatment of non-Hodgkin's lymphomas (NHL) in Indian children have been poor, due to inadequate chemotherapy and poor supportive care. In an attempt to overcome these problems, we conducted a clinical trial in Bombay with a new protocol, MCP842. PATIENTS AND METHODS: Seventy-four previously untreated patients < 25 years were entered on study at the Tata Memorial Hospital, Bombay. Patients with lymphoblastic lymphoma (LL) (38) without bone marrow involvement and all patients with small noncleaved cell lymphoma (SNCL) (18) and large cell lymphoma (LCL) (18) were eligible. Treatment consisted of alternating cycles of two regimens, A and B. Patients with St. Jude stages I and II received six cycles, and those with stages III or IV received eight cycles. A cycles included cyclophosphamide, adriamycin, vincristine and ara-C, and B cycles, etoposide, vincristine, methotrexate, ifosfamide and mesna. RESULTS: Complete response was achieved in 67 (91%) of patients. Event free survival (EFS) for all patients was 58%; 68% for patients with SNCL and LCL combined, and 48% for patients with LL. There was no significant difference in EFS by histology (LL versus non-LL), or stage. There were nine (12%) toxic deaths, two during induction and seven in patients in remission; six occurred in patients with LL. CONCLUSIONS: These results are better than past results in Bombay. Unlike earlier CCG protocols, in which the outcome between patients with LL and non-LL differed, this was not so in MCP842. Even patients with extensive LL without bone marrow disease received only eight cycles of therapy, suggesting that short duration therapy is curative in as many as half of such patients--an important observation in a country with limited resources.
Adolescent↗
Intraclonal molecular heterogeneity suggests a hierarchy of pathogenetic events in Burkitt's lymphoma.
BACKGROUND: Burkitt's lymphoma is a B-cell neoplasm characterized by a chromosomal translocation involving the c-myc gene. BL may carry, besides the c-myc translocation, several other lesions including a) mutations in c-myc, b) mutations in bcl-6, c) mutations in p53 and d) EBV genomes. In this report we describe a unique study of the timing of these genetic lesions during the evolution and progression of Burkitt's lymphoma. MATERIALS AND METHODS: From each of two patients with Burkitt's lymphoma, we established three different cell lines from different sites or at different times in the clinical course of the disease (diagnosis and relapse). Chromosomal aberrations were analyzed by karyotyping and the presence of molecular lesions determined by Southern blot, PCR, SSCP and sequence analyses. RESULTS: In each patient all the clones carry identical c-myc translocations, identical bcl-6 status (wild type or mutant) and the same productive VDJ rearrangement. However, within each individual patient, we could demonstrate the presence of intraclonal variation with respect to EBV, p53 mutations and c-myc mutations. CONCLUSIONS: c-myc translocation and bcl-6 mutations appear to be early events, mutations in the coding region of c-myc occur early but are an ongoing event, while mutations in the p53 gene seem to occur later. Discrete clonal bands reflecting independent EBV infection were observed in the cell lines from one HIV-associated Burkitt's lymphoma, suggesting the possibility that EBV infection may occur as a late event, at least in some HIV associated lymphomas.
Adult↗
Use of Epstein-Barr virus nuclear antigen-1 in targeted therapy of EBV-associated neoplasia.
To target expression of toxic genes to Epstein-Barr virus (EBV)-associated tumor cells, we have developed an EBV-driven enzyme prodrug system (EDEPS) that takes advantage of the trans-activating properties of EBNA1, a latent protein expressed in all EBV-containing cells, to direct expression of cytosine deaminase (CD) at high levels in those cells only. Plasmids were constructed in which the CD gene or a luciferase reporter gene were cloned downstream of the herpes simplex virus thymidine kinase (tk) promoter and the family of repeats (FR) sequence from the oriP region of EBV. Analysis of luciferase activity after transient transfection into a panel of EBV-negative or -positive human cell lines showed that the presence of the FR element enhanced transcription from the tk promoter in all EBV-positive cell lines, whereas transcription from tk was repressed in all EBV-negative cell lines, including B, T, and fibroblast cell lines. In clonogenicity assays following transfection with the CD vector, the presence of 5-fluorocytosine (5-FC) in the culture medium completely abolished cell growth in EBV-positive cell lines, but did not affect the growth of EBV-negative cell lines. This vector system should have wide applicability in that it allows targeted expression of any gene of interest to tumors that carry EBV, irrespective of the role EBV plays in their pathogenesis.
Antigens, Viral↗
Combination chemotherapy for advanced bilharzial bladder carcinoma.
BACKGROUND: Carcinoma of the bilharzial bladder, the most common cancer in Egyptian patients has been, until recently, largely treated by surgery. We have studied the activity of a series of single agents in phase II trials and identified a number of active agents. Here we report the results of a trial in which therapeutic combinations of the most active agents were administered in alternating cycles to patients who had never received chemotherapy. PATIENTS AND METHODS: The study included 30 patients with histologically proven inoperable (20), recurrent (5, 2 of whom subsequently developed metastases), or metastatic disease (5). There were 27 males and 3 females, with a median age of 48.5 years (range 29-65 years). Fourteen patients had squamous cell carcinoma, 12 had transitional cell carcinoma, 2 had adenocarcinoma, and the remaining 2 had undifferentiated carcinoma. Chemotherapy consisted of epidoxorubicin (120 mg/sqm i.v. d1) and vincristine (1.4 mg/sqm i.v., days 1 and 8) alternating with etoposide (100 mg/sqm i.v. infusion over 1 hour, days 1 to 5) and ifosfamide (1800 mg/sqm i.v. infusion over 2 hours, days 1 to 5). Mesna was given as a uroprotector at 40% of the ifosfamide dose at 0, 4, and 8 hours after the ifosfamide infusion. Courses were repeated every 3-4 weeks. RESULTS: Among the 22 evaluable patients, 8 (36.5%) had a partial and one (4.5%), a complete response, giving a response rate of 46%. Three more patients had responses that were less than a partial remission, and 6 patients showed disease stabilisation on chemotherapy. Toxicities were tolerable and consisted mainly of myelosuppression. Results were further analysed in relation to pathologic subtype, disease status at the start of chemotherapy, and the delivered dose intensity. No relationship was found between any of these parameters and response to therapy. CONCLUSION: Advanced bilharzial bladder cancer is relatively sensitive to combination chemotherapy, but complete remission and prolonged survival is rare in this subgroup of patients with advanced disease. Further studies will be needed to determine the relative efficacy of single agents and drug combinations.
Adult↗
Epstein-Barr virus (EBV)-associated smooth-muscle tumor arising in a post-transplant patient treated successfully for two PT-EBV-associated large-cell lymphomas. Case report.
The association of Epstein-Barr virus (EBV) with smooth-muscle tumors was recently reported in the setting of acquired immunodeficiency syndrome (AIDS) and post-transplantation. We report a case of an EBV-associated smooth-muscle tumor arising in a post-transplant (PT) patient who previously was treated successfully for two EBV-associated PT large-cell lymphomas. A 4-year-old girl required cardiac transplantation for dilated cardiomyopathy when she was aged 23 months. Her PT regimen included cyclosporine, azothiaprine, and diltiazem. At 16 months PT, she presented with anemia, guaiac-positive stools, and an abdominal mass diagnosed as diffuse large-cell lymphoma of B-cell phenotype. Immunosuppressive therapy was reduced, and interferon and i.v. immunoglobulin were initiated. She rapidly developed signs of rejection, and a cardiac biopsy was performed, revealing grade IIIB rejection. Subsequently, immunosuppressive therapy increased. At 23 months PT, a biopsy was done of a large pelvic mass that was diagnosed as immunoblastic large-cell lymphoma. After treatment with chemotherapy and retinoic acid, the size of the mass markedly decreased. Follow-up computed tomography scan revealed multiple liver nodules. A needle biopsy of the liver showed a smooth-muscle tumor of indeterminate grade. Both the lymphomas and the smooth-muscle tumor contained EBV within > 95% of tumor cells by Epstein-Barr (EBER1) in situ hybridization, were of strain type A by Epstein-Barr nuclear antigen-2 (EBNA-2) polymerase chain reaction (PCR) and contained an identical 30 base-pair deletion (amino acids 346-355) of the latent membrane protein (LMP)-1 oncogene by PCR analysis. Notably, the initial large-cell lymphoma and the subsequent immunoblastic lymphoma each contained a unique p53 mutation, suggesting that they were distinct. These data suggest that the same virus contributed to the pathogenesis of both the malignant lymphomas and the smooth-muscle tumor.
Abdominal Neoplasms↗
Adults and children with small non-cleaved-cell lymphoma have a similar excellent outcome when treated with the same chemotherapy regimen.
PURPOSE: We have used identical treatment protocols for adults and children with small non-cleaved-cell lymphoma (SNCL) for many years and report here the results of two successive treatment regimens in these age groups. PATIENTS AND METHODS: Seventy-two patients (39 adults and 33 children) were treated with protocol 77-04 between 1977 and 1985. All patients, except those with resected abdominal disease, received 15 cycles of a combination of cyclophosphamide (CTX), doxorubicin (ADR), prednisone (PRED), vincristine (VCR), high-dose methotrexate (MTX), and intrathecal (IT) therapy. Forty-one patients (20 adults and 21 children) were treated with protocol 89-C-41, which has been used since 1989. High-risk patients received four alternating cycles (with a total duration of 12 to 15 weeks) of an intensified version of protocol 77-04 without PRED (CODOX-M), and a new drug combination consisting of ifosfamide, etoposide, high-dose cytarabine (ara-C), and IT MTX (IVAC). Low-risk patients received three cycles of the CODOX-M regimen. High-risk patients were randomized to either receive or not receive granulocyte-macrophage colony-stimulating factor (GM-CSF). RESULTS: Event-free survival (EFS) in protocol 77-04 was 56% at 2 years and beyond. EFS in protocol 89-C-41 was 92% at 2 years and beyond. GM-CSF was associated with increased thrombocytopenia. CONCLUSION: Adults and children with SNCL have a similar prognosis when treated with the same chemotherapy. EFS in high-risk patients has been markedly improved by including IVAC in protocol 89-C-41, and excellent results can be achieved with only four cycles of therapy. In protocol 89-C-41, GM-CSF was not beneficial.
Adolescent↗
The investigation of Epstein-Barr viral sequences in 41 cases of Burkitt's lymphoma from Egypt: epidemiologic correlations.
BACKGROUND: Epstein-Barr virus (EBV) is associated with many human neoplasms, including Burkitt's lymphoma (BL). Endemic BL in central Africa is more often EBV-associated than BL in the United States, where seroconversion for EBV occurs somewhat later than in Africa. Therefore, the EBV association rate in BL may correlate more with the socioeconomic status of the population studied, which influences the age of EBV seroconversion, than with such factors as malaria, which may relate to the overall higher incidence rate in endemic regions. METHODS: Forty-one patients with BL in Egypt, which differs both climatically and racially from central African countries (i.e., Kenya, Uganda) where BL is endemic, were analyzed. All biopsies were evaluated for EBV-encoded RNAs (EBER1) by RNA in situ hybridization, analyzed for p53 protein expression using the monoclonal antibody D07, and immunophenotyped using a panel of monoclonal antibodies that included L26 (CD20), Leu 22 (CD43), and A6 (CD45RO). Twelve cases were evaluable for EBV subtype by polymerase chain reaction with EBV-specific primers. RESULTS: The median age at diagnosis was 9 years (range, 2-22 years). The biopsy site was extranodal in 29 patients and nodal in 12 patients. All 41 cases were documented as B-cell neoplasms. A hybridization signal for EBER1 RNA was identified in greater than 95% of the neoplastic cells in 30 of 41 cases (73%), whereas no signal was observed in 11 cases (27%). Epstein-Barr virus subtype 1 was found in 10 patients, subtype 2 in two patients. Immunostaining for p53 was observed in greater than 5% of the neoplastic cells in 9 of 37 cases (24%). No significant correlation was observed between EBV positivity and sex, biopsy site, or p53 immunostaining. CONCLUSIONS: The prevalence of EBV in BL from Egypt is slightly lower than in BL in endemic regions, but significantly higher than in sporadic BL. Epstein-Barr virus positivity probably reflects the socioeconomic status of the patient population, and age at seroconversion. The prevalence of EBV subtype 1 suggests that immunodeficiency does not play a role in Egyptian Burkitt's lymphoma, in contrast to endemic Burkitt's lymphoma, in which holoendemic malaria is thought to contribute to immunodeficiency, a higher incidence rate, and the observed prevalence of subtype 2.
Adolescent↗
Bone-marrow transplantation.
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Bone Marrow Transplantation↗
A mutant p21 cyclin-dependent kinase inhibitor isolated from a Burkitt's lymphoma.
The growth arrest mediated by p53 is caused at least in part by the p53 mediated expression of p21 (p21waf1/Cip1). Since only one-third of primary Burkitt's lymphomas (BL) demonstrate mutations in the p53 gene, we examined the structural integrity of the p21 coding region by single-strand conformational polymorphism and DNA sequence analysis to determine the extent to which this gene is mutated in BL. Of 34 BLs analyzed, a frequent change (38%) at codon 31 that replaced Ser with Arg was found in 13 samples, 10 of which were from Africa. This change at codon 31 is also detected in peripheral blood DNA from normal subjects and may thus represent a polymorphism. One BL cell line, DH978, carried a change at codon 63: Phe to Leu. This mutation was heterozygous, and both the wild-type and the mutated p21 mRNA were expressed in the tumor cell line. By transfection experiments, the mutant p21 was less efficient in suppressing clonogenicity than wild-type p21. To our knowledge, this is the only mutation described in p21. The availability of this mutant p21 should further help in functional studies of p21.
Base Sequence↗
Bone marrow transplantation for leukaemia: a lame stalking horse for use of high-technology medical care.
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Bone Marrow Transplantation↗
Mutations in the coding region of c-myc occur independently of mutations in the regulatory regions and are predominantly associated with myc/Ig translocation.
Constitutive expression of c-myc resulting from a chromosomal translocation, which juxtaposes c-myc to an immunoglobulin gene, is a pivotal lesion in Burkitt's lymphomas. This deregulated expression of c-myc is associated with mutations in the regulatory regions, i.e. the first exon and the first intron of c-myc in tumors where the chromosomal breakpoint is not itself within the regulatory region. Until recently it was widely believed that the c-myc protein in these tumors is wild type. We have demonstrated that in a fraction of Burkitt's lymphomas from Africa and from the continental USA, and in mouse plasmacytomas, the c-myc gene carries mutations in the coding region. We now show that, occasionally, such mutations are also present in multiple myelomas--tumors which do not carry translocations or amplifications of c-myc. We also show that the frequency of the c-myc coding region mutations in BL is independent of the frequency of mutations in the regulatory region. These results suggest that the mechanisms that induce missense mutations involving the coding region of c-myc may be different from those that lead to mutations in the regulatory regions.
Burkitt Lymphoma↗
Molecular epidemiology of acute lymphoblastic leukemia in Egypt.
We have characterized immunophenotypically defined acute lymphoblastic leukemia (ALL) in Egypt for rearrangements of the antigen receptor genes, and correlated this with rearrangements of ALL-1 and the presence of p53 mutations. Thirty-nine cases were analyzed for rearrangements of the immunoglobulin (Ig) and T-cell receptor (TCR) genes. All precursor B-cell ALLs (12 cases) contained rearranged Ig heavy-chain (JH) region which was biallelic in 92% of these tumors. In addition to JH rearrangements, TCR delta, beta and gamma rearrangements were observed in 80, 40 and 30% of these cases, respectively. TCR genes were invariably rearranged in T-cell ALLs (11 cases). A small fraction (2/11) of T-cell ALL showed concurrent IgJH rearrangement which was monoallelic. Simultaneous rearrangement of IgJH and TCR genes was also observed in both cases of biphenotypic ALL (coexpressing B and T markers). We observed marked heterogeneity in the pattern of rearrangement of antigen receptor genes in mixed-lineage leukemias (ALL coexpressing myeloid-associated markers), including the retention of germline configuration in two cases. Rearrangements of the ALL-1 gene were confined to the leukemias that demonstrated lineage infidelity. Mutations in p53 were infrequent and were present in only three of 47 ALL cases (6%) analyzed; two of these were mixed-lineage leukemias. These results suggest that mixed-lineage and biphenotypic leukemias accumulate pathogenetic lesions that are distinct from B- and T-cell ALL, and that ALL in developing countries includes molecular entities similar to those in developed countries.
Adolescent↗
p53 gene mutations are associated with decreased sensitivity of human lymphoma cells to DNA damaging agents.
The present study assessed the role of the p53 tumor suppressor gene in cell cycle arrest and apoptosis following treatment of Burkitt's lymphoma and lymphoblastoid cell lines with gamma-rays, etoposide, nitrogen mustard, and cisplatin. Cell cycle arrest was measured by flow cytometry; p53 and p21Waf1/Cip1 protein levels were measured by Western blotting; cell survival was measured in 72-96-h growth inhibition assays and by trypan blue staining, and apoptotic DNA fragmentation was assessed by either agarose gel electrophoresis or a modified filter elution method. We found that gamma-rays and etoposide induced a strong G1 arrest in the wild-type p53 lines while nitrogen mustard and cisplatin induced relatively little G1 arrest. All agents failed to induce G1 arrest in cells containing mutant p53 genes. The degree of G1 arrest observed with these agents correlated with the rate of p53 and p21Waf1/Cip1 protein accumulation: gamma-rays and etoposide induced rapid accumulation of both p53 and p21Waf1/Cip1; nitrogen mustard and cisplatin induced slow accumulation of p53 and no major accumulation of the p21Waf1/Cip1 protein. Despite differences in G1 arrest and kinetics of p53 or p21Waf1/Cip1 protein accumulation, all agents tended to decrease survival to a greater extent in the wild-type p53 lines compared to the mutant p53 lines. Cell death in the wild-type p53 lines was associated with intracellular DNA degradation into oligonucleosomal sized DNA fragments, indicative of apoptosis. We also observed an inverse sensitivity relationship between nitrogen mustard/cisplatin and etoposide in the mutant p53 lines and this was found to correlate with topoisomerase II mRNA levels in the cells. Our results suggest that p53 gene status is an important determinant of both radio- and chemosensitivity in lymphoid cell lines and that p53 mutations are often associated with decreased sensitivity to DNA damaging agents.
Apoptosis↗