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PubMed1984

Possible DNA-RNA tumor virus interaction in human lymphomas: expression of retroviral proteins in Ramos lymphoma lines is enhanced after conversion with Epstein-Barr virus.

Epstein-Barr virus (EBV)-genome-negative human lymphoma lines, Ramos and BJAB, can be converted by EBV in vitro into EBV-genome-positive virus nonproducer lines. These cell lines have been used to identify surface antigens unique to EBV, with the expectation that such determinants might be related to the antigenic target responsible for EBV-specific immunosurveillance. Antisera prepared in rabbits immunized with either whole cells or purified plasma membranes were used in immunoblot experiments to analyze antigenic differences resulting from expression of the resident EBV genome. Unexpectedly, an increase in polypeptides of 32 and 70 kilodaltons was consistently observed in the EBV-converted Ramos lines. In contrast, these antigens were not expressed in BJAB or in its EBV-converted lines. These data suggested that p32 and gp70 might be murine leukemia virus (MuLV)-coded antigens because Ramos, but not BJAB, had been passaged in athymic nude mice during establishment of this cell line. This conclusion was confirmed by using antisera specific for MuLV p30 and gp70. Retroviral antigens were expressed constitutively at low levels in Ramos. Quantitative immunoblotting showed that EBV conversion of Ramos amplified the expression of MuLV proteins 3- to 5-fold. The molecular mechanism responsible for the enhanced expression is unknown. The biological relevance of this phenomenon is also not clear, but the interaction between a DNA and a RNA tumor virus in a Burkitt lymphoma line that carries both viruses may have important biological consequences in relation to retrovirus latency and tumor induction. These results also show that caution must be used when ascribing "uniqueness" to EBV-determined antigens, particularly in the Ramos lines. This warning extends also to the use of Ramos cell lines as immunogens, because immunization of rabbits elicited antibodies that recognized proteins of the same size as the retroviral antigens.

Burkitt Lymphoma↗

PubMed2002

Primary cutaneous follicle center cell lymphoma and limited stage follicular non-Hodgkin's lymphoma: a comparison of clinical and biological features.

Primary cutaneous follicular lymphoma (PCFL) and nodal follicular lymphoma (NFL) are different entities, which, nevertheless, exhibit common features. The aim of this study was to compare the clinico-biological characteristics and the outcome of patients with PCFL and with limited stage NFL. A group of 22 consecutive patients with PCFL presenting with single or multiple cutaneous lesions was compared to a group of 21 patients with limited stage NFL. The median age was 56 and 55 years, respectively. The histologic features were compared, as well as treatment modalities and response. Treatment of PCFL consisted of restricted field radiotherapy (RT), chemotherapy (CHT) and combined modalities (CM) in 12, 5 and 5 cases, respectively. Among the 21 patients with NFL, RT was employed in 13, CHT in 7 and the CM in one patient. The response to treatment was: 17 complete responses, CR (12 RT, 2 CHT, 3 CM), 3 partial responses, PR (1 CHT, 2 CM) and 2 non-responses, NR (2 CHT) in the PCFL group, while in the NFL group 18 patients attained CR (13 RT, 4 CHT, 1 CM) and 3 PR (3 CHT). The relapse rate was 22.7 and 28.5% in PCFL and NFL, respectively (median follow up of 48 and 50 months). The estimated 4 years event free survival (EFS) in the PCFL and NFL patients were 68 and 70%, respectively, (P = 0.83). The estimated 4 years overall survival (OS) in the PCFL and NFL groups were 90% and 100% respectively, (P = 0.254). Among the 22 patients with PCFL, there was a higher incidence of large cells than in NFL, although the differences were not significant (P = 0.08). In conclusion, despite histologic (higher proportion of large cells) and biologic differences, cutaneous and limited stage NFL show similar responses to treatment, with similar relapse rates, EFS and OS.

Adult↗

PubMed2004

Fludarabine, cyclophosphamide and mitoxantrone for untreated follicular lymphoma: a report from the non-Hodgkin's lymphoma co-operative study group.

The aim of the study was to determine the safety and efficacy of the combination of fludarabine (FLU), cyclophosphamide (CY) and mitoxantrone (FLU/CY/MITO) in untreated follicular lymphomas (FL), Sixty patients with newly diagnosed stage II bulky to IV FL, median age 59 years (range 36-70), received FLU/CY/MITO regimen (FLU 25 mg/m2 days 1-3, CY 300 mg/m2 days 1-3, Mito 10 mg/m2 day 1). Patients received antibiotic oral prophylaxis during all treatments, and growth factors (G-CSF) when grade III granulocytopenia (WHO) occurred. The overall response rate was 87%: 46 patients achieved complete response (CR) (77%), 6 a partial response (10%) and 8 were non-responders. Fifty patients are surviving with a median observation time of 31 months. The 4-year estimated probability of overall survival and failure-free survival were 78.2% and 45% respectively. Thirty-five patients (58%) are still in CR. Sixty percent of patients experienced grade III-IV granulocytopenia. Two patients suffered grade III pulmonary infection and one grade III liver toxicity. In a subset of 46 patients, bcl-2 translocation was positive in bone marrow (BM) and/or peripheral blood (PB) of 36 patients. At the end of treatment, 25 of these patients had CR and 19 (76%) converted to polymerase chain reaction (PCR) negativity. FLU/CY/MITO regimen showed a high level of activity in follicular lymphoma. Toxicity, mainly hematological, was acceptable and the treatment was made feasible by the use of antibiotic prophylaxis and G-CSF. Significant non-hematological toxicities were seen, but no patients died. The conversion of bcl-2 from positive to negative by PCR in BM and/or PB suggests a possible role for this treatment in clearing minimal residual disease and improving patients' outcome.

Adult↗

PubMed1981

Natural antibodies to the human T cell lymphoma virus in patients with cutaneous T cell lymphomas.

Sera from patients with cutaneous T cell lymphoma and leukemia were screened for the presence of natural antibody to the human T cell lymphoma (leukemia) virus, HTLVCR, using a solid-phase radioimmunoassay. Sera from two patients, including patient CR, from whose cultured T lymphoblastic cell line (HUT102), the retrovirus HTLVCR was isolated, reacted specifically with proteins of HTLVCR. Serum from patient CR also reacted specifically with proteins of HTLVMB, an independent but highly related retroviral isolate from a patient with Sezary T cell leukemia. The specificity for HTLVCR proteins was demonstrated by solid-phase immunocompetition assays and competition radioimmunoprecipitation assays. Analysis of radioimmunoprecipitates indicated that the natural antibodies were directed against HTLVCR core proteins with molecular weights of 24,000 and 19,000 (p24 and p19). Whereas the serum reactivities for HTLVCR proteins were shown to be highly specific, additional reactivities seen against proteins of animal retroviruses including GaLV, SSV, FeLV, and BaEV were clearly shown not to be viral specific but rather were due to reactivity with cellular antigens contaminating the viral preparations or with related antigens present in fetal calf serum. These results demonstrating natural antibodies to HTLVCR provide the first evidence for a specific antibody response to a retrovirus in humans.

Antibodies, Viral↗

PubMed1981

Detection of the human T cell lymphoma virus p19 in cells of some patients with cutaneous T cell lymphoma and leukemia using a monoclonal antibody.

A monoclonal antibody specific for the internal p19 protein of a type-C retrovirus (HTLV) isolated from human neoplastic T cells has been developed. Its specificity has been shown by radioimmune precipitation and by affinity chromatography of iodinated HTLV proteins. By indirect immune fluorescence this antibody recognizes only HTLV-producing cells. Examination of cells from patients with cutaneous T cell lymphomas and leukemias and with other types of lymphomas and leukemias indicated that HTLV p19 expression is rare. The monoclonal antibody will be useful in determining the natural reservoir of HTLV, possibly in a subset of mature T cell neoplasias.

Animals↗

PubMed1999

How reliable is histologic examination of bone marrow trephine biopsy specimens for the staging of non-Hodgkin lymphoma? A study of hairy cell leukemia and mantle cell lymphoma involvement of the bone marrow trephine specimen by histologic, immunohistochemical, and polymerase chain reaction techniques.

Analysis of non-Hodgkin lymphoma (NHL) involvement of bone marrow trephine biopsy specimens by morphologic features and immunohistochemistry is often difficult, and the criteria for involvement are ill defined. We compared the morphologic and immunohistochemical analysis of B-cell NHL involvement with immunoglobulin heavy chain gene (IgH) rearrangement analysis by polymerase chain reaction (PCR) amplification of the complementarity determining region 3 (CDR3) in bone marrow biopsy specimens from patients with mantle cell lymphoma (n = 53) or hairy cell leukemia (n = 71). By combing morphologic features and phenotype, 54 specimens were considered positive, 62 negative, and 8 inconclusive. PCR analysis showed clonal IgH rearrangements in 46 positive and 6 inconclusive specimens. No clonal IgH rearrangements were present in 61 negative specimens. The 1 false-positive and most false-negative PCR results were likely due to sampling error or DNA degradation of the fixed tissues. In most cases, bone marrow involvement by NHL can be identified by histologic and immunohistochemical examination. Furthermore, clonality of the B-cell population can be detected by amplification of the IgH CDR3 on DNA extracted from bone marrow trephine biopsy sections, which can be helpful in cases diagnosed as inconclusive.

Bone Marrow Examination↗

PubMed1994

EORTC study of non-Hodgkin's lymphoma: phase III study comparing CHVmP-VB and ProMACE-MOPP in patients with stage II, III, and IV intermediate- and high-grade lymphoma.

In the EORTC lymphoma cooperative group, a randomized phase III study was done for patients with stage II, III, IV intermediate- and high-grade lymphoma. Eight courses of CHVmP-VB were compared to eight courses of ProMACE-MOPP. Response was evaluated after 8 courses. Of 430 patients entered, 346 were eligible for this first analysis. Additional radiotherapy was given at initial large masses or residual disease after three courses. Response rate was higher in the CHVmP-VB arm in comparison to the ProMACE-MOPP arm, 82% vs. 65% (p < 0.0005). In the ProMACE-MOPP arm, treatment had to be interrupted because of patient refusal in 7% of the patients. So far there has been no significant difference in freedom from progression at 5 years (49% vs. 47%), relapse-free survival (59% vs. 59%), or overall survival (55% vs. 49%). Patients with early response at 4 courses showed no better RFS in comparison with late responders between 4 and 8 courses. The International Index, based on age, stage, SLDH, performance status, and number of extranodal localizations showed a good prognostic significance in this series of patients.

Adult↗

PubMed1994

A phase III comparison of CHOP vs. m-BACOD vs. ProMACE-CytaBOM vs. MACOP-B in patients with intermediate- or high-grade non-Hodgkin's lymphoma: results of SWOG-8516 (Intergroup 0067), the National High-Priority Lymphoma Study.

BACKGROUND: CHOP is a four-drug, first-generation combination chemotherapy regimen that has cured approximately 30% of all patients with advanced stages of intermediate- or high-grade non-Hodgkin's lymphoma in national cooperative group trials. Initial single-institution studies of third-generation regimens such as m-BACOD, ProMACE-CytaBOM, and MACOP-B suggested that 55%-60% of these patients might be cured. PATIENTS AND METHODS: In order to make a valid comparison between these regimens, the Southwest Oncology Group and the Eastern Cooperative Oncology Group initiated a randomized phase III comparison of CHOP vs. m-BACOD vs. ProMACE-CytaBOM vs. MACOP-B. Endpoints of the study were response rate, time to treatment failure, overall survival, and severe or life-threatening toxicity. Received dose intensity calculations and subset analyses were also performed. RESULTS: 1138 patients were registered on this clinical trial. Each treatment arm contained between 218 and 233 eligible patients. Known prognostic factors were equally distributed. The initial results of this study were recently published. There were no significant differences in either the partial or complete response rates between treatment arms. Now after a median follow-up of 49 months and a maximum follow-up of 84 months, there is still no difference in time to treatment failure (p = 0.40) or overall survival (p = 0.68). No subset of patients was found to have significantly improved survival with the third-generation regimens. The received dose intensity data were comparable to previously published data for these regimens. Fatal toxicity was 1% for CHOP, 3% for ProMACE-CytaBOM, 5% for m-BACOD, and 6% for MACOP-B. CONCLUSION: Based on similar failure-free and overall survival with lower cost and lower severe toxicity, CHOP remains the standard chemotherapy for patients with advanced-stage, intermediate- or high-grade non-Hodgkin's lymphoma. New treatment strategies need to be developed to improve the prognosis of these patients.

Aged↗

PubMed2002

An international evaluation of CODOX-M and CODOX-M alternating with IVAC in adult Burkitt's lymphoma: results of United Kingdom Lymphoma Group LY06 study.

BACKGROUND: Burkitt's lymphoma (BL) is a rare and rapidly progressive form of B-cell non-Hodgkin's lymphoma. Cyclophosphamide, vincristine, doxorubicin, high-dose methotrexate (CODOX-M)/ifosfamide, etoposide and high-dose cytarabine (IVAC) is a highly effective alternating non-cross-resistant regimen developed by Magrath et al. (Magrath I., Adde M., Shad A. et al. J Clin Oncol 1996; 14: 925-934) at the US National Cancer Institute. The aim was to confirm these results in a larger, international, multi-centre study using International Prognostic Index-based criteria to assign prognostic groups, whilst slightly simplifying the protocol. PATIENTS AND METHODS: A phase II study where: (i) low risk (LR) patients were treated with three cycles of modified CODOX-M; and (ii) high risk (HR) patients received treatment with four cycles of alternating modified CODOX-M and IVAC chemotherapy. Target of 60 patients, fit for protocol treatment, from 16 to 60 years of age with locally diagnosed, non-HIV-related, non-organ-transplant-related BL. RESULTS: Results are given for 52 of 72 registered patients whose pathological eligibility was confirmed by central pathology review: 12 LR plus 40 HR. The majority of patients (n = 41) completed protocol treatment, but toxicity was severe, especially myelosuppression and mucositis. Overall, 2-year event-free survival (EFS) was 64.6% (95% CI 50.4% to 78.9%) and 2-year overall survival (OS) was 72.8% (95% CI 59.4% to 86.3%). For LR, 2-year EFS was 83.3% and OS was 81.5%. For HR, 2-year EFS was 59.5% and OS was 69.9%. CONCLUSIONS: This study confirms high cure rates with this CODOX-M/IVAC approach.

Adult↗

PubMed2006

Patients with grade 3 follicular lymphoma have prolonged relapse-free survival following anthracycline-based chemotherapy: the Nebraska Lymphoma Study Group Experience.

BACKGROUND: The aim of the study was to determine the outcome and clinical features predictive of survival in patients with follicular lymphoma (FL) treated aggressively and to determine the rate of disease-specific mortality in patients with grade 3 FL (FL3). MATERIALS AND METHODS: Four hundred and twenty-one patients with FL who were treated with various anthracycline-based chemotherapy regimens were included in this retrospective study. RESULTS: Patients with FL3 and a diffuse component of >50% had the worst outcome, with a hazard ratio of dying of 2.2 (95% CI 1.4-3.4) compared with patients with FL1 or FL2, and a ratio of 1.6 (95% CI 1.02-2.5) compared with FL3 with a diffuse component of < or =50% by multivariate analysis (P = 0.0026). Patients with FL3a had an outcome similar to those with FL3b. In patients with FL3 and a diffuse component of < or =50%, the overall and event-free survival curves showed a plateau for patients younger than 60 years of age. However, there were no differences in the cumulative incidence of relapse/progression or lymphoma-specific/treatment-related mortality between the two age groups. CONCLUSIONS: Less than half of the patients with FL3 and a diffuse component of < or =50% treated with anthracycline-based combination chemotherapy will relapse and relapses are uncommon after 6 years. Older patients should be offered the same aggressive chemotherapy as younger patients.

Adult↗

PubMed2006

The Follicular Lymphoma International Prognostic Index (FLIPI) and the histological subtype are the most important factors to predict histological transformation in follicular lymphoma.

BACKGROUND: Histological transformation (HT) is a well-known event in patients with follicular lymphoma (FL) conferring an unfavorable prognosis. The aim of the study was to analyze incidence and risk factors for HT in a large series of FL patients. PATIENTS AND METHODS: 276 patients (median age: 54 years; M139/F137) diagnosed with FL (42% grade 1, 51% 2, 7% 3) in a single institution were studied. Initial treatment consisted of combined chemotherapy in most cases. Median survival was 11.3 years. Main clinic and biological variables were assessed for HT and survival. RESULTS: 30 of 276 patients (11%) presented HT after a median follow-up of 6.5 years, with a risk of 15% and 22% at 10 and at 15 years, respectively. All HT corresponded to diffuse large B-cell lymphoma (DLBCL). Grade 3 histology, nodal areas >4, increased LDH and beta(2)-microglobulin, and high-risk IPI and FLIPI were associated with HT. In multivariate analysis, grade 3 histology and FLIPI retained prognostic significance. Only FLIPI predicted HT in grade 1-2 patients. 28 patients received salvage treatment for HT, with a CR rate of 52%. Median survival from transformation was 1.2 years, with 6/13 CR patients being alive >5 years after HT. CONCLUSION: FLIPI and histology were the most important variables predicting HT. Upon HT, only patients achieving CR reached prolonged survival, thus emphasizing the need for effective therapies once this event occurs.

Adult↗

PubMed1975

Alterations of glycolipid glycosyltrasnferase levels in lymphoma and lymphoid tissues of lymphoma-bearing hamsters.

Thymus from lymphoma-bearing hamsters in advanced stages of tumor growth showed enhanced activities of four glycolipid-glycosyltransferases which lead to the step-wise synthesis of lactosylceramide to Forssman hapten. The alpha-galactosyltransferase activity of the thymus was decreased until day 6 of inoculation but increased thereafter. The activities of all the transferases tested were significantly lowered in lymphoma tissue. The level of UDP-galactose pyrophosphatase did not correlate with the transferase activities.

Animals↗

PubMed2002

Interphase cytogenetic analysis of lymphoma-associated chromosomal breakpoints in primary diffuse large B-cell lymphomas of the central nervous system.

Primary central nervous system lymphomas (PCNSLs) are germinal center-derived diffuse large B-cell lymphomas (DLBCLs) arising in and remaining confined to the brain, the pathogenesis of which is poorly understood. We investigated 13 PCNSLs from immunocompetent patients by means of interphase cytogenetics on cryopreserved cells derived from stereotactic biopsies. Interphase fluorescence in situ hybridization (FISH) was performed for the detection of structural alterations affecting the IGH (14q32), IGK (2p12), IGL (22q11), BCL6 (3q27), MYC (8q24), CCND1 (11q13), MLT, and BCL2 (both 18q21) loci. Signal constellations indicating breakpoints within the IGH and IGK locus were detected in 5 and 1 PCNSLs, respectively. There was no evidence for a t(8;14), t(11;14), or t(14;18) in this series of tumors. Breakpoints in the BCL6 locus were observed in 3 of the 13 cases, and nuclear Bcl-6 protein expression was detected in 6 of 9 PCNSLs, including those with genomic alterations of the encoding locus. Gains of 18q21 represented the most frequent imbalances present in more than one third of all cases. Interestingly, these gains included the MLT gene. Thus, this study provides the first evidence for recurrent chromosomal translocations in PCNSLs. While they share similarities with extracerebral DLBCL with respect to the presence of IGH translocations, they appear to differ in the usage of translocation partner genes, which remain to be identified.

Adult↗

PubMed1986

Relapse with nodular lymphoma following combination chemotherapy for diffuse non-Hodgkin's lymphoma.

Histologic conversion within the non-Hodgkin's lymphomas is a well-described phenomenon. Conversion from an indolent to that of a more aggressive histologic pattern is the most frequently noted form of this variability. We describe two patients in whom relapse with an indolent nodular lymphoma was noted after combination chemotherapy for diffuse disease. Implications for diagnostic evaluation and therapy as well as the pathogenesis of this unique form of conversion are discussed.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed1990

Nodular histiocytic lymphoma, emphasizing results of stage I disease treated by radiotherapy. A report of the Japan Lymphoma Radiation Therapy Study Group (JLRTG).

The records of 49 patients with nodular histiocytic lymphomas (NH) who were treated from 1972 to 1985 in hospitals belonging to the JLRTG were retrospectively reviewed. The actuarial survival rate and relapse-free survival rate of all patients after 5 years were 55.0 and 51.3%, respectively. Twenty-one patients with stage I disease had a significantly better survival rate than did 12 patients with stage II disease (P less than 0.01). Without combination chemotherapy, all 15 patients with stage I NH treated by radiation therapy were in complete remission, and 14 of them remained alive and well. Among these 15 patients, no difference in relapse was observed between patients who received involved field irradiation (1 of 6) and those who received extended field irradiation (2 of 9). Patients with stage II or more NH should be treated with intensive chemotherapy and radiotherapy, as are patients with diffuse histiocytic lymphoma (DH). However, involved field radiotherapy with careful follow-up observation may be the treatment of choice for patients with stage I NH, provided their tumors are not bulky.

Adult↗

PubMed2005

Paraneoplastic pityriasis lichenoides in cutaneous lymphoma: case report and review of the literature on paraneoplastic reactions of the skin in lymphoma and leukaemia.

Paraneoplastic dermatoses are non-neoplastic skin disorders which occur in the context of an underlying malignant neoplasm. The classic paraneoplastic dermatoses are mostly associated with solid internal malignancies. They only rarely occur in the context of nodal or primary cutaneous lymphomas. Apart from these classic paraneoplastic dermatoses, there are additional skin disorders reported to occur in close association with haematological and lymphoproliferative disorders which can thus be regarded as paraneoplastic manifestations. We report for the first time two patients with pityriasis lichenoides et varioliformis acuta in association with mycosis fungoides. In addition, we review the literature on paraneoplastic dermatoses of the skin which have been described in patients with leukaemias and primary cutaneous lymphomas.

Adult↗

PubMed2005

Identification of APOBEC3B as a potential target for the graft-versus-lymphoma effect by SEREX in a patient with mantle cell lymphoma.

Recently, a graft-versus-lymphoma (GVL) effect has been shown in patients allografted for mantle cell lymphoma (MCL), but the antigenic targets of this response remain unclear. We screened an MCL cDNA expression library with sera at GVL response after allogeneic haematopoietic stem cell transplantation and isolated five genes including APOBEC3B. Antibody responses to APOBEC3B were correlated with clinical response. Furthermore, APOBEC3B-specific T-cell response was induced with one of the HLA-A*0201 binding peptides. In addition, APOBEC3B mRNA appeared to be upregulated in some MCL. These findings warrant further investigation of APOBEC3B as a candidate gene eliciting an effective immune response against MCL.

Antibodies, Neoplasm↗

PubMed2006

JSI-124 (cucurbitacin I) inhibits Janus kinase-3/signal transducer and activator of transcription-3 signalling, downregulates nucleophosmin-anaplastic lymphoma kinase (ALK), and induces apoptosis in ALK-positive anaplastic large cell lymphoma cells.

JSI-124 (cucurbitacin I) has been recently described as a specific inhibitor of signal transducer and activator of transcription-3 (STAT3). As STAT3 activation is pathogenetically important in anaplastic lymphoma kinase-positive anaplastic large cell lymphoma (ALK+ ALCL), we investigated whether JSI-124 can mediate significant inhibitory effects in this cell type. In two ALK+ ALCL cell lines (Karpas 299 and SU-DHL-1), JSI-124 significantly reduced the number of viable cells to 50% of that of negative controls at a dose of 5-10 micromol/l at 24 h and 1-1.25 micromol/l at 48 h. This decrease in viability was associated with apoptosis, as confirmed by the increase in the subG(0/1) fraction, poly(ADP-ribose)polymerase cleavage and expression of active caspase 3. JSI-124 decreased the phosphorylated-STAT3 and -Janus kinase-3 (JAK3) levels in a dose-dependent fashion, and these changes were coupled with significant decreases in several STAT3 downstream targets, including mcl-1, bcl-2, bcl-xL and cyclin D3. Interestingly, JSI-124 also dramatically decreased the protein levels of JAK3 and nucleophosmin (NPM)-ALK, and these effects were reversible by MG132. Our data support that JSI-124 is a potentially useful therapeutic agent for ALK+ ALCL. In addition to its role as a tyrosine kinase inhibitor, JSI-124 appears to be involved in regulating proteosome degradation for proteins such as JAK3 and NPM-ALK.

Antineoplastic Agents↗