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PubMed1999

Rapid expression cloning of human immunoglobulin Fab fragments for the analysis of antigen specificity of B cell lymphomas and anti-idiotype lymphoma vaccination.

An expression system for rapid and standardized production of human recombinant immunoglobulin Fab fragments in E. coli was developed. Functional folding of the Fab fragments was accomplished by the dicistronic expression vector pFab.gammakappa containing specialized leader sequences to direct the immunoglobulin heavy and light chains to the periplasmic bacterial space. A C-terminal hexahistidine tag of the Fd chain facilitated metal affinity chromatography and purification to homogeneity as assessed by SDS PAGE and silver staining. Specific antigen recognition by a hybridoma-derived Fab fragment was indistinguishable from that of the corresponding monoclonal antibody. This protocol may be useful for analysis of the antigen specificity of human B cells and for convenient production of lymphoma-derived idiotype protein for vaccination strategies. To obtain unmodified immunoglobulin cDNA sequences from small human biopsies for insertion into pFab.gammakappa, oligo(dG)-tailed cDNA was amplified with an oligo(dC)- and nested mu or kappa constant region-specific primers. Using single sets of primers for each class of immunoglobulin transcripts, the products of this anchored PCR reflected the relative abundance of the starting cell population and permitted reliable identification of clonal, lymphoma-derived sequences for subsequent expression cloning.

Cancer Vaccines↗

PubMed1986

Small noncleaved cell lymphoma: an immunophenotypic study of 18 cases and comparison with large cell lymphoma.

Eighteen cases of small noncleaved cell lymphoma (SNCL) were studied with a large panel of monoclonal antibodies applied to tissue frozen sections and compared with 18 cases of immunoglobulin-expressing diffuse large cell lymphoma (DLCL). Immunoglobulin expression was seen in all cases of SNCL, with a predominance of cases showing lambda light chain restriction. Expression of mu and delta heavy chains was common, but gamma and alpha chain expression was uncommon. In the cases of SNCL T015, B1, B2, 41H, BA-1, BA-2, Ia, CALLA, and OKT10 were generally expressed, and a large percentage of cells expressed Ki-67. Only rare expression of T05, Leu-8, and Leu-9 was seen, and in no case was reactivity with anti-Tac antibodies observed. In contrast, the immunoglobulin-expressing DLCLs showed the typical predominance of cases of kappa light chain restriction, a lower proportion of cases with mu or delta expression, and a higher proportion of cases with gamma expression. A lower incidence of Leu-8, T05, and Tac expression and a higher incidence of BA-1, CALLA, Ki-67 and OKT10 were seen in the SNCLs as compared with the DLCLs. It is concluded that immunologic studies may be of considerable aid in the differential diagnosis of SNCL and DLCL.

Abdominal Neoplasms↗

PubMed1999

Somatic mutation analysis of IgH variable regions reveals that tumor cells of most parafollicular (monocytoid) B-cell lymphoma, splenic marginal zone B-cell lymphoma, and some hairy cell leukemia are composed of memory B lymphocytes.

The cell of origin of parafollicular (monocytoid) B cell lymphoma (PBCL), splenic marginal zone lymphoma (SMZL), and hairy cell leukemia (HCL) is controversial. To better understand the relationship between these low-grade B-cell neoplasms, we analyzed the nucleotide sequences of the rearranged immunoglobulin heavy (IgH) chain variable (V) region of the clonal population of cells in five cases of PBCL, four cases of SMZL, and seven cases of HCL to determine whether these neoplasms could be differentiated by the degree of somatic mutation in the IgH V gene or by the IgH V gene family usage. DNA was extracted from diagnostic material and clonality confirmed by PCR. The DNA was reamplified using V heavy chain family specific primers, and the amplicons were sequenced. Sequences were compared with germline IgH V gene sequences, and base changes were determined to be silent or to represent amino acid replacements by using three different methods. Four of five (80%) cases of PBCL, three of four (75%) cases of SMZL, and three of seven (43%) cases of HCL showed evidence of antigen selection, suggesting that these neoplasms involved clonal expansions of postgerminal center memory lymphocytes. Only SMZL showed a preferential usage of V(H)1 family genes.

Adult↗

PubMed1996

Primary B-cell lymphoma of the breast in patient with smoldering type adult T-cell lymphoma.

We report a patient with primary B-cell lymphoma of the breast complicated by smoldering type adult T-cell leukaemia (ATL). A 52-year-old Japanese woman complained of a rapidly enlarging lump in her right breast. She had been diagnosed to have smoldering type ATL since the age of 49. Aspiration cytology and subsequent excisional biopsy revealed B-cell type lymphoma of the breast. A gallium-scintigram showed abnormal accumulation in the bilateral breasts. Radiology was adopted because the lesion was localized only in the breasts and associated with smoldering type ATL. The lesions disappeared after the treatment.

Breast Neoplasms↗

PubMedDate not supplied

Computer-assisted image analysis of small cell lymphoma of the thyroid gland. Comparison of nuclear parameters of small lymphocytes in lymphomas and Hashimoto's thyroiditis.

The nuclear parameters of the small lymphocytes in nine cases of small cell lymphomas of the thyroid gland and 17 cases of Hashimoto's thyroiditis were assessed by computer-assisted image analysis. The nuclear area, maximal, minimal and averaged Ferret diameters, perimeter, regularity factor and elongation factor were gauged. Statistically, the nuclear area was ascertained to be the optimum descriptor discriminating between small neoplastic and reactive lymphocytes. Application of a novel variable, combining a nuclear area cut-off value of 14 microm2 with a nuclear averaged Ferret diameter cut-off value of 4.5 micron, allows for the distinction - with a high degree of sensitivity and specificity - between small neoplastic lymphocytes in thyroidal lymphomas and the reactive lymphocytes in Hashimoto's thyroiditis.

Adult↗

PubMed1999

CHOP versus MACOP-B in aggressive lymphoma--a Nordic Lymphoma Group randomised trial.

BACKGROUND: The long-term survival of patients with advanced stage aggressive lymphoma has not improved significantly during the last twenty years. In a randomised trial, the efficacy of MACOP-B, a six-drug weekly chemotherapy regimen, was compared to CHOP, the current standard regimen, in terms of overall and failure-free survival, toxicity and health related quality of life. PATIENTS AND METHODS: Four hundred five patients with aggressive lymphoma, stage II-IV, age 18-67, were randomised to receive either 12 weeks of MACOP-B or 8 courses of CHOP over 24 weeks. Special emphasis was put in the definition of Ann Arbor stage in extranodal disease. A subset of 95 patients also entered a quality of life study, based on the EORTC QLQ-C30. RESULTS: Thirty-one patients were ineligible. Among the remaining 374 patients, the median age was 52 years. According to the age-adjusted International Prognostic Index, 37% were 'high-intermediate' or 'high-risk' patients. No difference could be demonstrated, either in overall survival (60% at five years in the MACOP-B group and 59% in the CHOP group) or in failure-free survival (47% at five years with MACOP-B and 44% with CHOP). In terms of quality of life, physical function and global quality of life were more impaired in patients receiving MACOP-B, who also exhibited more non-haematological toxicity. CONCLUSION: No superiority of MACOP-B compared to CHOP could be demonstrated. CHOP remains the treatment of choice in low-risk patients. At present, intensified or experimental treatment should be reserved for high-risk disease.

Adolescent↗

PubMed1991

A critical analysis of prognostic factors for survival in intermediate and high grade non-Hodgkin's lymphoma. Scotland and Newcastle Lymphoma Group Therapy Working Party.

Between 1979 and 1987 the Scotland and Newcastle Lymphoma Group registered 972 adults with Working Formulation high or intermediate grade non-Hodgkin's lymphoma. Clinical, pathological and investigational data were recorded prospectively on a computer database allowing analysis for prognostic factors. We have derived prognostically important characteristics and have tested prospectively the validity of the prognostic index on a geographically distinct sub-set of patients from the Edinburgh/Borders clinics. Multivariate analysis showed the following factors to be important in declining order of power; advancing age, worsening performance status, CNS/liver involvement, abnormal white cell count, 'B' symptoms and advancing clinical stage. Patient individual scores allowed them to be aggregated into one of three distinct prognostic groupings separated by arbitrary cut-points into a Best Group (39%) where the median survival exceeds 5 years (53% alive at 5 years), an Intermediate Group (30%) with median survival of 21 months (21% alive at 5 years), and a Worst Group (31%) whose median survival is 7 months (8% alive at 5 years). Similar prognostic group separations occurred when analysis was confined to: patients younger than 70 years; patients treated with initial chemotherapy; patients treated with initial radiotherapy; patients within any of the major pathological sub-groups.

Adult↗

PubMed1993

Primary gastrointestinal non-Hodgkin's lymphoma: a review of 175 British National Lymphoma Investigation cases.

A retrospective analysis was performed upon 175 patients with Non-Hodgkin's Lymphoma involving the gastrointestinal tract and entered into BNLI trials and studies between 1974-1988. Malignant histiocytosis of the intestine (MHI), which was present in 16 patients, was associated with a survival of less than 25% at 18 months, and probably accounted for the poor survival of patients with jejunal involvement. Histopathological evidence of tumour origin from mucosa-associated lymphoid tissue (MALT) was found in 50% of patients with gastric involvement and in 27% of those with intestinal involvement. The overall survival of the series as a whole was 44% at 10 years. Multivariate analysis identified evidence of tumour origin from MALT as the only factor to attain prognostic significance in patients with gastric involvement, and clinical stage and the presence of MHI as the only factors to attain prognostic significance in patients with intestinal involvement. It is suggested that there is a need for a large multicentre prospective study of GIT lymphoma.

Adolescent↗

PubMed2004

Fludarabine, adriamycin and dexamethasone (FAD) in newly diagnosed advanced follicular lymphoma: a phase II study by the British National Lymphoma Investigation (BNLI).

The optimal first-line treatment for symptomatic patients with advanced stage follicular lymphoma remains unclear. Fludarabine-based combination regimens have been extensively used in relapsed disease and merit consideration as first-line therapy. We here report the results of a phase II study of FAD (fludarabine, adriamycin, dexamethasone) regimen in 30 patients with advanced stage follicular lymphoma requiring treatment. The response rate was in excess of 90% with 39% achieving a complete remission. The major toxicity was myelosuppression, but only 3% of cycles were associated with grade IV leucopenia. The high response rate has not translated into major improvements in failure-free survival and consideration must be given to alternative treatment modalities to consolidate the high rate of initial responses.

Administration, Oral↗

PubMed2004

Graft-versus-lymphoma effect in refractory cutaneous T-cell lymphoma after reduced-intensity HLA-matched sibling allogeneic stem cell transplantation.

Cutaneous T-cell lymphomas (CTCL) are rare diseases that, in their advanced stages or in transformation, have a poor prognosis. Autologous stem cell transplantation (Au-SCT) after high-dose therapy has yielded disappointing results. Allogeneic transplantation (allo-SCT) provides the potential advantage of an immune-mediated graft-versus-lymphoma (GVL) effect. Reduced-intensity allo-SCT potentially offers a GVL effect, but with diminished toxicity related to the induction regimen; however, published experience with this approach in CTCL is limited. We report a series of three patients (age 35-49) with advanced, refractory (n=2) or transformed (n=1) CTCL who underwent reduced-intensity allo-SCT in the context of active disease. All three survived the peri-transplant period and, despite later having disease relapse, all exhibited evidence of a GVL effect. Relapses of the disease were in the context of immune suppression for graft-versus-host disease (GVHD), and when immune suppression was reduced, responses were regained. A comparison is made of these results to those in a review of the published literature to date. We conclude that while a GVL can be achieved for CTCL with reduced-intensity allogeneic transplantation, the clinical benefits are short lived and novel approaches are required to obtain sustained remissions.

Graft vs Tumor Effect↗

PubMed1997

Chronic malaria and splenic lymphoma: clues to understanding lymphoma evolution.

In west Africa, splenic lymphoma with villous lymphocytes and hyper-reactive malarial splenomegaly have many clinical and immunological features in common suggesting an aetiopathological link. We hypothesize that in hyper-reactive malarial splenomegaly the dysregulated immune response to repeated malaria infections results in a stimulated, proliferating pool of B cells in which perturbation of cell growth and apoptosis by environmental and other factors promotes the development of SLVL. In Africa these factors are likely to include infectious agents several of which have already been associated with B-cell non-Hodgkin's lymphomas.

Chronic Disease↗

PubMed2000

Leucoderma associated with flares of erythrodermic cutaneous T-cell lymphomas: four cases. The French Study Group of Cutaneous Lymphomas.

We describe four patients with erythrodermic cutaneous T-cell lymphomas (two with erythrodermic mycosis fungoides, and two with Sézary syndrome) who presented with extensive hypopigmented lesions that occurred during flares of their cutaneous disease. These cases must be distinguished from previously described hypopigmented mycosis fungoides where hypopigmented lesions were the sole manifestation of the lymphoma. In two cases a biopsy was performed on hypopigmented skin, showing an infiltrate of atypical lymphocytes with epidermotropism and absence of melanocytes, as in vitiligo. It is suggested that the hypopigmentation could be due to the cytotoxicity of tumour or reactional lymphocytes directed against melanocytes.

Aged↗

PubMed2001

Lymphoma-type adult T-cell leukaemia-lymphoma with a bulky cutaneous tumour showing multiple human T-lymphotropic virus-1 DNA integration.

Human T-lymphotropic virus-1 (HTLV-1) is considered to be the cause of adult T-cell leukaemia-lymphoma (ATL). Monoclonal integration of HTLV-1 proviral DNA, as is analysed by Southern blotting, has been demonstrated in ATL patients. Unusual integration patterns of HTLV-1 proviral DNA have occasionally been described, and it is suggested that the patterns have clinical implications for ATL pathophysiology. Multiple, complete and defective types of integration patterns, in that order, are apparently associated with prognoses from good to poor. We report a 73-year-old Japanese woman with lymphoma-type ATL and a bulky cutaneous tumour on the left thigh. Four bands of slightly differing intensity were seen after EcoRI digestion of skin and lymph node samples on Southern blot analysis of HTLV-1 proviral DNA. Analysis for T-cell receptor-beta gene revealed five novel bands after restriction enzyme digestion with HindIII, indicating that the patient has four separate tumour cell clones, each of which carries one copy of the provirus. She was treated with chemotherapy and radiation and remains under reasonable control despite some relapsing cutaneous nodules. The indolent course in this present case could be related to the multiple integration pattern of HTLV-1 proviral DNA detected.

Aged↗

PubMed2002

Establishment and characterization of a Kaposi's sarcoma-associated herpesvirus- and Epstein-Barr virus-negative malignant lymphoma cell line (OHK) with primary effusion lymphoma immunophenotype.

A novel cell line, designated OHK, was established from ascites of a 59-year-old Japanese woman with diffuse large B-cell lymphoma showing a peculiar serosal tropism, as seen in primary effusion lymphomas (PEL). OHK exhibited a large pleomorphic morphology with irregular nuclei and distinct nucleoli, and included immunoblastic and Reed-Sternberg-like giant cells. On ultrastructural examination, rich intermediate filaments, and well-developed Golgi apparati and rough endoplasmic reticulum, were seen. Immunophenotypically, OHK lacked T and B cell-associated antigens, and had CD10, CD30, CD33 and CD138 antigens. Although OHK cells did not express immunoglobulin (Ig) protein, Southern blot analysis demonstrated clonal rearrangements of Ig heavy and light chain genes. These observations suggest that OHK cells are derived from preterminally differentiated B cells, and that they have features of PEL. Kaposi's sarcoma-associated herpesvirus and Epstein-Barr virus were not detected. OHK displayed hyperploid karyotypes with multiple structural abnormalities, and produced some cytokines such as macrophage-colony-stimulating factor (M-CSF), granulocyte-CSF, interleukin 6 and transforming growth factor beta 1. In particular, vascular endothelial growth factor (VEGF), whose stimulation of vascular permeability is thought to be critical to the pathogenesis of PEL, was also produced in large quantities. These results indicate that OHK may be a useful tool for the investigation of PEL.

Ascitic Fluid↗

PubMed2001

Hodgkin's lymphoma of T-cell type: clonal association with a CD30+ cutaneous lymphoma.

The derivation of Reed-Sternberg cells in Hodgkin's lymphoma has been a subject of great interest. In most cases, Reed-Sternberg cells seem to be derived from germinal center B cells. In few sporadic cases, a T-cell origin has been shown. This article supports the concept of a T-cell derivation for rare cases of Hodgkin's lymphoma and provides evidence of a novel mechanism of pathogenesis from chronic inflammation in the skin.

Base Sequence↗

PubMed2001

[AIDS and non-Hodgkin's lymphoma: initial cardiac manifestations of highly malignant B-cell lymphoma 18 years after HIV infection].

HISTORY AND FINDINGS: A 35-year-old man who, as a result of intravenous drug abuse, had become infected with HIV 18 years previously, was admitted with signs of right-heart failure. Three months earlier a systolic murmur had first been heard in the 5th intercostal space parasternally. INVESTIGATIONS: Transesophageal echocardiography (TEE) demonstrated a 3 x 2 cm right atrial tumour, moderate to severe tricuspid regurgitation and pulmonary hypertension. Blood cultures grew Streptococcus. DIAGNOSIS, TREATMENT AND COURSE: Endocarditis with atrial thrombi and recurrent pulmonary emboli was diagnosed and treated with antibiotics and anticoagulants. Three weeks later the TEE showed an increase in the atrial tumour. Computed tomography of skull, thorax and abdomen did not demonstrate any significantly enlarged lymph nodes. Exploratory thoracotomy revealed an infiltrating highly malignant centroblastic non-Hodgkin's lymphoma (NHL) of almost the entire free wall of the right atrium. After two courses of chemotherapy (CHOP protocol) the size of the tumour had significantly decreased. CONCLUSION: The differential diagnosis of a right atrial tumour can be difficult in patients with HIV or AIDS. Even if the site is atypical and there is no lymphadenopathy, a lymphoma should be considered. In case of doubt a histological diagnosis via an exploratory thoracotomy should be performed.

Adult↗

PubMed2002

Update on erythrodermic cutaneous T-cell lymphoma: report of the International Society for Cutaneous Lymphomas.

Two conferences were sponsored by the International Society for Cutaneous Lymphomas (ISCL) to gain consensus on definitions and terminology for clinical use in erythrodermic cutaneous T-cell lymphoma (E-CTCL). Three subsets of E-CTCL were defined: Sézary syndrome ("leukemic phase" E-CTCL), erythrodermic mycosis fungoides (secondary E-CTCL that develops in patients with mycosis fungoides), and E-CTCL, not otherwise defined. The hematologic criteria recommended for Sézary syndrome are intended to identify patients with a worse prognosis compared with the other E-CTCL subsets and consist of one or more of the following: (1) an absolute Sézary cell count of 1000 cells/mm3 or more; (2) a CD4/CD8 ratio of 10 or higher caused by an increase in circulating T cells and/or an aberrant loss or expression of pan-T cell markers by flow cytometry; (3) increased lymphocyte counts with evidence of a T-cell clone in the blood by the Southern blot or polymerase chain reaction technique; or (4) a chromosomally abnormal T-cell clone. For staging purposes, it is proposed that these criteria define the B2 blood rating and that the B2 rating be considered equivalent to nodal involvement.

Dermatitis, Exfoliative↗

PubMed1982

Human T-cell leukemia-lymphoma virus (HTLV) is in T but not B lymphocytes from a patient with cutaneous T-cell lymphoma.

A human type C retrovirus, designated HTLV, previously was isolated from or identified in some patients with leukemias and lymphomas of mature T lymphocytes. HTLV is genetically and serologically distinct from any known animal retroviruses. The absence of HTLV proviral sequences in DNA from normal humans showed that HTLV is not a ubiquitous endogenous (germ-line transmitted) virus of humans. Antibodies to HTLV core proteins have been identified in some people with T-cell neoplasias and are particularly prevalent in Japanese with adult T-cell leukemia, suggesting that HTLV is acquired horizontally. However, it was possible that HTLV is transmitted through the germ line of some (possibly rare) families and is then expressed in the HTLV- positive malignancies. An opportunity to study this question was provided by the development of several T-cell lines and a B-cell provided by the development of several T-cell lines and a B-cell line from one HTLV-positive patient with a cutaneous T-cell lymphoma. Here we report that HTLV proteins or nucleic acids (or both) are found in three independently derived T-cell lines, all shown by HLA typing to have originated from the patient. In contrast, the B-cell line, the identity of which was also ascertained by HLA typing, contained no detectable HTLV protein, RNA, or proviral DNA. Because the sensitivity of the latter assay is more than sufficient to detect one proviral equivalent per haploid genome, the results indicate that HTLV was not transmitted to this patient through the germ line but rather was acquired by infection.

B-Lymphocytes↗