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PubMed1981

Restriction in IgM expression. III. Affinity analysis of monoclonal anti-lactose antibodies.

A clonal analysis has been made of the murine BALB/C response to lactose-containing immunogens with respect to the affinity restriction in IgM expression. Monoclonal IgM and IgG antibodies were prepared from antilactosyl hybridomas generated from mice immunized with p-aminophenyl-beta-lactoside (PAPL) coupled to BGG or with a vaccine of Streptococcus faecalis (Strain N). Association constants for the binding of monovalent derivatives of PAPL were measured by quenching fluorescence. These derivatives carried a probe (2,4-dinitrophenyl or 1-dimethylaminonaphthalene-5-sulfonyl) that served to quench the protein fluorescence when the ligand was complexed with the protein. The central finding was that with both immunogens a restriction in the affinity of IgM was demonstrated since the highest values exhibited by IgG antibody exceeded by at least a factor of 50 the highest comparable values of the association constants for IgM antibody. It is suggested that the hypothesis of germ-line restriction, previously proposed as the basis for the affinity restriction of IgM, may also be applicable to the T cell receptor since its distinctive properties parallel those of IgM antibody.

Animals↗
PubMed1993

Morphological and functional polymorphism within clonal thyroid nodules.

Thirty-nine thyroid nodules, removed because of recent growth, were analyzed morphologically by serial histological sections for the classical histomorphological hallmarks of follicular cell replication and for immunohistochemically demonstrable overexpression of the growth-associated ras-gene product p21ras. Clonal analysis was performed using the highly informative probe M27 beta that detects polymorphisms on the locus DXS255 of the X-chromosome. Twenty-four nodules were of clonal and 15 nodules were of poly-clonal origin. Only 3 out of the 24 clonal nodules were histomorphologically uniform. In all others, the structural hallmarks of active growth and the P21ras growth-marker expression were remarkably heterogeneous throughout the tumors. There were no histomorphological characteristics distinguishing these clonal tumors from polyclonal nodules. Even if a clonal thyroid tumor may be originally homogeneous in respect to the parameters studied here, mechanisms must exist that create wide heterogeneity of growth and of morphogenetic potential among the individual follicular cells during further expansion of the nodule. Thus, clonal nodules are much more common in nodular goiters than hitherto assumed on grounds of the classical morphological criteria. The diagnosis of a true monoclonal nodule can no longer rely on morphological and functional criteria alone but requires molecular or cytogenetic analysis of clonality.

Adult↗
PubMed1986

Phenotype, frequency, and EBV responsiveness of human marrow B and pre-B cells.

We have purified subpopulations of B lineage cells from human adult (rib) bone marrow by cell sorting and panning. Limiting dilution analysis was then used for a clonal analysis of cells able to secrete IgG, IgA, or IgM spontaneously or after infection with EBV. Nonproliferating, high rate IgG or IgA producers occurred at frequencies of about one per 1000 marrow mononuclear cells. Their frequency and Ig production was unaffected by EBV, and they appeared not to express EBNA after exposure to EBV. These cells were Ia+, B1+, and over 85% expressed sIg of the IgM/D (up to 75%) and/or IgG/A isotypes (40 to 60%). B cells committed to the secretion of IgM represent 2 to 10% of marrow B lymphocytes. They were found to be Ia+/B1+/B2+/CALLA- and C3b receptor (CR3)-cells, and most (greater than 90%) required infection with EBV and proliferation to develop into IgM-producing lymphocytes. Thirty to 40% of these cells did not express Ig (H or L chain) on their surface, and therefore resembled pre-B cells at the beginning of the 4- to 5-wk culture period. Proliferating pre-B cells from adult human marrow have been described, but their conversion into IgM-producing cells has not been formally demonstrated. Although EBV induces IgM production, the expression of EBNA, and several rounds of cell division in these cells, the induction of stable (greater than 5 wk) growth transformation represents a rare event in these pre-B cells: in several thousand limiting dilution wells, not a single culture of sIg-cells showed stable growth transformation. The dichotomy between EBV-induced high-rate IgM responses and absent growth transformation discriminates activation and transformation as distinct aspects of EBV-induced B cell "responses", and suggests that cellular properties play critical roles for viral transformation. We propose a model in which cellular target genes for transforming sequences in the EBV genome are transiently expressed during B cell differentiation.

Adult↗
PubMed1989

Phenotypic and functional analysis at the clonal level of infiltrating T lymphocytes in papillary carcinoma of the thyroid: prevalence of cytolytic T cells with natural killer-like or lymphokine-activated killer activity.

We investigated the phenotype and function of thyroid tumor-, metastatic lymph node-, and peripheral blood-derived T lymphocytes of four patients with papillary thyroid cancer. Both phenotypic analysis of freshly isolated cells and clonal analysis, using a high efficiency cloning technique, were performed. For comparison, intrathyroid and peripheral blood T lymphocytes derived from patients with autoimmune thyroid diseases (Graves' disease and Hashimoto's thyroiditis) have been studied. In papillary cancer, the phenotype of thyroid and lymph node-derived T lymphocytes did not differ from that of peripheral blood lymphocytes of the same patients or lymphocytes from normal peripheral blood. At variance with respect to autoimmune thyroid disease, activation markers were poorly represented. The functional analysis of T cell clones showed similar proportions of interleukin-2-producing (helper-inducer) clones in thyroid, lymph node, and peripheral blood, slightly lower than in Hashimoto's thyroiditis and slightly higher than in Graves' disease. With regard to effector function, we found lower proportion of clones with cytolytic activity in a lectin-dependent assay compared to that in Hashimoto's thyroiditis. Interestingly, however, the proportions of cytolytic clones displaying cytolytic activity against the neoplastic cell line K562 (natural killer-like activity) or fresh unrelated tumor cells (lymphokine-activated killer activity) were relatively high in thyroid cancer infiltrates.

Adult↗
PubMed2005

Prognostic significance of clonal diversity of immunoglobulin gene rearrangements in patients with diffuse large B-cell lymphoma.

Clonal diversity of the immunoglobulin (Ig) gene rearrangement represents the oligoclonality of B-cell neoplasm, and has been shown to be a marker for poor prognosis in acute lymphoblastic leukemia. However, no previous report has addressed its prognostic impact in diffuse large B-cell lymphoma (DLBCL). We investigated the clinical significance of clonal diversity in DLBCL patients. Lymph node samples from 98 DLBCL patients were examined for Ig heavy and light chain gene rearrangements using Southern blot analysis. Clonal diversity was defined as oligoclonality detected on Southern blotting as previously described, and PCR analysis for IgH oligoclonality was performed on parts of DLBCL samples with clonal diversity for confirming the Southern blot analysis results. We found that clonal diversity could be detected in 36 (36.7%) of DLBCL patients, and PCR analysis showed concordant results. Regarding the clinical relevance, clonal diversity was significantly associated with relapse or refractory disease. Survival analysis showed that clonal diversity is an independent prognostic factor in DLBCL (p=0.05, Cox's proportional hazard method), and stratified analyses found the most significant subgroup is the high-intermediate risk category (p=0.01, log-rank test). We conclude that clonal diversity of Ig gene rearrangements is associated with a high risk of relapse or refractory disease in DLBCL patients. It is also a factor of poor prognosis in DLBCL, especially for high-intermediate risk category.

Adolescent↗
PubMed1989

Cell-mediated suppression of human hematopoiesis: evaluation by limiting-dilution analysis of hematopoietic progenitors.

We have used limiting-dilution clonal analysis (LDA) in microwells to study the inhibitory effects of T lymphocytes (T-cells) or natural killer (NK) cells on human marrow progenitor cell growth. In four subjects with normal hematopoiesis, the growth of progenitors showed single-hit kinetics both before and after T-cell removal, indicating that, in the presence of colony-stimulating activity, T-cell have no effect on progenitor growth. In a patient with marrow hypoplasia associated with thymoma, hypogammaglobulinemia, and an increased number of suppressor T-cells (Good's syndrome), the progenitor growth deviated from linearity, demonstrating the presence of cells with suppressor activity. After T-cells were removed from this sample, the progenitor growth showed single-hit kinetics. The suppressive action of E-rosette-positive cells with NK or cytotoxic activities was also suggested in a patient with severe combined immune deficiency and in a patient with T gamma lymphocytosis. Poor progenitor-cell growth in three other patients with aplastic anemia was not significantly altered by T-cell removal. Thus, LDA of human hematopoietic progenitors is useful for evaluating cell-mediated interactions affecting hematopoiesis. This method may facilitate elucidation of mechanisms of myelosuppression in clinical settings.

Anemia, Aplastic↗
PubMed2001

Early mycosis fungoides: molecular analysis for its diagnosis and the absence of p53 gene mutations in cases with progression.

The histological diagnosis of initial mycosis fungoides (MF) and the molecular mechanisms that are responsible for its progression and transformation to the more highly malignant variants of MF remain largely unknown. Because of the rare occurrence of these tumours, the need for snap frozen skin biopsy specimens and the difficulty to obtain suitable material for karyotypic and genotypic analysis, specific cytogenetic and molecular lesions have not yet been identified. In particular the role of known oncogenes and tumour suppressor genes, including the p53 gene, in the pathogenesis and clinical progression of MF has not been extensively investigated. The present study was carried out using the polymerase chain reaction (PCR) technique combined with temperature gradient gel electrophoresis (TGGE) to detect mutations of the p53 gene in 58 patients with MF. TGGE analysis was also used in combination with clonality analysis by means of T-cell receptor gamma (TCRG) gene rearrangement studies to distinguish parapsoriasis en plaque and initial MF from patch/plaque stage MF. More than 83% of the diagnoses of initial MF could be confirmed using PCR-TGGE analysis. However, although the sensitive TGGE analysis was used for all exons, p53 gene polymorphisms were found in 4 and p53 gene mutation in only 1 of 58 biopsy specimens. It appears unlikely that p53 gene mutations play a role in either the pathogenesis of parapsoriasis and initial MF or their progression to advanced stages of MF. However, TCRG gene rearrangement studies by means of TCR-TGGE analysis may be useful for distinguishing histologically discordant cases of initial MF.

Biopsy↗
PubMed2000

Dietary 4-HPR suppresses the development of bone metastasis in vivo in a mouse model of prostate cancer progression.

The effects of the synthetic retinoid N-(4-hydroxyphenyl) retinamide (4-HPR) on prostate cancer metastasis in vivo were evaluated in the mouse prostate reconstitution (MPR) model. MPRs were produced by infection of either heterozygous (+/-) or nullizygous (-/-) p53-mutant fetal prostatic epithelial cells with the recombinant retrovirus Zipras/myc 9. Previous studies have documented that loss of p53 function potentiates metastasis in this model system. MPRs were grafted into homozygous (+/+) p53 male mice, fed a 4-HPR containing diet or a control diet and maintained until the status of tumor progression dictated sacrifice. Under these experimental conditions, treatment with 4-HPR did not have a significant effect on primary tumor wet weight for either p53 +/- or p53 -/- MPRs. For, p53 +/- MPRs the animals fed the 4-HPR diet had a slight improvement in survival and a significant reduction in the number of mesenteric metastases (P = 0.0477, t-test). Notably, in p53 +/- MPRs the incidence of metastasis to lumbar spine and sternum was 92% in the control animals compared to 54% in the 4-HPR treated animals (P = 0.035, chi2-test). In p53 -/- MPRs there was a trend toward a reduction in the number of soft tissue metastases to lung and liver in the 4-HPR group relative to the control diet group and a statistically significant reduction in the incidence of metastasis to bone was demonstrated in that 50% of control animals versus 30% of 4-HPR treated p53 -/- animals harbored bone metastases (P = 0 < 0.05, chi2-test). Cell lines were established from portions of the primary tumor and from selected metastatic deposits in each experimental group. Clonal analysis, by retroviral integration pattern, indicated increased clonal diversity in both the primary tumors and metastasis-derived cell lines from 4-HPR treated animals relative to the control animals. In vitro treatment with 4-HPR did not reveal discriminating differences between cell lines derived from primary tumors and bone metastases or control and treatment groups in regard to growth arrest or apoptotic responses. Overall these studies indicate limited anti-tumor and anti-metastatic activity in this highly aggressive in vivo mouse model of prostate cancer, yet 4-HPR treatment significantly suppressed the development of bone metastases in p53 +/- and p53 -/- MPRs revealing a novel and potentially clinically useful activity of this retinoid.

Animals↗
PubMed2005

Simultaneous development of lymphoma in recipients of renal transplants from a single donor: donor origin confirmed by human leukocyte antigen staining and microsatellite analysis.

BACKGROUND: Posttransplant lymphoproliferative disorders (PTLD) occur in 0.5% to 2.5% of cases in renal-transplant recipients. Epstein-Barr virus (EBV) is usually detected in the tumor cells, suggesting a role for this virus as an agent of B-cell proliferation. It is unusual for patients receiving allografts from the same donor to develop PTLD simultaneously. METHODS: we describe two patients who received renal allografts from the same donor and developed PTLD simultaneously. The presence of EBV in both tumors was confirmed. In this report, the origin of tumor cells was determined by immunohistochemical human leukocyte antigen (HLA) typing and microsatellite analysis. Clonality was studied by immunoglobulin gene rearrangement analysis. RESULTS: Our results suggest that the tumor originated from donor cells in both patients but, because immunoglobulin gene rearrangements were different, this could mean that lymphoid cells proliferate independently in each recipient. CONCLUSIONS: We propose the following pathogenesis: immortalization of passenger B lymphocytes by EBV, proliferation of these cells, and development of PTLD by means of immunosuppression, antigenic stimulation, and HLA mismatch.

Adult↗
PubMed2002

Clonality of multiple uterine leiomyomas.

OBJECTIVE: To study the clonality of uterine leiomyomas, especially the relationship between different nodules in multinodular cases. METHODS: Genomic DNA was extracted from fresh tissue samples and digested through incubation with Hpa II and amplified through nested polymerase chain reaction for phosphoglycerate kinase (PGK) gene. The products were treated with Bst XI and resolved on agarose gels. RESULTS: Among the 103 cases examined, 32 (31%) carried the polymorphic Bst XI site at the PGK locus. Eighty-nine tumors from the 29 cases were subjected to the cloning assay. Loss of polymorphism at the PGK locus was found in all tumor nodules, indicating the monoclonality of the tumor. The relationship between multiple tumors was also assessed by comparing their inactivated alleles. Seven nodules from a leiomyosarcoma were found to have originated from a single cell. However, the relationship was found to be more complicated, as demonstrated in 15 cases of multiple leiomyomas. The same inactivated allele was found in all nodules of 8 cases and in most nodules in 2 cases, while totally different inactivation patterns were observed in 5 cases. The difference was not associated with cell proliferation. CONCLUSIONS: Clonality analysis can be applied to define the clonality of focal or nodular lesions. Uterine leiomyomas are of clonal origin. Multiple uterine leiomyomas may be subtyped into fully independent and aggressive types as well as a mixed type of both.

Base Sequence↗
PubMed1998

Use of the bnx/hu xenograft model of human hematopoiesis to optimize methods for retroviral-mediated stem cell transduction (Review).

The potentiality of primitive human hematopoietic cells can be profoundly affected by in vitro culture. Due to the growing number of protocols proposed for stem cell gene therapy and ex vivo expansion, it is crucial to define methods to preserve the generative capacity of human stem cells in culture while promoting self-renewal divisions. Stem cell division, homing, and subsequent lineage development can only be studied definitively by marking of pluripotent cells, followed by tracking and clonal analysis of the progeny in a long-term transplantation system. We have developed a bnx/hu xenograft model, in which transduced human hematopoietic cells can be individually tracked into different lineages over the course of one year post-transplantation. The tracking is accomplished by single cell cloning of individual T lymphoid and myeloid progenitors recovered from the marrow of the mice, and clonal integration analysis by the sensitive technique of single-colony inverse PCR. All cells derived from a stem cell transduced by a retroviral vector will carry the unique restriction fragment length polymorphism (RFLP) created by the random integration event. We have used the bnx/hu xenograft system coupled with single-colony inverse PCR to determine that human stem cells require stromal support, fibronectin support with cytokines, or the presence of Flt3 ligand during a 72-h ex vivo culture to maintain the ability to sustain long-term multilineage hematopoiesis.

Animals↗
PubMedDate not supplied

Changes in heparan sulfate pattern but not in oncogene expression correlate with tumor growth in spontaneous transformation of cells.

For the clonal analysis of spontaneous malignant transformation of cells, a clonal cell line of low tumorigenicity, derived from a mouse embryo mass culture, was injected into syngeneic animals in a sufficient dose (10(7) cells) to produce tumors. Cell lines and clones produced from several such tumors had acquired a 10(4)- to 10(5)-fold higher level of tumorigenicity. Anchorage-independent growth did not co-select with tumorigenicity. There was no evidence for overexpression of proto-oncogenes in the highly tumorigenic clones; p53 protein and mRNA levels were also essentially equal and low. There was a specific structural difference in the O-sulfate residues in oligosaccharides of heparan sulfates in all the tumor cell lines when compared with their parent clone, similar to that observed before in SV40 virus-induced cell transformation (Winterbourne and Mora, 1978).

Animals↗
PubMed1997

A case report: immune responses and clinical course of the first human use of granulocyte/macrophage-colony-stimulating-factor-transduced autologous melanoma cells for immunotherapy.

The first use of granulocyte/macrophage-colony-stimulating-factor-transduced, lethally irradiated, autologous melanoma cells as a therapeutic vaccine in a patient, with rapidly progressive, widely disseminated malignant melanoma resulted in the generation of a novel antitumour immune response associated with partial, albeit temporary, clinical benefit. An initially negative reaction to non-transduced, autologous melanoma cells was converted to a delayed-type hypersensitivity (DTH) reaction of increasing magnitude following successive vaccinations. While intradermal vaccine sites showed prominent dendritic cell accrual, DTH sites revealed a striking influx of eosinophils in addition to activated/memory T lymphocytes and macrophages, recalling the histology of challenge tumour cell rejection in immune mice. Cytotoxic T lymphocytes (CTL) reactive with autologous melanoma cells were detectable at high frequency after vaccination, not only in limiting-dilution analysis, but also in bulk culture without added cytokines. Clonal analysis of CTL showed a conversion from a purely CD8+ response to a high proportion of CD4+ clones following vaccination. A prominent acute-phase response manifested by a five- to tenfold increase in C-reactive protein was observed, as was a systemic eosinophila. Vaccination resulted in the regression of axillary lymphatic metastases, stabilisation of pulmonary metastases, and a dramatic, reversible increase in cerebral oedema associated with multiple central nervous system metastases: however, lesions in the adrenal glands, pancreas and spleen proved refractory. The antitumour effects and immune response were not detectable 2 months following the last vaccination. Irradiation of the extensive cerebral metastases resulted in rapid deterioration and death of the patient.

Autopsy↗
PubMed1990

Automation of limiting dilution cytotoxicity assays.

Limiting dilution analysis is a valuable technique for the quantitation and clonal analysis of immunocompetent cells. However, manual processing of the large number of samples necessary for satisfactory statistical analysis is laborious, and consequently results in inaccuracies reflected as increased standard errors. We describe the application of an automated robotic liquid handling tool to process samples in limiting dilution cytotoxicity assays. Our studies have shown that automated liquid handling is more accurate than manual methods, and that errors are limited. This results in savings of both time and resources. Furthermore, the process may be adapted for the safe, remote handling of sterile cell cultures, and human pathogens.

Automation↗
PubMed2002

Application of molecular genetics to the diagnosis of lymphoid-rich effusions: study of 95 cases with concomitant immunophenotyping.

The cytological differentiation between reactive lymphocytosis and malignant lymphoma in serous effusions is often difficult. The present study was designed to evaluate the potential contribution of molecular genetic clonality analysis to a solution to this problem. We examined the cytological specimens of 95 consecutive patients collected during a 4-yr period, including 74 pleural, 20 peritoneal, and one pericardial fluids. Cytological diagnosis in the 95 lymphocyte-rich effusions was positive for lymphoma in 20 cases, suspicious for lymphoma in 26 cases, and negative in 49 cases. The analysis by ICC was not carried out, inconclusive, or noninterpretable in 25 cases. In five cases molecular genetic analysis was hampered by technical problems. By immunocytochemistry, eight additional cases of lymphoma were detected and lineage classification was achieved in 15 of the 20 cytologically positive effusions. PCR and Southern blot analysis were used to assess B- and T-cell clonality. Monoclonality was found in 40 (42%) of the 95 effusions analyzed. One-third of the effusions with a monoclonal B-cell gene rearrangement were detected by Southern blot analysis but not by the PCR performed in parallel. The results of molecular genetic analysis were corroborated by histological findings and/or clinical evolution in 15 cases. Our results indicate that molecular genetic analysis is a useful tool in the analysis of lymphocyte-rich serous effusions.

Adolescent↗
PubMed2000

Clonal expansion in evolution of chronic hepatitis to hepatocellular carcinoma as seen at an X-chromosome locus.

Clonal analysis has shown that hepatocellular carcinoma arises from a single cell. However, the clonality of precancerous lesions and adjacent nonneoplastic tissues is not clear. We analyzed a human androgen receptor locus to elucidate the clonal state of liver tissues including post-hepatitic lesions associated with hepatocarcinogenesis. The analysis was based on a restriction fragment length polymorphism involving an androgen receptor locus on the X chromosome, taking advantage of physiologic random inactivation by methylation of 1 of 2 X chromosomes in females during embryogenesis. Clonality was assessed in 79 randomly located tissue samples microdissected from noncirrhotic liver, including a total of 40 morphologically normal sites in 4 normal livers and 39 sites from a single HCV-infected liver. In addition, 51 regenerative nodules, 4 areas of adenomatous hyperplasia, and 18 hepatocellular carcinomas were sampled. All samples were obtained from livers involved by various neoplasms. Eight of forty samples (20.0%) from the four normal livers and 20 of the 39 samples (51.3%) from the single HCV-infected liver showed a monoclonal pattern. Moreover, 30 of 51 regenerative nodules (58.9%) showed a monoclonal pattern. No histologic differences were evident between mono- and polyclonal nodules. On the other hand, the 18 carcinomas and 4 areas of adenomatous hyperplasia all were monoclonal. Mean calculated monoclonal areas of normal liver and liver with chronic hepatitis were 1.1 and 3.3 mm(2). Our results suggest that areas representing a single clone of hepatocytes are present in normal liver, and these progressively expand as changes advance from chronic hepatitis to hepatocellular carcinoma.

Aged↗
PubMed2006

Phenotypic and functional characterization of human T cell clones indirectly activated against adult pig islet cells.

BACKGROUND: Xenotransplanted patients produce xenospecific IgG1 antibodies directed against epitopes other than Galalpha1,3Gal. IgG1 antibody production is believed to be dependent upon T cell help. Therefore, as a natural continuation of our work aimed at characterizing the xenoimmune antibody response against pig islet cells, we have also examined the T cell response. T cell reactivity against islet cells is believed to result from indirect antigen presentation, and our in vitro study was designed to mimic the response in vivo. The main purpose of this study was to characterize the phenotype, the immunological specificity and the functional capacity of indirectly activated T cell clones, reactive against pig islet cell antigens. MATERIALS AND METHODS: Human T cell clones, activated against pig islet cells in the presence of autologous antigen-presenting cells, were produced from limiting dilutions of bulk cultures. Clonality was investigated by T cell receptor Vbeta (TcRVbeta) expression analysis. Clonal specificity was studied in proliferation assays using different pig cells as stimulators. ELISpot experiments were performed to detect cytokine production patterns. The cytotoxic capacity of the clones was assessed using standard cell-mediated lysis tests and different porcine and human target cells. Several long-term bulk cultures of human lymphocytes, indirectly activated against pig islet cells, maintained for up to 60 days, were used as a control for possible bias in the selection of the clones. RESULTS: Nineteen CD4+ TcRValphabeta+ T cell clones were recovered. No activation of natural killer T cells or gammadelta-T cells was recorded. There was no bias in the TcRVbeta-usage. The immunological specificity differed between clones; some were specifically reactive against pig islet cell antigens, while others were reactive with antigens present on a variety of pig cells. All clones produced a broad spectrum of cytokines, e.g. interferon (IFN)-gamma, tumor necrosis factor (TNF)-alpha, interleukin (IL)5, IL10 and IL13, with no evidence of bias for a particular phenotype. None of the T cell clones were cytotoxic against pig islet cells, but two clones were cytotoxic against pig phytohemagglutinin (PHA)-blasts. CONCLUSION: The analysis of several, indirectly activated, human CD4+ T cell clones shows that the response against pig islet cells is heterogeneous both with regard to immunological specificity and functional characteristics. This heterogeneity was further confirmed by analysis of the long-term bulk cultures of human lymphocytes, indirectly activated against pig islet cells.

Animals↗
PubMed2000

Outcome of clonal hemophagocytic lymphohistiocytosis: analysis of 32 cases.

We studied the impact of clonality, determined by analysis of Epstein-Barr virus genome termini, T-cell receptor genes and clonal chromosomal abnormality, on the clinical outcome in 32 patients with hemophagocytic lymphohistiocytosis (HLH). Of the cases studied, 23 cases were EBV-clonal, 15 cases were TCR-clonal and 7 cases were cytogenetically clonal. Thirty patients were treated with immuno-chemotherapy and/or multiagents' chemotherapy and 4 received bone marrow transplantation. All 7 cases, in which cytogenetically abnormal clones were identified, were fatal (3-year survival by Kaplan-Meier analysis; 14%, 95%CI: 0-40%). None of these 7 cases received bone marrow transplantation. On the other hand, the 3-year survival of 23 clonal EBV-positive HLH cases including 4 cytogenetically abnormal cases was 64 % (95%CI: 42-84%), while that of 15 TCR-clonal cases was 53% (95%CI: 26-78%). Our observations suggest that cytogenetically abnormal cases are at extremely high risk, requiring intensive immuno-chemotherapy followed by prompt and timely allogeneic bone marrow transplantation.

Adolescent↗