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M Ladanyi

Publications and source records attributed to M Ladanyi.

At least 73 records · Page 4Linked to original sources
PubMed1996

CD30 (Ki-1)-positive malignant lymphomas: clinical, immunophenotypic, histologic, and genetic characteristics and differences with Hodgkin's disease.

This study compares the histologic and immunophenotypic features of 71 cases of primary CD30+ diffuse large-cell lymphomas (DLCL) and 128 cases of Hodgkin's disease (HD) and discusses the clinical features of 52 patients with CD30+ DLCL. It includes analysis of sites of involvement, staging, response to treatment, sites and treatment of recurrences, and disease-free and overall survival. Diagnostic immunophenotypic differences were found between CD30+ DLCL and HD. All cases of CD30+ DLCL were positive for one or more common or lineage-specific lymphocyte antigens or for EMA. In contrast, 96.9% of HD cases were negative for CD45, CD45-RO, CD43, and CD20. The four exceptions are discussed. All cases of HD were negative for EMA. In patients with CD30+ DLCL, a T-cell phenotype was found in 60%, a null-cell type in 22%, and a B-cell type in 18% of the cases. The median age of patients with T- and null-cell phenotype was 22 years (range, 4 to 72). Fifty-two percent of them had high-stage (III and IV) disease and 61% had extranodal involvement at presentation, including 25% with skin lesions. Lymph nodes draining the skin lesions became involved in seven of 11 patients. No patient had initial bone marrow involvement. Most patients were treated with chemotherapy, and 83% had a complete remission. Fifty-four percent remain free of disease with a median follow-up of 47 months. Thirteen patients (29%) had one or more recurrences and five of them remain free of disease after salvage therapy, with a median follow-up period of 79 months. The clinical stage did not affect survival, probably as a result of different therapy. The t(2;5) translocation was found in five of 15 patients who had cytogenetic abnormalities. Of the other 10 cases, the translocation was detected by reverse transcriptase-polymerase chain reaction (RT-PCR) in four of five cases studied. All nine cases were of T- or null-cell phenotype. The cases of B-cell CD30+ DLCL had a characteristic immunophenotype. All were negative for EMA. These patients were older and had frequent bone marrow involvement but no skin infiltration by lymphoma. All three patients who were human immunodeficiency virus-positive (HIV+) had lymphomas of B-cell lineage. Detection of the t(2;5) translocation by molecular genetics is a useful and highly specific marker in the differential diagnosis between HD and CD30+ DLCL.

Adolescent↗
PubMed1996

Human Epstein-Barr virus (EBV)-specific cytotoxic T lymphocytes home preferentially to and induce selective regressions of autologous EBV-induced B cell lymphoproliferations in xenografted C.B-17 scid/scid mice.

C.B-17 scid/scid (severe combined immunodeficiency [SCID]) mice inoculated with peripheral blood lymphocytes from Epstein-Barr virus (EBV)-seropositive donors, or with EBV-transformed lymphoblastoid B cell lines (EBV-LCL), develop lethal human EBV+ B cell lymphoproliferative disorders (EBV-LPD) with characteristics similar to those arising in immunodeficient patients. Using this model, we examined the capacity of human effector cells to control human EBV-LPD. SCID mice received rabbit anti-asialo GM1 antiserum to abrogate endogenous natural killer-cell function. Preliminary experiments showed that adoptive transfer of peripheral blood mononuclear cells (PBMC), purified T cells, interleukin (IL) 2-activated PBMC or anti-CD3-activated T cells derived from EBV-seropositive donors did not result in improved survival of treated mice (in vivo effector/target ratio 2:1 to 1:1). In contrast, EBV-specific cytotoxic T lymphocytes (CTL), derived from EBV-seropositive donors and expanded in vitro, exhibited strong EBV-specific and HLA-restricted activity both in vitro and in vivo. SCID mice inoculated intraperitoneally with autologous but not with HLA-mismatched EBV-LCL had significantly improved survival relative to untreated mice after inoculation of EBV-specific CTL either intraperitoneally (P<0.001) or intravenously (P<0.001) (in vivo effector/target ratio 1:1). SCID mice bearing large subcutaneous EBV+ tumors and treated intravenously with 10(7) EBV-specific CTL achieved complete tumor regression. Both CTL- and CTL-plus-IL-2-treated mice survived significantly longer than untreated animals or animals treated with IL-2 alone (P = 0.0004 and P<0.02, respectively). SCID mice bearing two subcutaneous EBV+ tumors, one autologous and the other HLA mismatched to the EBV-specific CTL donor, had regression of only the autologous tumor after intravenous infusion of 10(7) EBV-specific CTL. Moreover, we could demonstrate preferential homing of PKH26-labeled EBV-specific CTL to autologous but not to HLA-mismatched EBV+ tumors as early as 24 h after intravenous adoptive transfer. Immunophenotypic analyses also demonstrated preferential infiltration of T cells into the autologous EBV+ tumor in SCID mice bearing both the autologous and either fully HLA-mismatched or genotypically related haplotype-sharing EBV+ tumors. The human T cells infiltrating EBV+ tumors were CD3+ and, predominantly, CD8+CD4-. Our results indicate that EBV-specific CTL preferentially localize to and infiltrate EBV+ tumors bearing the appropriate HLA antigens and thereafter induce targeted regressions of disease.

Animals↗
PubMed1996

Administration of rabbit anti-asialo GM1 antiserum facilitates the development of human Epstein-Barr virus-induced lymphoproliferations in xenografted C.B-17 scid/scid mice.

Mice with severe combined immune deficiency (C.B-17 scid/scid [SCID mice]) lack functional B and T lymphocytes and are permissive for the growth of human xenografts. However, the development of functional NK cells is not affected by the scid mutation. Mouse NK cells express the surface glycolipid asialo GM1 and are implicated in the rejection of heterotransplanted cells. In the present study, we demonstrate that SCID mice treated with rabbit anti-asialo GM anti-serum (alpha-asialo GM1), for in vivo depletion of endogenous NK cell function, develop lethal Epstein-Barr virus (EBV)-induced lymphoproliferative disorders (EBV-LPD) at lower doses od inoculated EBV-transformed lymphoblastoid B cell lines (EBV-LCL) than untreated animals. Furthermore, at any given dose of EBV-LCL inoculated, EBV-LPD developed earlier and induced lethality sooner in alpha-asialo GM1-treated animals. We also demonstrate that SCID mice treated with alpha-asialo GM1 have reduction in the number of asialo GM1-expressing splenocytes. Moreover, splenic cell suspensions derived from alpha-asialo GM1-treated SCID mice show lower cytotoxicity against the mouse NK-sensitive cell line YAC-1 and human EBV-LCL than splenocytes obtained from untreated SCID mice.

Animals↗
PubMed1996

Molecular variant of the NPM-ALK rearrangement of Ki-1 lymphoma involving a cryptic ALK splice site.

The breakpoints of the translocation t(2;5)(p23;q35) associated with Ki-1-positive anaplastic large cell lymphoma (Ki-1 ALCL) have recently been cloned. They involve a novel tyrosine kinase gene, ALK, at 2p23 and the nucleophosmin gene, NPM, at 5q35. Reverse transcriptase-polymerase chain reaction (RT-PCR) with NPM and ALK primers detects a consistent fusion product in Ki-1 ALCL cases that have the translocation. In the course of a survey of 15 cases of Ki-1 ALCL, we identified a single case with a slightly smaller NPM-ALK RT-PCR product, among 12 cases positive for this fusion RNA. Sequencing of this novel NPM-ALK RT-PCR product showed an in-frame junction of NPM to ALK, 30 bases distal to the usual ALK junction site, but at the usual NPM Junction site. The predicted chimeric protein in this case is thus shorter by 10 amino acids, but the putative ALK catalytic domain remains intact. PCR with ALK primers bracketing the novel fusion point, performed on either cDNA or genomic DNA, yielded the same product, confirming that this novel ALK fusion point was located within an exon. Hybridization analysis of the genomic junction fragment isolated by long-range DNA PCR suggested that the ALK genomic breakpoint was also exonic. Cloning and sequencing of the genomic breakpoint confirmed that the break occurred within the 5' portion of the ALK exon participating in the fusion junction, 28 bases 3' to the normal ALK exon boundary, resulting in the use of a cryptic splice acceptor site two bases distal to the breakpoint. This case demonstrates that, in translocations resulting in chimeric transcripts, genomic breakpoints may rarely lie within an exon, provided that the reading frame is maintained and no domains presumed critical to tumorigenesis are deleted.

Amino Acid Sequence↗
PubMed1996

Intracranial desmoplastic small-cell tumor. Report of a case.

We report a case of desmoplastic small-cell tumor occurring in the CNS in relation to the tentorium in a 24-year-old man. Morphologically, the neoplasm had the typical appearance of small, round tumor cells of primitive appearance growing as well-defined nests separated by abundant desmoplastic stroma. The diagnosis was confirmed through the demonstration of immunoreactivity for keratin, desmin, and neuron-specific enolase and the detection by Southern blot analysis of a unique gene resulting from the fusion of the WT1 gene in chromosome 11 and the EWS gene in chromosome 22. This is the first documented instance of the occurrence of this tumor type at a distance from a mesothelial-lined surface.

Adult↗
PubMed1996

Detection of the NPM-ALK genomic rearrangement of Ki-1 lymphoma and isolation of the involved NPM and ALK introns.

The breakpoints of the translocation t(2;5)(p23;q35) associated with Ki-1-positive anaplastic large-cell lymphoma (Ki-1 ALCL) involve a novel tyrosine kinase gene, ALK, at 2p23 and the nucleophosmin gene, NPM, at 5q35. Reverse transcriptase-polymerase chain reaction (RT-PCR) using NPM and ALK primers detects a consistent fusion product in Ki-1 ALCL cases with the translocation, resulting from genomic breakpoints within the same respective introns of NPM and ALK. To examine the feasibility of long-range DNA PCR with the same exonic NPM and ALK primers for the detection of the genomic NPM-ALK rearrangement, we examined 20 cases of Ki-1 ALCL previously characterized by NPM-ALK RT-PCR. Ten cases were positive for the NPM-ALK fusion RNA and 10 were negative. We first confirmed that both the NPM and ALK normal introns are relatively short, approximately 1 and 2 kb, respectively, suggesting that the largest possible size for the chimeric NPM-ALK intron would be about 3 kb. All 10 cases positive by RT-PCR were also positive by long-range DNA PCR. The DNA PCR products ranged, as expected, from the sizes of the normal introns, between 0.5 and 2.5 kb. All 10 RT-PCR-negative cases were also negative by long-range DNA PCR, and control templates for RT-PCR and long-range DNA PCR were successfully amplified. Thus, we have shown that the introns involved by the NPM-ALK rearrangement seen in some Ki-1 lymphomas are relatively short, making the genomic rearrangement amenable to reliable detection by long-range DNA PCR. Furthermore, the variability observed in the sizes of chimeric introns in evidence against clustering of the genomic breakpoints within these introns.

Anaplastic Lymphoma Kinase↗
PubMed1996

Survival from locally invasive or widespread neuroblastoma without cytotoxic therapy.

PURPOSE: To test the hypothesis that cytotoxic therapy is not needed at diagnosis to assure the survival of most patients with non-stage 4 neuroblastoma. METHODS: Patients with non-stage 4 disease received no cytotoxic therapy in the absence of N-myc amplification. The International Neuroblastoma Staging System (INSS) was used. RESULTS: Of 84 consecutive patients with previously untreated, newly diagnosed neuroblastoma, 31 (37%) had non-stage 4 disease. All 31 patients initially received no cytotoxic therapy because none of them had N-myc amplification. Nine stage 1 patients are relapse-free. This report focuses on the 22 patients with locally invasive or distant disease: two stage 2A with gross residual tumor postsurgery, 11 stage 2B with ipsilateral or midline lymph node involvement, four stage 3, and five stage 4S. Eight of the 22 patients were older than 1 year. Postsurgery, 13 patients had visible residual disease, and two others had markedly increased urinary catecholamine levels for more than 1 year. Recurrent or enlarging tumors regressed spontaneously (n = 2) or were excised 5 to 39 months after diagnosis (n = 4). One of the latter had chromosome 1p deletions (common in poor-risk neuroblastoma) that were not detected in the patient's original tumor resected 23 months earlier--findings consistent with clonal evolution or multifocal disease. The patient received chemotherapy. All 22 patients are alive 24 to 98 months (median, 64) from diagnosis. CONCLUSION: Our results suggest that non-stage 4 patients without N-myc amplification can be spared cytotoxic therapy because (1) residual postsurgical or recurrent biologically favorable neuroblastoma rarely evolves into lethal stage 4 disease; and (2) neuroblastoma in lymph nodes has no prognostic significance. These findings are remarkable because no other cancer includes subtypes that are curable without therapy to ablate residual disease.

Adolescent↗
PubMed1996

International neuroblastoma staging system stage 1 neuroblastoma: a prospective study and literature review.

PURPOSE: To gain insight into the management of non-metastatic neuroblastoma by examining clinical and biologic features of International Neuroblastoma Staging System (INSS) stage 1 tumors. METHODS: Patients were staged by both the INSS and the Evans staging system and were evaluated for biologic prognostic factors. Patients with INSS stage 1 received no cytotoxic therapy. The literature was reviewed for clinical and biologic data about INSS stage 1. RESULTS: We evaluated 10 consecutive patients (median age, 17.5 months) with INSS stage 1; all remain disease-free (median follow-up duration, > 5 years). Tumors were in the abdomen (n = 6), chest (n = 3), or pelvis (n = 1). Neuroblastoma involved margins of resection in six tumors. Poor-prognostic biologic findings included tumor-cell diploidy (n = 2) and unfavorable Shimada histopathology (n = 2). Two patients were to receive chemotherapy for, respectively, a tumor deemed unresectable and a tumor classified as Evans stage III; second opinions resulted in surgical management alone in each case. Published reports confirm that some INSS stage 1 patients (1) are at risk for overtreatment, and (2) have poor-prognostic biologic findings yet do well. CONCLUSION: Surgery alone suffices for INSS stage 1 neuroblastoma, even if biologic prognostic factors are unfavorable, microscopic disease remains after surgery, and tumor size is suggestive of "advanced-stage" status in other staging systems. Attempts to resect regionally confined neuroblastomas should take precedence over immediate use of cytotoxic therapy; otherwise, some patients may receive chemotherapy or radiotherapy unnecessarily.

Adolescent↗
PubMed1995

Proteinaceous (angiocentric sclerosing) lymphadenopathy: a polyclonal systemic, nonamyloid deposition disorder.

Proteinaceous lymphadenopathy with hypergammaglobulinemia (PLWH) is an exceedingly rare disease of unknown etiology. Described primarily as a pathologic entity, relatively little is known about its clinical manifestations or its response to therapy. The disease is often referred to and treated as an unusual form of plasma cell dyscrasia or light chain deposition disease. We have recently encountered a young patient with PLWH who presented with generalized lymphadenopathy, marked liver function abnormalities, hypocomplementemia, cryoglobulinemia, decreased T4/T8 ratio, and ophthalmopathy. Contrary to the notion that PLWH is a clonal disorder, we found no evidence of clonality in this patient. The most characteristic finding in this and in another patient, previously seen at our institution, was marked angiocentric hyaline sclerosis of the small and mid-sized blood vessels of involved lymph nodes and organs. Based on these findings, we propose the term angiocentric sclerosing lymphadenopathy, which more accurately defines this clinicopathologic entity that appears to be distinct from light chain deposition disease and other plasma cell dyscrasias.

Adult↗
PubMed1995

Characterization of the genomic breakpoint and chimeric transcripts in the EWS-WT1 gene fusion of desmoplastic small round cell tumor.

Desmoplastic small round cell tumor is a recently recognized distinctive tumor shown to be associated with a recurrent translocation, t(11;22)(p13;q12), and rearrangement of the genes for Ewing sarcoma (EWS) and Wilms tumor (WT1). A genomic DNA fragment containing the EWS-WT1 gene fusion has been isolated from a desmoplastic small round cell tumor, and the breakpoint has been characterized. The breakpoints involve the intron between EWS exons 7 and 8 and the intron between WT1 exons 7 and 8. Chimeric transcripts corresponding to the fusion gene were detected in four of six cases studied. Analysis of these transcripts show an in-frame fusion of RNA encoding the amino-terminal domain of EWS to both alternatively spliced forms of the last three zinc fingers of the DNA-binding domain of WT1. Desmoplastic small round cell tumor represents the third tumor type associated with translocation of EWS and the first tumor associated with consistent translocation of WT1. The chimeric products are predicted to modulate transcription at WT1 target sites and contribute to development of this unique tumor.

Abdominal Neoplasms↗
PubMed1995

MDM2 and CDK4 gene amplification in Ewing's sarcoma.

Amplification of the MDM2 gene, which maps to chromosome band 12q13 and encodes a p53-binding protein, may result in functional inactivation of p53 and has been observed in various bone and soft tissue sarcomas. Published studies have included few cases of Ewing's sarcoma (ES) or peripheral neuroectodermal tumour (PNET), a tumour group in which alterations of the p53 pathway have so far not been extensively studied. We examined two ES cell lines, RD-ES and SK-ES-1, and 30 specimens from 27 patients (24 ES, 6 PNET; 19 primary, 4 local recurrence, 7 metastasis) for MDM2 gene amplification by Southern blot analysis. All 30 clinical specimens had been confirmed to contain sufficient ES/PNET DNA by the demonstration of a rearrangement of the t(11;22)-associated EWS gene using an EWS cDNA probe on the same blots. MDM2 gene amplification was detected in 3 of 30 specimens (10 per cent), including two ES and one PNET, but in neither of the cell lines. The three cases with amplification were morphologically typical primary tumours. Two of the three cases also showed co-amplification of the CDK4 gene, which encodes a cyclin-dependent kinase and also maps to band 12q13. Clinically, all three cases had metastatic disease at diagnosis, compared with only 1 of 15 MDM2-negative cases where the primary tumour was studied. The difference was statistically significant (P = 0.005), suggesting an association of MDM2 amplification with advanced stage.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1995

The emerging molecular genetics of sarcoma translocations.

Many types of sarcomas are characterized by specific chromosomal translocations which are likely to be of etiologic significance. The recent elucidation of the molecular structure of the several of these translocations has revealed some striking similarities. Nearly all appear to result in the production of novel, tumor-specific chimeric transcription factors. Furthermore, six of the translocations, namely the t(11;22), t(21;22), and t(7;22) of Ewing's sarcoma, the t(12;22) of clear cell sarcoma, the t(12;16) of myxoid liposarcoma, and the t(11;22) of desmoplastic small round cell tumor, achieve this following a peculiar pattern, consisting in the fusion of a gene with an RNA-binding domain (EWS or TLS) with a transcription factor gene (FLI1, ERG, ETV1, ATF-1, CHOP, or WT1). The observation that the different translocation partners of the EWS gene are specifically associated with several distinct types of primitive sarcomas suggests a model in which the translocation partner supplying the DNA-binding domain confers the target specificity of the transcriptional activation mediated by these chimeric proteins, whereas the partner supplying the N-terminal domain and promoter region determines their transactivation potential and expression level. Further analysis of the normal functions and expression patterns of these genes should yield insights into the histogenesis of these different tumor types and into normal tissue development and differentiation. Clinically, our new understanding of the molecular structure of these translocations opens new avenues for molecular diagnosis and investigative therapeutics.

Base Sequence↗
PubMed1995

Detection of chimeric transcripts in desmoplastic small round cell tumor and related developmental tumors by reverse transcriptase polymerase chain reaction. A specific diagnostic assay.

Desmoplastic small round cell tumor is a recently described entity associated with fusion of the EWS and WT1 genes and with expression of a chimeric transcript. To investigate the structure and potential diagnostic utility of the detection of EWS-WT1 chimeric RNA in desmoplastic small round cell tumor, 12 examples of this entity and 49 other tumors that enter in its differential diagnosis were studied by reverse transcriptase polymerase chain reaction for the presence of EWS-WT1, EWS-FLI-1, PAX3-FKHR, and PAX7-FKHR chimeric transcripts. EWS-WT1 was detected in 11 of 12 desmoplastic small round cell tumors but not in any other tumor type studied, including 17 Wilms' tumors, 10 Ewing's sarcomas/primitive neuroectodermal tumors, 13 alveolar rhabdomyosarcomas, and 9 embryonal rhabdomyosarcomas. One desmoplastic small round cell tumor was found to have a variant EWS-WT1 chimeric product that included exon 8 of EWS EWS-FLI-1 chimeric RNA was present in all Ewing's sarcoma/primitive neuroectodermal tumor and not identified in any other tumor types, including desmoplastic small round cell tumor. PAX3/PAX7-FKHR chimeras were present in 9 of 13 alveolar rhabdomyosarcomas but not in any other tumors. Detection of chimeric transcripts by reverse transcriptase polymerase chain reaction is a very specific aid in differential diagnosis of developmental tumors and further establishes desmoplastic small round cell tumor as a distinct entity.

Adolescent↗
PubMed1995

Molecular diagnosis of synovial sarcoma and characterization of a variant SYT-SSX2 fusion transcript.

The translocation t(X;18)(p11;q11) is seen in > 80% of synovial sarcomas (SS) with informative karyotypes. The breakpoints of the t(X;18) have been cloned and shown to involve two novel genes, SSX (at Xp11) and SYT (at 18q11), which produce a chimeric SYT-SSX transcript as a result of the translocation. Recently, SSX has been shown to be duplicated, with both copies, SSX1 and SSX2, located within distinct subregions of Xp11. We performed a reverse transcriptase polymerase chain reaction (RT-PCR) assay for both chimeric SYT-SSX transcripts in a series of 35 SS (29 monophasic, 6 biphasic) to assess its usefulness in molecular diagnosis and to evaluate the incidence of molecular variants. Of the 35 cases, 29 (83%) showed a specific SYT-SSX RT-PCR product, using a consensus primer for SSX1 and SSX2 Upon excluding three negative cases that had poor quality RNA, the proportion of positives rose to 91% (29/32). The 29 positive cases were further studied using primers specific for either SSX1 or SSX2; 19 cases were positive for SYT-SSX1 and 10 for SYT-SSX2. The relationship of histological subtype (monophasic versus biphasic) to SSX1 or SSX2 involvement was not statistically significant. In a single histologically unremarkable monophasic SS, a slightly larger SYT-SSX2 RT-PCR product was observed. Sequencing of this novel variant showed a 129-bp segment inserted between the usual SYT and SSX2 fusion points, of which 126 bp were derived from a more proximal (5') portion of SSX2 The 3 bp immediately 5' to the fusion point could not be assigned to either SYT or SSX2 and may represent an insertion-deletion or a cryptic splicing event. This fragment maintains the reading frame of the chimeric product and encodes a predicted protein larger by 43 amino acids, which nevertheless replaces the region homologous to the transcriptional repression domain Kruppel-associated box, recently recognized in the 5' portion of the SSX genes, with all but the 3' end of the SYT transcript. Thus, a diagnosis of SS may be confirmed in > 90% of cases using RT-PCR detection of the chimeric transcript resulting from the t(X;18), and the incidence of molecular variants appears low.

Adolescent↗
PubMed1995

Primary lymphomatous effusions in AIDS: a morphological, immunophenotypic, and molecular study.

Lymphomas were documented in pleural effusions or ascites in 18 human immunodeficiency virus-positive (HIV+) patients. Eleven of 12 with clinical data had acquired immunodeficiency syndrome before the diagnosis of lymphoma. In 13 of 15 with data available, a body cavity was the site of initial presentation of lymphoma. Cytological subtypes were large cell immunoblastic, n = 7; large cell anaplastic, n = 6; and large cell NOS, n = 5. The high incidence of anaplastic large cell lymphoma and the conspicuous absence of Burkitt's lymphoma differ strikingly from HIV-associated lymphomas generally. Immunophenotypically, two cases were B-cell (CD19/20+, sIg+, CD/5-), one was T-cell (CD3+, CD5+, CD4+, CD8-, CD19/20-, sIg-), and 15 were null (CD45+, HLA-DR+ CD19/20-, sIg-, CD3/5-). This 83% incidence of null immunophenotype contrasts sharply with a 9% incidence among 35 tissue-based lymphomas in HIV+ patients that were similarly studied and a 0% null immunophenotype among 11 lymphomatous effusions in patients without HIV risk factors. Seven of the 18 HIV-associated lymphomas expressed CD30. Four of five cases with null immunophenotype showed Ig heavy-chain gene rearrangement, two had clonal Epstein-Barr virus integration, and none had MYC protooncogene rearrangement. These cases belong to a subgroup of high-grade HIV-associated lymphomas that occur in the setting of profound immunosuppression in which immunoblastic morphology predominates and MYC rearrangement is encountered only infrequently.

Acquired Immunodeficiency Syndrome↗