Biomedical subjects

R Willemze

Publications and source records attributed to R Willemze.

At least 91 records · Page 5Linked to original sources

PubMed2000

Frequency of central nervous system involvement in primary cutaneous B-cell lymphoma.

BACKGROUND: Primary cutaneous B-cell lymphoma (CBCL) constitutes approximately 20% of all primary cutaneous lymphomas. Apart from primary cutaneous large B-cell lymphoma presenting on the legs (PCLBCL-leg), primary CBCLs run an indolent clinical course, rarely disseminate to extracutaneous sites, and have an excellent prognosis. Because of recent observations in two patients who developed central nervous system (CNS) involvement, follow-up data of all primary CBCL patients registered at the Dutch Cutaneous Lymphoma Group between 1985 and 1998 were investigated for evidence of CNS involvement. METHODS: Follow-up data from 160 primary CBCLs were evaluated. This group included 122 primary cutaneous follicle center cell lymphomas (PCFCCLs), 16 primary cutaneous immunocytomas or marginal zone B-cell lymphomas, and 22 PCLBCL-leg. RESULTS: Of all 160 patients with primary CBCLs, 11 died of lymphoma, including 4 of 122 patients (3%) with PCFCCL and 7 of 22 patients (32%) with PCLBCL-leg. Four of these 11 patients, including 3 with PCFCCL and 1 with PCLBCL-leg, had developed CNS involvement 3-93 months (median, 30 months) after diagnosis. All patients died 1-9 months (median, 7 months) after the development of CNS involvement. In the group of 122 patients with PCFCCL, CNS involvement occurred in 3 of 7 patients (43%) who developed extracutaneous disease and accounted for 3 of 4 lymphoma-related deaths (75%). CONCLUSIONS: The results of this study indicate that approximately 2% of all primary CBCLs may develop CNS involvement. Whereas, in rare PCFCCL patients, developing extracutaneous disease CNS involvement was an important cause of death, patients with PCLBCL-leg and secondary CBCL died more frequently due to involvement of non-CNS organ systems.

Aged↗

PubMed2000

High incidence of alternatively spliced forms of deoxycytidine kinase in patients with resistant acute myeloid leukemia.

Deficiency of functional deoxycytidine kinase (dCK) is a common characteristic for in vitro resistance to cytarabine (AraC). To investigate whether dCK is also a target for induction of AraC resistance in patients with acute myeloid leukemia (AML), we determined dCK messenger RNA (mRNA) expression in (purified) leukemic blasts and phytohemagglutinin-stimulated T cells (PHA T cells) from patients with chemotherapy-sensitive and chemotherapy-resistant AML. In control samples from healthy donors (PHA T cells and bone marrow), only wild-type dCK complementary DNA (cDNA) was amplified. Also, in (purified) leukemic blasts from patients with sensitive AML, only wild-type dCK cDNAs were observed. These cDNAs coded for active dCK proteins in vitro. However, in 7 of 12 (purified) leukemic blast samples from patients with resistant AML, additional polymerase chain reaction fragments with a deletion of exon 5, exons 3 to 4, exons 3 to 6, or exons 2 to 6 were detected in coexpression with wild-type dCK. Deletion of exons 3 to 6 was also identified in 6 of 12 PHA T cells generated from the patients with resistant AML. The deleted dCK mRNAs were formed by alternative splicing and did code for inactive dCK proteins in vitro. These findings suggest that the presence of inactive, alternatively spliced dCK mRNA transcripts in resistant AML blasts may contribute to the process of AraC resistance in patients with AML. (Blood. 2000;96:1517-1524)

Acute Disease↗

PubMed2000

Primary and secondary cutaneous CD30(+) lymphoproliferative disorders: a report from the Dutch Cutaneous Lymphoma Group on the long-term follow-up data of 219 patients and guidelines for diagnosis and treatment.

To evaluate our diagnostic and therapeutic guidelines, clinical and long-term follow-up data of 219 patients with primary or secondary cutaneous CD30(+) lymphoproliferative disorders were evaluated. The study group included 118 patients with lymphomatoid papulosis (LyP; group 1), 79 patients with primary cutaneous CD30(+) large T-cell lymphoma (LTCL; group 2), 11 patients with CD30(+) LTCL and skin and regional lymph node involvement (group 3), and 11 patients with secondary cutaneous CD30(+) LTCL (group 4). Patients with LyP often did not receive any specific treatment, whereas most patients with primary cutaneous CD30(+) LTCL were treated with radiotherapy or excision. All patients with skin-limited disease from groups 1 and 2 who were treated with multiagent chemotherapy had 1 or more skin relapses. The calculated risk for systemic disease within 10 years of diagnosis was 4% for group 1, 16% for group 2, and 20% for group 3 (after initial therapy). Disease-related 5-year-survival rates were 100% (group 1), 96% (group 2), 91% (group 3), and 24% (group 4), respectively. The results confirm the favorable prognoses of these primary cutaneous CD30(+) lymphoproliferative disorders and underscore that LyP and primary cutaneous CD30(+) lymphomas are closely related conditions. They also indicate that CD30(+) LTCL on the skin and in 1 draining lymph node station has a good prognosis similar to that for primary cutaneous CD30(+) LTCL without concurrent lymph node involvement. Multiagent chemotherapy is only indicated for patients with full-blown or developing extracutaneous disease; it is never or rarely indicated for patients with skin-limited CD30(+) lymphomas. (Blood. 2000;95:3653-3661)

Adolescent↗

PubMed2000

Effect of centre on outcome of bone-marrow transplantation for acute myeloid leukaemia. Acute Leukaemia Working Party of the European Group for Blood and Marrow Transplantation.

BACKGROUND: There is increasing pressure for the recognition and replication of good clinical practice. We undertook a study to assess the variability in outcome of allogeneic bone-marrow transplantation among major European centres. METHODS: We studied 13 centres, including 522 patients (aged 16-55 years), which had undertaken more than 30 bone-marrow transplantations between Jan 1, 1987, and Dec 31, 1995, for acute myeloid leukaemia in first complete remission. We undertook a (global) multivariate analysis of all factors known previously to influence outcome and a stratified analysis that initially defined, by multivariate analysis, significant variables in this study and then used a proportional-hazard model including centres. FINDINGS: The overall results at 3 years were 57% (95% CI 53-61) for leukaemia-free survival (LFS), 23% (19-27) for relapse incidence (RI), and 26% (22-30) for treatment-related mortality (TRM) with a range for centres of 36-75%, 10-37%, and 8-54%, respectively. Both methods of analysis showed the centre effect to be highly significant for LFS and TRM, but not for RI. Variables associated with a significantly poor outcome were age over 43 years (p=0.01), time from diagnosis to first complete remission longer than 65 days (p=0.02), and centre (p=0.013) for LFS, and age over 43 years (p=0.023), time from first complete remission to transplantation of longer than 93 days (p=0.03), and centre (p=0.001) for TRM. Moreover, different centres had different prognostic criteria for good-risk or bad-risk patients indicating that risk factors do not have the same impact in each individual centre. INTERPRETATION: The outcome of bone-marrow transplantation for acute myeloid leukaemia in first complete remission is influenced by the centre in which the procedure is done, even with adjustment for known prognostic risk factors. Significant prognostic factors vary among centres, which means that the relative risk is not the same in each individual centre. However, centres may treat populations with different risks of as yet unidentified prognostic factors. Experience may partly account for the difference in outcome among centres.

Adolescent↗

PubMed2000

DFFRY codes for a new human male-specific minor transplantation antigen involved in bone marrow graft rejection.

Graft rejection after histocompatibility locus antigen (HLA)-identical stem cell transplantation results from the recognition of minor histocompatibility antigens on donor stem cells by immunocompetent T lymphocytes of recipient origin. T-lymphocyte clones that specifically recognize H-Y epitopes on male target cells have been generated during graft rejection after sex-mismatched transplantation. Previously, 2 human H-Y epitopes derived from the same SMCY gene have been identified that were involved in bone marrow graft rejection. We report the identification of a new male-specific transplantation antigen encoded by the Y-chromosome-specific gene DFFRY. The DFFRY-derived peptide was recognized by an HLA-A1 restricted CTL clone, generated during graft rejection from a female patient with acute myeloid leukemia who rejected HLA-phenotypically identical bone marrow from her father. The identification of this gene demonstrates that at least 2 genes present on the human Y-chromosome code for male-specific transplantation antigens.

Amino Acid Sequence↗

PubMed2000

Mycosis fungoides: disease evolution and prognosis of 309 Dutch patients.

OBJECTIVES: To determine the disease course of Dutch patients with mycosis fungoides and to define factors related to disease progression and survival. DESIGN: A multicenter, 13-year, retrospective cohort analysis. SETTING: Eight dermatology departments collaborating in the Dutch Cutaneous Lymphoma Group. PATIENTS: Three hundred nine patients with mycosis fungoides registered between October 1985 and May 1997, including 89 patients with limited patches or plaques (stage Ia), 135 with generalized patches or plaques (stage Ib), 46 with skin tumors (stage Ic), 18 with enlarged but uninvolved lymph nodes (stage II), 18 with lymph node involvement (stage III), and 3 with visceral involvement (stage IV). MAIN OUTCOME MEASURES: Response to initial treatment, sustained complete remission, actuarial disease progression, and overall and disease-specific survival per clinical stage. RESULTS: The median follow-up was 62 months (range, 1-113 months). For the entire group, the actuarial overall and disease-specific survival was 80% and 89% at 5 years, and 57% and 75% at 10 years, respectively. The actuarial 5-year disease-specific survival of patients with stage Ia, Ib, and Ic disease was 100%, 96%, and 80%, respectively, and only 40% for patients with stage III disease. Using multivariate analysis, the presence of extracutaneous disease, the type and extent of skin involvement, the response to initial treatment, and the presence of follicular mucinosis were independently associated with higher disease progression and mortality rates. The calculated risks of disease progression at 5 and 10 years gradually increased from 4% to 10% for those with stage Ia disease, from 21% to 39% for those with stage Ib disease, and from 32% to 60% for those with stage Ic disease; for those with stage III disease, the risk remained at 70% at 5 and 10 years. The overall risk of disease progression at 5 and 10 years was 24% and 38%, respectively, for the total study group. CONCLUSION: At least within the first 10 years after diagnosis, disease progression and mycosis fungoides-related mortality occur in only a subset of patients generally presenting with advanced disease.

Adult↗

PubMed2000

Epstein-Barr virus is present in neoplastic cytotoxic T cells in extranodal, and predominantly in B cells in nodal T non-Hodgkin lymphomas.

Epstein-Barr virus (EBV)-positive T non-Hodgkin lymphomas (T-NHLs) have been described, but it is at present unknown how EBV infects T lymphocytes. It has been postulated that cytotoxic T cells (CTLs) or natural killer (NK) cells can be infected by EBV during the killing of an EBV-infected target cell. The objective of this study was therefore to determine whether the neoplastic cells in EBV-positive T-NHLs (n=221) of various locations have a cytotoxic phenotype. To identify EBV-harbouring cells, combinations were used of EBV-encoded RNA (EBER) in situ hybridization (RISH) and immunohistochemistry for T- and B-cell markers and the cytotoxic proteins TIA-1 and granzyme B. EBV was detected in the neoplastic cells of all nasal T-NHLs (n=9), 5/34 gastrointestinal (GI) T-NHLs, and 2/6 lung T-NHLs, but not in primary cutaneous T-NHLs (n=103). Moreover, EBV was found in the neoplastic cells of 2/48 nodal anaplastic large cell lymphomas (ALCLs), but not in neoplastic T cells of other nodal T-NHLs. However, 5/17 nodal peripheral T-NHLs not otherwise specified (PTCLs NOS) and 1/4 T-prolymphocytic leukaemias did contain EBV-positive non-T cells. Double staining revealed that in EBV-positive extranodal T-NHLs (n=16), the EBER-positive cells had a cytotoxic phenotype (TIA-1- and/or granzyme B-positive). In nodal non-ALCL T-NHLs, the EBER-positive cells were not positive for TIA-1 or granzyme B, nor did they express CD3, CD21 or HECA452. Instead, most of these cells expressed the B-cell marker CD20. These PTCLs NOS with EBER-positive cells showed features of AILD-like T-NHL. It is concluded that neoplastic cells of EBV-positive extranodal T-NHLs always have a cytotoxic phenotype, supporting the view that EBV can infect CTLs. In nodal non-ALCL T-NHL, EBV is only found in T-NHL with AILD-like features and is present in B cells, where it may contribute to the outgrowth of a malignant B-cell clone.

Antigens, CD20↗

PubMed2000

The role of metalloproteinases and adhesion molecules in interleukin-8-induced stem-cell mobilization.

The chemokine interleukin-8 (IL-8) is a potent chemoattractant and activator of neutrophils. Upon systemic injection, IL-8 induces an immediate neutropenia followed by a rebound granulocytosis. In this report, we discuss the effects of IL-8 on the mobilization of hematopoietic stem cells. Within 20 minutes following a single intraperitoneal injection in mice, IL-8 induces the mobilization of hematopoietic progenitor cells (HPC) with colony-forming, radioprotective, and long-term lymphomyeloid resubpopulating ability. Mobilization can be specifically prevented by pretreatment with antibodies against the beta2 integrin LFA-1 (CD11a). In monkeys, IL-8 Induces the rapid release of the metalloproteinase gelatinase-B concurrent with the mobilization of HPC. The latter effect can be prevented by blocking gelatinase-B activity using specific monoclonal antibodies, suggesting the involvement of gelatinase-B as a mediator of HPC mobilization. These results are consistent with the hypothesis that neutrophils are major regulators of stem-cell mobilization through the release of metalloproteinases (MMPs) that cleave extracellular matrix molecules to which HPC are attached.

Animals↗

PubMed2000

The generation of dendritic-like cells with increased allostimulatory function from acute myeloid leukemia cells of various FAB subclasses.

To increase the immunogenicity of leukemic cells, attempts were made to generate dendritic-like antigen presenting cells (DC) from AML blasts from 14 patients with AML FAB classifications M0-M5. Leukemic cells were cultured in the presence or absence of various cytokines including GM-CSF, SCF, TNF-alpha, IL-4, and gamma-interferon. After various intervals recovery of viable cells was measured and expression of CD80, CD86, CD40, CD54, CD58, and CD11a was analyzed by flow cytometry. Functionally, DC derived from six AML samples were tested in a mixed lymphocyte response (MLR) using HLA-DR mismatched donor T cells as responder cells. Proliferation (5/14) or increased survival (7/14) of AML cells was observed in the presence of GM-CSF, SCF, and TNF-alpha. Only in the AML M2, M3, and M4 FAB subtypes proliferation was found. GM-CSF, SCF, and TNF-alpha induced morphologic changes typical for DC and increased the expression of costimulatory and adhesion molecules. No significant effect of IL-4 or gamma-interferon was observed. The day of maximal expression of these molecules varied. In cases with minor upregulation of CD80 or CD86, no further stimulation using CD40-L activation was observed. In the three cases tested, the DC-like cells retained the chromosomal abnormalities present in the original AML cells. In five out of six cases tested an increase in allostimulatory capacity was found at the day of maximal expression of costimulatory and adhesion molecules. In two patients a decrease in stimulatory capacity was found at day 7 compared with day 2 correlating with a decreased expression of these molecules. In conclusion, AML cells can be induced to increase their stimulatory capacity by upregulating costimulatory and adhesion molecules.

Acute Disease↗

PubMed2000

Expression and induction of costimulatory and adhesion molecules on acute myeloid leukemic cells: implications for adoptive immunotherapy.

OBJECTIVE: Previously, we observed an increased recognition of malignant cells by cytotoxic T lymphocytes (CTL) when the target cells were cultured in vitro for 24 hours. In this study, we analyzed the expression of costimulatory and adhesion molecules on acute myeloid leukemia (AML) cells and determined whether 24-hour culture of the cells was associated with upregulation of these molecules. We analyzed whether this incubation period improved recognition of AML cells by CTL. MATERIALS AND METHODS: Expression of costimulatory and adhesion molecules on leukemic blasts of 34 patients comprising each AML FAB subclassification were analyzed directly and after 24 hours of culture, and the recognition of these AML cells by an HLA-A2 restricted CTL clone was determined. Blocking studies were performed with antibodies against CD54, CD58, and CD11a. RESULTS: Immunophenotyping showed a low expression of CD80 and CD40 and a variable CD86 expression on most AML cells. CD54 expression was generally low, CD58 expression was high, and CD11a expression was variable, with a higher expression in AML M0, M1, M4, and M5. Twenty-four hours of culture resulted in a significant upregulation of CD40, CD54, and CD58. Impaired recognition of AML cells by the HLA-A2 restricted CTL clone was enhanced 100-200% by 24 hours of preincubation of the leukemic cells. Blocking studies showed the importance of multiple adhesion molecules on the AML cells. CONCLUSION: Low expression of multiple costimulatory and adhesion molecules on AML could be upregulated by 24 hours of culture, which was associated with increased recognition of the AML blasts by CTL. Blocking multiple adhesion molecules completely abolished CTL recognition, showing the importance of the combination of these molecules for T-cell interaction with AML.

Acute Disease↗

PubMed2000

Rationale of a new classification for the group of primary cutaneous lymphomas.

In the last decade many studies showed that primary cutaneous lymphomas have another clinical behavior and prognosis, and therefore require a different therapeutic approach, as compared with their primary nodal equivalents. Because, until recently, classification systems for non-Hodgkin's lymphomas were purely based on histologic criteria, and did not recognize the special character of these lymphomas, primary cutaneous lymphomas were not uncommonly diagnosed incorrectly and/or treated inappropriately with unnecessarily aggressive therapies. For that reason the Cutaneous Lymphoma Group of the European Organization for Research and Treatment of Cancer (EORTC) proposed a separate classification for the group of primary cutaneous lymphomas. This EORTC classification is consistently based on a combination of clinical, histologic, immunophenotypical and genetic criteria, and includes well-defined and recognizable disease entities. It contains a limited number of cutaneous T-cell lymphomas and cutaneous B-cell lymphomas, which together constitute more than 95% of all primary cutaneous lymphomas. Herein, the rationale and the basic principles of the EORTC classification are presented, and the relationship between the EORTC classification and other recent classification systems, such as the Revised European-American Classification for Lymphoid Neoplasms (REAL classification) and the proposed World Health Organization classification, are discussed.

Classification↗

PubMed2000

HLA-DR4 is associated with a diminished risk of the development of chronic myeloid leukemia (CML). Chronic Leukemia Working Party of the European Blood and Marrow Transplant Registry.

CML is characterized by the chromosomal translocation t(9;22) (q34;q11) resulting in the chimeric bcr-abl oncogene that encodes P210 fusion proteins with novel amino acid sequences in the breakpoint region. If these peptides derived from P210 are presented by HLA molecules on the cell membrane of leukemic cells an immunological response may occur. Recent studies using synthetic peptides identical to the bcr-abl fusion region revealed that some peptides are capable of binding to the class I molecules HLA-A2,-A3,-A11 and -B8 and the class II molecules HLA-DR1, -DR2, -DR3, -DR4 and -DR11. Moreover T cell responses have been induced against bcr-abl-derived synthetic peptides bound to some of these HLA molecules. For HLA class I, we have previously shown that individuals expressing HLA-A3 and -B8 have a diminished risk of development of CML. To assess a similar protective effect of class II molecules we performed a large multi-center study. This study compared the frequencies of HLA-DR1, -DR2, -DR3, -DR4 and -DR11 of patients with CML from the database of the EBMT (n = 1462) with unaffected individuals from the registry of Bone Marrow Donors Worldwide (n = 500 596). Patients and controls were matched per country. This analysis yielded significantly lower odds ratios (ORs) of 0.86 (95% CI 0.75-0.98) for HLA-DR3 and of 0.80 (95% CI 0.71-0.89) for HLA-DR4. The OR was 0.91 (95% CI 0.80-1.04) for HLA-DR1, 1.05 (95% CI 0.94-1.18) for HLA-DR2 and 0.87 (95% CI 0.74-1.01) for HLA-DR11. To assess a possible effect of the linkage disequilibrium between HLA-B8 and HLA-DR3 we found that coexpression of HLA-B8 and HLA-DR3 gave an OR of 0.84 (95% CI 0.72-0.98), whereas HLA-DR3 positive/HLA-B8 negative individuals showed an OR of 1.02 (95% CI 0.84-1.24). This means that the protective effect of HLA-DR3 of the development of CML was probably caused by its linkage disequilibrium with HLA-B8. In contrast, as there is no linkage disequilibrium of HLA-DR4 with HLA-A3 or HLA-B8, the results indicate that HLA-DR4 expression itself is associated with a diminished incidence of CML possibly by the presentation of bcr-abl breakpoint peptides in these HLA molecules on the membrane of the leukemic cells.

Bone Marrow Transplantation↗

PubMed2000

Mantle cell lymphoma proliferates upon IL-10 in the CD40 system.

Mantle cell lymphoma (MCL) is a B cell non-Hodgkin's lymphoma, characterized by a poor response to therapy and short survival. To assess the proliferative capacity, we cultured MCL cells, using irradiated 3T6 mouse fibroblasts transfected with human CD40L ('CD40 system') in the presence of different cytokines. Proliferation was measured by 3H-thymidine incorporation and by CFSE fluorescence. Thirteen out of 16 MCL cases proliferated well in the CD40 system. In 10 cases a strong response upon further addition of IL-10 was seen, whereas IL-4 had an additional effect in only four cases. CFSE staining of cells before and after culture showed an increased number of cell divisions in the IL-10/CD40L stimulated cells. The MCL cells remained CD5+CD19+. Neither plasma cell differentiation nor isotype switching was seen. The light chain expression was strictly monoclonal. IL-1beta, IL-2, IL-6, G-CSF and GM-CSF did not stimulate MCL proliferation. IL-10 receptor expression correlated with the response to IL-10 in the culture system and the effect of added IL-10 could be blocked by antibodies directed against IL-10 and the IL-10 receptor. Autocrine IL-10 production by the MCL cells was detected in eight of 10 cases tested. IL-10 receptor blocking decreased proliferation when no exogenous IL-10 was used in four of seven cases tested. EBV assessed by EBER in situ hybridization was not detected in six cases tested. In conclusion, MCL can successfully be cultured upon CD40 stimulation if 3T6 CD40L+ cells are used. In this context IL-10 is a costimulatory factor. IL-10 receptor expression seems to correlate with response to CD40 crosslinking and IL-10. Autocrine IL-10 production might play a role in the proliferation of this lymphoma. This culture system may be useful to test new treatment strategies for this, thus far, therapy-resistant lymphoma.

Animals↗

PubMed2000

A novel RT-PCR-based protein activity truncation assay for direct assessment of deoxycytidine kinase in small numbers of purified leukemic cells.

In vitro studies have demonstrated that deoxycytidine kinase (dCK) plays a crucial role in the mechanism of resistance to cytarabine (AraC). The resistant phenotype in vitro is always a result of mutational inactivation of dCK, leading to defects in the metabolic pathways of AraC. Although inactivation of dCK has shown to be one of the major mechanism of resistance to AraC in vitro, limited in vivo data are available. To improve research concerning the involvement of dCK inactivation in patients with acute myeloid leukemia (AML), we have set up a protocol that allows direct assessment of dCK expression and activity in primary human cells. In this protein activity truncation assay (PAT assay), the complete coding region of dCK is amplified by RT-PCR and a T7 RNA polymerase promoter sequence is introduced upstream of the coding region in a nested PCR reaction. After in vitro transcription-translation dCK proteins are analyzed for their molecular weight and phosphorylating capacities. We show that this relatively quick method can be used in purified, primary human leukemic blasts. In addition, inactivation of dCK by point mutations, deletions or genomic rearrangements can easily be detected in AraC-resistant cell lines. This novel assay may contribute to further elucidate the mechanism of AraC resistance in vivo.

Acute Disease↗

PubMed2000

Expression of Fas and Fas-ligand in primary cutaneous T-cell lymphoma (CTCL): association between lack of Fas expression and aggressive types of CTCL.

BACKGROUND: Fas (CD95; APO-1) is a transmembrane protein that mediates apoptosis upon cross-linking with Fas-ligand (Fas-L). Interaction of Fas-L expressed by cytotoxic T cells with Fas-expressing tumour cells plays an important part in antitumour immune responses. OBJECTIVES: We aimed to investigate Fas and Fas-L expression in frozen and paraffin-embedded material from a large group of patients with cutaneous T-cell lymphoma (CTCL). METHODS: Immunostaining with monoclonal antibodies against Fas and Fas-L was performed in material from 23 patients with mycosis fungoides (MF), 10 with lymphomatoid papulosis (LyP), 10 with CD30-positive primary cutaneous large T-cell lymphoma (LTCL) and nine with CD30-negative LTCL. The results were correlated with the type and stage of CTCL and clinical features. RESULTS: Expression of Fas by the large majority of the neoplastic T cells was observed in 15 of 15 cases of plaque-stage MF, 10 of 10 cases of LyP and 10 of 10 cases of CD30-positive LTCL, but only in four of 12 cases of tumour-stage MF and two of nine cases of CD30-negative LTCL. In three of four MF patients in whom both plaques and tumours could be studied, a significant decrease in Fas expression was observed with progression from plaque-stage to tumour-stage disease. Fas-L was expressed by > 50% of the neoplastic T cells in 46 of 56 biopsies, and no clear relationship with type of CTCL and clinical behaviour was observed. CONCLUSIONS: This study demonstrates loss of Fas expression in aggressive types of CTCL, but not in indolent types of CTCL. These data suggest that loss of Fas receptor expression may be one of the mechanisms that allow tumour cells to escape an effective immune response, and may contribute to the unfavourable prognosis of some types of CTCL.

Antigens, Neoplasm↗

PubMed2000

Primary cutaneous lymphomas.

Primary cutaneous lymphomas have a distinct clinical behavior and prognosis, and therefore require a different therapeutic approach, as compared with their primary nodal equivalents. The European Organization for Research and Treatment of Cancer (EORTC) classification for primary cutaneous lymphomas recognizes a limited number of cutaneous T-cell lymphomas and cutaneous B-cell lymphomas and is at present the best guide to optimal management and treatment of these conditions. Herein, the relationship between the EORTC classification and the recently published World Health Organization classification is discussed, and recent developments regarding the main types of cutaneous T-cell lymphomas and cutaneous B-cell lymphomas recognized in the EORTC classification are presented.

Humans↗

PubMed2000

ALK expression in extranodal anaplastic large cell lymphoma favours systemic disease with (primary) nodal involvement and a good prognosis and occurs before dissemination.

AIMS: In anaplastic large cell lymphoma (ALCL), the site of origin has been described as an important prognostic factor. Recently, a fusion protein containing anaplastic lymphoma kinase (ALK) was described in systemic nodal ALCL, and shown to be associated with a good prognosis. The aims of this study were to investigate whether the presence of ALK protein differs between ALCL of different sites of origin; to determine whether ALK expression occurs before dissemination to other sites; and, finally, to investigate whether the site of origin remains a prognostic parameter in ALK negative ALCL. METHODS: ALK expression, as detected by immunohistochemistry using the monoclonal antibodies ALK1 and ALKc, was studied in 85 ALCLs from different sites of origin. In 22 patients, ALK expression was studied in multiple biopsies from different sites (including 13 skin, 16 lymph node, and nine other). Overall survival time was analysed using the Kaplan Meier method. RESULTS: ALK expression was found in 20 of 51 systemic ALCLs with (primary) nodal involvement. No ALK expression was found in 15 primary cutaneous, 14 gastrointestinal, and five nasal ALCLs. Multiple and subsequent biopsies of patients showed ALK expression to be identical to that seen in the primary diagnostic biopsy. Kaplan Meier survival curves showed that in ALK negative ALCLs originating from different sites, primary cutaneous cases are associated with an excellent overall survival, whereas the other cases show a comparable five years survival of less than 40%. CONCLUSIONS: If present, ALK expression favours systemic ALCL with (primary) nodal involvement, and can be used in differentiating between extranodal involvement of systemic (nodal) ALCL and primary extranodal ALCL. ALK is expressed consistently in multiple biopsies of a given patient, indicating that the chromosomal abnormality leading to aberrant ALK expression occurs before dissemination to other sites. Finally, in ALK negative non-cutaneous ALCLs, different sites of origin show comparable poor survival.

Adolescent↗

PubMed2000

EORTC classification for primary cutaneous lymphomas: a comparison with the R.E.A.L. Classification and the proposed WHO Classification.

Primary cutaneous lymphomas differ significantly from their nodal equivalents in clinical behaviour and prognosis, and often require a different therapeutic approach. Since currently used classification systems for non-Hodgkin lymphomas do not or insufficiently recognize the special character of these lymphomas, primary cutaneous lymphomas are not uncommonly diagnosed incorrectly, and/or treated inappropriately with unnecessarily aggressive therapies. For that reason the Cutaneous Lymphoma Group of the European Organization for Research and Treatment of Cancer (EORTC) has recently proposed a separate classification for the group of primary cutaneous lymphomas. The EORTC Classification is consistently based on a combination of clinical, histological, immunophenotypical and genetic criteria, and includes well-defined and recognizable disease entities. It contains a limited number of cutaneous T-cell lymphomas and cutaneous B-cell lymphomas, which comprise more than 95% of all primary cutaneous lymphomas. The clinical significance of this classification has been validated by long-term follow-up data of more than 800 patients with a primary cutaneous lymphoma. The basic principles of the EORTC Classification will be presented, and current controversies between the EORTC Classification on the one hand, and the R.E.A.L. Classification and the proposed WHO Classification on the other will be discussed.

Europe↗