[Angio-oedema and urticaria as side effects of frequently used drugs]. / Angio-oedeem en urticaria bij frequent gebruikte geneesmiddelen.

Angio-oedema and urticaria can be symptoms of both allergic (IgE-mediated) and non-allergic drug hypersensitivity reactions. Non-allergic drug reactions, that may have a similar clinical presentation as allergic drug reactions, are not caused by an IgE-mediated immune mechanism. Because of unfamiliarity with non-allergic drug reactions and the unclear time course between drug use and reactions, the relationship with the responsible drug is often not recognized, leading to unnecessary patient risks. In the present article three patients with angio-oedema and urticaria as side effects of frequently used drugs (ACE-inhibitors, NSAIDs and betalactams) are presented and discussed. Patient A was a 69-year-old man with ACE-inhibitor induced angio-oedema. Patient B was a 40-year-old woman with urticaria and angio-oedema after ingestion of a NSAID caused by a non-allergic drug reaction. Patient C was a 54-year-old woman who developed an anaphylactic shock because of a type I allergy to betalactams.

Results of radiotherapy in 153 primary cutaneous B-Cell lymphomas classified according to the WHO-EORTC classification.

OBJECTIVE: To evaluate the results of radiotherapy in patients with primary cutaneous B-cell lymphoma (CBCL) classified according to the criteria of the World Health Organization-European Organization for Research and Treatment of Cancer (WHO-EORTC) classification. DESIGN: Multicenter, 20-year, retrospective, cohort analysis. SETTING: Eight dermatology departments collaborating in the Dutch Cutaneous Lymphoma Group. PATIENTS: From 1985 until 2005, a total of 153 patients with CBCL were initially treated with radiotherapy with curative intent. These cases were classified according to the WHO-EORTC classification and consisted of 25 primary cutaneous marginal zone lymphomas (PCMZLs), 101 primary cutaneous follicle center lymphomas (PCFCLs), and 27 primary cutaneous large B-cell lymphomas, leg type (PCLBCLs, LT). Interventions Local radiotherapy with a median dose of 40 Gy (range, 20-46 Gy) applied to all visible skin lesions. MAIN OUTCOME MEASURES: Complete remission rate, relapse rate, 5-year relapse-free survival, 5-year overall survival, and 5-year disease-specific survival. RESULTS: Complete remission was reached in 151 of 153 patients (99%). Relapse rates for PCMZL, PCFCL, and PCLBCL, LT were 60%, 29%, and 64%, and the 5-year disease-specific survival was 95%, 97%, and 59%, respectively. The PCFCLs presenting on the legs had a higher relapse rate (63%) and a much lower 5-year disease-specific survival (44%) than PCFCLs at other sites (relapse rate, 25%; 5-year disease-specific survival, 99%). CONCLUSIONS: Radiotherapy is a suitable treatment for a large group of patients with CBCL. However, patients with PCFCL presenting with lesions on the leg and patients with PCLBCL, LT display a more unfavorable clinical course and should therefore be treated with more aggressive treatment modalities.

Reclassification of 300 primary cutaneous B-Cell lymphomas according to the new WHO-EORTC classification for cutaneous lymphomas: comparison with previous classifications and identification of prognostic markers.

PURPOSE: In the new WHO-European Organisation for Research and Treatment of Cancer (WHO-EORTC) classification for cutaneous lymphomas three major groups of primary cutaneous B-cell lymphoma (CBCL) are distinguished: primary cutaneous marginal zone B-cell lymphoma (PCMZL) and primary cutaneous follicle center lymphoma (PCFCL) with a good prognosis, and primary cutaneous large B-cell lymphoma, leg type (PCLBCL-LT), with an intermediate-level prognosis. This study aimed to assess the clinical significance of the new classification compared with previous classification schemes (EORTC 1997; WHO 2001) and to define prognostic factors within the newly defined categories. PATIENTS AND METHODS: In the present study clinical data and histologic sections of 300 patients with CBCL, formerly classified according to the EORTC classification, were reviewed and reclassified according to the WHO and the new WHO-EORTC classification schemes. RESULTS: After reclassification, the study comprised 71 patients with PCMZL, 171 patients with PCFCL, and 58 patients with PCLBCL-LT, showing 5-year disease-specific survivals of 98%, 95%, and 50%, respectively. When compared with the EORTC and WHO schemes, 5.3% and 36.3% of patients with CBCL were reclassified into another prognostic category. Multivariate analysis of PCFCL revealed localization on the leg and expression of FOXP1 as independent parameters associated with a poor prognosis. Expression of Bcl-2 or MUM-1 had no significant effect on survival in this group. In PCLBCL-LT, no independent prognostic parameters were found. CONCLUSION: These results emphasize the clinical significance of the WHO-EORTC classification, but suggest that within the group of PCFCL, distinction should be made between lymphomas presenting on the legs and lymphomas presenting at other sites.

Array-based comparative genomic hybridization analysis reveals recurrent chromosomal alterations and prognostic parameters in primary cutaneous large B-cell lymphoma.

PURPOSE: To evaluate the clinical relevance of genomic aberrations in primary cutaneous large B-cell lymphoma (PCLBCL). PATIENTS AND METHODS: Skin biopsy samples of 31 patients with a PCLBCL classified as either primary cutaneous follicle center lymphoma (PCFCL; n = 19) or PCLBCL, leg type (n = 12), according to the WHO-European Organisation for Research and Treatment of Cancer (EORTC) classification, were investigated using array-based comparative genomic hybridization, fluorescence in situ hybridization (FISH), and examination of promoter hypermethylation. RESULTS: The most recurrent alterations in PCFCL were high-level DNA amplifications at 2p16.1 (63%) and deletion of chromosome 14q32.33 (68%). FISH analysis confirmed c-REL amplification in patients with gains at 2p16.1. In PCLBCL, leg type, most prominent aberrations were a high-level DNA amplification of 18q21.31-q21.33 (67%), including the BCL-2 and MALT1 genes as confirmed by FISH, and deletions of a small region within 9p21.3 containing the CDKN2A, CDKN2B, and NSG-x genes. Homozygous deletion of 9p21.3 was detected in five of 12 patients with PCLBCL, leg type, but in zero of 19 patients with PCFCL. Complete methylation of the promoter region of the CDKN2A gene was demonstrated in one PCLBCL, leg type, patient with hemizygous deletion, in one patient without deletion, but in zero of 19 patients with PCFCL. Seven of seven PCLBCL, leg type, patients with deletion of 9p21.3 and/or complete methylation of CDKN2A died as a result of their lymphoma. CONCLUSION: Our results demonstrate prominent differences in chromosomal alterations between PCFCL and PCLBCL, leg type, that support their classification as separate entities within the WHO-EORTC scheme. Inactivation of CDKN2A by either deletion or methylation of its promoter could be an important prognostic parameter for the group of PCLBCL, leg type.

Expression of B-cell transcription factors in primary cutaneous B-cell lymphoma.

Expression patterns of eight transcription factors involved in different stages of B-cell development were investigated in a large group of primary cutaneous B-cell lymphomas and compared with expression patterns during normal B-cell development. The following transcription factors were investigated: Pax-5, PU.1, Oct2, BOB.1, Bcl-6, Mum1/IRF4, Blimp-1 and FOXP1. Primary cutaneous large B-cell lymphomas, leg type showed aberrant coexpression of Bcl-6 and Mum1/IRF4 and in addition strong expression of FOXP1. Expression of FOXP1 and Mum1/IRF4 strongly suggests an activated B-cell type of origin. In contrast, primary cutaneous follicle center lymphomas showed expression of Bcl-6, Pax-5, PU.1, Oct2 and BOB.1, but not of Mum1/IRF4, Blimp-1 and FOXP1. Primary cutaneous marginal zone B-cell lymphoma showed expression of Pax-5, PU.1, Oct2 and BOB.1, but not Bcl-6 by the neoplastic B-cells, and Mum1/IRF4 and Blimp-1 by the neoplastic plasma cells. In conclusion, in primary cutaneous follicle center lymphoma and primary cutaneous marginal zone B-cell lymphoma expression patterns were observed similar to their supposed benign counterparts, germinal center B-cells and postgerminal center B-cells, respectively, which might reflect their indolent clinical behaviour and excellent prognosis. In contrast, the activated B-cell expression pattern in the group of primary cutaneous large B-cell lymphoma, leg type may contribute to its poor prognosis and Mum1/IRF4 and FOXP1 may serve as additional diagnostic markers for this type of primary cutaneous B-cell lymphoma.

Distinct types of primary cutaneous large B-cell lymphoma identified by gene expression profiling.

In the European Organization for Research and Treatment of Cancer (EORTC) classification 2 types of primary cutaneous large B-cell lymphoma (PCLBCL) are distinguished: primary cutaneous follicle center cell lymphomas (PCFCCL) and PCLBCL of the leg (PCLBCL-leg). Distinction between both groups is considered important because of differences in prognosis (5-year survival > 95% and 52%, respectively) and the first choice of treatment (radiotherapy or systemic chemotherapy, respectively), but is not generally accepted. To establish a molecular basis for this subdivision in the EORTC classification, we investigated the gene expression profiles of 21 PCLBCLs by oligonucleotide microarray analysis. Hierarchical clustering based on a B-cell signature (7450 genes) classified PCLBCL into 2 distinct subgroups consisting of, respectively, 8 PCFCCLs and 13 PCLBCLsleg. PCLBCLs-leg showed increased expression of genes associated with cell proliferation; the proto-oncogenes Pim-1, Pim-2, and c-Myc; and the transcription factors Mum1/IRF4 and Oct-2. In the group of PCFCCL high expression of SPINK2 was observed. Further analysis suggested that PCFCCLs and PCLBCLs-leg have expression profiles similar to that of germinal center B-cell-like and activated B-cell-like diffuse large B-cell lymphoma, respectively. The results of this study suggest that different pathogenetic mechanisms are involved in the development of PCFCCLs and PCLBCLs-leg and provide molecular support for the subdivision used in the EORTC classification.