[Cutaneous leishmaniasis in Germany-still a travel-related disease]. / Kutane Leishmaniasis in Deutschland ­ Weiterhin eine Reisedermatose.

Cutaneous leishmaniasis is an infectious disease caused by several Leishmania species. It is transmitted to humans by the bite of the infected female phlebotomus sandfly. Today, more than 1 billion people in leishmaniasis endemic areas are at risk of infection. More than 1.5 million new cases of cutaneous leishmaniasis occur every year. On the basis of two cases, we show that cutaneous leishmaniasis is still an imported tropical disease in Germany. However, due to the increasing intercontinental travel, cases may increase. Therefore, cutaneous leishmaniasis should be considered in the differential diagnosis in patients with nonhealing wounds, ulcers, papules or nodules and the corresponding travel history.

Prevalence of genetically defined tumor cells in CD7 as well as CD26 positive and negative circulating T-cell subsets in Sézary syndrome.

For diagnosis and monitoring of Sézary syndrome flow cytometric quantification of CD7- and CD26- T-cells is widely used. Because antigen loss is a characteristic but not disease-specific finding we investigated the significance of this approach. Therefore we analyzed the prevalence of tumor cells in FACS-sorted CD7+/- as well as CD26+/- circulating T-cells applying a clone-specific qualitative and quantitative T-cell receptor PCR. Tumor cells varied considerably in the CD7+ and CD7- cell subset but were largely confined to the CD26- population. We conclude that quantification of CD26- T-cells reflects the tumor cell amount more accurate and should be preferred in the clinical setting.

Hepatosplenic T-cell lymphomas and therapy with TNF-alpha-blocking biologics: a risk for psoriasis patients?

Tumor necrosis factor (TNF)-alpha antagonists have considerably improved the therapeutic approach to chronic inflammatory disorders including psoriasis vulgaris. Recently, some cases of highly aggressive hepatosplenic T-cell lymphoma (HSTCL) have developed in patients with inflammatory bowel diseases (IBD) being treated with infliximab or adalimumab. Analysis of the published data suggests that the emergence of HSTCL is favored by the combination of purine analogues and infliximab or adalimumab in the therapy of a granulomatous inflammation involving Vdelta1(+)gammadelta T cells. Because psoriasis vulgaris is different from IBD in regard to the type of inflammation, the concomitant therapies used and the tissue-specific subsets of gammadelta T cells, the use of infliximab or adalimumab in psoriasis may not necessarily be associated with an increase in the risk of HSTCL.

Emerging drugs in cutaneous T cell lymphoma.

BACKGROUND: Mycosis fungoides (MF) represents the most common type of primary cutaneous T cell-lymphomas (CTCL), which are characterized by a clonally proliferation of malignant CD4+ lymphocytes in the skin. OBJECTIVE: Skin-directed treatment regimens, like phototherapy and corticosteroids, are commonly used in early stages; systemic treatments and chemotherapies are used in advanced stages. Because conventional treatments usually end in a transient remission without curative results, there is a high need for new therapeutic strategies with acceptable side effects. METHODS: Literature and reference research was done by using the data bank PubMed, and updates of ongoing studies were taken out of ASCO and ASH annual meeting abstracts. RESULTS/CONCLUSIONS: This article gives an overview of the various medications in current use, with emphasis on emerging drugs with novel therapeutic targets.

Complete clinical remission of tumor-stage mycosis fungoides after acute extensive skin necroses, granulomatous reaction, and fever under treatment with bexarotene, vorinostat, and high-dose fenofibrate.

Mycosis fungoides and its variants are a distinct entity with a variable, but well-characterized clinical course. We report on a 51-year-old patient with tumor-stage mycosis fungoides who developed several unusual features such as extensive necrosis of lymphoma lesions, granulomatous reaction, and venular thromboses while under treatment with bexarotene, vorinostat, and high-dose fenofibrate. After surgical removal of skin necroses, the patient recovered and was in complete clinical remission. Possible causal factors such as blastic transformation; hematophagic syndrome; or bacterial, fungal, or viral infection could be excluded. We hypothesize that combination of the high-dose fenofibrate (400 mg) with the retinoid X receptor ligand bexarotene and vorinostat might have induced an increased rate of apoptosis in lymphoma cells in our patient resulting in an extensive release of lymphoma antigens. Augmented antigen release along with changes in local cytokine milieu might have induced macrophage activation and granuloma formation.

Cutaneous lymphomas in Germany: an analysis of the Central Cutaneous Lymphoma Registry of the German Society of Dermatology (DDG).

BACKGROUND: Primary cutaneous lymphomas form a heterogeneous group of lymphatic neoplasias. They manifest themselves on the skin and are the second most frequent group of non-Hodgkin lymphoma (NHL) following gastrointestinal lymphomas. The number of epidemiologic studies is small due to limited availability and limited comparability on population-based data. PATIENTS AND METHODS: In the present study the first evaluation of the German Central Registry for Cutaneous Lymphomas (ZRKL) of the German Society of Dermatology (DDG) is undertaken on the basis of 998 patients. The epidemiology of cutaneous lymphomas in Germany is compared to other national or regional lymphoma registries. RESULTS: Based on the registration of 998 patients from 26 clinics in Germany,a clear predominance of cutaneous T-cell lymphomas (85 %) in comparison to cutaneous B-cell lymphomas (14 %) is seen. The most frequent representative of CTCL is mycosis fungoides,composing 62 % of cases with a slight predominance of men (M:F = 1.6:1). Differences are also seen in stage of the disease at first presentation of patients with cutaneous lymphomas.While, for example, 80 % of patients with mycosis fungoides in Germany present in early stages (I-IIA),in the USA 34 % of patients are in the tumor stage or have organ involvement at presentation. CONCLUSIONS: The ZRKL of the DDG for the first time presents epidemiologic data from Germany, allowing comparison with other nations for the study of etio-logical factors and socioeconomic influences. Further, the ZRKL supports the development of uniform and quality-oriented diagnostic criteria and therapeutic options. Finally, the ZRKL provides a foundation for future intensive study of clinical and scientific questions regarding cutaneous T- and B-cell lymphomas.

Vorinostat combined with bexarotene for treatment of cutaneous T-cell lymphoma: in vitro and phase I clinical evidence supporting augmentation of retinoic acid receptor/retinoid X receptor activation by histone deacetylase inhibition.

The retinoid X receptor (RXR)-agonist bexarotene and the histone deacetylase inhibitor (HDACI) vorinostat are each established monotherapies for cutaneous T-cell lymphomas (CTCLs). We investigated the combination of HDACI and retinoic acid receptor (RAR)/RXR agonists in vitro and in a phase I, multicenter, open-label, two-part dose-escalation study. The combination of bexarotene with a HDACI in vitro leads to cooperative activation of gene transcription and reduction of cell viability in human tumor cell lines. The primary clinical objective was to determine the maximum tolerated dose (MTD) of bexarotene plus vorinostat in 23 patients with CTCLs. The MTD for part I was established at vorinostat 200 mg/day plus bexarotene 300 mg/m(2)/day. The MTD for part II was not reached. Four patients had an objective response and seven patients experienced pruritus relief. We conclude that concomitant administration of vorinostat and bexarotene is feasible only if lower doses of each drug are administered relative to the product label monotherapy doses.

Evaluation of T-cell clonality in archival skin biopsy samples of cutaneous T-cell lymphomas using the biomed-2 PCR protocol.

Recently, several European centers of lymphoma diagnosis and research developed various polymerase chain reaction (PCR) methods for clonality analysis in suspect T-cell and B-cell proliferations (Biomed-2 Concerted Action). They have mainly been applied to frozen material of systemic B-cell and T-cell malignancies. Thus far, only limited data exist with regard to cutaneous T-cell lymphoma (CTCL) and paraffin-embedded material. Thus, we applied the Biomed-2 T-cell receptor (TCR) gamma and TCRbeta PCR as well as an in-house TCRgamma PCR to a collection of 107 archival skin samples (84 CTCL, 3 systemic TCL and 20 controls). As a result, the Biomed-2 TCRgamma PCR revealed 81% clonality, the in-house TCRgamma method revealed 86% clonality, and the Biomed-2 TCRbeta revealed 78% clonality in CTCL samples generating at least the 300 bp fragment in the Biomed-2 control PCR. We found clonal TCRbeta rearrangements in 5 of 17 CTCL samples that were polyclonal in the Biomed-2 TCRgamma PCR. By combining all Biomed-2 assays, one or more clonal rearrangements were detected in 87% of CTCL and in all 3 systemic TCLs. By combining all TCR PCR assays applied here, clonality was shown in 90% of the CTCL cases. In conclusion, we showed that the Biomed-2 TCR PCR worked well with DNA from paraffin-embedded tissue, revealing a high-clonality detection rate in CTCL, and thus should be highly recommended for routine molecular analysis. In addition, the performance of our in-house TCRgamma assay verifies our previously published findings on clonally expanded T-cells in CTCL.

Dominance of nonmalignant T-cell clones and distortion of the TCR repertoire in the peripheral blood of patients with cutaneous CD30+ lymphoproliferative disorders.

The CD30-positive cutaneous lymphoproliferative disorders (CLPD) include lymphomatoid papulosis (LyP) and primary cutaneous anaplastic large T-cell lymphoma (cALCL). Despite the malign-appearing histology, an excellent prognosis and spontaneous regression of single lesions characterize LyP. Even after years of clinical remission newly erupting lesions often harbor a T-cell clone identical to the initial one. This fact raises the question whether the clonal T-cell population persists in the peripheral blood. Therefore we investigated genomic DNA of 126 samples of lesional skin and peripheral blood from 31 patients with CLPD, obtained during both active disease and clinical remission. We performed molecular genetic analysis by combining T-cell receptor (TCR)-gamma PCR with the GeneScan technique and assessed the TCR repertoire in selected blood samples by beta-variable complementarity-determining region 3 (CDR3) spectratyping qualitatively and quantitatively. We were able to detect a clonal T-cell population in 36/43 (84%) skin samples and in 35/83 (42%) blood samples. Comparison of the compartments in each patient demonstrated different T-cell clones in skin and blood, suggesting a reactive nature of the clonal T cells in the blood. Moreover, CDR3 spectratyping revealed a restricted T-cell repertoire in the blood, suggesting T-cell stimulation by an unknown antigen.

Zanolimumab, a human monoclonal antibody targeting CD4 in the treatment of mycosis fungoides and Sézary syndrome.

BACKGROUND: The most common type of primary cutaneous T cell-lymphomas (CTCLs), which are characterised by a clonal proliferation of malignant skin-homing CD4(+) lymphocytes, is mycosis fungoides (MF) and its rare leukaemic variant Sézary syndrome (SS). OBJECTIVE: Zanolimumab is a high affinity human monoclonal IgG1k antibody, targeting the CD4-molecule. It exhibits cytotoxic and antiproliferative effects and has previously shown efficacy in CTCLs. METHODS: Literature and reference research was done by using Pubmed and updates of ongoing studies were taken from American Society of Clinical Oncology (ASCO) and American Society of Hematology (ASH )annual meeting abstracts. RESULTS: This article gives an overview about efficacy, tolerability and safety as well as chemistry, pharmacodynamics and pharmacokinetics of zanolimumab in the treatment of CTCLs.

Yttrium-90 ibritumomab tiuxetan radioimmunotherapy in primary cutaneous B-cell lymphomas: first results of a prospective, monocentre study.

Radioimmunotherapy with Yttrium-90 ((90)Y) ibritumomab tiuxetan (IT) has been shown to be effective in systemic B-cell lymphomas. We conducted a pilot study to evaluate the outcome and assess complications of (90)Y IT therapy in patients with primary cutaneous B-cell lymphomas (PCBCL). Ten patients, all but one, with relapsed PCBCL were included and treated with rituximab (250 mg m(-2)/body surface) on days 1 and 8 followed by a single dose of (90)Y IT (11-15 MBq kg(-1)). The overall response rate was 100%. The complete response rate was 100%. The median time to relapse was 12 months. Ongoing remissions were achieved in four patients (median follow-up 19 months). Transient and reversible myelosuppression (grade 3-4) was the most frequent adverse event. Radioimmunotherapy with (90)Y IT is an effective treatment in relapsed primary cutaneous follicle centre lymphomas and diffuse large B-cell lymphoma leg-type. Further investigations in controlled randomised clinical trials evaluating the role of (90)Y IT versus rituximab in PCBCL are needed.

Early TCR-beta and TCR-gamma PCR detection of T-cell clonality indicates minimal tumor disease in lymph nodes of cutaneous T-cell lymphoma: diagnostic and prognostic implications.

The lymph nodes are generally the first extracutaneous manifestation in patients with cutaneous T-cell lymphoma (CTCL); however, their early involvement is difficult to assess. The aim of our study was to define the diagnostic and prognostic value of T-cell clonality analysis for a more precise assessment of lymph node involvement in CTCL. T-cell clonality was determined by 2 independent polymerase chain reaction (PCR) assays, namely a recently developed T-cell receptor-beta (TCR-beta) PCR technique as well as an established TCR-gamma PCR. T-cell clonality was found in 22 of 22 lymph nodes with histologically detectable CTCL involvement as well as in 7 of 14 histologically noninvolved dermatopathic lymph nodes. The clonal T-cell populations in the lymph nodes were in all cases identical to those detected in the corresponding skin lesions, identifying them as the tumor cell population. T-cell clonality was not found in any of the 12 dermatopathic lymph nodes from 12 patients with inflammatory skin diseases. Clonal T-cell detection in 7 of 14 dermatopathic lymph nodes of patients with CTCL was associated with limited survival (74 months; confidence interval [CI], 66-82 months) as in patients with histologically confirmed lymph node involvement (41 months; CI, 35-47 months), whereas all patients without T-cell clonality in the lymph nodes (7 patients) were alive at the last follow-up. Thus, T-cell clonality analysis is an important adjunct in differentiating benign dermatopathic lymphadenitis from early CTCL involvement.

Familial aquagenic urticaria associated with familial lactose intolerance.

Aquagenic urticaria is a rare disorder characterized by the occurrence of pruritus and wheals after temporary contact with water. The familial occurrence of aquagenic urticaria over 3 generations is reported here in association with familial lactose intolerance, a condition in which the enzyme lactase encoded on chromosome 2, is deficient. In two patients, a young man and his mother, we verified the appearance of pruritic hives 5 to 10 minutes after contact with water of any temperature. Other types of physical urticaria were absent, and mastocytosis was excluded by extensive laboratory investigations; lactose intolerance was confirmed in both patients by H(2)-exhalation test. In these patients the clinical symptoms did not respond to antihistamines or UV-radiation therapy. Four other members of the family had wheals from water contact, two of whom had lactose intolerance. Two other members had lactose intolerance only. Although the association of aquagenic urticaria with lactose intolerance may be coincidental, attention is drawn to the fact that the 2 conditions, known to be familial, may coexist in the same family, possibly based on an association of gene loci.

[Temporary tattooing with henna induces contact allergy to textile dyes]. / Temporäre Tätowierung mit Henna induziert Kontaktallergie auf Textilfarbstoffe.

A woman developed widespread contact dermatitis after temporary tattooing with henna, caused by paraphenylenediamine (PPD) which had been added to the henna as an enhancer. The patient recovered after treatment; a week later an acute generalized rebound occurred after she wore dark clothing (black chador). Patch tests revealed type-IV allergy to PPD, along with multiple sensitisations to other textile dyes (disperse orange 3, para-aminoazobenzole, Bismark brown R). Temporary henna tattoos are not always harmless holiday souvenirs. The addition of color enhancers such as PPD into henna may lead to multiple contact allergies to other textile dyes.

Single-cell analysis of CD30+ cells in lymphomatoid papulosis demonstrates a common clonal T-cell origin.

Lymphomatoid papulosis (LyP) represents an intriguing cutaneous T-cell lymphoproliferative disorder with a histologic appearance resembling malignant lymphoma. This finding strongly contrasts with the benign clinical course of the disease. However, in 10% to 20% of cases, LyP can precede, coexist with, or follow malignant lymphoma. In these cases, the same T-cell population has been shown to be present in the LyP as well as in the associated lymphoma. In most LyP cases, there is-despite the sometimes extremely long course of the disease-no evolution of a secondary lymphoma. The investigation of these uncomplicated LyP cases for the presence of clonal T-cell receptor rearrangements has produced heterogeneous results. This might be explained by biologic or technical reasons arising from analyzing whole tissue DNA extracts. To definitively clarify whether the large atypical CD30(+) cells in LyP without associated lymphoma all belong to the same clone or represent individually rearranged T cells, we analyzed the T-cell receptor-gamma rearrangements of single CD30+ as well as of single CD30- cells isolated from 14 LyP lesions of 11 patients. By using this approach we could demonstrate that the CD30+ cells represent members of a single T-cell clone in all LyP cases. Moreover, in 3 patients the same CD30+ cell clone was found in anatomically and temporally separate lesions. In contrast, with only a few exceptions, the CD30- cells were polyclonal in all instances and unrelated to the CD30+ cell clone. Our results demonstrate that LyP unequivocally represents a monoclonal T-cell disorder of CD30+ cells in all instances.