Recent detailed genomic analysis of mycosis fungoides (MF) identified suppressor of cytokine signaling 1 (SOCS1), an inhibitor of JAK/STAT signaling, as one of the frequently deleted tumor...Show moreRecent detailed genomic analysis of mycosis fungoides (MF) identified suppressor of cytokine signaling 1 (SOCS1), an inhibitor of JAK/STAT signaling, as one of the frequently deleted tumor suppressors in MF, and one-copy deletion of SOCS1 was confirmed in early-stage MF lesions. To better understand the functional role of SOCS1 in the genesis of MF, we used a genetically engineered mouse model emulating heterozygous SOCS1 loss in skin resident CD4+ T cells. In these mice an experimentally induced contact-allergic reaction was maintained for 20 weeks. Ten weeks after discontinuing contact-allergic challenges, only the skin with locally one-copy deletion of Socs1 in CD4+ T cells still showed high numbers of CD3+/CD4+ Socs1 k.o. cells in the dermis (p ＜ 0.0001) with prevalent Stat3 activation (p ＜0.001). And in one out of 9 mice, this had progressed to far more dramatic increases, including the thickened epidermis, and with an explosive growth of Socs1 k.o. T cells in circulation; indicative of cutaneous lymphoma. Hence, we show that Socs1 mono-allelic loss in CD4+ T cells locally in protractedly inflamed skin results in autonomous skin inflammation with features of early-stage MF. Show less
Purpose: Total skin electron beam therapy (TSEBT) is used mostly in the treatment of cutaneous T cell lymphoma. In this study we describe the results of TSEBT applied in the Netherlands using two... Show morePurpose: Total skin electron beam therapy (TSEBT) is used mostly in the treatment of cutaneous T cell lymphoma. In this study we describe the results of TSEBT applied in the Netherlands using two different schedules, a conventional dose schedule of 35 Gy and a low-dose schedule of 12 Gy. We aimed to evaluate the treatment results in and compare treatment outcomes between the two treatment groups and to further define indications for both doses.Methods: In the LUMC, Leiden, we performed a retrospective analysis of 51 patients treated with TSEBT between January 2008 and December 2018, with follow-up untill December 2019. Thirty one patients were treated with 35 Gy and twenty with 12 Gy. The dose was chosen based on the severity of skin involvement. Outcome measures were time to meaningful progression, survival, response rate and toxicity.Results: Time to meaningful progression was 5.1 months with no significant differences between dose groups (P = 0.77). Overall survival was 27.4 months. Both time to progression and survival were significantly better for T2 vs T3 stage. Overall response rate was 80.4 %. Both dose groups showed improvement of symptoms. Treatment was generally well tolerated.Conclusions: Both high-dose and low-dose TSEBT offer similar results for TMP and OS. It remains unclear which patients benefit most from a high-dose schedule. We propose to use the low-dose schedule as a standard for TSEBT and use supplementary boosts or escalation to high-dose treatment for patients unresponsive to the low-dose schedule. Show less
Musiek, A.C.M.; Rieger, K.E.; Bagot, M.; Choi, J.N.; Fisher, D.C.; Guitart, J.; ... ; Kim, Y.H. 2021
The CCR4-directed monoclonal antibody mogamulizumab has been shown to significantly improve progression-free survival and overall response rate compared with vorinostat in adults with relapsed... Show moreThe CCR4-directed monoclonal antibody mogamulizumab has been shown to significantly improve progression-free survival and overall response rate compared with vorinostat in adults with relapsed/refractory mycosis fungoides (MF) and Sezary syndrome (SS). One of the most common adverse events seen with mogamulizumab in MF/SS patients is rash. Because of the protean nature of MF/SS and the variable clinical and histopathological features of mogamulizumab-associated rash, healthcare providers may have difficulty distinguishing rash from disease, and may not be aware of appropriate treatment strategies for this generally manageable adverse event. The objective of this report was to combine results from published literature with experiences and recommendations from multiple investigators and institutions into clinical best practice recommendations to assist healthcare providers in identifying and managing mogamulizumab-associated rash. Optimal management, which includes biopsy confirmation and steroid treatment, requires a multidisciplinary approach among oncology, dermatology, and pathology practitioners. Show less
Folliculotropic mycosis fungoides (FMF) is a distinct variant of mycosis fungoides (MF), the most prevalent type of cutaneous T cell lymphoma. FMF accounts for approximately 10% of all MF cases and... Show moreFolliculotropic mycosis fungoides (FMF) is a distinct variant of mycosis fungoides (MF), the most prevalent type of cutaneous T cell lymphoma. FMF accounts for approximately 10% of all MF cases and is generally characterized by distinct clinical , histopathologic and prognostic features. The studies in this thesis were aimed to address questions regarding clinical staging, disease course, suitable treatment and prognosis of subgroups of patients with FMF. Show less
We present the case of a 50-year-old patient with folliculotropic mycosis fungoides (FMF) unresponsive to retinoids and the chemotherapeutic regimens CHOP, gemcitabine, and brentuximab-vedotin.... Show moreWe present the case of a 50-year-old patient with folliculotropic mycosis fungoides (FMF) unresponsive to retinoids and the chemotherapeutic regimens CHOP, gemcitabine, and brentuximab-vedotin. During immunosuppressive therapy, the patient developed extensive progressive molluscum contagiosum. The mollusca did not respond to topical imiquimod but showed a swift complete response to interferon-alpha 2a (IFNa). Recently, the patient started with alemtuzumab as induction therapy for an allogenic stem cell transplantation and simultaneously continued IFNa therapy. (C) 2019 The Author(s) Published by S. Karger AG, Basel Show less
The studies described in this thesis focused on identifying diagnostic and prognostic markers in tumor stage mycosis fungoides (stage IIB) and Sézary syndrome. Sézary syndrome is a type of... Show moreThe studies described in this thesis focused on identifying diagnostic and prognostic markers in tumor stage mycosis fungoides (stage IIB) and Sézary syndrome. Sézary syndrome is a type of cutaneous T-cell lymphoma, characterized by an erythroderma, lymphadenopathy and malignant T cells in skin, lymph nodes and blood. Especially in the early stages of disease, it can be difficult to differentiate Sézary syndrome from erythrodermic inflammatory dermatoses. The studies identified immunohistochemical (TOX), immunophenotypic (CD7, CD26), molecular (STAT4, TWIST1, DNM3/ PLS3) and epigenetic (CMTM2) markers that are useful as additional diagnostic markers to discriminate Sézary syndrome from erythrodermic inflammatory dermatoses. Of the molecular markers, PLS3 expression was an important prognostic factor in Sézary syndrome. In addition, it was shown that the number of tumors and time interval between tumor formation differs greatly among patients with mycosis fungoides stage IIB and these differences correlate with survival. Patients that developed four or more tumors during the first 6 months after diagnosis of stage IIB have a poor prognosis. Show less
Trautinger, F.; Eder, J.; Assaf, C.; Bagot, M.; Cozzio, A.; Dummer, R.; ... ; Knobler, R. 2017
The research described in the thesis is focused at identifying molecular aberrations contributing to the pathogenesis of CTCL. In search for differences in chromosomal alterations underlying the... Show moreThe research described in the thesis is focused at identifying molecular aberrations contributing to the pathogenesis of CTCL. In search for differences in chromosomal alterations underlying the different clinical behavior and prognosis of patients with mycosis fungoides (MF) and S_zary syndrome (Sz) the DNA copy number alterations of MF were investigated and compared with the previously published profile of Sz. Several alterations of prognostic value were identified. Gene expression data of MF was integrated with DNA copy number alterations to search for genes contributing to tumorigenesis and possible therapeutic targets. With the same purpose gene expression data of MF was compared to normal controls, to identify genes dysregulated otherwise than due to copy number alteration. Additionally miRNA profiles of MF and Sz were elucidated to determine their possible role as gene expression regulator. DNA copy number alterations and gene expression profiles were analyzed of primary cutaneous anaplastic large cell lymphoma and peripheral T cell lymphoma not otherwise specified to gain insight in the molecular mechanisms underlying the different clinical aggressiveness. Show less
The purpose of this thesis was to obtain more insight into T-cell clonality in blood of mycosis fungoides (MF) patients. Investigation of the frequency of blood T-cell clonality clearly indicated... Show moreThe purpose of this thesis was to obtain more insight into T-cell clonality in blood of mycosis fungoides (MF) patients. Investigation of the frequency of blood T-cell clonality clearly indicated early dissemination of neoplastic T-cells into skin and blood as a sign of physiological recirculation. Nevertheless, circulating clonal T-cells not associated with a cutaneous clone were found in substantial numbers of MF patients and controls. This phenomenon remained obscure; we termed it T-cell Expansion of Undetermined Significance (TExUS). Qualitative investigation of T-cell clonality in blood samples at the initial diagnosis of MF could not predict the clinical course. Chromosomal analysis confirmed previous data demonstrating an early dissemination of the T-cell clone. Complex chromosomal aberrations were found exclusively in clonal T-lymphocytes. Characteristic combinations of chromosomal aberrations were found; some alterations seemed to be prognostically significant. Comparison of our in-house TCR_ assay with the Biomed-2 protocol verified our findings. Since detection of T-cell clonality by PCR assays fails in a substantial portion of CTCL samples, but succeeds in various benign conditions, accurate integration of clinical, histomorphological, immunohistochemical data still represents the golden diagnostic standard. Demonstration of a T-cell clone only supplements the diagnosis of CTCL. Show less
