[Show abstract][Hide abstract] ABSTRACT: Purpose:
Advanced-stage mycosis fungoides (MF; stage IIB to IV) and Sézary syndrome (SS) are aggressive lymphomas with a median survival of 1 to 5 years. Clinical management is stage based; however, there is wide range of outcome within stages. Published prognostic studies in MF/SS have been single-center trials. Because of the rarity of MF/SS, only a large collaboration would power a study to identify independent prognostic markers.
Patients and methods:
Literature review identified the following 10 candidate markers: stage, age, sex, cutaneous histologic features of folliculotropism, CD30 positivity, proliferation index, large-cell transformation, WBC/lymphocyte count, serum lactate dehydrogenase, and identical T-cell clone in blood and skin. Data were collected at specialist centers on patients diagnosed with advanced-stage MF/SS from 2007. Each parameter recorded at diagnosis was tested against overall survival (OS).
Staging data on 1,275 patients with advanced MF/SS from 29 international sites were included for survival analysis. The median OS was 63 months, with 2- and 5-year survival rates of 77% and 52%, respectively. The median OS for patients with stage IIB disease was 68 months, but patients diagnosed with stage III disease had slightly improved survival compared with patients with stage IIB, although patients diagnosed with stage IV disease had significantly worse survival (48 months for stage IVA and 33 months for stage IVB). Of the 10 variables tested, four (stage IV, age > 60 years, large-cell transformation, and increased lactate dehydrogenase) were independent prognostic markers for a worse survival. Combining these four factors in a prognostic index model identified the following three risk groups across stages with significantly different 5-year survival rates: low risk (68%), intermediate risk (44%), and high risk (28%).
To our knowledge, this study includes the largest cohort of patients with advanced-stage MF/SS and identifies markers with independent prognostic value, which, used together in a prognostic index, may be useful to stratify advanced-stage patients.
Journal of Clinical Oncology 10/2015; DOI:10.1200/JCO.2015.61.7142 · 18.43 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background
Endothelial protein C receptor (EPCR) predominantly expressed on endothelial cells plays a critical role in the regulation of coagulation system and also mediates various cytoprotective effects by binding and activating protein C. So far, the role of EPCR has not been studied in systemic sclerosis (SSc).Objectives
To investigate the potential contribution of EPCR to the development of SSc.MethodsEPCR expression was examined in skin samples and cultivated dermal microvascular endothelial cells by immunostaining, immunoblotting, and/or quantitative reverse transcription PCR. Fli1 binding to the EPCR promoter was assessed by chromatin immunoprecipitation. Serum EPCR levels were determined by enzyme-linked immunosorbent assay in 65 SSc and 20 healthy subjects.ResultsEPCR expression was decreased in dermal small vessels of SSc lesional skin compared with those of healthy control skin. Transcription factor Fli1, whose deficiency is implicated in SSc vasculopathy, occupied the EPCR promoter and EPCR expression was suppressed in Fli1 siRNA-treated endothelial cells and dermal small vessels of Fli1+/- mice. In SSc patients, decreased serum EPCR levels were associated with diffuse skin involvement, interstitial lung disease and digital ulcers. Furthermore, serum EPCR levels inversely correlated with plasma levels of plasmin-α2-plasmin inhibitor complex (PIC). Importantly, bosentan significantly reversed circulating EPCR and PIC levels in SSc patients and the expression of Fli1 and EPCR in dermal small vessels was elevated in patients treated with bosentan compared to untreated patients.Conclusions
Endothelial EPCR down-regulation due to Fli1 deficiency may contribute to hyper-coagulation status leading to tissue fibrosis and impaired peripheral circulation in SSc.This article is protected by copyright. All rights reserved.
British Journal of Dermatology 09/2015; DOI:10.1111/bjd.14183 · 4.28 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Vorinostat is the first histone deacetylase inhibitor approved for cutaneous T cell lymphoma (CTCL).(1) Although in vitro effects of this drug on various types of cells have been studied,(2-5) little is known about how this drug has clinical effects on CTCL patients. As many chemokines are reported to reflect disease activity of CTCL, suggesting their important roles in disease progression,(6) we investigated variation of serum chemokine levels during oral vorinostat therapy in a Sézary syndrome (SS) patient. This article is protected by copyright. All rights reserved.
This article is protected by copyright. All rights reserved.
British Journal of Dermatology 02/2015; 173(2). DOI:10.1111/bjd.13696 · 4.28 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Early cutaneous T cell lymphoma clinically and histologically resembles benign inflammatory skin diseases, which sometimes makes it difficult to reach a correct diagnosis. It is recently reported that thymocyte selection-associated high mobility group box factor (TOX) serves as a molecular marker for histological diagnosis of early-stage mycosis fungoides (MF). To examine whether TOX could be a marker of tumour cells in different types of cutaneous lymphoma, we investigated immunohistochemical staining for TOX with the lesional skin of patch, plaque, and tumour MF, Sézary syndrome (SS), lymphomatoid papulosis (LyP), primary cutaneous anaplastic large cell lymphoma (PCALCL), adult T cell leukemia/lymphoma (ATLL), peripheral T-cell lymphoma, not otherwise specified (PTCL, NOS), atopic dermatitis (AD), and normal skin. TOX and CCR4 messenger RNA (mRNA) levels in lesional skin of MF/SS were also examined. Immunohistological staining showed that a high specific nuclear staining of TOX was observed at a high frequency in MF, SS, and PTCL, NOS. Tumour cells in LyP, PCALCL, and ATLL showed a slightly dim nuclear staining of TOX. TOX(+) cells in MF and LyP expressed surface molecules characteristics of tumour cells in these diseases. Lesional skin of SS expressed higher levels of TOX mRNA, compared to normal skin or MF lesional skin. Moreover, TOX expression significantly correlated with CCR4 expression. TOX may be a specific marker for tumour cells in some types of cutaneous lymphoma.
Archives for Dermatological Research 09/2014; 306(9). DOI:10.1007/s00403-014-1501-7 · 1.90 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Dear Editor,Paraneoplastic pemphigus (PNP) is a rare autoimmune mucocutaneous disorder which is predominantly associated with lymphoproliferative disorders including non-Hodgkin lymphoma, B-chronic lymphocytic leukemia, Castleman disease, and Waldenström macroglobulinemia . PNP is characterized by painful mucosal erosion with frequent skin eruption, histological changes of acantholysis or lichenoid/interface dermatitis, and serum autoantibodies against plakin family proteins [2, 3]. Although the cause of PNP is not identified in most cases, previous literatures have indicated that PNP may be triggered by specific treatment modalities for lymphoid neoplasms. Patients with lymphoid malignancies were recurrently affected by PNP within several cycles of fludarabine-containing therapy [4–7] or after local radiotherapy [8–10]. Here, we describe the first case of PNP occurring after bendamustine and rituximab therapy for follicular lymphoma.A 77-year-old Japanese woman was diagnosed with f ...
Annals of Hematology 09/2014; 94(4). DOI:10.1007/s00277-014-2202-1 · 2.63 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Purpose:
Atopic dermatitis is characterized by decreased expression of filaggrin and loricrin. Patients with atopic dermatitis often suffer from skin infections, which are also frequently seen in patients with cutaneous T-cell lymphoma (CTCL). In this study, we aimed to investigate the skin barrier in CTCL.
We assessed skin moisture and transepidermal water loss (TEWL) in patients with CTCL. We next examined mRNA expression levels of filaggrin, loricrin, and antimicrobial peptides (AMP) in skin samples of CTCL, using skin from healthy volunteers and patients with atopic dermatitis or psoriasis as controls. Immunostainings for filaggrin, loricrin, and S100 proteins were also performed.
Lower levels of skin moisture accompanied by higher levels of TEWL were seen in lesional skin of CTCL than in normal skin. CTCL lesional skin contained lower levels of filaggrin and loricrin mRNA than normal skin, which was also true with atopic dermatitis and psoriatic skin. mRNA expression levels of filaggrin in CTCL skin negatively correlated with disease severity markers. Expression levels of AMPs in lesional skin of CTCL and atopic dermatitis were significantly lower than in psoriatic skin. Immunohistochemistry confirmed decreased expression of filaggrin and loricrin in CTCL, atopic dermatitis, and psoriatic skin and enhanced expression of S100 proteins in psoriatic skin.
Our results show that there is barrier dysfunction in CTCL skin, similar to what is seen with atopic dermatitis skin. In addition, low AMP expression in CTCL skin was documented when compared with psoriatic skin, which may explain frequent infections that can occur in patients with CTCL.
Clinical Cancer Research 06/2014; 20(16). DOI:10.1158/1078-0432.CCR-14-0077 · 8.72 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Tumor genesis and development are driven by a combination of intrinsic events such as oncogene activation and tumor-suppressor gene inactivation, and extrinsic events that are dependent on the interaction with the stroma. Different types of growth factors, cytokines and chemokines secreted by the surrounding stromal cells are thought to play key roles in solid tumor progression. Accumulating evidence indicates that the immunological milieu plays an essential role in tumor development, not only in solid tumors, but also in hematopoietic malignancies. Understanding the interactions between tumor cells and microenvironment in mycosis fungoides (MF) and Sézary syndrome (SS) could provide a basis for the development of new treatments for these diseases that are sometimes resistant to current therapies. This article focuses on the wide variety of cell types and immunological milieus, affecting the characteristic features of MF and SS, such as skin-homing of tumor cells, T-helper type 2-dominant tumor microenvironment, accumulation of dermal dendritic cells, epidermal hyperplasia, angiogenesis and pruritus.
The Journal of Dermatology 01/2014; 41(1):11-8. DOI:10.1111/1346-8138.12305 · 2.25 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Depsipeptide (FK228), a histone deacetylase inhibitor, was recently approved for use in cutaneous T-cell lymphoma. Roxithromycin (RXM) is a macrolide antibiotic that can induce apoptosis of some T-cell lines. In this study, we investigated whether combination of FK228 and RXM had a synergistic inhibitory effect on cell survival of various lymphoma cells and which signaling pathway was affected by the drugs in the presence or absence of chemokines, which were reported to inhibit apoptosis of some tumor cells. FK228 and RXM additively decreased the number of HUT-78, Ki-JK and EL-4 lymphoma cells at doses over 50 nmol/L and 50 μmol/L, respectively. These drugs inhibited phosphorylation of Akt and extracellular signal-regulated kinase (ERK) of EL-4 cells in a dose-dependent manner. Significant association between ERK phosphorylation and cell number or annexin V(+) cells suggested that the ERK pathway may be critical for survival of EL-4 cells. Combination of 10 or 50 nmol/L of FK228 and 10 μmol/L of RXM decreased cell number of HUT78 and EL-4 compared to a single use of each drug. Our in vitro study suggested that combination of FK228 and RXM may be helpful for enhancing tumor killing effects. Although further study is necessary, this combination may be applicable to patients with cutaneous T-cell lymphoma in the future.
The Journal of Dermatology 01/2014; 41(1):57-62. DOI:10.1111/1346-8138.12351 · 2.25 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: IL-32 is a pro-inflammatory cytokine expressed by activated natural killer cells, T cells, keratinocytes, and fibroblasts. In this study, we examined the role of IL-32 in cutaneous T-cell lymphoma (CTCL), including mycosis fungoides (MF) and Sézary syndrome (SS). IL-32 mRNA expression levels in lesional skin of MF patch, plaque, and tumor were increased compared to those of normal skin, which positively correlated with CCL17 and CCL18 mRNA expression levels. Serum IL-32 levels positively correlated with disease activity within each patient. Immunostaining showed that keratinocytes expressed IL-32 in lesional skin of MF patch and plaque, while in MF tumor, atypical T cells in the dermis strongly expressed IL-32. We also showed that IL-32 dose-dependently accelerated proliferation of MF and SS cell lines in vitro, which was inhibited by blocking mitogen-activated protein kinase and NF-κB-mediated signaling. Addition of anti-IL-32 antibodies in culture decreased proliferation of SS cells and viability of MF cells, suggesting that IL-32 serves as an autocrine growth factor. In conclusion, our results suggest that IL-32 plays a role in formation and maintenance of CTCL lesions, providing a possible therapeutic target for patients with this disease.Journal of Investigative Dermatology accepted article preview online, 13 November 2013. doi:10.1038/jid.2013.488.