Proteasome inhibition as a novel mechanism of the proapoptotic activity of γ-secretase inhibitor I in cutaneous T-cell lymphoma.

2013 Mar 

Biskup E, Kamstrup MR, Manfé V, Gniadecki R.

Source

Department of Dermatology, Bispebjerg Hospital, University of Copenhagen, Bispebjerg Bakke 23, Copenhagen-2400, Denmark.

Abstract

Background  

We have previously discovered that Notch1 is expressed on malignant T cells in cutaneous T-cell lymphoma(CTCL), and is required for survival of CTCL cell lines. Notch can be inhibited by γ-secretase inhibitors (GSIs), which differ widely in their ability to induce apoptosis in CTCL. Objectives  To investigate whether GSI-I, in addition to inhibiting Notch, induces apoptosis in CTCL by proteasome inhibition, as GSI-I is very potent and has structural similarity to the proteasome inhibitor MG-132. Methods  Cell lines derived from CTCL (MyLa, SeAx, JK, Mac1 and Mac2a) were treated with GSI-I and two other proteasome inhibitors (MG-132 and bortezomib). The effects on cell viability, apoptosis and proteasome activity were measured, as was the impact on the prosurvival, nuclear factor κB (NF-κB) pathway. Results  In CTCL, GSI-I had proteasome-blocking activity with a potency comparable to the proteasome inhibitors MG-132 and bortezomib. 

Proteasome inhibition was the main mechanism responsible for GSI-I-induced cell death, as tiron, a compound known to reverse the effect of MG-132, restored proteasome activity and largely abrogated the cytotoxic effect of GSI-I. Although inactivation of NF-κB is an important mechanism of action for proteasome inhibitors, we demonstrated an apparent activation of NF-κB. Furthermore, we showed that while the tumour suppressor protein p53 was induced during proteasome inhibition, it was dispensable for CTCL apoptosis, as both SeAx cells, which harbour p53 mutations that attenuate the apoptotic capacity, and HuT-78 cells, which have a deleted p53 gene, demonstrated potent apoptotic response. Conclusions  GSI-I represents an interesting drug with a dual mechanism of action comprising inhibition of both Notch and the proteasome.

PubMed

Array-CGH Analysis of Cutaneous Anaplastic Large Cell Lymphoma.

2013

Szuhai K, van Doorn R, Tensen CP, Van Kester.

Source

Department of Molecular Cell Biology, Leiden University Medical Center, Leiden, The Netherlands.

Abstract

This chapter describes a study in which the pattern of numerical chromosomal alterations in cutaneous anaplastic large cell lymphoma (C-ALCL) tumor samples was defined using array-based comparative genomic hybridization (CGH). First, the array-based CGH technique applied is outlined in detail. Next, its application in the analysis of C-ALCL tumor specimens is described. This approach resulted in the identification of highly recurrent chromosomal alterations in C-ALCL that include gain of 7q31 and loss on 6q16-6q21 and 13q34, each affecting 45% of the patients. The pattern characteristic of C-ALCL differs markedly from chromosomal alterations observed in other CTCL such as mycosis fungoides and Sézary syndrome and yielded several candidate genes with potential relevance in the pathogenesis of C-ALCL.

PubMed

Indolent course of cutaneous gamma-delta T-cell lymphoma.

Feb 2013

Endly DC, Weenig RH, Peters MS, Viswanatha DS, Comfere NI.

Source

College of Osteopathic Medicine, Midwestern University, Glendale, AZ, USA.

Abstract

Cutaneous gamma-delta T-cell lymphoma  is a rare malignancy that typically displays an aggressive clinical course. We present an unusual case of a 57-year-old woman with a 3-year history of lower extremity nodules. Histopathologic, immunophenotypic and molecular genetic studies revealed a clonal, predominantly pannicular gamma-delta T-cell infiltrate, leading to a diagnosis of cutaneous lymphoma. The clinical course was characterized by rapid improvement within months of starting systemic corticosteroids, with relapse in ulcerations but no new lesions more than 3 years after onset of disease. Our case and seven previously reported patients with indolent and relatively localized cutaneous lymphoma provide evidence that not all cases of this entity carry a poor prognosis. This indolent subset adds complexity to treatment of cutaneous lymphoma.

Wiley Online

The antihistamines clemastine and desloratadine inhibit STAT3 and c-Myc activities and induce apoptosis in cutaneous T-cell lymphoma cell lines.

Feb 2013

Döbbeling U, Waeckerle-Men Y, Zabel F, Graf N, Kündig TM, Johansen P.

Source

Department of Dermatology, University Hospital Zurich, Zurich, Switzerland.

Abstract

Mycosis fungoides and its leukaemic counterpart Sézary syndrome are the most frequent cutaneous T-cell lymphomas (CTCL), and there is no cure for these diseases. We evaluated the effect of clinically approved antihistamines on the growth of CTCL cell lines. CTCL cell lines as well as blood lymphocytes from patients with Sézary syndrome were cultured with antihistamines, and the cell were analysed for proliferation, apoptosis and expression of programmed death molecules and transcription factors. The two antihistamines clemastine and desloratadine, currently used for symptom alleviation in allergy, induced potent reduction of the activities of the constitutively active transcription factors c-Myc, STAT3, STAT5a and STAT5b in mycosis fungoides and Sézary syndrome cell lines. This inhibition was followed by apoptosis and cell death, especially in the Sézary syndrome-derived cell line Hut78 that also showed increased expression of the programmed death-1 (PD-1) after clemastine treatment. In lymphocytes isolated from Sézary syndrome patients, the CD4-positive fraction underwent apoptosis after clemastine treatment, while CD4-negative lymphocytes were little affected. Because both c-Myc and STAT transcription factors are highly expressed in proliferating tumours, their inhibition by clemastine, desloratadine and other inhibitors could complement established chemotherapies not only for cutaneous T-cell lymphomas but perhaps also other cancers.

PubMed

TCR-γ Expression in Primary Cutaneous T-cell Lymphomas.

Jan 2013

Rodríguez-Pinilla SM, Ortiz-Romero PL, Monsalvez V, Tomás IE, Almagro M, Sevilla A, Camacho G, Longo MI, Pulpillo A,Diaz-Pérez JA, Montes-Moreno S, Castro Y, Echevarría B, Trébol I, Gonzalez C, Sánchez L, Otín AP, Requena L,Rodríguez-Peralto JL, Cerroni L, Piris MA.

Source

*CNIO Lymphoma Group Departments of †Pathology ‡‡‡Dermatology, Fundación Jiménez Díaz Departments of ‡Dermatology §§§Pathology, Hospital Universitario 12 de Octubre §Pathology Department, Hospital de Torrejón de Ardoz Departments of **Dermatology ∥∥Pathology, Hospital Universitario Gregorio Marañón ***Dermatology Department, Hospital Universitario de Getafe, Getafe †††Immunohistochemistry Unit, Biotechnology Programme, CNIO, Madrid ∥Dermatology Department, Hospital Universitario Juan Canalejo, La Coruña ¶Dermatology Department, Hospital de San Juan, Alicante #Dermatology Department, Hospital Universitario Reina Sofía, Córdoba ††Dermatology Department, Hospital Universitario Virgen del Rocío, Sevilla §§Pathology Department, Hospital Universitario Marqués de Valdecilla, Santander ¶¶Dermatology Department, Hospital Virgen del Castillo, Murcia ##Dermatology Department, Hospital Santiago Apostol, Vitoria, Spain ‡‡UCSD Moores Cancer Center, La Joya, CA ∥∥∥Department of Dermatology, Research Unit Dermatopathology, Medical University of Graz, Graz, Austria.

Abstract

Primary cutaneous γδ T-cell lymphomas (PCGD-TCLs) are considered a subgroup of aggressive cytotoxic T-cell lymphomas (CTCLs). We have taken advantage of a new, commercially available antibody that recognizes the T-cell receptor-γ (TCR-γ) subunit of the TCR in paraffin-embedded tissue. We have analyzed a series of 146 primary cutaneous T-cell lymphomas received for consultation or a second opinion in the CNIO Pathology Department. Cases were classified according to the World Health Organization 2008 classification as mycosis fungoides (MF; n=96), PCGD-TCLs (n=5), pagetoid reticulosis (n=6), CD30 primary cutaneous anaplastic large cell lymphomas (n=5), primary cutaneous CD8 aggressive epidermotropic CTCLs (n=3), primary cutaneous CTCL, not otherwise specified (n=4), and extranodal nasal-type NK/T-cell lymphomas primarily affecting the skin or subcutaneous tissue (n=11). Sixteen cases of the newly named lymphomatoid papulosis type D (LyP-D; n=16) were also included. In those cases positive for TCR-γ, a further panel of 13 antibodies was used for analysis, including TIA-1, granzyme B, and perforin. Clinical and follow-up data were recorded in all cases. Twelve cases (8.2%) were positive for TCR-γ, including 5 PCGD-TCLs, 2 MFs, and 5 LyP-Ds. All 5 PCGD-TCL patients and 1 MF patient died of the disease, whereas the other MF patient and all those with LyP-D were alive. All cases expressed cytotoxic markers, were frequently CD3/CD8, and tended to lose CD5 and CD7 expressions. Eight of 12 and 5 of 11 cases were CD30 and CD56, respectively. Interestingly, 5/12 TCR-γ-positive cases also expressed TCR-BF1. All cases analyzed were negative for Epstein-Barr virus-encoded RNA. In conclusion, TCR-γ expression seems to be rare and is confined to cytotoxic primarycutaneous TCLs. Nevertheless, its expression is not exclusive to PCGD-TCLs, as TCR-γ protein can be found in other CTCLs. Moreover, its expression does not seem to be associated with bad prognosis by itself, as it can be found in cases with good and bad outcomes.

American Journal of Surgical Pathology

Positron Emission Tomography Revealed Diffuse Involvement of the Lower Legs and Occult Extracutaneous Lesions in Subcutaneous Panniculitis-Like T-cell Lymphoma.

Jan 2013 

Mitsuhashi K, Momose M, Masuda A, Tsunemi Y, Motoji T.

Source

From the *Department of Hematology, †Department of Diagnostic Imaging and Nuclear Medicine, ‡Department of Surgical Pathology, and §Department of Dermatology, Tokyo Women's Medical University, Tokyo, Japan.

Abstract

ABSTRACT: 

Subcutaneous panniculitis-like T-cell lymphoma (SPTCL) is a very rare type of cutaneous lymphoma that localizes primarily in the subcutaneous adipose tissue without palpable involvement of the lymph nodes. Most often, it presents as multiple, painless, subcutaneous nodules on the extremities and trunk. In this study, we describe an unusual case of SPTCL that mimicked phlegmonous inflammation; PET/CT revealed massive diffuse involvement of the lower legs, low-grade nodal active disease, and occult involvement of the intra-abdominal visceral fat. A repeat PET/CT study after CHOP chemotherapy revealed complete resolution of abnormal FDG uptake in the initially involved sites.

PubMed

Composite lymphoma of mycosis fungoides and cutaneous small B-cell lymphoma in a 73-year-old male patient.

Jan  2013

Whitling NA, Shanesmith RP, Jacob L, McBurney E, Sebastian S, Wang E, Wang AR.

Source

Department of Pathology, Tulane University, New Orleans, LA, USA 70112.

Abstract

Composite lymphoma of T-cell and B-cell type is uncommon, and the one occurring primarily on skin is extremely rare. Herein, we report a unique case of composite lymphoma of mycosis fungoides and cutaneous small B-cell lymphoma in a 73-year-old male patient. The patient presented with multiple erythematous patches, plaques, and nodules on the upper arms, scalp, and trunk. Four punch biopsies of arm and scalp lesions demonstrated lymphoid infiltrate in superficial to deep dermis with a characteristic zone distribution of T-cell and B-cell components. T cells were distributed in papillary and perifollicular dermis and displayed a larger size with convoluted nuclei, whereas B cells were small sized, assuming nodular infiltrate in mid-deep dermis with coexpression of CD5. Molecular test detected clonal rearrangement of both TCRG and IGH/K genes with identical amplicons for each gene in all 4 biopsies. Clinical staging revealed no extracutaneous lesions. A multidisplinary approach is emphasized to establish a definitive diagnosis.

PubMed

New Insights into Associated Co-morbidities in Patients with Cutaneous T-cell Lymphoma (Mycosis Fungoides).

Jan 2013

Hodak E, Lessin S, Friedland R, Freud T, David M, Pavlovsky L, Shapiro J, Cohen AD.

Source

Department of Dermatology, Rabin Medical Center, Petah Tiqva, 49100, Peath Tiqva, Israel. hodake@post.tau.ac.il.

Abstract

Studies of associated cancer in patients with mycosis fungoides (MF) have focused primarily on secondary cancers in North American and European populations. This study investigated the association between MF and malignancies, anxiety and depression in the Israeli population. Data on Israeli patients with MF and age- and gender-matched controls were collected from a database of population- based cohort (683 patients; 1,700 controls) and an institution- based cohort (343 patients; 846 controls) and analysed by univariate and multivariate methods. MF was significantly associated with Hodgkin's lymphoma in both cohorts (multivariate odds ratio (OR) 7.83, univariate OR ∞, respectively); acute leukaemia (multivariate OR 10.1, first cohort) and lung cancer (multivariate OR 10.15, second cohort). MF was significantly associated with anxiety and depression (multivariate OR 1.59, OR 1.51, respectively in first cohort). The current study provides support to the associations between MF and other cancers: Hodgkin's lymphoma, acute leukaemia and lung cancer. The study also em-phasizes the association between MF and anxiety and depression.

Medical Journals

Serum-soluble Herpes Virus Entry Mediator Levels Reflect Disease Severity and Th2 Environment in Cutaneous T-cell Lymphoma

Serum-soluble Herpes Virus Entry Mediator Levels Reflect Disease Severity and Th2 Environment in Cutaneous T-cell Lymphoma


Tomomitsu Miyagaki, Makoto Sugaya*, Hiraku Suga, Hanako Ohmatsu, Hideki Fujita, Yoshihide Asano, Yayoi Tada, Takafumi
Kadono and Shinichi Sato
Department of Dermatology, Faculty of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan. *E-mail: sugayam-der@h.u-tokyo.ac.jp

Activated T cells express LIGHT, an acronyme for lymphotoxin-like, exhibits inducible expression, and competes with HSV glycoprotein D for herpesvirus entry mediator (HVEM) a receptor expressed by T lymphocytes (1). LIGHT binds to 3 distinct receptors: HVEM, lymphotoxin β receptor, and decoy receptor 3 (2). Of these, HVEM is expressed by many cell types (1). LIGHT-HVEM interactions activate T cells and natural killer (NK) cells to produce T helper type (Th) 1 cytokines (3–7).

Many patients with cutaneous T-cell lymphoma (CTCL) in the advanced stages have eosinophilia and high levels of immunoglobulin E, suggesting that Th2 is dominant in these patients (8, 9).

We reported recently that low HVEM expression on dermal fibroblasts in lesional skin of advanced CTCL attenuates the expression of Th1 chemokines, which may contribute to a shift to a Th2-dominant microenvironment (10). However, little is known about the soluble
form of HVEM (sHVEM) and its ligand, LIGHT, in CTCL. The aim of this study was to measure sHVEM and LIGHT levels in the sera of patients with CTCL.

working link not available

Medical Journals

Treatment of advanced cutaneous T-cell lymphomas with non-pegylated liposomal doxorubicin - Consensus of the lymphoma group of the Working Group Dermatologic Oncology.

Jan 2013

Assaf C, Becker JC, Beyer M, Cozzio A, Dippel E, Klemke CD, Kurschat P, Weichenthal M, Stadler R.

Source

Department of Dermatlogy, Helios Clinic Krefeld, Germany Department of Dermatology and Venereology, University of Graz, Austria Department of Dermatolgogy, Venereology and Allergology, Charité- University Medicine Berlin, Germany Department of Dermatology, University Clinic Zurich, Switzerland Department of Dermatolgoy, Municipal Clinic Ludwigshaven, Germany Department of Dermatology, University of Mannheim, Germany Department of Dermatology and Venereology, University of Cologne, Germany Department of Dermatology, University of Kiel, Germany Department of Dermatolgy, Johannes Wesling Clinic Minden, Germany.

Abstract

Background: Systemic treatment with pegylated liposomal doxorubicin is an established second-line treatment of advancedcutaneous T-cell lymphoma. Pegylated liposomal doxorubicin (PLD) is currently unavailable, therefore, clinical studies investigating the efficacy of non-pegylated liposomal formula (NPLD) have been analyzed. 

Methods: Since clinical trials comparing PLD and NPLD in CTCL do not exist, the clinical use of NPLD including safety and efficiency profile in other types of non-Hodgkin lymphoma were analyzed. 

Results: Clinical trials show a comparable efficacy of NPLD and PLD in non-Hodgkin lymphoma. The dosage of NPLD used in the treatment of systemic lymphoma within polychemotherapy regimens was 50 mg/m(2) every three weeks. Overall response was 75-95 %, including a complete remission rate of 65-80 % and 2- and 3-year overall survival rates of 55-75 %. These data indicate that the non-pegylated formula of doxorubicin has a similar antitumor effect as the pegylated one but shows reduced cardiotoxicity. The palmoplantar erythrodysesthesia frequently observed in PLD has not been observed with the use of the NPLD. 

Conclusions: The clinical use of NPLD in the treatment of CTCL is reasonable. In analogy to the clinical trials of NPLD in non-Hodgkin lymphoma a dosage of 50 mg/m(2) every three weeks is recommended for the treatment of CTCL.

Wiley Online

Primary cutaneous CD30-positive anaplastic large-cell lymphoma of the external auditory canal.

Dec 2012

Marçal N, Campelos S, Dias L, Gonçalves M, Pereira G, Godinho T.

Source

Department of Otorhinolaryngology, Hospital de São Marcos, Sete Fontes, S. Victor 4701-243 Braga, Portugal. nunomarcal.orl@gmail.com.

Abstract

Primary cutaneous T-cell lymphoma is rare. Cutaneous lymphoma is defined as primary when there is an absence of nodal or systemic disease during the first 6 months following diagnosis. We report what we believe to be the first documented case of a primary cutaneous CD30-positive anaplastic large-cell lymphoma of the external auditory canal. The patient was an elderly woman who presented with progressively worsening right otalgia and hypoacusis. Otoscopy revealed an erythematic, ulcerative, nonbleeding, localized lesion in the anterosuperior area of the external auditory canal. The patient underwent an excisional biopsy, and after the diagnosis was established, she underwent 22 sessions of radiotherapy. During follow-up, she exhibited no evidence of recurrence.

PubMed

Dermatopathology Update.

Dec 2012

[Article in English, Spanish]

Fernández-Figueras MT, Puig L.

Source

Servicio de Anatomía Patológica, Hospital Universitari Germans Trias i Pujol, Badalona, España; Departamento de Ciencias Morfológicas, Universitat Autònoma de Barcelona, Barcelona, España. Electronic address: maiteffig@gmail.com.

Abstract

This past year has seen a wealth of new developments in dermatopathology that appear to herald the dawning of a new era. Advances in molecular biology and the simplification of techniques have put molecular tests within reach of routine clinical practice and led to a radical change in our approach to lesions such as melanoma; in the future, the genetic characterization of these lesions will be an essential requirement for establishing diagnosis, prognosis, and therapy. 

Technological innovations have also reached dermatology departments: the introduction of ultrasound scans has propitiated the use of fine-needle aspiration cytology, which allows samples to be stained and studied immediately, thereby facilitating diagnosis of superficial and lymph-node lesions, and allowing staging of tumors such as melanoma. Targeted cancer therapies have led to the introduction of more sensitive and specific systems for identifying new targets, have reawakened interest in forgotten diseases such as aggressive basal cell carcinoma, and have led to dermatological reactions that, together with those caused by biologic drugs, we are just beginning to recognize. Consolidated techniques such as immunohistochemistry continue to advance with the addition of new antibodies that contribute considerably to improved diagnosis.

New clinicopathologic diseases have also been described or characterized this year, including 2 new types of melanoma, and progress has been made in our knowledge of other diseases, such as primary cutaneous CD4(+) small/medium-sized pleomorphic T-cell lymphoma. These topics, together with new developments in adnexal tumors, alopecia, and other lesions, will be discussed in this review.

PubMed