Transcriptome sequencing analysis of ursolic acid-mediated proliferation suppression on cutaneous T-cell lymphoma cells

Background:Ursolic acid is a triterpenoid compound found in natural plants that exhibits antiproliferative effects in various cancer cells.Our study is the first to demonstrate the strong inhibitory effects of ursolic acid on the proliferation of cutaneous T-cell lymphoma(CTCL)cells.We aimed to further investigate the underlying mechanism of the proliferation inhibition induced by ursolic acid in CTCL cells using transcriptome sequencing.Methods:Cell counting kit-8 assays were used to observe the effects of six traditional medicine monomers on the proliferation of CTCL cells.Transcriptome sequencing was used to identify differentially expressed genes after ursolic acid treatment.Bioinformatics analysis was performed to determine the potential mechanism.Real-time quantitative PCR and western blotting analyses were performed to confirm the sequencing results and verify the possible mechanisms of ursolic acid-mediated proliferation inhibition in CTCL cells.Results:Ursolic acid exhibited the strongest inhibitory effect on the proliferation of CTCL cells among the six traditional medicine monomers.Transcriptome sequencing analysis showed that 2,466 genes were significantly altered.Combined with Kyoto Encyclopedia of Genes and Genomes functional enrichment analysis and protein-protein interaction network analysis,the interaction of various pathways and signaling molecules,such as tumor necrosis factor-α,NLR family pyrin domain containing 1,c-Jun N-terminal kinase,and melanoma differentiation-associated gene 5,accounted for the anti-tumor effects of ursolic acid in CTCL cells.Conclusion:Ursolic acid significantly inhibited the proliferation of CTCL cells,and our study laid a theoretical foundation for the future treatment of CTCL using ursolic acid.

Palliative Local Radiotherapy in the Treatment of Tumor-stage Cutaneous T-cell Lymphoma/ Mycosis Fungoides

Objective To determine the efficacy of palliative radiotherapy in treating tumor-stage cutaneous T-cell lymphoma/mycosis fungoides(MF).Methods From January 2008 to January 2013,a total of 11 patients with tumor-stage MF were treated with local radiation therapy in Peking Union Medical College Hospital.The median age of these patients was 53.36±14.45 years.Female-male ratio was 1:1.2.The average course of disease was 10.82±3.37 years.All the patients were treated with local electronic beam irradiation with a total median dosage of 48.55±9.51(40-74) Gy in an average of 24.55±5.57(20-40) fractions,5 fractions per week.Results The median follow-up time was 55.27±29.3(13-103) months.No severe acute or chronic side effects of irradiation were observed.Complete clinical response(CR) rate of the radiated sites was 54.5%(6/11),partial response(PR) rate was 36.4%(4/11),and the overall response rate(CR+PR) was 90.9%.One patient showed no response.Conclusion Local radiotherapy with psolaren plus ultraviolet A and/or interferon maintaining treatment is an effective palliative therapy in the treatment of tumor-stage MF patients.

Epigenetics of cutaneous T-cell lymphoma:biomarkers and therapeutic potentials

Cutaneous T-cell lymphomas(CTCLs)are a heterogeneous group of skin-homing non-Hodgkin lymphomas.There are limited options for effective treatment of patients with advanced-stage CTCL,leading to a poor survival rate.Epigenetics plays a pivotal role in regulating gene expression without altering the DNA sequence.Epigenetic alterations are involved in virtually all key cancerassociated pathways and are fundamental to the genesis of cancer.In recent years,the epigenetic hallmarks of CTCL have been gradually elucidated and their potential values in the diagnosis,prognosis,and therapeutic intervention have been clarified.In this review,we summarize the current knowledge of the best-studied epigenetic modifications in CTCL,including DNA methylation,histone modifications,micro RNAs,and chromatin remodelers.These epigenetic regulators are essential in the development of CTCL and provide new insights into the clinical treatments of this refractory disease.

Low Dose Total Skin Electron Beam Radiation in Cutaneous T-Cell Lymphoma: Review

The treatment of advanced stage MF is especially challenging as single agent overall response rates are in the 35% range and chronic recurrence is the rule. The treatment of CTCL across all stages of disease is aimed at the goal of achieving and sustaining remission. Increasingly, low dose total skin electron beam therapy (TSEBT) is being utilized as a skin directed component in combination therapy for advanced stage CTCL. Researchers are seeking to better define the utility of low dose TSEBT as a method of debulking skin disease while simultaneously treating other disease compartments and in combination with sustained maintenance therapies of both the skin directed and systemic varieties. Data exists showing the efficacy of low dose TSEBT in early and advanced disease. There is also data documenting prolonged treatment responses with TSEBT plus adjuvant skin directed therapies such as PUVA and topical nitrogen mustard. Emerging data examining the role of low dose TSEBT in the prestem cell transplant preparation is also promising. This brief review summarizes the utility of low dose TSEBT in multiagent treatment regimens in CTCL.

Atypical Cutaneous Lymphoproliferative Disorder: A Fatal Mimic of Cutaneous T-Cell Lymphoma in a Patient with HIV Infection

Atypical cutaneous lymphoproliferative disorder (ACLD) is a rare condition that has been associated with HIV infection. Patients with ACLD present with diffuse, erythematous and pruritic skin lesions accompanied by generalized lymphadenopathy. The clinical characteristics of ACLD overlap most notably with several other conditions including Mycosis Fungoides/Sézary Syndrome (MF/SS), a cutaneous lymphoma of T-cell lineage. Unlike Mycosis Fungoides, the noxious infiltrates of ACLD are not monoclonal but polyclonal and consist of cytotoxic CD8+ T-cells instead of CD4+ T-cells or B-cells. Highly active antiretroviral therapy (HAART) has been reported to improve ACLD. We describe the case of a Caucasian man with longstanding HIV infection who presented with severe erythroderma. Skin and lymph node biopsies showed polyclonal CD8+ T-cell infiltrates. Gene rearrangement studies did not reveal an obvious clonal disorder. Hallmark peripheral blood findings consisting of a severe depletion of CD4+ T-lymphocytes and markedly elevated CD8+ cells provided an important diagnostic clue. Despite the purported benefits of HAART in ameliorating this disorder, erythroderma and extreme pruritus improved only after the patient began taking mycophenolate mofetil and hydroxyurea. Unfortunately, he succumbed to complications of methicillin-resistant Staphylococcus aureus septicemia. We alert readers to this rare HIV-associated condition which may mimic other benign and malignant skin conditions and briefly discuss diagnostic and therapeutic options.

Natural killer reprogramming in cutaneous T-cell lymphomas: Facts and hypotheses

To better understand the pathogenesis of Sézary cells, distinguish them from reactive skin-infltrating T-cells and improve disease treatment, efforts have been made to identify molecular targets deregulated by the malignant process. From immunophenotypic analysis and subtractive differential expression experiments to pan-genomic studies, many approaches have been used to identify markers of the disease. During the last decade several natural killer （NK） cell markers have been found aberrantly expressed at the surface of Sézary cells. In particular, KIR3DL2/CD158k, expressed by less than 2% of healthy individuals CD4＋ T-cells, is an excellent marker to identify and follow the tumor burden in the blood of Sézary syndrome patients. It may also represent a valuable target for specifc im-munotherapy. Other products of the NK cluster on chromosome 19q13 have been detected on Sézary cells, raising the hypothesis of an NK reprogramming process associated with the malignant transformation that may induce survival functions.

Rothmund-thomson syndrome and cutan T-cell lymphoma in childhood

We report a 3-year-old girl suffering from RothmundThomson Syndrome (RTS). The patient at birth had multiplex anomalies: poikilodermatous rash, sceletal abnormalities: palatoschisis, micrognathi, aplasia radii, hypoplastic right and left thenar and thumbs, pesequinus on both site, ectopy renis. The patient in the later ages was detected dental malformation, facial dysmorfism. At the age 3, she had lasion in her muscle. After biopsy, histological examination showed cutan T-cell lymphoma. The patient is the first case who had cutan T-cell lymphoma associated with RTS in this young age.

Primary Cutaneous Gamma Delta T Cell Lymphoma: A Clinicopathological Analysis

Primary cutaneous gamma-delta T-cell lymphoma (PCGD-TCL) is a very uncommon and extremely aggressive tumor, and is described in the newly re-vised World health organization for research and treatment of cancer classification of cutaneous lymphomas. A 43-year-old male patient presented with a 4 months history of cutaneous lesion over upper lip, without plaque and any constitutional symptom. Histopathological examination of skin biopsy revealed infiltration of atypical lymphocytes with hyperchromatic irregular nuclei. Immunophenotyping pattern of skin biopsy was compatible with PCGD-TLC. It is a highly aggressive tumor resistant to chemotherapy, immunotherapy, and radiation therapy. The GDTCL is characterized by a worse prognosis with a median survival of 15 months. Early diagnosis is essential and aggressive therapy is necessary.

Primary cutaneous anaplastic large cell lymphoma with subsequent leg involvement

Primary cutaneous anaplastic large cell lymphoma(CALCL)is regarded as an indolent type of cutaneous T-cell lymphoma.However,a few recent publications revealed that C-ALCL patients with initial leg involvement had significantly worse survival than those without initial leg involvement.Herein,we report a case of C-ALCL with subsequent leg involvement,which led to death after chemoradiation therapy.A 75 years old Japanese man presented with multiple erythematous nodules in his left arm and the side of his left chest.Histopathological and immunohistochemical studies led to the diagnosis of primary C-ALCL.At the initial diagnosis,no leg lesion was found.One year after the initial diagnosis,C-ALCL appeared in his right lower thigh and left hip.Radiation therapy,low-dose etoposide and CHOP therapy were performed;however,the patient died of malignant lymphoma 4 years after the initial diagnosis.We speculated that the occurrence of subsequent leg involvement may also be indicative of a worse prognosis,as in the case with initial leg involvement in C-ALCL.Therefore,we propose that C-ALCL patients with initial or subsequentleg involvement should be classified as a distinct clinicopathological variant of C-ALCL("leg-type"involvement)and that they may require intense therapy.

Clinicopathology, immunophenotype, T cell receptor gene rearrangement, Epstein-Barr virus status andp53 gene mutation of cutaneous extranodal NK/T-cell lymphoma, nasal-type

Background Extranodal natural killer/T-cell （NK/T cell） lymphoma, nasal-type, is a rare lymphoma. Skin is the second most common site of involvement after the nasal cavity/nasalpharynx. The aim of this study was to investigate the clinicopathologic features, immunophenotype, T cell receptor （TCR） gene rearrangement, the association with Epstein-Barr virus （EBV） infection and p53 gene mutations of the lymphoma. Methods The clinicopathologic analysis, immunohistochemistry, in situ hybridization for EBERI/2, TCR gene rearrangement by polymerase chain reaction （PCR）, mutations of p53 gene analyzed by PCR and sequence analysis were employed in this study. Results In the 19 cases, the tumor primarily involved the dermis and subcutaneous layer. Immunohistochemical staining showed that most of the cases expressed CD45RO, CD56, CD3E, TIA-1 and GrB. Three cases were positive for CD3 and two cases were positive for CD30. Monoclonal TCRy gene rearrangement was found in 7 of 18 cases. The positive rate of EBERI/2 was 100%. No p53 gene mutation was detected on the exon 4-9 in the 18 cases. Fifteen cases showed Pro （proline）/Arg （arginine） single nucleotide polymorphisms （SNPs） on the exon 4 at codon 72. The expression of p53 protein was 72% （13/18）immunohistochemically. Conclusions Cutaneous NK/T-cell lymphoma is a rare but highly aggressive lymphoma with poor prognosis. No p53 gene mutation was detected on the exon 4-9, and Pro/Arg SNPs on p53 codon 72 were detected in the cutaneous NK/T-cell lymphoma. The overexpression of p53 protein may not be the result of p53 gene mutation.

Sezary syndrome： a rare form of cutaneous T-cell lymphoma

Sezary syndrome （SS） is an erythrodermic, aggressive, cutaneous T-cell lymphoma （CTCL） characterized by a malignant T-cell clone that localizes in the blood and skin, and its diagnosis is based on clinical, histological and biological features. Here we describe a typical case of SS.

阴茎皮肤T细胞淋巴瘤继发Fournier坏疽(1例报告)

目的:探讨阴茎皮肤T细胞淋巴瘤的临床表现、病理特点、诊断和治疗。方法:男性患者,49岁,因阴茎皮肤红斑溃破后阴茎肿胀伴发热2个月,抗感染治疗无效。包皮背侧切开术后病情无好转,并继发阴茎皮肤Fournier坏疽。再行清创引流,病变组织送病理检查。结果:病理证实为阴茎皮肤T细胞淋巴瘤,免疫组化染色CD3(++)、CD45RO(++)、CD30(-)、CD79a(-)、CD20(-)、HMB45(-)。给予干扰素和窄波紫外线治疗2周无效,出现阴茎海绵体坏死、阴囊皮肤溃烂,行阴囊内容物和阴茎全切除,病理证实海绵体和右侧睾丸受累。结论:阴茎皮肤T细胞淋巴瘤是一种罕见的阴茎部肿瘤,因早期缺乏特异性临床表现而易被误诊,病理检查是确诊依据。

A case of advanced mycosis fungoides with comprehensive skin and visceral organs metastasis:sensitive to chemical and biological therapy

Mycosis fungoides is a common cutaneous T-cell lymphoma,which is usually characterized by chronic,indolence progression,with absence of typical symptoms in early stage,metastasis to lymph nodes,bone marrow and visceral organs in later stage and ultimately progression to systemic lymphoma.It can result in secondary skin infection which is a frequent cause of death. At present,no curative therapy existed.Therapeutic purpose is to induce remission,reduce tumor burden and protect immune function of patients.A case of patient with advanced severe mycosis fungoides receiving CHOP plus interferon a -2a was reported here,with disease-free survival of 7 months and overall survival of over 17.0 months,and current status as well as developments of mycosis fungoides were briefly introduced.

Overview of genetic signaling pathway interactions within cutaneous malignancies

Melanoma and non-melanoma cutaneous malignancies are some of the leading causes of cancer-related death in the United States.Though melanoma is more known to have a high mortality rate,the total mortality per year is nearly equal for between melanoma and non-melanoma skin cancer.Moreover,the non-melanoma types of cutaneous malignancies have potential to become locally invasive and even metastasize with very little to no treatment options when advanced.The development of these malignancies involves various genetic pathways through the four hallmarks of cancer development:malignant cell growth,apoptosis evasion,the use of supporting stroma and vascularization,and modulating and promoting an inadequate immune response.The genetic signaling pathways of basal cell carcinoma,squamous cell carcinoma,verrucous carcinoma,basosquamous cell carcinoma,melanoma,and cutaneous T-cell lymphoma interact with each other through genetic predisposition as well as with environmental exposures.Furthermore,solar ultraviolet radiation and chronic inflammatory states are found to initiate the progression of many of these cutaneous malignancies.This paper includes validated models of genetic pathways,emerging pathways,and crosstalk between genetic pathways through the four hallmarks of cancer development.Moreover,unlike most reviews addressing oncogenetics of the well-recognized,as well as newly discovered,genetic pathway mutations,this review stresses that these pathways are not fixed but rather exist in dynamic,interrelated,interactive,complex,and adaptive flux states.

High Dose Rate (HDR) Brachytherapy for Mycosis Fungoides of the Wrist

Mycosis fungoides (MF) is the most common cutaneous T-cell lymphoma accounting for approximately half of all cutaneous T-cell lymphomas. Radiation therapy is an effective treatment for early stage MF and has been shown to result in long-term disease-free intervals, with even curative potential. Radiation is also effective as palliative treatment for the localized lesion resistant to the topic or other treatments. In the current study, we report using high dose rate (HDR) radiation treatment for a patient with resistant mycosis fungoides involving the wrist. We report a convenient treatment with an ideal radiation dose distribution, and a excellent clinical outcome.