Oncogenomic analysis of mycosis fungoides reveals major differences with Sezary syndrome

Mycosis fungoides (MF), the most common cutaneous T-cell lymphoma, is a malignancy of mature, skin-homing T cells. Sézary syndrome (Sz) is often considered to represent a leukemic phase of MF. In this study, the pattern of numerical chromosomal alterations in MF tumor samples was defined using array-based comparative genomic hybridization (CGH); simultaneously, gene expression was analyzed using microarrays. Highly recurrent chromosomal alterations in MF include gain of 7q36, 7q21-7q22 and loss of 5q13 and 9p21. The pattern characteristic of MF differs markedly from chromosomal alterations observed in Sz. Integration of data from array-based CGH and gene-expression analysis yielded several candidate genes with potential relevance in the pathogenesis of MF. We confirmed that the FASTK and SKAP1 genes, residing in loci with recurrent gain, demonstrated increased expression. The RB1 and DLEU1 tumor suppressor genes showed diminished expression associated with loss. In addition, it was found that the presence of chromosomal alterations on 9p21, 8q24, and 1q21-1q22 was associated with poor prognosis in patients with MF. This study provides novel insight into genetic alterations underlying MF. Furthermore, our analysis uncovered genomic differences between MF and Sz, which suggest that the molecular pathogenesis and therefore therapeutic requirements of these cutaneous T-cell lymphomas may be distinct.     

No evidence of HTLV-I infection in patients with mycosis fungoides and Sezary syndrome

The involvement of human T-cell lymphotropic virus type I (HTLV-I) in the etiology of cutaneous T-cell lymphomas (CTCL) is still controversial. The aim of the study was to evaluate the role of HTLV-I in the pathogenesis of mycosis fungoides (MF) and Sezary syndrome (SS) in Polish patients. The studied group consisted of 42 patients with MF, 5 with SS and 25 with chronic dermatitis. DNA was extracted from snap-frozen and paraffin-embedded skin biopsies and from peripheral blood. Polymerase chain reaction (PCR or nested PCR) was carried out for amplification of different regions of HTLV-I genome. Primer sets flanking pX, p 19, U5, tax and pol genes were used in the investigation. The presence of HTLV-I antibody was examined in 46 sera samples with the use of anti-HTLV-I/II EIA test. HTLV-I antibodies were not detected in any collected sera samples. PCR with two primer sets homologous to the pX region of HTLV-I showed negative results in all samples investigated. To confirm these results two other primer pairs specific for U5 and gag regions were designed. With these primer pairs no PCR product, except that in positive control, was observed. For more sensitive amplification a nested-PCR with pol and tax specific primers was performed. HTLV-I probably does not play an important role in the pathogenesis of MF in Polish patients.     

A novel lymphocyte differentiating factor in serum of patients with mycosis fungoides and Sezary syndrome.

Sera from 13 patients with mycosis fungoides and 2 with Sezary syndrome were tested for activity that induces lymphocyte differentiation. Induction of Thy-1.2 antigen and surface immunoglobulin were used, respectively, to measure T- and B-cell differentiation. The indicator cells were null lymphocytes from the spleens of congenitally athymic nude mice. Normal serum induced some T-cell but no B-cell differentiation. The T-cell-inducing activity was ascribed to thymic hormone and declined with advancing age. A totally different pattern emerged with patient serum. T-cell-inducing activity was significantly more active than in normal serum (p less than 0.001). This activity did not decline with advancing age and was not inhibited by a concentration of ubiquitin, which blocks nonspecific beta-adrenergic induction. B-cell-inducing activity was also present. This novel serum factor (or factors) is a potent inducer of T- and B-lymphocyte differentiation and is associated with neoplastic lymphoproliferation of the T-cell series.     

Evolving insights in the pathogenesis and therapy of cutaneous T-cell lymphoma (mycosis fungoides and Sezary syndrome)

Cutaneous T-cell lymphomas (CTCL) are a heterogeneous group of malignancies derived from skin-homing T cells. The most common forms of CTCL are Mycosis Fungoides (MF) and Sezary Syndrome (SS). Accurate diagnosis remains a challenge due to the heterogeneity of presentation and the lack of highly characteristic immunophenotypical and genetic markers. Over the past decade molecular studies have improved our understanding of the biology of CTCL. The identification of gene expression differences between normal and malignant T-cells has led to promising new diagnostic and prognostic biomarkers that now need validation to be incorporated into clinical practice. These biomarkers may also provide insight into the mechanism of development of CTCL. Additionally, treatment options have expanded with the approval of new agents, such as histone deacetylase inhibitors. A better understanding of the cell biology, immunology and genetics underlying the development and progression of CTCL will allow the design of more rational treatment strategies for these malignancies. This review summarizes the clinical epidemiology, staging and natural history of MF and SS; discusses the immunopathogenesis of MF and the functional role of the malignant T-cells; and reviews the latest advances in MF and SS treatment.     

Phase 2 study of alemtuzumab (anti-CD52 monoclonal antibody) in patients with advanced mycosis fungoides/Sezary syndrome

This phase 2 study evaluated the safety and efficacy of alemtuzumab in 22 patients with advanced mycosis fungoides/Sézary syndrome (MF/SS). Most patients had stage III or IV disease, reduced performance status, and severe itching. The overall response (OR) rate was 55%, with 32% of patients in complete remission (CR) and 23% in partial remission (PR). Sézary cells were cleared from the blood in 6 of 7 (86%) patients, and CR in lymph nodes was observed in 6 of 11 (55%) patients. The effect was better on erythroderma (OR, 69%) than on plaque or skin tumors (OR, 40%) and in patients who had received 1 to 2 previous regimens (OR, 80%) than in those who had received 3 or more prior regimens (OR, 33%). Itching, self-assessed on a 0 to 10 visual analog scale, was reduced from a median of 8 before treatment to 2 at end of therapy. Median time to treatment failure was 12 months (range, 5-32+ months). Cytomegalovirus (CMV) reactivation (causing fever without pneumonitis and responding to ganciclovir) occurred in 4 (18%) patients. Six additional patients had suspect or manifest infection (fever of unknown origin, 3; generalized herpes simplex, 1; fatal aspergillosis, 1). One patient had fatal Mycobacterium pneumonia at 10+ months. All serious infectious adverse events (except CMV) occurred in patients who had received 3 or more prior regimens. Progression of squamous cell skin carcinoma was noted in 1 patient. Alemtuzumab shows promising clinical activity and an acceptable safety profile in patients with advanced MF/SS, particularly in patients with erythroderma and severe itching and those who were not heavily pretreated.     

Atypical mycosis fungoides with cerebral involvement

Summary This report concerns a 17-year-old male patient with atypical mycosis fungoides (m.f.). Initial examination revealed generalized lymphoma and uncharacteristic livid skin efflorescence. The patient developed bone marrow involvement and meningeal leukaemia 6 months later. Diagnosis was confirmed by immunohistochemistry and electron microscopy. Aggressive chemotherapy yielded no response.     

A retrospective comparative outcome analysis following systemic therapy in Mycosis fungoides and Sezary syndrome

Cutaneous T‐cell lymphomas (CTCL), with few exceptions, remain incurable and treatment is largely palliative. We performed a retrospective analysis of systemic treatment outcomes of patients diagnosed with MF/SS. We identified 223 patients with MF/SS evaluated at a single institution from 1997 to 2013. Disease stage at diagnosis, time of treatment, and treatments received were retrospectively analyzed using our CTCL database. The primary endpoint was time to next treatment (TTNT). Treatment outcomes were analyzed using Kaplan–Meier method and comparisons among groups were made using log‐rank analysis. A superior TTNT was associated with retinoid or interferon therapies when compared with HDAC inhibitors or systemic chemotherapy. Retinoids and interferon were associated with superior TTNT in both limited‐stage and advanced stage disease. Extracorporeal photophoresis (ECP) had a superior TTNT in Sezary Syndrome. HDAC inhibitors and chemotherapy were associated with inferior TTNT in both limited stage disease and advanced stage disease. With the exception of interferon, retinoids, or ECP, durable responses are rarely achieved with systemic therapies in MF/SS patients, particularly those with advanced‐stage disease. Therefore, clinical trial participation with novel agents should be encouraged. Am. J. Hematol. 91:E491–E495, 2016. © 2016 Wiley Periodicals, Inc.     

Sclerodactyly in a patient with mycosis fungoides

A 44-year-old man had mycosis fungoides and generalized plaque disease involving 80% of his skin surface with diffuse lymphadenopathy and alopecia of the scalp and groin. In addition, distal to the wrist, there were sclerodermatous changes involving the skin of the hands with associated sclerodactyly of all digits with loss of normal palmar creases. There were no subungual telangiectasis or digital ulcers. The changes in the hand that occurred in this case, no doubt arose as a result of the patient's neoplasm. Abnormalities of collagen biosynthesis and degradation probably occur with mycosis fungoides as a result of the extensive infiltration of the epidermis and dermis with malignant cells. To our knowledge, the association of sclerodactyly with mycosis fungoides has not been previously reported.     

Pre-eclampsia is associated with Helicobacter pylori seropositivity in Italy

OBJECTIVES: Pre-eclampsia (PE) is characterized by an excess of inflammation and endothelial dysfunction. Helicobacter pylori (H. pylori) causes chronic inflammatory changes and endothelial damage. We investigated the prevalence of seropositivity for IgG against H. pylori and cytotoxin-associated antigen A (CagA) in PE patients and the presence of H. pylori DNA in their placentas. METHODS: We tested 47 pregnant women with PE and 47 with uneventful pregnancies for serum antibodies against H. pylori (enzyme immunoassays) and CagA protein (immunoblot assays). In 20 of them (10 normal and 10 PE) we assessed the presence, in the placenta, of H. pylori DNA by means of nested polymerase chain reaction (PCR). The odds ratios (OR) and 95% confidence intervals (CI), adjusted for parity, were calculated using logistic regression analysis to assess the risk of PE associated with H. pylori infection. RESULTS: Helicobacter pylori seropositivity frequency was higher in mothers with PE (51.1%) compared to women with uneventful pregnancy (31.9%) (OR, 2.668; 95% CI, 1.084-6.566; P = 0.033). The difference was even greater for CagA seropositivity (80.9 and 14.9%, respectively) (OR, 26.035; 95% CI, 8.193-82.729; P < 0.001). All placentas were negative for H. pylori DNA. CONCLUSIONS: Helicobacter pylori, and especially strains carrying the CagA gene, may contribute to the inflammatory mechanisms involved in the pathogenesis of PE.     

Minimal change glomerulonephropathy and interstitial infiltration with mycosis fungoides

The nephrotic syndrome developed in a patient with mycosis fungoides shortly after systemic involvement by his tumor occurred. Renal biopsy examination revealed atypical lymphocytic interstitial infiltration and changes consistent with minimal change glomerulonephropathy. The patient's proteinuria decreased following steroid therapy. This is the first report of an association between minimal change glomerulonephropathy and a proven T-cell malignant lymphoma. The implications are discussed with reference to the literature.     

Combined therapy for patients with mycosis fungoides.

In a comprehensive mycosis fungoides program, 60 patients have been seen with a pathologic diagnosis of this disease. Forty-four patients with advanced disease were referred for radiation therapy. Three treatment techniques were identified in which 14 patients were treated with localized fields using electrons or whole-body electron-beam therapy with doses of less than 3000 rads, 21 patients were treated using the Stanford technique with tissue doses of between 3000 and 4000 rads, and nine patients were treated with six cycles of mechlorethamine, vincristine, prednisone, and procarbazine or cyclophosphamide, vincristine, prednisone, and procarbazine following the electron-beam therapy. The actuarial survival rate was 45% at 1 year for the 14 patients with localized electron-beam therapy, whereas the actuarial survival rates were 83% for patients treated with whole-body electron-beam therapy and 100% for patients treated with whole-body electron-beam therapy followed by four-drug chemotherapy. The recurrence-free interval for these three groups correlates with these observations. A central nervous system recurrence has been observed in the combined-therapy group.     

Anti-hepatitis C virus seropositivity is not associated with metabolic syndrome irrespective of age,gender and fibrosis

Although many studies have tried to clarify the association between hepatitis C virus (HCV) infection and metabolic syndrome, few studies have comprehensively assessed their relationship stratified by different demographic characteristics. We aimed to investigate the correlation between metabolic syndrome and anti-HCV seropositivity in Taiwan. This study enrolled consecutive subjects who had received health check-up services at Taipei Veterans General Hospital from 2002 to 2009. Metabolic syndrome was diagnosed according to the criteria defined by the International Diabetes Federation Task Force on Epidemiology and Prevention. Among the 30616 subjects enrolled in this study, the prevalence of positive anti-HCV serology was 2.7%, and 28.8% were diagnosed with metabolic syndrome. By multivariate analysis, metabolic syndrome was associated with higher body mass index, older age, male sex, a higher level of alanine aminotransferase, gamma-glutamyltransferase, platelet count and the presence of fatty liver whereas anti-HCV seropositivity was not an independent variable for metabolic syndrome. Further stratifying the subjects by age and sex, and there was still no significant difference in HCV status between those with and without metabolic syndrome. Moreover, the stage of liver fibrosis represented by aspartate aminotransferase to platelet ratio index was also not correlated with metabolic syndrome in the subjects with anti-HCV seropositivity. In conclusion, although subjects with anti-HCV seropositivity had higher fasting glucose levels and lower cholesterol and triglyceride levels compared to those with negative anti-HCV test, anti-HCV seropositivity was not associated with metabolic syndrome based on the current diagnostic criteria irrespective of age, gender and the stage of hepatic fibrosis.