Mycosis Fungoides Patients Research Articles

Experimental modifications lead to an improved SNV detection in panel sequencing of a mycosis fungoides patient

Experimental modifications lead to an improved SNV detection in panel sequencing of a mycosis fungoides patient

Cobomarsen, an oligonucleotide inhibitor of miR-155, co-ordinately regulates multiple survival pathways to reduce cellular proliferation and survival in cutaneous T-cell lymphoma.

miR-155, a microRNA associated with poor prognosis in lymphoma and leukaemia, has been implicated in the progression of mycosis fungoides (MF), the most common form of cutaneous T-cell lymphoma (CTCL). In this study, we developed and tested cobomarsen (MRG-106), a locked nucleic acid-modified oligonucleotide inhibitor of miR-155. In MF and human lymphotropic virus type 1 (HTLV-1+) CTCL cell lines invitro, inhibition of miR-155 with cobomarsen de-repressed direct miR-155 targets, decreased expression of multiple gene pathways associated with cell survival, reduced survival signalling, decreased cell proliferation and activated apoptosis. We identified a set of genes that are significantly regulated by cobomarsen, including direct and downstream targets of miR-155. Using clinical biopsies from MF patients, we demonstrated that expression of these pharmacodynamic biomarkers is dysregulated in MF and associated with miR-155 expression level and MF lesion severity. Further, we demonstrated that miR-155 simultaneously regulates multiple parallel survival pathways (including JAK/STAT, MAPK/ERK and PI3K/AKT) previously associated with the pathogenesis of MF, and that these survival pathways are inhibited by cobomarsen invitro. A first-in-human phase 1 clinical trial of cobomarsen in patients with CTCL is currently underway, in which the panel of proposed biomarkers will be leveraged to assess pharmacodynamic response to cobomarsen therapy.

Retinoic acid receptor agonist as monotherapy for early-stage mycosis fungoides: does it work?

Background: Retinoids exert their biologic effects by binding to intracellular retinoic-acid receptors (RARs) and/or retinoid X receptors (RXRs). Early-stage mycosis fungoides (MF) has been effectively treated with bexarotene, an RXR-agonist, with overall response (OR) rates 54–67% and complete response (CR) rates 7–27%. Data on RAR-agonist monotherapy are limited.Objective: To analyze the effectiveness of RAR-agonist monotherapy for early-stage MF.Methods: Data on patients with early-stage MF treated with acitretin/isotretinoin monotherapy at a tertiary cutaneous lymphoma clinic in 2010–2017 were collected retrospectively from the medical files.Results: Thirty-five patients (26 males) of median age 50 years (range 8–83) with early-stage MF (IA 9, IB 26) underwent 37 treatment events: 25 acitretin and 12 isotretinoin at a median dosages of 0.3 mg/kg (range 0.2–0.9) and 0.2 mg/kg (range 0.1–0.7), respectively. Median time to maximal response was 6 months for both (range 1–10 for acitretin, 3–16 for isotretinoin); median treatment duration was 10 months (range 3–46) for acitretin, and 9 months (range 3–55) for isotretinoin. OR was 64% for acitretin and 80% for isotretinoin, and CR, 4% and 8%, respectively. Side-effect profiles were as previously reported for retinoids.Conclusions: Early-stage MF patients may benefit from low dose RAR-agonist monotherapy, although the CR rate is low.

Indeterminate Cell Histiocytosis and Mycosis Fungoides. A Hitherto Unreported Association

Indeterminate Cell Histiocytosis and Mycosis Fungoides. A Hitherto Unreported Association

Clinical outcomes and prognostic factors in patients with mycosis fungoides who underwent radiation therapy in a single institution.

PurposeWe aimed to evaluate clinical outcomes including progression-free survival (PFS), overall survival (OS), partial response, and complete response in patients who underwent radiation therapy (RT) for mycosis fungoides (MF). Also, we sought to find prognostic factors for clinical outcomes.Materials and MethodsTotal 19 patients confirmed with MF between 1999–2015 were retrospectively reviewed. Clinical and treatment characteristics, clinical outcomes, and and toxicities were analyzed.ResultsEleven patients were treated with total skin electron beam radiotherapy (TSEBT) and 8 patients with involved field radiation therapy (IFRT) with median dose of 30 Gy, respectively. The median time interval from diagnosis to RT was 2.6 months (range, 0.4 to 87.3 months). The overall response rate was 100%; 11 patients (57.9%) had a complete response and 8 patients (42.1%) a partial response. The presence of positive lymph node at the time of consultation of RT was associated with lower OS (p = 0.043). In multivariate analysis, PFS was significantly lower for patients with increased previous therapies experienced following RT (p = 0.019) and for patients showing PR during RT (p = 0.044). There were no reported grade 3 or more skin toxicities related with RT.ConclusionBoth IFRT and TSEBT are effective treatment for MF patients. Patients with short disease course before RT or complete response during RT are expected to have longer PFS. Positive lymph node status at the initiation of RT was associated woth poor OS, suggesting other treatment modalities such as low-dose RT for patients with low life-expectancy.

Total Skin Electron Irradiation and Sequential Malignancies in Mycosis Fungoides Patients: Longitudinal Study

AimsTo determine the role of total skin electron irradiation (TSEI) as a cause of second malignancies in mycosis fungoides patients. Materials and methodsMycosis fungoides patients referred to TSEI were followed in a longitudinal study. Other diagnosed malignancies were obtained after cross-matching with the Israel National Cancer Registry database. ResultsBetween 1974 and 2010, 197 patients were treated: 134 (68%) men, 63 (32%) women; mean age 58 ± 17years. Topical/systemic treatment was given to 134 (68%) patients. TSEI was given to 104 (68.9%) patients. Seven (4.6%) received sub-TSEI and 40 (26.5%) received focal electron irradiation fields. Forty-six (23%) patients did not receive radiotherapy. The second primaries rate was 6.7 times higher in male mycosis fungoides patients and 13.1 times higher in female mycosis fungoides patients than in the general Israeli population. Malignant melanoma developed in eight patients after radiotherapy, in one patient without irradiation. The skin-related cancer rate after irradiation versus no irradiation was higher (P = 0.018). Combination radiotherapy with psoralen + ultraviolet A and/or nitrogen mustard yielded 11 cases of skin cancer versus no cases without irradiation. ConclusionsMycosis fungoides patients have a high incidence of sequential malignancies. TSEI is associated with higher ‘skin-related cancer’ rates. Close longitudinal follow-up of mycosis fungoides patients is obligatory.

Mycosis fungoides progression could be regulated by microRNAs

Differentiating early mycosis fungoides (MF) from inflammatory dermatitis is a challenge. We compare the differential expression profile of early-stage MF samples and benign inflammatory dermatoses using microRNA (miRNA) arrays. 114 miRNAs were found to be dysregulated between these entities. The seven most differentially expressed miRNAs between these two conditions were further analyzed using RT-PCR in two series comprising 38 samples of early MFs and 18 samples of inflammatory dermatitis. A series of 51 paraffin-embedded samples belonging to paired stages of 16 MF patients was also analyzed. MiRNAs 26a, 222, 181a and 146a were differentially expressed between tumoral and inflammatory conditions. Two of these miRNAs (miRNA-181a and miRNA-146a) were significantly deregulated between early and advanced MF stages. Bioinformatic analysis showed FOXP3 expression to be regulated by these miRNAs. Immunohistochemistry revealed the level of FOXP3 expression to be lower in tumoral MFs than in plaque lesions in paraffin-embedded tissue. A functional study confirmed that both miRNAs diminished FOXP3 expression when overexpressed in CTCL cells. The data presented here suggest that the analysis of a restricted number of miRNAs (26a, 222, 181a and 146a) could be sufficient to differentiate tumoral from reactive conditions. Moreover, these miRNAs seem to be involved in MF progression.

Methotrexate in the treatment of mycosis fungoides - a multicenter observational study in 79 patients.

The first report concerning methotrexate (MTX) in the treatment of Mycosis fungoides (MF) was published in 1964 by Wright. The mechanism of MTX action in the treatment of primary cutaneous T-cell lymphoma (CTCL) has been not explained in detail yet (the anti-inflammatory, immunomodulating, immunosuppressive, and cytostatic actions have been under discussion). This is a retrospective analysis of 79 MF patients in 4 dermatology clinical centers in Poland. Data are presented in terms of the duration, use of MTX, the effectiveness of treatment with MTX in terms of time required to achieve remission, the disease stage, route of administration, age at diagnosis and the dosage. Moreover, the occurrence of side effects depending on the route of administration and duration of therapy with MTX was analyzed. The analysis has revealed that 56 patients (70,9%) had achieved remission on the MTX. The remission began in the 1st month of therapy in 20% of patients, lasted 4 to 6 months in 50% of cases. At least 12 months' remission was confirmed in 25% of patients (2-year-long only in 10% and 3-year-long in 5% of patients). The time to remission was related to the stage of disease at diagnosis as well as to minimal and maximal dose of MTX. The total therapeutic dose of MTX was found important for the course of the disease: higher total dose had prolonged the remission. Despite the common use of MTX in MF patients, relatively few clinical studies have been published. The response of MF subjects to MTX seems to depend on the stage and, more importantly, the dose of MTX treatment. Methotrexate appears to be an effective treatment at every stage of MF; however, it is not devoided of side effects such as infections and elevated level of aminotransferases, which are most common.

Potential of narrow-band ultraviolet B to induce sustained durable complete remission off-therapy in patients with stage I mycosis fungoides

Narrow-band ultraviolet B (NB-UVB) is a first-line therapy for stage I mycosis fungoides (MF), with a complete response in 75%-85% of patients. However, data on long-term disease-free survival (DFS) after therapy are scarce. To assess the long-term DFS after NB-UVB treatment of stage I MF. We used a historic cohort of all stage I MF patients achieving a complete response with NB-UVB who discontinued treatment before 2011. Age at the beginning of phototherapy, sex, stage, skin phototype, number of treatments, total dose, and the length of DFS was collected. Of the 117 patients who started NB-UVB, 93 patients (80%) had a complete response and 56 (60%) were disease free as of March 2017. In a multivariate analysis, DFS was affected independently by age and disease stage only. DFS was longerfor patients <50years old (124months) than those ≥50years old (91months, P=.01) and longer for stage IA patients (131months) than stage IB patients (87.6months, P=.001). The study was retrospective in nature. After a single course of NB-UVB, over a half of stage I MF patients achieved >5years of DFS and were potentially cured. Thus, NB-UVB can be considered a disease-modifying therapy.

PSS5 - Health Insurance Status and Outcomes Among Adults with Mycosis Fungoides in the United States

Previous studies examining the association between insurance status and outcomes in various cancers have demonstrated delayed care and poorer outcomes for Medicaid patients. Early recognition and treatment in MF is essential for survival, highlighting the importance of quality access to care. Studies evaluating insurance status and survival outcomes in mycosis fungoides (MF) are limited. We examined the association between health insurance status and survival in MF. This was a population-based cross-sectional analysis of 2,153 patients with MF using the Surveillance, Epidemiology and End Results (SEER) database. Adult patients between the ages of 18 and 65 with a diagnosis of MF and known insurance status were included. The outcomes recorded were overall survival and cause-specific survival. The survival differences of patients with Medicaid insurance and private insurance were assessed by Kaplan-Meier analysis and log-rank test. Multivariate Cox analyses were performed to analyze the effect of insurance status on overall and cancer-specific mortality. Propensity score matching was performed to reduce the potential selection bias. In multivariate analysis, patients with Medicaid insurance were more likely to die of any cause (hazard ratio [HR], 2.17, 95% confidence interval [CI], 1.20-3.68; p=0.012) and MF (HR, 3.21, 95% CI, 1.60-6.00; p=0.002) than patients with non-Medicaid insurance. In propensity score matched analysis, controlling for clinicopathologic and sociodemographic characteristics, this difference remained for overall survival (p=0.026) and MF-specific survival (p=0.0015). Patients insured by Medicaid were more likely to experience reduced overall survival and MF-specific survival even after accounting for clinical and sociodemographic factors. Addressing barriers to care may help improve outcomes and reduce disparities among MF patients.

Decreased IL-10-producing regulatory B cells in patients with advanced mycosis fungoides

Historically, Bcells have been considered as positive regulators of humoral immune responses. Specific B-cell subsets, however, negatively regulate immune responses and are termed "regulatory B cells" (Bregs). Recently, Bregs have been linked to not only inflammatory and autoimmune diseases, but also malignancies via suppressing anti-tumour immunity. To investigate the involvement of Bregs in advanced mycosis fungoides (MF). The frequency of CD19+CD24hiCD27+ memory B cells and CD19+CD24hiCD38hi transitional B cells (which enrich IL-10-producing Bregs) was examined in peripheral blood from patients with advanced MF (n=11) and healthy controls (n=9) by flow cytometry. The frequency of IL-10-producing Bregs was also measured by flow cytometry. The correlation between frequency or number of B-cell subsets and disease severity markers was also analysed. The frequency of CD19+CD24hiCD27+ Bcells, CD19+CD24hiCD38hi Bcells, and IL-10-producing Bcells was decreased in peripheral blood of advanced MF patients. The frequency and number of these B-cell subsets inversely correlated with serum soluble IL-2 receptor and serum lactate dehydrogenase levels. The development of IL-10-producing Bregs is impaired in patients with advanced MF and a decrease in IL-10-producing Bregs may play an important role in the progression of advanced MF.

Mycosis fungoides in patients with psoriasis: an ongoing issue.

Mycosis fungoides in patients with psoriasis: an ongoing issue.

Eosinophilic infiltrate resembling eosinophilic cellulitis (Wells syndrome) in a patient with mycosis fungoides

Mycosis fungoides (MF) is a T-cell, non-Hodgkin lymphoma that primarily involves the skin. Extracutaneous involvement, such as in the parotidgland, is characteristic of end-stage disease. Eosinophilic cellulitis, or Wells syndrome, is a rare inflammatory dermatitis that involves a dermal infiltrate of eosinophils. We report a case of an 80-year-old man with a long-standing diagnosis of stage IIB MF who acutely developed parotid gland involvement and marked hypereosinophilia that most likely represented eosinophilic cellulitis. Activated T cells from his MF were likely a trigger factor for the development of his eosinophilic cellulitis. To our knowledge, this is the first reported case of an MF patient with atypical parotid gland involvement andeosinophilic cellulitis.

Etoposide as a single agent in the treatment of mycosis fungoides: A retrospective analysis.

Several chemotherapy agents have shown efficacy in the treatment of mycosis fungoides (MF). In the literature, there is limited data on the use of single agent etoposide for MF. We aimed to retrospectively review our experience with single agent etoposide in the treatment of advanced-stage or refractory early-stage MF with focus on analyzing its efficacy and safety. We included 13 MF patients who were treated with single agent etoposide. Patients were identified through the Cutaneous T Cell Lymphoma Database of Indiana University that involves patients treated from 2006 to 2016. Overall nine patients (69%) responded to treatment. No complete response was identified. Median time to response was 12.5 weeks (range: 6-25.4). Median duration of response was 43 weeks (range: 5-60) and median time to treatment failure was 31.3 weeks (range: 12.4-230). Hematological toxicity was observed in eight patients including two patients with grade 4 neutropenia and/or lymphopenia leading to sepsis. Higher doses of etoposide were significantly correlated with higher grades of anemia, neutropenia or lymphopenia (p < .05). Our study demonstrates that etoposide is an effective treatment for MF and may be considered in selected patients with progressive MF who have failed other treatments.

Presence of Chlamydophila pneumoniae DNA in blood cells is a frequent event in patients with the late stage of primary cutaneous lymphomas and with atopic dermatitis.

IntroductionMicrobial infection and associated super antigens have been implicated in the pathogenesis of cutaneous T-cell lymphoma (CTCL), and many patients die from complicating bacterial infections. It has been postulated that Chlamydophila pneumoniae (C. pneumoniae) infection may be involved in the pathogenesis of Mycosis fungoides (MF) but published data are limited and controversial.AimTo analyze the frequency of (C. pneumoniae) DNA presence in blood samples of lymphoma cases.Material and methodsUsing Q-PCR method we analyzed the presence of DNA in the blood samples obtained from 57 patients with CTCL (55 – mycosis fungoides (MF)/Sézary syndrome (SS), one primary cutaneous anaplastic large cell lymphoma (CD30+) and one NKT cell lymphoma) and 3 patients with cutaneous B-cell lymphomas, and 120 individuals from control groups (40 patients with psoriasis, 40 patients with atopic dermatitis and 40 healthy controls).Results Chlamydophila pneumoniae DNA was identified in 13 of 55 cases in the MF/SS group (23.6%), in 1 patient with CD30+ large cell lymphoma and in 1 of 3 patients with B-cell lymphoma. The presence of C. pneumoniae was confirmed in 1 of 40 psoriatic patients (2.5%), in 5 of 40 patients with atopic dermatitis (12.5%) and in none of 40 healthy individuals. Presence of C. pneumoniae DNA in MF patients was strongly associated with disease progression; rs = 0.756; p = 0.0123 for groups IA → IVB, and was noted more frequently in advanced (III + IV) stages than in early (I–II) stages (p = 0.0139). There are no differences in the mean age of MF/SS patients with and without infection.ConclusionsThe presence of C. pneumoniae DNA in the blood cells is a frequent event in late stages of MF/SS and may be explained by Th2 shift and suppression of the immune system during the course of the disease.

Common Presentations of Mycosis Fungoides in Pakistani Population: A Clinicopathological Study

Objective: To study the different clinical, pathological and immunophenotypic features in patients of Mycosis fungoides presenting to Civil Hospital Karachi. Methods: A case series consisting of 10 patients was conducted at the Dermatology department of Civil Hospital Karachi, from January 2013 to December 2016.A Performa was used after written consent from the patients and the head of the department to record the history, physical examination and laboratory findings. Results: Out of the 10 patients, 3 had stage IIB, 3 had stage III, 1 patient evolved from stage III to IV and 3 had stage IV disease, 2 patients were in erythrodermic stage, while 1 evolved from the erythrodermic stage to the tumor stage. 3 patients showed psoriasiform appearance, 3 showed tumor d emblee stage, while only 1 patient revealed poikilodermatous appearance. Male to female ratio was 5:1. Histopathological and immunophenotypic markers were consistent with those of mycosis fungoides. Five patients were previously treated as eczema or psoriases. Conclusion: Knowledge about the varied presentations of mycosis fungoides would lead to better understanding, and help us with the diagnostic challenges in our population

Phase 1 Study of the Safety and Efficacy of MRG-106, a Synthetic Inhibitor of microRNA-155, in CTCL Patients

Phase 1 Study of the Safety and Efficacy of MRG-106, a Synthetic Inhibitor of microRNA-155, in CTCL Patients

Therapeutic reduction of cell-mediated immunosuppression in mycosis fungoides and Sézary syndrome.

Tumor progression is associated with progressive immunosuppression mediated in part by T regulatory cell(s) (Treg) and/or myeloid-derived suppressor cell(s) (MDSC). Development of strategies to reduce populations of immune cells with suppressive function in cancer patients may enable the induction or recovery of immunity against tumor cells, which may limit or reverse disease progression. With a goal of developing Treg and MDSC neutralizing strategies to treat mycosis fungoides (MF) and Sézary syndrome (SzS), we determined the association between disease stage and suppressor cell populations in patients with MF/SzS, including those responding to therapy. We found elevations in Treg populations, across Treg subtypes, in patients with SzS, and these Treg markedly suppressed proliferation of autologous CD4+CD25- responder T cells. Interestingly, while MDSC numbers were not increased in MF/SzS patients, MDSC from patients with stage IB and above produced significantly more reactive oxygen species than those from stage IA MF patients and control cohorts. Therapy with the CD25-targeting agent denileukin diftitox or IFN-α2b was associated with a reduction in Treg numbers or MDSC function, respectively. These studies identify potential mechanisms of action for these therapies and support the development of coordinated strategies targeting both Treg and MDSC activities in patients with MF/SzS.

Folliculotropism Does Not Affect Overall Survival in Mycosis Fungoides: Results from a Single-Center Cohort and Meta-Analysis

Background: Folliculotropic mycosis fungoides (FMF) is a distinct subtype of mycosis fungoides (MF) with unique clinicopathological features. The medical literature suggests that FMF has a more aggressive course and worse survival than classic MF. Previous studies do not use standardized treatment, and no studies have reported an association between treatment response and overall survival (OS). Objective: To compare OS for MF, FMF, and Sézary syndrome (SS) patients. Methods: Data were collected retrospectively from 218 patients (171 MF, 15 SS, 32 FMF) treated in a single academic center between 1970 and 2016. Results: Negative predictors of OS were age (OR = 1.07), male sex (OR = 1.63), and stage IIB, III, and IV (OR = 4.10, 5.42, and 7.54, respectively, vs. stage IA). Lack of initial PUVA response was strongly associated with negative OS (OR = 3.08). Kaplan-Meier analysis of age-, sex-, and stage-matched MF and FMF patients found similar OS between the 2 groups. The 5-year OS was 91% for FMF and 74% for MF. Meta-analysis of current data and 2 published studies where survival of FMF patients was compared to MF did not reveal statistically significant differences between these 2 diseases. Conclusions: When patients were matched for age, sex, and disease stage, folliculotropism did not affect OS in MF.

Plasma miR-155, miR-203, and miR-205 are Biomarkers for Monitoring of Primary Cutaneous T-Cell Lymphomas.

Primary cutaneous T-cell lymphomas (CTCL) affect the skin and tend to transform and spread. CTCL involves primarily the Mycosis fungoides (MF) and more aggressive Sezary syndrome (SS). Oncogenic microRNAs (miRs) are stable epigenetic inhibitors often deregulated in the tumour and detectable as biomarkers in non-cellular fractions of peripheral blood. The tumour-specific expression of miR-155, miR-203, and miR-205 was shown to correctly diagnose CTCL. We herein asked whether these microRNAs can be used as plasma biomarkers for clinical CTCL monitoring. Patients with CTCL (n = 10) and controls with non-malignant conditions (n = 11) repeatedly donated plasma samples every ca. five months. MicroRNAs were detected in the plasma samples by specifically-primed RT-PCR followed by multivariate analyses of the miR expression dynamics. We herein established the plasma miR-classifier for detecting CTCL based on the miR-155 upregulation and miR-203/miR-205 downregulation with 100% specificity and 94% sensitivity. The 3-miR-score in the consecutive samples coincided with the clinical outcome of MF and SS patients such as the therapy response or changes in the clinical stage or tumor size. Quantitation of the selected microRNAs in plasma is a specific and straightforward approach for evaluating CTCL outcome representing, thus, a valuable tool for CTCL diagnostics and therapy response monitoring.