Early Mycosis Fungoides Patients Research Articles

Dysregulation of Plasma miR-146a and miR-155 Expression Profile in Mycosis Fungoides Is Associated with rs2910164 and rs767649 Polymorphisms.

Diagnosis of Mycosis Fungoides (MF) may be challenging, due to its polymorphic nature. The use of miRNAs as biomarkers to assist in diagnosis has been investigated, mainly in skin lesion biopsies. The purpose of this study is to evaluate the plasma levels of miR-146a and miR-155 in MF patients and to investigate their association with SNPs of their genes. Plasma miRNAs were quantified by RT-qPCR. Genomic DNA was used for SNPs' genotyping by Sanger sequencing. Plasma levels of miR-146a and miR-155 were significantly higher in patients vs. controls, in early MF patients vs. controls, and in advanced vs. early MF patients. Both miRNAs' levels were significantly higher in stage IIB vs. early-stage patients. miR-155 plasma levels were significantly higher in patients with skin tumors or erythroderma. CC genotype (rs2910164 C>G) was significantly more frequent in healthy controls and associated with lower MF risk and lower miR-146a levels. The AA genotype (rs767649 T>A) was significantly more frequent in patients and correlated with increased MF risk and increased miR-155 levels. The combination of GG+AA was only detected in patients and was correlated with higher MF susceptibility. Increased mir-146a and mir-155 plasma levels in MF is an important finding to establish putative noninvasive biomarkers. The presence of SNPs is closely associated with miRs' expression, and possibly with disease susceptibility.

Bio-P-07 - Evaluation of mir-146a and mir-155 plasma expression levels in patients with mycosis fungoides and detection of single nucleotide polymorphisms in their sequence

<h3>Introduction:</h3> Mycosis fungoides (MF), the most common form of cutaneous T-cell lymphomas presents with a broad spectrum of clinical and histopathologic manifestations. Diagnosis is often delayed, especially at the early stages. Clinicopathologic correlation and integration of molecular data is essential for a timely diagnosis and treatment. The use of microRNAs as biomarkers in biopsies and/or biological fluids has gained great interest over the last years. The aim of the present study was to analyze the expression levels of microRNAs (mir)-146a and -155 in the plasma of MF patients and healthy volunteers and to detect the presence of single nucleotide polymorphisms (SNPs) in their genes. <h3>Patients and methods:</h3> The appropriate sample size for statistical power equal to 0.94 (1–β=94%) and significance level at 0.05 (α=5%) was determined by a pilot study, using G.Power 3.1.9.2. The optimal sample size was calculated at n=82, with a ratio of MF patients/healthy individuals equal to 1:1. All samples were derived from consenting individuals. The mirs' plasma expression was evaluated with real-time quantitative reverse transcription PCR, and the relative quantity was calculated by the 2^–ΔCt method using cel-mir-39 as reference gene. In a subset of patients, the promoter region and/or the pre-microRNA genomic region of these mirs were scanned for the presence of SNPs in DNA extracted from white blood cells, by Sanger sequencing. Statistical analysis was performed with the statistical package IBM SPSS 25. <h3>Results:</h3> Plasma levels of mir-146a and mir-155 were significantly higher in patients with MF as compared to healthy volunteers (p=0.001 and p=0.028 respectively). Moreover, plasma levels were higher in patients with early MF vs healthy individuals (p=0.001 and p<0.001, for mir-146a and -155, respectively). Patients with advanced MF demonstrated higher expression levels of mir-146a and -155, when compared to early MF patients (p=0.009 and p=0.002). A positive correlation was detected between plasma levels of the two mirs in patients' samples (p<0.001). No correlation was detected between the expression of either mir and age/gender of the patients. The genotypes' frequencies for rs2910164 (CC/CG/GG) were 0.05/0.45/0.55 for MF patients and 0.1/0.54/0.36 for controls. The genotypes' frequencies for rs767649 (TT/AT/AA) were 0.76/0.18/0.06 for MF patients and 0.9/0.1/0 for controls. There was no significand difference in the genotype patterns between patients and controls for either SNP. No SNPs were detected in the pre-mir-155 sequence. <h3>Discussion:</h3> The presence of SNPs regulating mirs' function may need to be evaluated in larger cohorts, while the detection of increased mir-146a and mir-155 plasma levels in MF patients is an important finding in the attempt to establish putative non-invasive biomarkers for prompt diagnosis, prognosis, and adequate therapy of these patients.

Ultraviolet A1 Phototherapy in the Treatment of Early Mycosis Fungoides

Background: Phototherapy has been the mainstay of therapies for early mycosis fungoides (MF). The beneficial role of ultraviolet (UV) light on MF is suggested by the observation that lesions occur on non-sun-exposed areas. Therapeutic light sources that are available today are broadband UVB, psoralen and UVA, narrowband UVB, and long-wave UV (UVA1). Current literature provides increasing evidence on the use of UVA1 to treat MF. Aim: To investigate the treatment responses of early MF patients treated with fixed 30 J/cm² doses of UVA1 phototherapy. Material and Methods: Nineteen patients with early MF, stage IA-IIA of the TNM staging system, received fixed 30 J/cm² doses of UVA1, given 5 times weekly over 5 weeks. Therapeutic effectiveness was assessed by clinical examination and was confirmed by histological evaluation. Results: Of the 19 patients, complete responses were achieved in 12 (63%) and partial responses were achieved in 7 (37%) patients after UVA1 radiation exposures. During the study, UVA1 therapy was well tolerated. During the follow-up, 7 (58%) of the 12 patients with complete response relapsed within 3 months of the UVA1 therapy. Conclusion: The current study provides clinical and histological evidence for the effectiveness of UVA1 (30 J/cm² 5 times a week for 5 weeks) as a skin-directed therapy in the treatment of early MF; however, such a treatment failed to maintain a long and sustained response. Thus, studies to identify the optimal dosing protocol regarding the therapeutic efficacy, the factors affecting relapse time/rate, and the necessity of maintenance treatment are needed.

Combined therapy of psoralen plus ultraviolet A followed by narrow band ultraviolet B photochemotherapy for early stage mycosis fungoides

Only a few clinical reports in the treatment of early mycosis fungoides (MF)(IA, IB, IIA stage) are available in the literature. The purpose of this study was to compare the efficacy and safety of narrow-band UVB and psoralen plus ultraviolet A (PUVA) photochemoterapy in 24 patients with early-stage MF, and explore a new approach for the treatment of early mycosis fungoides. A total of 24 identified early mycosis fungoides patients received PUVA, NB-UVB and a combined therapy of PUVA followed by NB-UVB (n = 9/6/9) irradiation. A retrospective study was carried out to analyze the sex, age of onset, TNM stage, treatment, and duration of treatment, and times of treatment, duration of maintenance treatment, effective and recurrence in these patients. The data were analyzed using SPSS 17.0 and a two-sided test at the α = 0.05 level of significance was conducted. Of the 24 patients studied, the average treatment was 104.5 (95% CI, 75.71-133.29) times. The average duration of treatment was 12.88 (95% CI, 9.90-15.85) months. The average maintenance treatment time was 11.08 (95% CI, 2.13-20.04) months. The effective rate (CR+PR) of PUVA treatment was 88.9%, recurrence rate was 11.1% (n = 9). In the NB-UVB treatment group, the effective rate was 100.0%, and the recurrence rate was 33.3% (n = 6). In the PUVA followed by NB-UVB (combination therapy) treatment group, the effective rate was 77.8% and the recurrence rate was 55.6% (n = 9). There were no significant differences among the three groups in terms of number of treatments, treatment duration, maintenance treatment duration, effective rate and recurrence rate (P > 0.05). PUVA and NB-UVB are effective and safe in the targeted therapy of early stage mycosis fungoides. The combined therapy of PUVA followed by NB-UVB can reduce the total PUVA dose and risk of developing skin cancer.

Long-term follow-up of early mycosis fungoides patients treated with narrowband ultraviolet B phototherapy

Background: Narrowband ultraviolet B (UVB) provides complete response (CR) in 54–91% of early mycosis fungoides (MF) patients. Data concerning relapse rate and relapse-free interval after discontinuation of therapy need clarification. The purpose of this study was to evaluate the relapse rate and the relapse-free intervals of early MF patients after achieving complete response with narrowband UVB phototherapy. Methods: Retrospective evaluation of data, which belong to early MF patients treated with narrowband UVB phototherapy between May 2000 and July 2010, and followed-up until May 2012 in a single institution, for the occurrence of relapse and the time to relapse. Results: Of 31 patients, who were followed-up for a mean of 56.5 ± 30.2 months (median 55 months, range 20–120 months), relapse was observed in 11 (35.5%) patients, within a mean of 28.8 ± 18.2 months (median 33 months, range 4–59 months), whereas 20 (64.5%) patients stayed relapse-free for a mean of 54.2 ± 28.8 months (median 55.5 months, range 20–119 months). Patients received maintenance phototherapy with a median duration of 12 months (range 1–30 months) after achieving complete response. Conclusion: Results indicate that narrowband UVB phototherapy may induce low relapse rates and long relapse-free intervals for early MF.

Hydrochlorothiazide and cutaneous T cell lymphoma

Mycosis fungoides (MF) and leukemic Sézary syndrome (SS) are the most common cutaneous T cell lymphomas (CTCL), but their etiology remains unknown. After patients were observed with hydrochlorothiazide (HCTZ)-associated CTCL, HCTZ was examined as a putative chronic antigen in a cohort of prospectively staged patients. Demographic and drug exposure data was examined from 1443 confirmed MF and SS patients. Hypertensive CTCL patients were divided into HCTZ users or nonusers for statistical analysis by chi-square and t tests. Causality in a case series was rated by the Naranjo Adverse Drug Reaction Probability Scale. A total of 815 of 1443 MF and SS patients (56.5%) were hypertensive; 205 (25.2%) were taking HCTZ at initial staging. Comparing stage of patients who were using or not using HCTZ, the most significant difference was between stage I and stage IV (odds ratio of 0.45; 95% confidence interval of 0.25-0.78, P = .003), demonstrating reduced likelihood of being stage IV in patients who were on HCTZ. Seventy-seven percent of the MF patients on HCTZ were stage I. A total of 125 patients of 196 (63.8%) started HCTZ prior to developing CTCL lesions, and 35 of 121 (28.0%) started within 1 year of first skin rash. Thirty-six of 125 patients (28.8%) experienced complete or partial remissions after discontinuing HCTZ. A monoclonal T cell receptor rearrangement was detected more frequently in the hypertensive stage I patients not taking HCTZ as compared with those who were (55.3% vs 69.1%, P = .032). Three patients were rechallenged and developed MF lesions that resolved or improved with discontinuation. HCTZ is commonly prescribed and may be a putative antigen in a small subset of early MF patients. Careful drug histories and a trial off medication are warranted.

Treatment of Early Stages of Mycosis Fungoides with Narrowband Ultraviolet B

Background: Narrowband ultraviolet B (UVB) phototherapy is increasingly used in mycosis fungoides (MF). Objective: We report on the results obtained in a prospective series of early MF patients receiving this therapeutic regimen. Methods: In total, 22 patients were treated. Therapeutic results were evaluated on clinical, histological and molecular levels. Patients were then submitted to a clinical follow-up. Results: The cumulative number of treatments ranged from 22 to 48 (mean: 29). A complete clinical remission (CCR) was obtained in 18/22 patients, and a partial clinical remission in 4 cases. Complete or partial histological responses were achieved in 9/15 (all in CCR) and 4/15 patients, respectively. The molecular response was evaluated in 12 patients, and a disappearance of the dominant T cell clone in the skin was obtained in only 3 cases. After 4–48 months of follow-up (mean 20.1 months), 7/18 patients in CCR (39%) relapsed. Conclusion: Narrowband UVB phototherapy is a well-tolerated treatment of early-stage MF, and its efficiency is maximal in very early stages (Ia). Even though clinical results seem very similar to PUVA through indirect and tentative comparisons with historical series, relapses tend to occur earlier than with PUVA, especially when an incomplete histological or molecular response was achieved.

A Circulating T Cell Clone in Early Mycosis Fungoides Is Not a Negative Prognostic Factor When the Disease Is Treated by a Combination of PUVA + Interferon α.

In patients with early Mycosis Fungoides (MF), a dominant T-cell receptor (TCR) gene rearrangement can be detected in the skin in 50–75% of cases, while in 15–40%, an identical T-cell clone is detectable also in the peripheral blood This may indicate an unfavourable subset of patients.We observed on omogeneus group of early MF patients all receiving the some protocol. The purpuose of this study were: - T-cell receptor gene rearrangement analisys of peropheral blood samples; - evaluation of the prognostic impact of T-cell monoclonality on CR and relapse rate.44 patients diagnosed as having MF at early stage (25 M, 19 F; mean age 58.7 yrs, range 34–77; 11 in stage IA, 28 in stage IB, 5 in stage IIB) and showing a dominant T cell clone in the skin lesions at diagnosis, were included in the present study. Peripheral blood samples were collected for DNA extraction at diagnosis. PCR amplification for TCRγ gene was performed as previously reported by Ashton-Key et al. (1997) in all 44 cases both in peripheral blood and skin and reduplicated: amplification products were visualised by 10% polyacrylamide gel electrophoresis. Peripheral blood samples were considered positive for a circulating T cell clone only if the monoclonal signals in peripheral blood and skin were reproducible and overlapping.All patients received the same treatment, consisting of a combination protocol with low-dose IFNα + PUVA for 14 months, and then followed up. Clinical response to the therapy and further disease recurrences were registered.After a mean time of 6.02 months (range, 1–21), 7 patients failed to respond to combination therapy, while 37 obtained a clinical complete remission (CCR). Among them, 15 experienced a disease recurrence during the follow-up (mean time, 29.8 months, range, 1–77 months).PCR analysis of TCRγ gene showed in the peripheral blood the same T-cell clone detected in the skin in 16 cases (36.4%). Failure to obtain a CCR was found in 3 out of 28 cases without a T cell clone in peripheral blood (10.7%) and in 4 out 16 cases with a circulating T cell clone (25%; c2 test: P=0.41, NS). Disease recurrence was observed in 9 out of 25 cases without a T cell clone in peripheral blood (36%) and in 6 out of 12 cases with a circulating T cell clone (50%; c2 test: P=0.65, NS). Disease-free survival curves plotted by Kaplan-Meier method showed that patients with and without a circulating T cell clone did not behave differently and that half of the patients would have experienced a relapse after a similar period of time (34 and 36 months, respectively, for patients with TCRg+ and − peripheral blood; log rank test, P=0.79).PCR analysis of TCRγ gene rearrangement analysis has allowed us to detect monoclonality in the peripheral blood in 36% of early MF cases with a documented monoclonality in the skin. At this stage of the disease a circulating T cell clone could indicate a subset of patients in which skin-directed therapies are more likely to fail to completely eradicate the malignant cells. Interestingly, our data seems to show that the negative influence of a circulating clone can be bypassed by the combination of a skin-directed therapy like PUVA and the systemic immunoregulatory effects of IFNα.