Multiple plaques on the hands and feet. Mycosis fungoides (MF) palmaris et plantaris (MFPP).
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Aged, 80 and over↗
Biomedical subjects
Madeleine Duvic
Publications and source records attributed to Madeleine Duvic.
Abnormal expression of interleukin-23 in mycosis fungoides/Sézary syndrome lesions.
Progression of mycosis fungoides (MF) to Sézary syndrome (SS) is accompanied by a shift from a T(H)1 to a T(H)2 cytokine profile. Interleukin (IL)-23 is a novel cytokine that shares a common p40 subunit with the T(H)1 inducer, IL-12. IL-23 induces a third profile, T(H)IL-17, that is dominant in inflammation and autoimmunity. Although IL-23 induces an eczematous-like skin reaction in mice, and is expressed in T(H)1-mediated skin disorders such as psoriasis, it has not been evaluated in MF/SS. To study the role of IL-23 in MF/SS development, 40 MF/SS lesions of all stages were immunohistochemically analyzed with a novel anti-human IL-23 antibody raised against full-length human IL-23. IL-23 was detected with the catalyzed signal amplification system. The intensity and frequency of IL-23 staining were semi-quantitatively graded in both the dermal infiltrate and the epidermis. Increased expression of IL-23 was observed throughout the epidermal keratinocytes and in dermal lymphocytes compared to normal skin. IL-23 intensity did not differ significantly among the stages of MF/SS; however, in stage IVB patients, we observed lower frequency of IL-23 expression in dermal lymphocytes than in other stage patients [P = 0.13, analysis of variance (ANOVA)]. Interestingly, clusters of atypical lymphocytes, especially the epidermotropic tumor cells, demonstrated weak or absent IL-23 staining in 18 of 40 (45%) lesions. This finding was present in 4 of 5 (80%) of the stage IVB lesions and 7 of 11 (64%) of the lesions from Sézary patients. These findings indicate that abnormal IL-23 expression may play a role in the pathogenesis and progression of MF/SS.
Disease Progression↗
Genetic variants of the vitamin D receptor gene alter risk of cutaneous melanoma.
Sunlight causes DNA damage but also induces production of vitamin D whose metabolite 1,25-(OH)2D3 has antiproliferative and pro-differentiative effects in both melanocytes and cutaneous melanoma (CM) cells mediated through the vitamin D receptor (VDR). We hypothesized that genetic polymorphisms of VDR are associated with risk of CM. In a hospital-based case-control study of 602 non-Hispanic white CM patients and 603 cancer-free control subjects frequency matched by age and sex, we genotyped two VDR polymorphisms (TaqI and FokI) and assessed their association with CM risk. We found that a significantly decreased risk was associated with VDR-TaqI Tt (adjusted odds ratio (OR), 0.70; 95% confidence interval (CI), 0.54-0.90) and Tt+tt (OR=0.70; 95% CI, 0.55-0.89) genotypes, compared with the VDR-TaqI TT genotype, whereas an increased risk was associated with VDR-FokI Ff genotype (OR=1.32; 95% CI, 1.03-1.68), and a borderline significantly increased risk was associated with Ff+ff (OR=1.26; 95% CI, 1.00-1.59) genotypes, compared with the VDR-FokI FF genotype. In conclusion, genetic variants (i.e., TaqI t protective allele and FokI f risk allele) in VDR may alter risk of CM.
Alleles↗
A phase II open-label study of recombinant human interleukin-12 in patients with stage IA, IB, or IIA mycosis fungoides.
BACKGROUND: Interleukin-12 (IL-12) increases Th(1) cytokines, natural killer (NK) cells, and cytotoxic T-cell activities. Progression of mycosis fungoides is associated with Th(2) cytokines produced by a clonal proliferation of epidermotropic T-helper cells. OBJECTIVE: To determine the safety and efficacy of subcutaneous recombinant human IL-12 (rhIL-12) in early mycosis fungoides (MF; stage IA-IIA) in a multi-center, open label clinical trial. METHODS: rhIL-12 was administered biweekly (100 ng/kg for 2 weeks; 300 ng/kg thereafter). A modified severity-weighted assessment tool (SWAT) and the longest diameter of 5 index lesions measured efficacy. RESULTS: Twenty-three MF patients (stage IA, 12 patients; IB, 9; and IIA, 2) had previously received >3 therapies. Ten of 23 patients (43%) achieved partial responses (PR); 7 (30%) achieved minor responses; and 5 (22%) had stable disease. The duration of PRs ranged from 3 to more than 45 weeks. Twelve (52%) ultimately progressed with mean time to progressive disease of 57 days (range, 28-805). Ten completed 6 months of therapy; 1 completed 24 months. Of patients not completing 6 months of therapy, 6 progressed and 6 others discontinued because of adverse events or withdrew consent. Seventeen patients had treatment-related adverse events that were generally mild or moderate in severity, including asthenia, headache, chills, fever, injection site reaction, pain, myalgia, arthralgia, elevated aspartate and alanine aminotransferase levels, anorexia, and sweating. One patient in PR died of hemolytic anemia, possibly exacerbated by rhIL-12 treatment. LIMITATIONS: The original company was purchased during the conduct of the trial and rhIL-12 is currently unavailable. The quality of life data were not available for inclusion. CONCLUSION: Twice-weekly subcutaneously administered rhIL-12 (100 ng/kg escalated to 300 ng/kg) showed antitumor activity with a response rate of 43% in refractory patients. It was relatively well-tolerated in early-stage MF.
Adjuvants, Immunologic↗
Phase 2 trial of oral vorinostat (suberoylanilide hydroxamic acid, SAHA) for refractory cutaneous T-cell lymphoma (CTCL).
The activity and safety of the histone deacetylase inhibitor vorinostat (suberoylanilide hydroxamic acid, SAHA) were evaluated in patients with refractory cutaneous T-cell lymphoma (CTCL). Group 1 received vorinostat 400 mg daily, group 2 received vorinostat 300 mg twice daily for 3 days with 4 days rest, and group 3 received vorinostat 300 mg twice daily for 14 days with 7 days rest followed by 200 mg twice daily. Treatment continued until disease progression or intolerable toxicity. The primary objective was to determine the complete and partial response (PR) rate. Time to response (TTR), time to progressive disease (TTP), response duration (DOR), pruritus relief, and safety were determined. Thirty-three patients who had received a median of 5 prior therapies were enrolled. Eight patients achieved a PR, including 7 with advanced disease and 4 with Sézary syndrome. The median TTR, DOR, and TTP for responders were 11.9, 15.1, and 30.2 weeks, respectively. Fourteen of 31 evaluable patients had pruritus relief. The most common drug-related AEs were fatigue, thrombocytopenia, diarrhea, and nausea. The most common grade 3 or 4 drug-related AEs were thrombocytopenia and dehydration. Vorinostat demonstrated activity in heavily pretreated patients with CTCL. The 400 mg daily regimen had the most favorable safety profile and is being further evaluated.
Adult↗
4-Nitroquinoline-1-oxide-induced mutagen sensitivity and risk of nonmelanoma skin cancer: a case-control analysis.
The UV radiation-mimetic chemical 4-nitroquinoline-1-oxide (4-NQO) is thought to induce squamous cell carcinoma (SCC) similar to those induced by UV radiation in animals. Therefore, we tested the hypothesis that cellular sensitivity to 4-NQO is associated with risk of developing skin cancer in a case-control study of 191 patients with nonmelanoma skin cancer (NMSC; 81 SCC and 110 basal cell carcinoma (BCC)) and 176 cancer-free controls. Short-term blood cultures were treated with 4-NQO at a final concentration of 10 microM for 24 hours and scored for chromatid breaks in 50 well-spread metaphases. We found that the mean frequency of chromatid breaks per cell (b/c) was significantly higher in the cases (mean+/-SD, 0.46+/-0.43 for SCC and 0.43+/-0.38 for BCC) than in the controls (0.25+/-0.25; P<0.001 for both comparisons) and were associated with more-than-twofold increased risk for both SCC and BCC after adjustment for known risk factors. Therefore, our findings support the notion that sensitivity to 4-NQO reflects susceptibility to UV-induced NMSC. However, there is a lack of correlation between UVB-induced b/c and 4-NQO-induced b/c in this study population. Therefore, these findings need to be verified by additional studies.
4-Nitroquinoline-1-oxide↗
Genetic variants of the ADPRT, XRCC1 and APE1 genes and risk of cutaneous melanoma.
Sunlight causes various kinds of DNA damage, including oxidative lesions that are removed effectively by the base excision repair (BER) pathway, in which ADPRT, XRCC1 and APE1 play a key role. However, genetic variation in these genes may alter their functions. We hypothesized that ADPRT, XRCC1 and APE1 polymorphisms are associated with risk of cutaneous melanoma (CM). In a hospital-based case-control study of 602 CM patients and 603 cancer-free control subjects frequency matched on age, sex and ethnicity, we genotyped for three non-synonymous single nucleotide polymorphisms (SNPs) (i.e. the ADPRT Val762Ala, XRCC1 Arg399Gln and APE1Asp148Glu) and assessed their associations with risk of CM. We found no significant difference in the allele frequencies between cases and controls for any of these three SNPs. However, we found that, compared with the APE1 Asp/Asp genotype, a significantly decreased risk of CM was associated with the APE1 Asp/Glu [adjusted odds ratio (OR), 0.60; 95% confidence interval (CI), 0.41-0.86], Glu/Glu (OR, 0.58; 95% CI, 0.38-0.88) and combined APE1 Asp/Glu+Glu/Glu (OR, 0.59; 95% CI, 0.42-0.83) genotypes, but not for other XRCC1 variant genotypes. Moreover, there was evidence for a possible gene-gene interaction between XRCC1 and APE1 variants in the association with risk of CM (P=0.030). We conclude that the APE1 Glu variant may have an effect or interact with XRCC1 in the etiology of CM or in linkage disequilibrium with other untyped protective alleles. Larger studies with more SNPs in the BER genes are needed to verify these findings.
Adult↗
Thyrotoxicosis after denileukin diftitox therapy in patients with mycosis fungoides.
CONTEXT: Denileukin diftitox is a recombinant novel fusion protein of diphtheria toxin and the ligand-binding domain of human IL-2. Denileukin diftitox binds to the high-affinity IL-2 receptor on the cell surface, and it is internalized by endocytosis and enzymatically cleaved. The cytotoxic A-fragment of the toxin inhibits protein synthesis and causes cell death. OBJECTIVE: The objective of this study was to recognize thyrotoxicosis in association with denileukin diftitox therapy. DESIGN: This study was a retrospective case series. SETTING: The setting of this study was a comprehensive cancer center. PATIENTS: Eight mycosis fungoides patients who were receiving 9 or 18 microg/kg.d iv denileukin diftitox for 5 d every 3 wk were identified with thyrotoxicosis. INTERVENTION(S): Thyroid testing was performed. Hypothyroidism after thyrotoxicosis was treated. RESULTS: In eight mycosis fungoides patients who developed transient thyrotoxicosis during therapy, thyroid function tests were normal before onset of therapy. Clinical thyrotoxicosis developed within days of the first cycle of denileukin diftitox therapy in four patients and after the second cycle in the other four patients. Symptoms included tremors, nervousness, tachycardia, diarrhea, and weight loss. After cessation of denileukin diftitox, thyrotoxicosis resolved in all patients; two became euthyroid, and five became hypothyroid, requiring levothyroxine therapy. One patient was lost to follow-up. CONCLUSIONS: Monitoring thyroid function before and during treatment with denileukin diftitox is recommended. Symptomatic thyrotoxicosis may be missed due to other acute reactions to the drug, and subsequent hypothyroidism may develop.
Aged↗
The use of topical calcineurin inhibitors in dermatology: safety concerns. Report of the American Academy of Dermatology Association Task Force.
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Administration, Topical↗
Major histocompatibility complex class I chain-related gene A polymorphisms and extended haplotypes are associated with familial alopecia areata.
Alopecia areata (AA) is characterized by hair loss in patches and may progress to total loss of scalp hair, or total loss of scalp and body hair. The major histocompatibility complex (HLA) is associated with susceptibility to AA, as well as other autoimmune diseases. In addition to HLA molecules, non-HLA molecules including the major histocompatibility complex class I chain-related gene A (MICA), a stress-inducible antigen, are also associated with several autoimmune diseases. To investigate associations between AA and the HLA loci, two genes and eight microsatellite markers spanning the HLA region were genotyped. MICA(*)6 was significantly associated with all phenotypes of AA (P=0.0083), whereas MICA(*)5.1 was significantly associated with patchy AA (P=0.029). Extended haplotype analysis shows the significant associations of haplotypes HLA-DQ1-DR6-MICA(*)5.1 (P=0.004) and HLA-DQB1*0201-DR3-MICA(*)5.1 (P=0.009) with AA. These results suggest that MICA is both a potential candidate gene and part of an extended HLA haplotype that may contribute to susceptibility to and severity of AA.
Alleles↗
CD25 expression is correlated with histological grade and response to denileukin diftitox in cutaneous T-cell lymphoma.
Denileukin diftitox (Ontak), a recombinant fusion protein of diphtheria toxin and ligand, IL-2, binds to the IL-2 receptor, is internalized, and causes cell death. Denileukin diftitox was approved for the treatment of cutaneous T-cell lymphomas (CTCLs) with CD25+ expression. We prospectively stained lesional skin biopsy specimens from 113 mycosis fungoides and Sézary Syndrome patients for activation markers CD25 and CD30 to correlate expression with clinical tumor-node metastasis (TNM) stage, histologic grade, and response to denileukin diftitox. High expression was defined as positivity of > or =20% of lesional T-cells using immunohistochemistry (IHC). CD25 and CD30 expression was more common in lesions from advanced patients (P = 0.04 and 0.002, respectively). Advanced TNM (T3 or T4) was significantly associated with intermediate-grade (P = 0.002) and large-cell transformation histology (P = 0.04). Of interest, clinical responses were observed in 78.5% of patients with high CD25 expression versus 20% with low to undetectable CD25 expression (P = 0.01) among 24 patients receiving standard 5-day infusions of denileukin diftitox at 18 microg/kg/day. These data suggest that high CD25 expression by IHC is associated with advanced CTCL and with clinical response to denileukin diftitox therapy.
Adult↗
Photopheresis versus transimmunization?
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Humans↗
High flotillin-2 expression is associated with lymph node metastasis and Breslow depth in melanoma.
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Gene Expression Regulation, Neoplastic↗
Polymorphisms of the FAS and FAS ligand genes associated with risk of cutaneous malignant melanoma.
The FAS/FAS ligand (FASLG) system has a key role in regulating cell growth and thus tumorigenesis. Functional promoter polymorphisms of the FAS and FASLG genes alter the transcriptional activities, but no published study has investigated the role of these polymorphisms in the etiology of cutaneous malignant melanoma (CMM). In a hospital-based, case-control study of 602 non-Hispanic white CMM patients and 603 cancer-free age- and sex-matched control subjects, we genotyped FAS-1377G>A, FAS-670A>G, FASLG-844T>C and FASLG-IVS2nt-124G>A polymorphisms and assessed their respective associations with CMM risk. We found that an increased risk of CMM was associated with the FAS-1377GG [adjusted odds ratio (OR)=1.32; 95% confidence interval (CI)=1.00-1.75 for -1377GG] and -670AA (adjusted OR=1.28; 95% CI=1.00-1.65 for -670AA) genotypes compared to the -1377AA/AG and -670AG/GG genotypes, respectively; an increased risk of CMM was associated with the FASLG-IVS2nt-124AG+GG (OR=1.54; 95% CI=1.18-2.01) genotype compared to the AA genotype, but no evident risk was associated with any of the FAS-844T>C genotypes. In the combined analysis of these four variant alleles, we found that, compared to those having 0-3 variants, those having 4-8 variant alleles had a significantly increased risk for CMM (OR=1.38; 95% CI=1.10-1.73), and this risk was more pronounced in subgroups of old (>50 years) males, and those who were at low risk of sunlight-induced CMM, except for having fair skin colour, moles, dysplastic nevi and a family history of cancer. In conclusion, genetic variants in the FAS and FASLG genes may contribute to the etiology of CMM in the general population, particularly in those with a low risk of sunlight-induced CMM.
Alleles↗
Cutaneous manifestations of Hodgkin's disease.
BACKGROUND: Cutaneous manifestations associated with Hodgkin's Disease (HD) have not been well described. Most existing studies of the cutaneous manifestations of HD are individual case reports or literature reviews. The goal of this study was to define the spectrum of cutaneous manifestations of HD, as observed by the consulting dermatologist at a cancer center. METHODS: The tumor registry database maintained by the Department of Medical Informatics and the M.D. Anderson Visits database over a 5-year period was searched to identify patients with a diagnosis of HD and an appointment with Dermatology. The medical records were reviewed to determine frequency and presentation of cutaneous findings in HD. RESULTS: The search identified a total of 1049 registered patients with HD, of which 88 were seen at the Dermatology Clinic. Of these 88 patients evaluated by dermatology, 47 patients had either paraneoplastic cutaneous manifestations associated with HD (n = 45) or cutaneous HD (n = 3). The most common paraneoplastic skin manifestations were eczema (n = 18) and pruritus (n = 17), mycosis fungoides (n = 11), and erythema nodosum (n = 3). Mycosis fungoides, observed in 1% of the patients with HD at MDACC, was more than 290 times more common in patients with HD than in the general population. CONCLUSION: Although pruritus is the most commonly recognized presenting symptom of Hodgkin's lymphoma, new onset of eczema should also be considered as a possible warning sign deserving further investigation. Patients with adult-onset pruritus or eczema should be evaluated for possible HD with full lymph-node exam, CBC with differential, and chest X-ray. Erythema nodosum and mycosis fungoides should also be considered as cutaneous manifestations of HD.
Adolescent↗
Polymorphisms in the DNA repair genes XPC, XPD, and XPG and risk of cutaneous melanoma: a case-control analysis.
Sunlight causes DNA damage, including bulky lesions that are removed effectively by the nucleotide-excision repair (NER) pathway. There are at least eight core NER proteins participating in the pathway, and genetic variations in their genes may alter NER functions. We hypothesized that some NER variants are associated with risk of cutaneous melanoma. In a hospital-based case-control study of 602 non-Hispanic White patients with cutaneous melanoma and 603 age- and sex-matched cancer-free controls, we genotyped five common non-synonymous single-nucleotide polymorphisms identified to date and assessed their associations with risk of cutaneous melanoma. We found that a significantly increased risk of cutaneous melanoma was associated with XPD 751Lys/Gln [adjusted odds ratio (OR), 1.55 and 95% confidence interval (95% CI), 1.12-2.16] and XPD 751Gln/Gln (OR, 1.66; 95% CI, 1.03-2.68) genotypes compared with the XPD 751Lys/Lys genotype as well as XPD312Asp/Asn (OR, 1.54; 95% CI, 1.11-2.12) and XPD312Asn/Asn (OR, 1.75; 95% CI, 1.05-2.90) genotypes compared with the XPD 312Asp/Asp genotype. This increased risk was not observed in the other three XPC and XPG single-nucleotide polymorphisms. Moreover, the number of the observed XPD at-risk genotypes (i.e., 312Asn/Asn+Asn/Asp and 751Gln/Gln+Lys/Gln) was associated with cutaneous melanoma risk in a dose-response manner (OR, 1.47; 95% CI, 0.97-2.23 for one at-risk genotype; OR, 1.83; 95% CI, 1.29-2.61 for two at-risk genotypes; P(trend) < 0.001). However, we found no evidence of any interaction between XPD genotypes with XPC and XPG genotypes or the known risk factors. We concluded that genetic variants of the XPD gene might serve as biomarkers for susceptibility to cutaneous melanoma.
Case-Control Studies↗
Atypical CD8+ cutaneous T-cell lymphoma after immunomodulatory therapy.
Systemic immunomodulatory agents have recently been approved for the treatment of rheumatoid arthritis and psoriasis. Although lymphomas are known to emerge in the setting of immunosuppressive therapy, it has not been well described or established for the newer biologic immune response modifiers. Herein, we describe 2 patients who developed unusual CD8+ cutaneous lymphoproliferative disorders after treatment with efalizumab and infliximab. The mechanisms and occurrence of lymphoma after immune response modifiers are discussed.
Antibodies, Monoclonal↗
Treatment of mycosis fungoides with denileukin diftitox and oral bexarotene.
Cutaneous T-cell lymphomas, including mycosis fungoides and Sezary syndrome, are often responsive to treatment, but current therapies have not been shown to increase survival, and in advanced stages, durable remissions are hard to achieve. We present a patient who was initially misdiagnosed with psoriasis and, 16 years later, was diagnosed with mycosis fungoides. Denileukin diftitox was used as a tumor debulking agent to give a partial response that was further improved with a combination of systemic interferon/oral bexarotene and skin-directed psorlen plus UV-A. The purpose of this case report is to show the value of sequential combination therapy for improving overall response.
Administration, Oral↗