Linda Moreau

Deregulation in STAT signaling is important for cutaneous T-cell lymphoma (CTCL) pathogenesis and cancer progression.

Deregulation of STAT signaling has been implicated in the pathogenesis for a variety of cancers, including CTCL. Constitutive activation of STAT5 and STAT3 was observed in early and late stages of CTCL, respectively. In early stages, IL-2, IL-7 and IL-15 signaling via JAK1 and JAK3 kinases is believed to be responsible for activating STAT5, while in advanced stages development of IL-21 autocrine signaling is thought to be important for STAT3 activation. Recent molecular evidence further suggests that upregulation of STAT5 in early disease stages results in increased expression of oncogenic miR-155 microRNA that subsequently targets STAT4 expression on mRNA level. STAT4 signaling is known to be critical for T helper (Th) 1 phenotype differentiation and its loss results in a switch from Th1 to Th2 phenotype in malignant T cells. During this switch the expression of STAT6 is often upregulated in CTCL. In advanced stages, activation of STAT3 and STAT5 may become completely cytokine-independent and be driven only via constitutively active JAK1 and JAK3 kinases. Further research into the molecular pathogenesis of JAK/STAT signaling in this cancer may enable us to develop effective therapies for our patients.

The Use of Transcriptional Profiling to Improve Personalized Diagnosis and Management of Cutaneous T-cell Lymphoma (CTCL)

Purpose: Although many patients with mycosis fungoides presenting with stage I disease enjoy an indolent disease course and normal life expectancy, about 15% to 20% of them progress to higher stages and most ultimately succumb to their disease. Currently, it is not possible to predict which patients will progress and which patients will have a stable disease. Previously, we conducted microarray analyses with RT-PCR validation of gene expression in biopsy specimens from 60 patients with stage I–IV cutaneous T-cell lymphoma (CTCL), identified three distinct clusters based upon transcription profile, and correlated our molecular findings with 6 years of clinical follow-up. Experimental Design: We test by RT-PCR within our prediction model the expression of about 240 genes that were previously reported to play an important role in CTCL carcinogenesis. We further extend the clinical follow-up of our patients to 11 years. We compare the expression of selected genes between mycosis fungoides/Sézary syndrome and benign inflammatory dermatoses that often mimic this cancer. Results: Our findings demonstrate that 52 of the about 240 genes can be classified into cluster 1–3 expression patterns and such expression is consistent with their suggested biologic roles. Moreover, we determined that 17 genes (CCL18, CCL26, FYB, T3JAM, MMP12, LEF1, LCK, ITK, GNLY, IL2RA, IL26, IL22, CCR4, GTSF1, SYCP1, STAT5A, and TOX) are able to both identify patients who are at risk of progression and also distinguish mycosis fungoides/Sézary syndrome from benign mimickers. Conclusions: This study, combined with other gene expression analyses, prepares the foundation for the development of personalized molecular approach toward diagnosis and treatment of CTCL. Clin Cancer Res; 21(12); 2820–9. ©2015 AACR.

Demographic patterns of cutaneous T-cell lymphoma incidence in Texas based on two different cancer registries

Cutaneous T‐cell lymohomas (CTCLs) are rare, but potentially devastating malignancies, with Mycosis fungoides and Sézary Syndrome being the most common. In our previous study, we identified and described regions of geographic clustering of CTCL cases in Texas by analyzing ~1990 patients using two distinct cancer registries. In the current work, we describe in detail demographic patterns for this malignancy in our study population and apply logistic regression models to analyze the incidence of CTCL by sex, race, age, and clinical stage at the time of diagnosis. Furthermore, using Fishers exact test, we analyze changes in incidence over time in the identified Houston communities with unusually high CTCL incidence. While CTCL primarily affects Caucasian individuals >55 years old, we confirm that it presents at a younger age and with more advanced disease stages in African‐American and Hispanic individuals. Also, we demonstrate a significant increase in CTCL incidence over time in the identified communities. Spring, Katy, and Houston Memorial areas had high baseline rates. Furthermore, a statistically significant disease surge was observed in these areas after ~2005. This report supplements our initial study documenting the existence of geographic clustering of CTCL cases in Texas and in greater detail describes demographic trends for our patient population. The observed surge in CTCL incidence in the three identified communities further argues that this malignancy may be triggered by one or more external etiologic agents.

Ectopic expression of embryonic stem cell and other developmental genes in cutaneous T-cell lymphoma

Cutaneous T-cell lymphoma (CTCL) is a potentially devastating malignancy. The pathogenesis of this cancer remains poorly elucidated. Previous studies focused on analysis of expression and function of known oncogenes and tumor suppressor genes. However, emerging reports highlight that it is also important to analyze the expression of genes that are ectopically expressed in CTCL (e.g., embryonic stem cell genes (ESC), cancer testis (CT) genes, etc.). Currently, it is not known whether ESC genes are expressed in CTCL. In the current work, we analyze by RT-PCR the expression of 26 ESC genes, many of which are known to regulate pluripotency and promote cancer stem cell-like phenotype, in a historic cohort of 60 patients from Boston and in a panel of 11 patient-derived CTCL cell lines and compare such expression to benign inflammatory dermatoses that often clinically mimic CTCL. Our findings document that many critical ESC genes including NANOG, SOX2, OCT4 (POU5F1) and their upstream and downstream signaling members are expressed in CTCL. Similarly, polycomb repressive complex 2 (PRC2) genes (i.e., EZH2, EED, and SUZ12) are also expressed in CTCL lesional skin. Furthermore, select ESC genes (OCT4, EED, TCF3, THAP11, CHD7, TIP60, TRIM28) are preferentially expressed in CTCL samples when compared to benign skin biopsies. Our work suggests that ESC genes are ectopically expressed together with CT genes, thymocyte development genes and B cell-specific genes and may be working in concert to promote tumorigenesis. Specifically, while ESC genes may be promoting cancer stem cell-like phenotype, CT genes may be contributing to aneuploidy and genomic instability by producing aberrant chromosomal translocations. Further analysis of ESC expression and function in this cancer will greatly enhance our fundamental understanding of CTCL and will help us identify novel therapeutic targets.

Allergic contact dermatitis from cocamidopropyl betaine, cocamidoamine, 3-(dimethylamino)propylamine, and oleamidopropyl dimethylamine: co-reactions or cross-reactions?

We present the case of a patient with facial dermatitis caused by sensitization to cocamidopropyl betaine. The patient also had positive patch-test reactions to cocamidoamine, 3-(dimethylamino)propylamine, and oleamidopropyl dimethylamine. The presence of 3-(dimethylamino)propylamine as an impurity in all of these substances can be hypothesized to explain these simultaneous reactions.

Cross-reactions among parabens, para-phenylenediamine, and benzocaine: a retrospective analysis of patch testing.

Background: Parabens are alkyl ester derivatives of para‐hydroxybenzoic acid and are the most commonly used preservatives in the cosmetic industry. Cross‐reactions with para‐amino compounds, namely, benzocaine and para‐phenylenediamine (PPD), have been reported but are thought to be extremely rare. Objective: To evaluate the rate of cross‐reactivity between parabens, PPD, and benzocaine in a population of patients patchtested in a hospital‐based contact dermatitis clinic. Methods: A retrospective analysis of 4,368 patients consecutively patch‐tested between July 1989 and June 2005. Results: Our study demonstrated that the rate of cross‐reactions to parabens in PPD‐ and benzocaine‐positive patients combined is 2%. Conclusion: This cross‐reaction rate is significant in the tested population but still falls within the previously reported rates of sensitivity to parabens in the general population (0 to 3.5%).

Allergic contact dermatitis associated with reactive dyes in a dark garment: a case report

In this study, we present a case of a patient who has not been occupationally exposed to reactive dyes, but did present with a dermatitis from wearing a dark cotton garment. The patient experienced reactivation of his dermatitis when rewearing a new unwashed dark T‐shirt made of 100% cotton (in fact, the patient reported that it had to be washed at least 3 times before the skin reaction disappeared). He presented positive patch tests to 6 reactive dyes from Chemotechnique® textile series. The clothing could not be proved as the true cause of the dermatitis, but resolution occurred upon removal of the suspected garment. This suggests that contact allergy to the reactive dyes (he did not react to any other dyes and his garment was a natural fabric) was likely responsible. With this report, we would like to emphasize that reactive dyes, as a class, should be considered as potential allergens, both occupationally and from non‐occupational exposure such as garments. If garments containing reactive dyes are not properly rinsed in the manufacturing process, we believe that excess of dye can be retained that may cause allergic contact dermatitis (ACD). As the reactive dyes and their hydrolysis products are very water‐soluble, they can be easily washed off to prevent ACD.

Allergic contact dermatitis to idebenone used as an antioxidant in an anti‐wrinkle cream

A 47-year-old Caucasian woman went to a beauty salon and received a facial treatment with an ‘anti-aging’ cream. Within 24 hr, she developed a severe, oedematous and vesicular dermatitis of the face, ears, and neck. The lesions were treated with a 2-week course of oral prednisone and lasted for 3 weeks. Patch testing was performed 3 months later with theNorthAmerican Contact Dermatitis Group standard series and with the antimicrobials/ vehicles/cosmetics series (both from ChemotechniqueDiagnostics,Malmö, Sweden). Allergens were applied on Finn Chambers (Epitest Ltd Oy, Tuusula, Finland) mounted on Scanpor tape (Norgeplaster Alpharma AS, Vennesla, Norway) and on IQ Chambers (Chemotechnique Diagnostics, Malmö, Sweden). Also, a small sample of the cream was obtained from the beauty salon and was tested. Readings were done on day 2 and day 3, and the reactions were rated according to the International Contact Dermatitis Research Group standards. The only reaction to the anti-aging cream and was rated 2þ on day 2 and 3þ on day 4. The manufacturer obligingly provided a patch testing kit, with the individual ingredients of the cream premixed in petrolatum at the concentration used in the finished product. On the 2-day reading, a 2þ reaction was obtained that became 3þ on day 4 (Fig. 1). The allergen was identified as idebenone 0.5%. No reaction was observed in 20 control subjects tested with the same ingredient.

Allergic contact dermatitis to epoxy resin in microscopy immersion oil: Cases from Canada

The presence of epoxy resin in a reformulated immersion oil for microscopy has caused an epidemic of occupational contact dermatitis in laboratory technicians from some European centers. We report 6 additional cases, the mode of presentation of which was similar to the European patients. All patients were patch tested to the undiluted oil, and some were tested to the European or North American standard series and to an extensive series of glues and adhesives allergens. At 96 hours, all 6 patients displayed a strong 2+ to 3+ reaction to the undiluted oil. Two patients were not further tested, but in the remaining 4, positive reactions were seen to epoxy resin from the standard tray. One patient reacted to cycloaliphatic epoxy resin, and 2 displayed positive tests to the reactive diluents phenyl glycidyl ether and cresyl glycidyl ether. These further cases confirm the strong sensitizing properties of this particular immersion oil. The product, manufactured by Leica Microsystems (Wetzlar, Germany), since has been withdrawn from sale.

Gene expression analysis in Cutaneous T-Cell Lymphomas (CTCL) highlights disease heterogeneity and potential diagnostic and prognostic indicators

ABSTRACT Cutaneous T-Cell Lymphomas (CTCL) are rare, but potentially devastating malignancies, whose pathogenesis remains poorly elucidated. Unfortunately, currently it is not possible to predict based on the available criteria in which patients the cancer will progress and which patients will experience an indolent disease course. Furthermore, at early stages this malignancy often masquerades as psoriasis, chronic eczema or other benign inflammatory dermatoses. As a result, it takes on average 6 y to diagnose this lymphoma since its initial presentation. In this study, we performed transcription expression profiling using TruSeq targeted RNA gene expression on 181 fresh and formalin-fixed and paraffin-embedded (FFPE) skin samples from CTCL patients and patients affected by benign inflammatory dermatoses that often mimic CTCL clinically and on histology (e.g., psoriasis, chronic eczema, etc.) We also analyzed multiple longitudinal biopsies that were obtained from the same patients over time. Our results underscore significant molecular heterogeneity with respect to gene expression between different patients and even within the same patients over time. Our study also confirmed TOX, FYB, LEF1, CCR4, ITK, EED, POU2AF, IL26, STAT5, BLK, GTSF1 and PSORS1C2 genes as being differentially expressed between CTCL and benign skin biopsies. In addition, we found that differential expression for a subset of these markers (e.g., TOX, FYB, GTSF1 and CCR4) may be useful in prognosticating this disease. This research, combined with other molecular analyses, prepares the foundation for the development of personalized molecular approach toward diagnosis and management of CTCL.