Search

PDF file - 164KB, Detailed description of RT-PCR analysis of CT genes expression in CTCL patient-derived cell lines.

PDF file - 324KB, Detailed description of RT-PCR analysis of CT genes expression in CTCL patients.

Purpose: The pathogenesis of cutaneous T-cell lymphoma (CTCL) remains only partially understood. A number of recent studies attempted to identify novel diagnostic markers and future therapeutic targets. One group of antigens, cancer–testis (CT) antigens, normally present solely in testicular germ cells, can be ectopically expressed in a variety of cancers. Currently, only a few studies attempted to investigate the expression of CT antigens in CTCL.Experimental Design: In the present work, we test the expression of CT genes in a cohort of patients with CTCL, normal skin samples, skin from benign inflammatory dermatoses, and in patient-derived CTCL cells. We correlate such expression with the p53 status and explore molecular mechanisms behind their ectopic expression in these cells.Results: Our findings demonstrate that SYCP1, SYCP3, REC8, SPO11, and GTSF1 genes are heterogeneously expressed in patients with CTCL and patient-derived cell lines, whereas cTAGE1 (cutaneous T-cell lymphoma-associated antigen 1) was found to be robustly expressed in both. Mutated p53 status did not appear to be a requirement for the ectopic expression of CT antigens. While T-cell stimulation resulted in a significant upregulation of STAT3 and JUNB expression, it did not significantly alter the expression of CT antigens. Treatment of CTCL cells in vitro with vorinostat or romidepsin histone deacetylase inhibitors resulted in a significant dose-dependent upregulation of mRNA but not protein. Further expression analysis demonstrated that SYCP1, cTAGE1, and GTSF1 were expressed in CTCL, but not in normal skin or benign inflammatory dermatoses.Conclusions: A number of CT genes are ectopically expressed in patients with CTCL and can be used as biomarkers or novel targets for immunotherapy. Clin Cancer Res; 20(14); 3799–808. ©2014 AACR.

Supplementary Tables 1-4, Figure 1. Supplementary Table 1. Primers used for RT-PCR experiments. Supplementary Table 2. Detailed description of the 52 genes that fit into the three signature pattern expression model and their putative functions in CTCL and other malignancies. Supplementary Table 3. Multivariate analysis of patient characteristics that are associated with clinical disease progression. Supplementary Table 4. Description of genes that are able to distinguish CTCL from benign dermatoses and their putative roles in CTCL and other malignancies. Supplementary Figure 1. A. WIF1 (Wnt Inhibitory Factor 1) gene is expressed in normal skin and CTCL lesional skin in a subset of patients. B. Correlation of WIF1 expression in CTCL patients with disease progression. Kaplan-Meier analysis documents that loss of WIF1 expression is associated with poor CTCL disease progression (left panel, p=0.002). Disease progression is defined as a progression to a higher clinical stage and/or death. Loss of WIF1 is also associated with poor cancer specific survival (right panel, p=0.012).

PDF file - 177KB, JUNB and PLK1 are heterogeneously expressed in CTCL lesional skin, normal skin and benign inflammatory dermatoses skin samples.

PDF file - 209KB, Primers used for RT-PCR experiments.

PDF file - 211KB, T cell stimulation with P+I does not result in a significant mRNA upregulation of CT genes across a panel of CTCL patient-derived cell lines.

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.

PDF file - 66KB, Expression of cTAGE1 and GTSF1 in PBMCs isolated from S�zary Syndrome patients or patients with Benign Inflammatory Dermatoses (BID).

PDF file - 2210KB, Effect of HDAC inhibitors on mRNA expression of CT genes in Hut78 cells.

Epidermal growth factor receptor inhibitors (EGFRi) are now standard of care in patients with EGFR mutations in non-small cell lung cancer (NSCLC) and are increasingly being used in other EGFR mutated cancers, including gastrointestinal, and head and neck. However, EGFRi are well known to cause acneiform eruptions, which are shown to positively correlate with tumor response to treatment, but may be severe enough to cause interruption of their treatment. Although most guidelines call for the use of tetracyclines to treat these acneiform eruptions, there is mounting evidence for the use of systemic retinoids instead. The objective of this review is to summarize available data on the use of systemic retinoids for management of acneiform eruptions on EGFRi. This study was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. MEDLINE and EMBASE were searched from database inception until December 10th, 2021. All articles were screened and relevant data extracted independently in duplicate by two reviewers. In total, 16 case reports, case series and retrospective reviews were included. Forty-three patients were treated with retinoids for their acneiform eruption due to EGFRi. The majority (77%) noted moderate to significant improvement after treatment initiation with minimal adverse events (16%). The findings of this systematic review suggest that systemic retinoids are a safe and effective therapy for the management of acneiform eruptions induced by EGFRi.

Prurigo pigmentosa (PP) is an uncommon inflammatory dermatosis first described in 1971. It is characterized by recurrent crops of pruritic erythematous papulovesicles that resolve with a macular reticulated hyperpigmentation. The exact etiology is yet to be determined, however with the expanded application of the ketogenic diet (KD) in recent years, conditions accompanied with ketosis are more commonly being described in association with PP. Antibiotics as well as resolution of ketosis can effectively treat the dermatitis. Given the publicity and growing popularity of the ketogenic diet and numerous references to the "Keto-Rash" on social media, we reviewed the KD-induced PP cases to raise awareness of this increasingly recognized entity and provide an update to clinicians, particularly dermatologists, regarding this possible side effect of KD.

Nail matricectomy is indicated in the management of painful onychodystrophies, including recalcitrant onychocryptosis, onychogryphosis, onychauxis, and refractory onychomycosis. Although many matricectomy methods have been described, with phenolization being the best studied, no one method has clearly emerged as superior. We present a series of 14 patients who underwent a total of 18 matricectomies with either phenolization or electrodessication (ED) in a private dermatology office, and describe a simple and effective variation of the ED technique using a modified hyfrecator tip. A video demonstration of this technique is included. We also describe ED matricectomy in the context of a review of the literature, ascertaining recurrence rates, complication rates, healing time, and patient satisfaction. The nuances of technique specifics (such as the use of adjunct methods and antibiotics), as well as outcome predictors and measurements have been highlighted. We found ED to be comparable to other forms of matricectomy, with the advantages of ease of use, minimal complications, and good satisfaction rates.

Treatment with programmed cell death 1 inhibitors is associated with a wide range of cutaneous immune-related adverse events, with lichenoid eruptions representing one of the major cutaneous toxicities. We describe the case of an 81-year-old man with metastatic melanoma treated with pembrolizumab who subsequently developed a delayed-onset generalized lichenoid dermatitis. After failing multiple lines of systemic immunosuppression, narrowband ultraviolet B (NBUVB) phototherapy three times per week for 17 sessions resulted in a significant clinical response in his cutaneous eruption and was well tolerated. NBUVB is a safe, lower-cost modality that induces local, skin-specific immunosuppression without the toxicities of traditional systemic immunosuppressive agents. To date, this is the first report of use of NBUVB in immune-related lichenoid dermatitis resistant to multiple standard therapies.

Apremilast is an orally administered small molecule that specifically inhibits the phosphodiesterase-4 enzyme and modulates the immune system by increasing the levels of intracellular cyclic adenosine monophosphate (cAMP) and inhibiting IL-2 & 8, interferon-γ and tumor necrosis factor (TNF) production. It is FDA approved for the treatment of psoriasis, psoriatic arthritis, and oral ulcers of Behcet's disease. More recently, apremilast has been used off-label to treat varied dermatological diseases where systemic corticosteroids or immunosuppressive agents were not effective. We review the efficacy and safety of apremilast in the treatment of aphthous stomatitis, Behcet's disease, chronic actinic dermatitis, atopic dermatitis, cutaneous sarcoidosis, hidradenitis suppurativa, lichen planus, and discoid lupus erythematosus in cases where standard treatment has failed.

Background The McGill Faculty of Medicine implemented a new undergraduate medical curriculum in 2013 with additional preclinical lectures in dermatology. At the time of writing, no Canadian prospective study has been published on undergraduate dermatology training in the context of a complete curricular renewal. Objectives Our study was designed to determine the impact of increasing preclinical teaching in dermatology on medical students’ diagnostic accuracy and learning retention of common dermatoses encountered in primary care. Methods A standardized questionnaire was administered to the Classes of 2015, 2016, 2017, and 2018 in 6 versions for a total of 6 times over their 4 years of training. Each version featured 10 photographs of common dermatoses encountered in primary care. Students were invited to participate anonymously and on a voluntary basis. Results A small absolute, but statistically significant difference, of 3% was detected in the fourth and final year of training between the old curriculum (average score = 70%, standard deviation = 15%) and the new curriculum (average score = 73%, standard deviation = 15%), P = .03. Furthermore, the Class of 2018’s performance improved year by year over the entire 4 years of the new curriculum. Conclusions Additional preclinical lectures in dermatology do improve medical students’ diagnostic accuracy of common dermatoses encountered in primary care. Furthermore, they do retain their learning throughout the preclinical and clerkship years.

Primary cutaneous B-cell lymphomas (PCBCLs) are a heterogeneous group of extranodal lymphomas1 . Primary cutaneous marginal zone lymphoma (MZL) and follicle center lymphoma (FCL), the most prevalent PCBCLs, are typically indolent.

Background: Clustering of patients with cutaneous T-cell lymphoma (CTCL) was reported in several jurisdictions around the world. This rare cancer is known to affect spouses and in some cases multiple members of the same family. These combined results suggest the existence of external disease triggers/promoters. We recently conducted the first comprehensive analysis of CTCL incidence and mortality in Canada, which revealed case clustering in several regions. Objectives: To extend our previous analysis on CTCL incidence across Canada and to provide all the collected data on CTCL patient incidence in Canada during the period of 1992 to 2010. Methods: Clinical parameters for patients with CTCL in Canada were analyzed using 2 independent population-based cancer registries: Canadian Cancer Registry and Le Registre Québécois du Cancer. The CTCL incidence rates were examined on different geographical levels, including provinces/territories, cities, and forward sortation areas. Results: Our findings further corroborate our earlier observations of higher CTCL incidence in Newfoundland and Labrador, maritime provinces (Nova Scotia and New Brunswick), and prairie provinces (Manitoba and Saskatchewan). Also, most cities with high CTCL incidence were located in these provinces. Extensive mapping of high-incidence postal codes supports case clustering in a number of communities that are located in the proximity of industrial centres and seaports. Conclusions: Detailed analysis of CTCL incidence in Canada is critical to fully understand the burden of this disease in our country, to begin the search for a possible external trigger for this lymphoma, and to reform how health care resources are distributed throughout the country to better serve Canadian patients with CTCL.

BACKGROUND Previous reports of geographic clustering of cutaneous T-cell lymphoma (CTCL) in Texas, Pittsburgh, and Sweden as well as the occurrence of CTCL in married couples and family members raise a possibility of the existence of an external and potentially preventable trigger(s) for this rare skin cancer. METHODS The authors studied CTCL incidence and mortality in Canada using 3 distinct population-based cancer databases. Data on patients' sex, age at the time of diagnosis, subtype of CTCL malignancy, reporting province, city, and postal code were analyzed. CTCL cases were mapped across Canada using geographic information systems software. RESULTS In total, 6685 patients with CTCL were identified in Canada during 1992 through 2010 (CTCL incidence rate, 11.32 cases per million individuals per year), of which 58% were males. The mean age at diagnosis was 59.4 ± 21.5 years. Geographic analysis of patients revealed increased CTCL incidence on the provincial and city levels in several eastern provinces and in Manitoba. An analysis according to postal codes (Forward Sortation Area [FSA]) identified select communities in which several high-incidence FSAs were contiguous or adjacent. Several of these FSAs were located in industrial regions of Canadian cities. Conversely, 3 of 8 low-incidence FSAs were clustered in Ottawa, Ontario, which has very little industrial presence. An analysis of CTCL mortality in Canada corroborated the current incidence findings. CONCLUSIONS The current results provide a comprehensive analysis of CTCL burden in Canada and highlight several important areas of geographic case clustering. These findings argue that industrial exposures may play an important role in promoting CTCL pathogenesis. Cancer 2017;123:3550-67. © 2017 American Cancer Society.

BACKGROUND: Cutaneous T-cell lymphomas (CTCLs) (mycosis fungoides and its leukemic variant, Sezary syndrome) are rare malignancies. Reports of the occurrence of mycosis fungoides in married couples and families raise the possibility of an environmental trigger for this cancer. Although it has been suggested that CTCL arises from inappropriate T-cell stimulation, to the authors’ knowledge no preventable trigger has been identified to date. METHODS: Using region, zip code, age, sex, and ethnicity, the authors analyzed the demographic data of 1047 patients from Texas who were seen in a CTCL clinic at The University of Texas MD Anderson Cancer Center during 2000 through 2012 (the MDACC database) and 1990 patients who were recorded in the population-based Texas Cancer Registry between 1996 and 2010. Subsequently, data from both databases were cross-analyzed and compared. RESULTS: The current study findings, based on the MDACC database, documented geographic clustering of patients in 3 communities within the Houston metropolitan area, in which CTCL incidence rates were 5 to 20 times higher than the expected population rate. Analysis of the Texas Cancer Registry database defined the CTCL population rate for the state to be 5.8 cases per million individuals per year (95% confidence interval, 5.5-6.0 per million individuals per year), thus confirming the observations from the MDACC database and further highlighting additional areas of geographic clustering and regions spared from CTCL in Texas. CONCLUSIONS: The current study documented geographic clustering of CTCL cases in Texas and argued for the existence of yet unknown external causes/triggers for this rare malignancy. Cancer 2015;000:000-000. V C 2015 American Cancer Society.

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.

Lentinula edodes, or shiitake mushroom (SM), is typically grown in Eastern Asia and used in traditional Asian medicine and cuisine. Recently, SM became popular in Western culture and is now the second most commonly consumed mushroom in the world.1, 2 Although rare, adverse reactions to SM have been previously reported. In mushroom farm workers, contact dermatitis, contact urticaria, rhinitis, and hypersensitivity pneumonitis have been described. In the general population, oral intake of raw SM has been associated with a typical flagellate eruption, known as shiitake dermatitis (SD).3 Shiitake dermatitis, also termed shiitake toxicoderma or flagellate mushroom dermatitis, classically manifests 12 hours to 5 days after the ingestion of SM.1, 4 Since its first description in 1977, SD has been described in approximately 100 patients, predominantly Japanese.3, 5 Recently, a few cases were reported in Europe and in the United States.1 The mechanism underlying SD has not been fully elucidated. Although the eruption is usually considered nonallergic,6 5 cases of SD resulted in positive delayed skin prick testing, suggesting that delayed-type systemic hypersensitivity may be important in its pathogenesis.2, 3, 4, 7, 8, 9 We report the first case of SD in Canada and, to our knowledge, the first case of pustular SD. In our patient, positive delayed skin prick testing to SM was documented.

Previous reports of geographic clustering of cutaneous T-cell lymphoma (CTCL) in Texas, Pittsburgh, and Sweden as well as the occurrence of CTCL in married couples and family members raise a possibility of the existence of an external and potentially preventable trigger(s) for this rare skin cancer.The authors studied CTCL incidence and mortality in Canada using 3 distinct population-based cancer databases. Data on patients' sex, age at the time of diagnosis, subtype of CTCL malignancy, reporting province, city, and postal code were analyzed. CTCL cases were mapped across Canada using geographic information systems software.In total, 6685 patients with CTCL were identified in Canada during 1992 through 2010 (CTCL incidence rate, 11.32 cases per million individuals per year), of which 58% were males. The mean age at diagnosis was 59.4 ± 21.5 years. Geographic analysis of patients revealed increased CTCL incidence on the provincial and city levels in several eastern provinces and in Manitoba. An analysis according to postal codes (Forward Sortation Area [FSA]) identified select communities in which several high-incidence FSAs were contiguous or adjacent. Several of these FSAs were located in industrial regions of Canadian cities. Conversely, 3 of 8 low-incidence FSAs were clustered in Ottawa, Ontario, which has very little industrial presence. An analysis of CTCL mortality in Canada corroborated the current incidence findings.The current results provide a comprehensive analysis of CTCL burden in Canada and highlight several important areas of geographic case clustering. These findings argue that industrial exposures may play an important role in promoting CTCL pathogenesis. Cancer 2017;123:3550-67. © 2017 American Cancer Society.

Although familial aggregation of lymphoproliferative disorders has been described, heredity has not been implicated in the etiology of primary cutaneous B-cell lymphomas (PCBCL). We report herein the first case of 2 young monozygotic twins with PCBCL. The first twin was an 18-year-old woman when she presented with multiple skin nodules on the thorax and head. Histology showed an atypical small B-cell proliferation, consistent with primary cutaneous marginal zone lymphoma (PCMZL). Molecular genetics studies demonstrated B-cell clonality. Seven years later, the second twin developed her first lesion that was histologically similar to that of her twin. She subsequently developed other clinically similar lesions. Histology was consistent with PCMZL and showed B-cell clonality. Occurrence of PCBCL in these monozygotic twins raises the possibility of a genetic risk factor. Further study of such rare cases may offer valuable insights into the molecular basis of the etiology and pathogenesis of this unusual disorder.

Background: Bullous lupus erythematosus is a rare disease that is extremely rare in childhood (with only seven previous reports) and difficult to control. Objective: Herein is presented the youngest patient reported with this condition, and a novel, safe, and effective treatment regimen is described. Methods: Through study, perseverance, serendipity, and creativity, a safe and effective regimen was developed. Results: The combination of mycophenolate mofetil and erythromycin (plus sun protection) was found to be efficacious. Conclusion: It is proposed that the two medications act synergistically, with the “antibiotic” acting as a antiinflammatory agent, but at a different point in the inflammatory cascade than mycophenolate mofetil. This suggests the approach of using common, inexpensive, and benign antibiotics to potentiate, and perhaps decrease the use of, immunomodulatory agents in autoimmune and autoinflammatory diseases.

Background: Nonattendance at scheduled appointments is a major problem. Previous studies have shown rates between 17 and 31%. Most US studies found the type of payer to be the greatest determinant of attendance rates. Objectives: This study examines the no-show rate in a private dermatology practice under a single universal payer model, including the effects of old versus new patient, gender, day of the week, month, and weather. Results: The overall rate of nonattendance was lower than in all previous studies (7.79%), with the only statistically significant variable being established versus new patients. Limitations: Certain demographic data investigated in previous studies (eg, age, socioeconomic status) were not assessable. Data are from a single office. Conclusion: The no-show rate in a single universal payer, private practice model is low, especially for established patients.

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.

Erythromelalgia is characterized by spontaneous recurrent episodes of redness, heat, and pain of the extremities that can be triggered or worsened by heat. Raynaud's phenomenon occurs in response to cold exposure and presents as pallor of the fingers or toes, often followed by cyanosis and rubor. Although the 2 conditions may appear to be opposites in symptomatology and clinical presentation, there are very rare reports of their coexistence. A case of coexistent erythromelalgia and Raynaud's phenomenon is presented. The pathophysiology is reviewed to elucidate a common mechanism underlying some cases of the 2 seemingly opposite conditions. A review of the literature indicates that causative and pathophysiologic similarities between the 2 conditions may exist in some cases. Rare reports of coexistence of the 2 disease processes further strengthen such research findings.

Cutaneous T-cell lymphomas (CTCLs) (mycosis fungoides and its leukemic variant, Sezary syndrome) are rare malignancies. Reports of the occurrence of mycosis fungoides in married couples and families raise the possibility of an environmental trigger for this cancer. Although it has been suggested that CTCL arises from inappropriate T-cell stimulation, to the authors' knowledge no preventable trigger has been identified to date.Using region, zip code, age, sex, and ethnicity, the authors analyzed the demographic data of 1047 patients from Texas who were seen in a CTCL clinic at The University of Texas MD Anderson Cancer Center during 2000 through 2012 (the MDACC database) and 1990 patients who were recorded in the population-based Texas Cancer Registry between 1996 and 2010. Subsequently, data from both databases were cross-analyzed and compared.The current study findings, based on the MDACC database, documented geographic clustering of patients in 3 communities within the Houston metropolitan area, in which CTCL incidence rates were 5 to 20 times higher than the expected population rate. Analysis of the Texas Cancer Registry database defined the CTCL population rate for the state to be 5.8 cases per million individuals per year (95% confidence interval, 5.5-6.0 per million individuals per year), thus confirming the observations from the MDACC database and further highlighting additional areas of geographic clustering and regions spared from CTCL in Texas.The current study documented geographic clustering of CTCL cases in Texas and argued for the existence of yet unknown external causes/triggers for this rare malignancy.

Purpose: The pathogenesis of cutaneous T-cell lymphoma (CTCL) remains only partially understood. A number of recent studies attempted to identify novel diagnostic markers and future therapeutic targets. One group of antigens, cancer–testis (CT) antigens, normally present solely in testicular germ cells, can be ectopically expressed in a variety of cancers. Currently, only a few studies attempted to investigate the expression of CT antigens in CTCL. Experimental Design: In the present work, we test the expression of CT genes in a cohort of patients with CTCL, normal skin samples, skin from benign inflammatory dermatoses, and in patient-derived CTCL cells. We correlate such expression with the p53 status and explore molecular mechanisms behind their ectopic expression in these cells. Results: Our findings demonstrate that SYCP1, SYCP3, REC8, SPO11, and GTSF1 genes are heterogeneously expressed in patients with CTCL and patient-derived cell lines, whereas cTAGE1 (cutaneous T-cell lymphoma-associated antigen 1) was found to be robustly expressed in both. Mutated p53 status did not appear to be a requirement for the ectopic expression of CT antigens. While T-cell stimulation resulted in a significant upregulation of STAT3 and JUNB expression, it did not significantly alter the expression of CT antigens. Treatment of CTCL cells in vitro with vorinostat or romidepsin histone deacetylase inhibitors resulted in a significant dose-dependent upregulation of mRNA but not protein. Further expression analysis demonstrated that SYCP1, cTAGE1, and GTSF1 were expressed in CTCL, but not in normal skin or benign inflammatory dermatoses. Conclusions: A number of CT genes are ectopically expressed in patients with CTCL and can be used as biomarkers or novel targets for immunotherapy. Clin Cancer Res; 20(14); 3799–808. ©2014 AACR.

Background: Lichen planopilaris (LPP) is believed to be a follicular variant of lichen planus that affects pilosebaceous units, mainly of the scalp. An extremely rare variant of LPP is a linear form, which follows the lines of Blaschko. Of the five previously documented cases of linear LPP, all were limited to the face. Objective: We report the case of a 34-year-old male who presented with a nonpruritic eruption on the trunk consisting of erythematous, keratotic, folliculocentric papules following Blaschko's lines. Results: Biopsy revealed lichenoid and interface dermatitis involving the basilar epidermis and hair follicles, as well as apoptotic keratinocytes, consistent with LPP. Conclusion: This represents the first documented case of LPP, following the Blaschko's lines, in a nonfacial distribution.

Deregulation of STAT signaling has been implicated in the pathogenesis for a variety of cancers, including CTCL. Recent reports indicate that loss of STAT4 expression is an important prognostic marker for CTCL progression and is associated with the acquisition of T helper 2 cell phenotype by malignant cells. However, little is known about the molecular mechanism behind the downregulation of STAT4 in this cancer. In the current work we test the expression of STAT4 and STAT6 via RT-PCR and/or Western Blot in CTCL lesional skin samples and in immortalized patient-derived cell lines. In these malignant cell lines we correlate the expression of STAT4 and STAT6 with the T helper (Th) phenotype markers and test the effect of Histone Deacetylase (HDAC) inhibitors and siRNA-mediated knock down of miR-155 on STAT4 expression. Our findings demonstrate that STAT4 expression correlates with Th1 phenotype, while STAT6 is associated with the Th2 phenotype. Our results further document that STAT4 and STAT6 genes are inversely regulated in CTCL. Treatment with HDAC inhibitors upregulates STAT4 expression, while at the same time decreases STAT6 expression in MyLa cells. Also, siRNA-mediated knock down of miR-155 leads to upregulation in STAT4 expression in MyLa cells. In summary, our results suggest that loss of STAT4 expression and associated switch to Th2 phenotype during Mycosis Fungoides progression may be driven via aberrant histone acetylation and/or upregulation of oncogenic miR-155 microRNA.

Cutis marmorata telangiectatica congenita is an uncommon, generally congenital, cutaneous condition. The major skin findings are persistent, fixed cutis marmorata, telangiectasia, and phlebectasia; often, there is associated skin atrophy and ulceration as well. Significantly, two-thirds of patients have other congenital anomalies, although often minor ones. We report a series of eight children with cutis marmorata telangiectatica congenita, including one with associated congenital hypothyroidism, a relationship that has never before been noted.

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.

Cutaneous T-cell lymphomas (CTCLs) are a group of lymphoproliferative disorders affecting the skin. The etiology of CTCLs is unknown, and the pathogenesis remains elusive.1 Yet CTCL provides an interesting setting for studying the link between inflammation and cancer, since lymphocytic infiltrate is the hallmark of both. Early stages of CTCL mimic benign inflammatory disorders, including psoriasis and eczema, with malignant T cells homing to the skin. This disease usually remains indolent as isolated patches and plaques for many years, but in 10–20% of cases it can progress to form tumors and/or disseminate to lymph nodes, blood and visceral organs.1 Patients with advanced stages of CTCL often succumb to sepsis secondary to breakdown of the skin barrier function and immune suppression. Clinicians specializing in treating this cancer often face a number of important challenges. First, how to diagnose and distinguish early stages of CTCL from other benign inflammatory dermatoses? Second, how to predict which 10–20% of patients are likely to progress toward advanced stages, and, finally, how to achieve a cure of the disease with minimal toxicities? To answer these questions, better understanding of molecular CTCL carcinogenesis is urgently needed, where identified molecular players can be used as novel diagnostic/prognostic markers as well as targets for therapy. In the article by Kopp et al., the authors establish STAT5-mediated upregulation of mir-155 as an important step in CTCL carcinogenesis.2 Indeed, microRNA (miRNA) studies only recently became a prominent part of CTCL research. Specifically, Ralfkiaer et al. identified a set of miRNA classifiers that can be employed to distinguish early stages of CTCL from other benign inflammatory conditions.3 Still, unfortunately, functional data on miRNA remains sparse and has only begun to emerge in the last few years. miR-155 was recently highlighted as being upregulated in CTCL.3 This gene is a well-studied miRNA that is crucial for inflammation and is often overexpressed in various cancers. In their seminal article Kopp et al. discovered a link between miR-155 expression and JAK/STAT signaling in CTCL.2 They provide evidence that miR-155 is induced via transcription factor STAT5 through either cytokine (IL-2/IL-15)-dependent or constitutive activation in malignant and non-malignant T cells, including PBMCs and primary CTCL cells (Fig. 1). Furthermore, they found miR-155 to be involved in malignant proliferation. Their results are intriguing, because they connect some of the major hallmarks in CTCL: an increased expression of oncomiR-155, deregulation of JAK/STAT signaling pathways, and a persistent activation of STAT transcription factors.2,4 Figure 1. STAT5 signaling trans activates miR-155 expression, which can be blocked upstream at the level of JAK kinase signaling by tofacitinib inhibitor. While aberrant activation of multiple STAT proteins has been observed in various cancers, until recently, CTCL research has primarily focused on STAT3 as the major culprit in the effects of aberrant JAK/STAT signaling.5 Yet several studies have also implicated STAT5 as being aberrantly activated in malignant T cells. However, little was known about downstream targets and cellular consequences of STAT5 activation in CTCL. Now Kopp et al. document that this well-described oncomiR, miR-155, is a novel downstream target of STAT5 and is involved in malignant proliferation of T cells.2 Since miR-155 has also been implicated in genomic instability in cancer, it is possible that STAT5, via induction of miR-155, also drives genomic instability, a key feature of CTCL. As mentioned above, one of the major obstacles in managing CTCL is our inability to consistently achieve cure of this cancer. Due to its heterogeneity, there is no common genetic aberration or biomarker providing a reliable therapeutic target for patients. To achieve effective cure, CTCL therapy is in need of new targets and treatment strategies. Kopp et al. showed that treatment of malignant cells with JAK inhibitor tofacitinib (CP 690 550) strongly inhibits miR-155 expression and STAT5 activation. These results suggest a therapeutic potential of JAK inhibitors. Tofacitinib is already clinically approved for treatment of rheumatoid arthritis and is now being tested in clinical trials for psoriasis.6 It would be very interesting to evaluate the potential of tofacitinib in combination with already existing therapies for CTCL. In summary, these combined results hold great potential for diagnosis and treatment of CTCL.

The clinical experience of two US Army dermatologists during the recent Gulf War (Operation Desert Shield/Storm) are presented, with comparison with dermatologic experience in previous wars and in civilian practice.