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Cutaneous melanoma (CM) is a significant contributor to skin cancer-related mortality globally and in Canada. Despite the well-established link between ultraviolet (UV) radiation exposure and skin cancer risk, there remains a gap in population-level interventions and persistent misconceptions about sun exposure and impact of environment on individual behavior.

Systemic treatment patterns and related mental health disorders and economic burden among patients with psoriasis are largely unknown.

An otherwise healthy 25-year-old Syrian man arrived in Canada as part of the country's Syrian refugee program. The patient presented to our dermatology clinic with nonresolving indurated plaques on his [...]

ABSTRACTCancer meiomitosis is defined as the concurrent activation of both mitotic and meiotic machineries in neoplastic cells that confer a selective advantage together with increased genomic instability. MeiCT (meiosis-specific cancer/testis) genes that perform specialized functions in the germline events required for the first meiotic division are ectopically expressed in several cancers. Here we describe the expression profiles of meiCT genes and proteins across a number of cancers and review the proposed mechanisms that increase aneuploidy and elicit reduction division in polyploid cells. These mechanisms are centered on the overexpression and function of meiCT proteins in cancers under various conditions that includes a response to genotoxic stress. Since meiCT genes are transcriptionally repressed in somatic cells, their target offers a promising therapeutic approach with limited toxicity to healthy tissues. Throughout the review, we provide a detailed description of the roles for each gene in the context of meiosis and we discuss proposed functions and outcomes resulting from their ectopic reactivation in cancer.

BackgroundOcular surface squamous neoplasia (OSSN) is the most common non-pigmented ocular surface malignancy. It is classified as invasive OSNN (IOSSN) when the underlying stroma are infiltrated by dysplastic squamous epithelial cells through the basement membrane. Here, we present the descriptive epidemiology and geographical distribution of IOSSN in Canada.MethodsWe determined the incidence and geographical distribution of IOSSN cases diagnosed between 1992 and 2010 using two independent population-based cancer registries: the Canadian Cancer Registry and Le Registre Québécois du Cancer.ResultsThe mean annual age-standardised incidence rate (WHO 2000–2025) of IOSSN for 1992–2010 was 0.45 cases per million individuals per year with an average annual percent increase in incidence of 4.5%. IOSSN localisation to the conjunctiva was documented in at least 57% of the reported cases. IOSSN exhibited a male predilection ratio of 3.3:1.0 with a mean age at diagnosis of 69 years. Incidence rates of IOSSN across Canadian provinces and cities showed no significant differences from the crude national average.ConclusionsOur results, particularly concerning IOSSN patient age and male predilection, corroborate with data reported from the USA. Additional studies are needed to determine whether the observed increase in incidence rate over the study period (1992–2010) is significant.

BackgroundOphthalmic lymphoma (OL) is the most common orbital tumour, particularly in older individuals. Little is known about the epidemiology and geographic distribution of OL in Canada. Descriptive demographic statistics are an important first step in understanding OL burden and are necessary to inform comprehensive national cancer prevention programmes.MethodsWe determined patterns of incidence and geographical distribution of the three major subtypes of OL: extranodal marginal zone B cell lymphoma, follicular lymphoma (FL) and diffuse large B cell lymphoma. Here, we used cases that were diagnosed during 1992–2010 using two independent population-based cancer registries, the Canadian Cancer Registry and Le Registre Québécois du Cancer (LRQC).ResultsThe OL mean annual age-standardised incidence rate for 1992–2010 was 0.65 cases per million people per year with an average annual increase in the incidence rate of 4.5% per year. The mean age of diagnosis was 65 years. OL incidence rate was the highest in the cities located along the heavily industrialised Strait of Georgia in British Columbia.ConclusionsOur data on patient age, sex and temporal trends showed similarities with data reported in the USA and Denmark. Additional studies are needed to determine whether the observed increase in OL incidence is genuine or spurious.

Purpose:To determine the incidence rates and geographic distribution of retinoblastoma in Canada to aid cancer control programs.Methods:Patients with retinoblastoma whose data were available from the Canadian Cancer Registry (CCR) and Le Registre Québécois du Cancer (LRQC) were studied. Using third edition International Classification of Diseases for Oncology (ICD-O) codes, the authors examined the incidence rates and geographic distribution of patients with retinoblastoma between 1992 and 2010. Patient data including sex, age, and laterality of the retinoblastoma were analyzed.Results:Between 1992 and 2010 in Canada, the average annual incidence rate of retinoblastoma was 11.58 cases per 1 million children younger than 5 years (95% CI [confidence interval]: 10.48 to 12.76). The incidence rate was stable over time, with an average age at diagnosis of 2.30 ± 6.85 years and no gender predilection. The laterality of the reported cases was 81.48% for uni-lateral cases and 18.52% for bilateral cases. Provincially, Nova Scotia had twice the national average and the highest incidence rates of retinoblastoma across the Canadian provinces.Conclusions:This is the first study to define the disease burden of retinoblastoma and to highlight important longitudinal, geographic, and spatial differences in the distribution of retinoblastoma in Canada between 1992 and 2010. The results of this study indicate continuity of clinical trends between Canada, the United States, and other developed countries.[[J Pediatr Ophthalmol Strabismus. 2019;56(2):124–130.]

BackgroundIn the developed countries, uveal melanoma is the most common primary intraocular malignancy in adults. Little is known about the epidemiological and geographical distribution of uveal melanoma in Canada.MethodsTo determine the incidence patterns and geographical distribution of uveal melanoma cases in Canada, we conducted the first comprehensive, population-based national study of this malignancy across all Canadian provinces and territories during 1992–2010 years. We examined two independent population-based registries: the Canadian Cancer Registry and Le Registre Québécois du Cancer using corresponding International Classification of Diseases for Oncology-3rd edition codes for all histological subtypes of uveal melanoma.ResultsWe report that 2215 patients were diagnosed with uveal melanoma, of which 52.1% were males. The average -annual incidence rate of uveal melanoma in Canada was 3.75 cases per million individuals per year (95% CI 3.60 to 3.91). Overall, we report a steady increase in uveal melanoma incidence with an annual increase of 0.074 cases per million individuals per year. Significant differences in the incidence rates of uveal melanoma between Canadian provinces and territories were noted, where the highest crude incidence was in British Columbia and Saskatchewan with rates of 6.38 and 5.47 cases per million individuals per year, respectively.ConclusionsThis work, for the first time, defines the disease burden of uveal melanoma in Canada and highlights important longitudinal, geographical and spatial differences in the distribution of uveal melanoma in Canada.

BackgroundMelanoma is the most common primary malignancy of the eye in adults. While the epidemiology of uveal melanoma has recently been described in Canada, little is known about the epidemiology and geographic distribution of patients with conjunctival melanoma (CM) in Canada.MethodsWe conducted a population-based study of CM incidence across all Canadian provinces and territories during 1992–2010 using two independent population-based registries.Results190 patients were diagnosed with CM in Canada from 1992 to 2010. 55.3 % of these patients were men. The mean annual incidence rate of CM in Canada was 0.32 cases per million individuals (0.35 and 0.29 cases per million individuals for men and women, respectively). The incidence rates for Canadian provinces demonstrated that the eastern provinces of Nova Scotia and New Brunswick had higher age-adjusted incidence rates than the national average, with rates of 0.52 and 0.47 cases per million individuals per year, respectively.ConclusionsThis analysis demonstrates novel variations in CM incidence rates between different Canadian provinces. These results taken together with the data reported from the USA confirm the North-to-South geographic gradient of increasing CM incidence. This research highlights that the epidemiology of CM in North America is comparable to that of cutaneous malignant melanoma in contrast to the trends for uveal melanoma distribution.

Sézary syndrome (SS) is an aggressive leukemic variant of cutaneous T-cell lymphoma (CTCL) with a median life expectancy of less than 4 years. Although initial treatment responses are often good, the vast majority of patients with SS fail to respond to ongoing therapy. We hypothesize that malignant T cells are highly heterogeneous and harbor subpopulations of SS cells that are both sensitive and resistant to treatment. Here, we investigate the presence of single-cell heterogeneity and resistance to histone deacetylase inhibitors (HDACi) within primary malignant T cells from patients with SS. Using single-cell RNA sequencing and flow cytometry, we find that malignant T cells from all investigated patients with SS display a high degree of single-cell heterogeneity at both the mRNA and protein levels. We show that this heterogeneity divides the malignant cells into distinct subpopulations that can be isolated by their expression of different surface antigens. Finally, we show that treatment with HDACi (suberanilohydroxamic acid and romidepsin) selectively eliminates some subpopulations while leaving other subpopulations largely unaffected. In conclusion, we show that patients with SS display a high degree of single-cell heterogeneity within the malignant T-cell population, and that distinct subpopulations of malignant T cells carry HDACi resistance. Our data point to the importance of understanding the heterogeneous nature of malignant SS cells in each individual patient to design combinational and new therapies to counter drug resistance and treatment failure.

Immunostaining of non-adherent cells is commonly performed after adhesion of cells onto microscope slides either using cytocentrifugation or with the help of charged coating substrates. These techniques, however, require either specialized equipment or significant preparation time. Here, we describe a method for immunofluorescent staining of lymphocytes within multi-well culture plates, where cells suspended in phosphate buffered saline (PBS) are adhered to either the plastic well bottom or glass coverslips by gravity sedimentation. This technique requires only common laboratory materials, no coating steps, and allows for densely adherent cell coverage with 1 × 106cells. Our data show that suspension of cells in PBS, but not serum-containing growth medium, allows for adhesion to plastic or glass after 30 min of gravity sedimentation. We show that this method is applicable for immunofluorescent staining of both primary human lymphocytes and immortalized lymphoma cells, and that it preserves cell morphology.

A 39-year-old woman with a history of regional enteritis presented with an itchy rash on a tattoo on her left leg that she had received two weeks earlier (Figure 1A). [...]

A 51-year-old man presented with a 6month history of asymptomatic eruptive skin-coloured lesions in his groin (Figure 1). He did not report any high-risk sexual behaviour leading up to development [...]

Cutaneous T-cell lymphoma (CTCL) is characterized by proliferation of malignant T cells in a chronic inflammatory environment. With disease progression, bacteria colonize the compromised skin barrier and half of CTCL patients die of infection rather than from direct organ involvement by the malignancy. Clinical data indicate that bacteria play a direct role in disease progression, but little is known about the mechanisms involved. Here, we demonstrate that bacterial isolates containing staphylococcal enterotoxin A (SEA) from the affected skin of CTCL patients, as well as recombinant SEA, stimulate activation of signal transducer and activator of transcription 3 (STAT3) and upregulation of interleukin (IL)-17 in immortalized and primary patient–derived malignant and nonmalignant T cells. Importantly, SEA induces STAT3 activation and IL-17 expression in malignant T cells when cocultured with nonmalignant T cells, indicating an indirect mode of action. In accordance, malignant T cells expressing an SEA-nonresponsive T-cell receptor variable region β chain are nonresponsive to SEA in monoculture but display strong STAT3 activation and IL-17 expression in cocultures with SEA-responsive nonmalignant T cells. The response is induced via IL-2 receptor common γ chain cytokines and a Janus kinase 3 (JAK3)-dependent pathway in malignant T cells, and blocked by tofacitinib, a clinical-grade JAK3 inhibitor. In conclusion, we demonstrate that SEA induces cell cross talk–dependent activation of STAT3 and expression of IL-17 in malignant T cells, suggesting a mechanism whereby SEA-producing bacteria promote activation of an established oncogenic pathway previously implicated in carcinogenesis.

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.

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.

Skin lesions from mycosis fungoides (MF) patients display an increased expression of interleukin-15 (IL-15), IL-17F, and other cytokines implicated in inflammation and malignant cell proliferation in cutaneous T-cell lymphoma (CTCL). In the leukemic variant of CTCL, Sézary syndrome (SS), IL-2 and IL-15 trigger activation of the Jak-3/STAT3 pathway and transcription of IL17A gene, whereas it is unknown what causes IL-15 expression, Jak3/STAT3 activation, and production of IL-17F in MF. Here, we studied the expression and regulation of IL-15 and its relation to IL-17F in MF cell lines and skin lesions from 60 MF patients. We show that: (1) the spontaneous IL-15 mRNA expression is resistant to Jak3 and STAT3 inhibitors at concentrations that profoundly inhibit STAT3 activation and IL-17F mRNA expression; (2) anti-IL-15 antibody blocks STAT3 activation induced by exogenous IL-15 in non-malignant MF T cells, whereas the spontaneous STAT3 activation and IL-17F expression in malignant T cells is not inhibited; (3) patients display heterogeneous IL-15/IL-17F mRNA expression patterns in skin lesions; and (4) IL-15 expression (in contrast to IL-17F) is not associated with progressive disease. Taken together, these findings indicate that IL-15 and IL-17F are differentially regulated and expressed in MF. We propose that IL-15 and IL-17F are markers for different inflammatory environments and play distinct roles in the development and progression of MF.

Inappropriately regulated expression of interleukin (IL)-17A is associated with the development of inflammatory diseases and cancer. However, little is known about the role of other IL-17 family members in carcinogenesis. Here, we show that a set of malignant T-cell lines established from patients with cutaneous T-cell lymphoma (CTCL) spontaneously secrete IL-17F and that inhibitors of Janus kinases and Signal transducer and activator of transcription 3 are able to block that secretion. Other malignant T-cell lines produce IL-17A but not IL-17F. Upon activation, however, some of the malignant T-cell lines are able to coexpress IL-17A and IL-17F, leading to formation of IL-17A/F heterodimers. Clinically, we demonstrate that IL-17F messenger RNA expression is significantly increased in CTCL skin lesions compared with healthy donors and patients with chronic dermatitis. IL-17A expression is also increased and a significant number of patients express high levels of both IL-17A and IL-17F. Concomitantly, we observed that the expression of the IL-17 receptor is significantly increased in CTCL skin lesions compared with control subjects. Importantly, analysis of a historic cohort of 60 CTCL patients indicates that IL-17F expression is associated with progressive disease. These findings implicate IL-17F in the pathogenesis of CTCL and suggest that IL-17 cytokines and their receptors may serve as therapeutic targets.

Psoriasis is a chronic inflammatory skin disorder characterized by keratinocyte hyperproliferation, leukocyte infiltration, and alterations in cytokine production. Recent work documented that the inappropriately activated T helper cells 1 and 17 lymphocytes play a critical role in disease initiation and progression by elaborating an array of inflammatory cytokines that deregulate normal keratinocyte proliferation and differentiation. The key signal to suppress keratinocyte growth is the transforming growth factor (3 (TGF-β) protein, the expression of which is documented to be increased in psoriatic patients. Despite the observed upregulation in TGF-β signal, psoriatic keratinocytes continue to proliferate in response to other signals. Thus, there appears to be discordance between high levels of TGF-β at a lesion site and increased keratinocyte growth. Recently we identified CD109, a glycosyl-phosphatidylinositol (GPI)-anchored protein, as a novel regulator of the TGF-β signaling. CD109 is expressed on the keratinocyte cell surface and is released via an endogenous lipase into the extracellular milieu. Membrane-anchored CD109 has been documented to bind the TGF-β protein as well as interact with the TGF-β receptor and alter its stability and function. We describe here the paradoxical discordance between high TGF-β levels and the lack of proliferation inhibition in psoriatic skin. We also highlight the possible importance of CD109 as a critical TGF-β signaling modulator in psoriasis. Further understanding of CD109 and TGF-β signaling in psoriasis may lead to development of new, effective therapies.

The Androgen Receptor (AR) is a steroid transcription factor, the activity of which is the primary focus of androgen ablation therapies for advanced prostate cancer. In prostate cancers, the AR acquires gain-of-function changes allowing it to drive prostate cancer cell survival and proliferation in a cell-autonomous manner. As part of this malignancy-associated gain-of-function, AR acquires a role in licensing for DNA replication in prostate cancer cells. In its role as a licensing factor, AR must be degraded during mitosis in order to allow re-licensing in the subsequent cell cycle. This conclusion is supported by the demonstration that acute enhanced expression of AR in prostate cancer cells results in its incomplete degradation in mitosis. This lack of mitotic AR degradation inhibits subsequent cell proliferation due to the inability to re-license all origins of replication needed for the next round of cell division. These data provide a unifying paradigm to clarify a number of unresolved observations in prostate cancer research. In addition, they provide a rationale for a new therapeutic approach for prostate cancer based upon stabilization of AR.

ABSTRACTCTCL follows different courses depending on the clinical stage at the time of diagnosis. Patients with early stage Mycosis Fungoides (MF) variant of CTCL may experience an indolent course over decades, whereas patients with advanced MF and Sézary Syndrome (SS) disease at diagnosis, often succumb within 5 years. Even within early stage CTCL/MF, a minority of patients will progress to more advanced stages. We recently generated RNA sequencing data on 284 CTCL-relevant genes for 157 patients and identified differentially expressed genes across stages I-IV. In this study, we aim to validate robust molecular markers linked to disease progression and survival. We performed multiple hypothesis testing-corrected analysis of variance (ANOVA) on the expression of individual genes across all CTCL samples and early stage (≤IIA) CTCL/MF patients. We used in silicoimmune cell-type deconvolution from gene expression data to estimate immune cell populations. Based on the analysis of all CTCL samples, we identified TOX, FYB, and CD52as predictors of disease progression and poor survival. Among early stage (≤IIA) CTCL/MF patients, these 3 genes, along with CCR4, were valuable to predict disease progression. We validated these 4 genes in 3 independent, external Sézary Syndrome patient cohorts with RNA-Sequencing data. In silicoimmune cell-type deconvolution revealed that neutrophil infiltration in early stage MF conveyed a higher risk for disease progression. Also, NK cell infiltration in late stage MF/SS correlated with improved survival. TOX, FYB, CCR4and CD52are robust disease progression and decreased survival biomarkers in CTCL.

ABSTRACTCutaneous 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, GTSF1and PSORS1C2genes 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, GTSF1and 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.

ABSTRACTMost skin malignancies are caused by external and often preventable environmental agents. Multiple reports demonstrated that cutaneous T-cell lymphomas (CTCL) can occur in married couples and cluster in families. Furthermore, recent studies document geographic clustering of this malignancy in Texas as well as in other areas of the United States. Multiple infectious, occupational, and medication causes have been proposed as triggers or promoters of this malignancy including hydrochlorothiazide diuretics, Staphylococcus aureus, dermatophytes, Mycobacterium leprae, Chlamydia pneumoniae, human T-Cell lymphotropic virus type 1 (HTLV1), Epstein-Barr virus (EBV), and herpes simplex virus (HSV). In this report, we review recent evidence evaluating the involvement of these agents in cancer initiation/progression. Most importantly, recent molecular experimental evidence documented for the first time that S. aureuscan activate oncogenic STAT3 signaling in malignant T cells. Specifically, S. aureusEnterotoxin type A (SEA) was recently shown to trigger non-malignant infiltrating T cells to release IL-2 and other cytokines. These signals upon binging to their cognate receptors on malignant T cells are then able to activate STAT3 and STAT5 oncogenic signaling and promote cancer progression and IL-17 secretion. In light of these findings, it might be important for patients with exacerbation of their CTCL symptoms to maintain high index of suspicion and treat these individuals for S. aureuscolonization and/or sepsis with topical and systemic antibiotics.

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.