Early Organ Metastasis in Granulomatous Mycosis Fungoides: A Systematic Review.

BACKGROUND: Granulomatous mycosis fungoides (GMF) is a rare form of cutaneous T-cell lymphoma characterized by a granulomatous inflammatory infiltrate. OBJECTIVE: The impact of granulomatous inflammation on the prognosis of the disease remains controversial as there are both favorable and unfavorable outcomes documented. METHODS: We performed a systematic review of 116 GMF cases previously described in the literature. RESULTS: In contrast to the classic Alibert-Bazin type of mycosis fungoides (MF), cutaneous lesions in GMF tend to involve distal extremities (lower legs, feet, hands) early in the disease course. In the literature, 30% of GMF patients developed organ metastasis, most frequently to the lung. The median time to stage progression was 25 months. CONCLUSION: GMF is an aggressive form of mycosis fungoides. Therefore, screening for distant metastases should be considered at presentation and repeated during follow-up.

Skin disorders and interstitial lung disease: Part I-Screening, diagnosis, and therapeutic principles.

Numerous inflammatory, neoplastic, and genetic skin disorders are associated with interstitial lung disease (ILD), the fibrosing inflammation of lung parenchyma that has significant morbidity and mortality. Therefore, the dermatologist plays a major role in the early detection and appropriate referral of patients at risk for ILD. Part 1 of this 2-part CME outlines the pathophysiology of ILD and focuses on clinical screening and therapeutic principles applicable to dermatological patients who are at risk for ILD. Patients with clinical symptoms of ILD should be screened with pulmonary function tests and high-resolution chest computed tomography. Screening for pulmonary hypertension should be considered in high-risk patients. Early identification and elimination of pulmonary risk factors, including smoking and gastroesophageal reflux disease, are essential in improving respiratory outcomes. First-line treatment interventions for ILD in a dermatological setting include mycophenolate mofetil, but the choice of therapeutic agents depends on the nature of the primary disease, the severity of ILD, and comorbidities and should be the result of a multidisciplinary assessment. Better awareness of ILD among medical dermatologists and close interdisciplinary collaborations are likely to prevent treatment delays improving long-term outcomes.

Implementation of Teledermatology in Alberta, Canada: A Report of One Thousand Cases.

BACKGROUND: Teledermatology utilizes photoimaging and background information to allow dermatologists to remotely provide a diagnosis to practitioners. ConsultDerm is an asynchronous, web-based teledermatology software that allows practitioners to submit their electronic referrals for assessment by board-certified dermatologists. OBJECTIVE: Our study aimed to retrospectively analyze teledermatology's utilization in Canada by using the teledermatology platform ConsultDerm. METHODS: After implementing inclusion criteria, 1000 patients were selected, and relevant demographic and clinical information were extracted for data analysis. In addition, an online survey with pre-formulated questions was distributed to 7 dermatologists currently using the ConsultDerm platform to determine their experience in utilizing teledermatology. RESULTS: Of the 1000 patients, 66.5% had not received treatment prior to their teledermatology referral, and on average, patients experienced symptoms for 489.5 days prior to their referral. Diagnoses made were categorized by conditions, most common being dermatitis (37.1%), followed by acneiform conditions (10.6%), benign lesions/neoplasms (12.1%), infections (9.4%), and dyspigmentation (3.1%). Most consults originated from small population centers, and the referring practitioners were predominantly family physicians. Dermatologists utilizing the platform expressed ease of use, however, areas of improvement were identified such as increasing the quality of imaging and more detailed patient history. CONCLUSION: Through our analysis of 1000 cases, we identified how a teledermatology consultation could be used to assess a wide variety of cutaneous conditions, improving access for patients who may face barriers to seeing a dermatologist.

A Clinician's Guide to Topical Retinoids.

Retinoids are defined as molecules that bind to and activate retinoic acid receptors to influence the proliferation and differentiation of cells. Topical retinoids have evolved over the past several decades, being used in multiple dermatological conditions. This review aims to differentiate between synthetic and natural retinoids, discuss the pharmacology behind topical retinoids, highlight clinical applications, and categorize all the commercially available agents, including combination products. Understanding retinoid affinities for unique receptor subtypes can impact clinical decisions, resulting in optimizing treatment and enhancing patient adherence.

Patterns of Gene Expression in Cutaneous T-Cell Lymphoma: Systematic Review of Transcriptomic Studies in Mycosis Fungoides.

Mycosis fungoides (MF) is the most prevalent type of skin lymphoma. In its early stages, it has a favorable prognosis. However, in its late stages, it is associated with an increased risk of mortality. This systematic review aimed to identify the transcriptomic changes involved in MF pathogenesis and progression. A literature search was conducted using the database PubMed, followed by the extraction of 2245 genes which were further filtered to 150 recurrent genes that appeared in two or more publications. Categorization of these genes identified activated pathways involved in pathways such as cell cycle and proliferation, chromosomal instability, and DNA repair. We identified 15 genes implicated in MF progression, which were involved in cell proliferation, immune checkpoints, resistance to apoptosis, and immune response. In highlighting the discrepancies in the way MF transcriptomic data is obtained, further research can focus on not only unifying their approach but also focus on the 150 pertinent genes identified in this review.

Galectin-9 expression defines exhausted T cells and impaired cytotoxic NK cells in patients with virus-associated solid tumors.

BACKGROUND: We have previously reported that the upregulation of galectin-9 (Gal-9) on CD4+ and CD8+ T cells in HIV patients was associated with impaired T cell effector functions. Gal-9 is a ligand for T cell immunoglobulin and mucin domain-3, and its expression on T cells in cancer has not been investigated. Therefore, we aimed to investigate the expression level and effects of Gal-9 on T cell functions in patients with virus-associated solid tumors (VASTs). METHODS: 40 patients with VASTs through a non-randomized and biomarker-driven phase II LATENT trial were investigated. Peripheral blood mononuclear cells and tumor biopsies were obtained and subjected to immunophenotyping. In this trial, the effects of oral valproate and avelumab (anti-PD-L1) was investigated in regards to the expression of Gal-9 on T cells. RESULTS: We report the upregulation of Gal-9 expression by peripheral and tumor-infiltrating CD4+ and CD8+ T lymphocytes in patients with VASTs. Our results indicate that Gal-9 expression is associated with dysfunctional T cell effector functions in the periphery and tumor microenvironment (TME). Coexpression of Gal-9 with PD-1 or T cell immunoglobulin and ITIM domain (TIGIT) exhibited a synergistic inhibitory effect and enhanced an exhausted T cell phenotype. Besides, responding patients to treatment had lower Gal-9 mRNA expression in the TME. Translocation of Gal-9 from the cytosol to the cell membrane of T cells following stimulation suggests persistent T cell receptor (TCR) stimulation as a potential contributing factor in Gal-9 upregulation in patients with VASTs. Moreover, partial colocalization of Gal-9 with CD3 on T cells likely impacts the initiation of signal transduction via TCR as shown by the upregulation of ZAP70 in Gal-9+ T cells. Also, we found an expansion of Gal-9+ but not TIGIT+ NK cells in patients with VASTs; however, dichotomous to TIGIT+ NK cells, Gal-9+ NK cells exhibited impaired cytotoxic molecules but higher Interferon gamma (IFN-γ) expression. CONCLUSION: Our data indicate that higher Gal-9-expressing CD8+ T cells were associated with poor prognosis following immunotherapy with anti-Programmed death-ligand 1 (PD-L1) (avelumab) in our patients' cohort. Therefore, for the very first time to our knowledge, we report Gal-9 as a novel marker of T cell exhaustion and the potential target of immunotherapy in patients with VASTs.

Galectin-9 Expression Defines a Subpopulation of NK Cells with Impaired Cytotoxic Effector Molecules but Enhanced IFN-γ Production, Dichotomous to TIGIT, in HIV-1 Infection.

NK cell functions are tightly regulated by the balance between the inhibitory and stimulatory surface receptors. We investigated the surface expression of galectin-9 (Gal-9) and its function in NK cells from HIV-infected individuals on antiretroviral therapy, long-term nonprogressors, and progressors compared with healthy controls. We also measured the expression of TIGIT and TIM-3 on different NK cell subpopulations and compared their functionality to Gal-9 + NK cells. Our data demonstrated significant upregulation of Gal-9 on NK cells in HIV-infected groups versus healthy controls. Gal-9 expression was associated with impaired expression of cytotoxic effector molecules granzyme B, perforin, and granulysin. In contrast, Gal-9 expression significantly enhanced IFN-γ expression in NK cells of HIV-1-infected individuals. We also found an expansion of TIGIT + NK cells in HIV-infected individuals; however, dichotomous to Gal-9 + NK cells, TIGIT + NK cells expressed significantly higher amounts of cytotoxic molecules but lower IFN-γ. Moreover, lower expression of cytotoxic effector molecules in Gal-9+ NK cells was associated with higher CD107a expression, which suggests indiscriminate degranulation. Importantly, a positive correlation between the plasma viral load and Gal-9+ NK cells was observed in progressors. Finally, we found that a cytokine mixture (IL-12, IL-15, and IL-18) can improve effector functions of Gal-9+ NK cells in HIV-infected individuals, although, such an effect was observed for Gal-9- NK cells, as well. Overall, our data highlight the important role of Gal-9 in dysfunctional NK cells and, more importantly, a dichotomy for the role of Gal-9 versus TIGIT and suggest a potential new avenue for the development of therapeutic approaches.

Correlation of transferrin receptor (CD71) with Ki67 expression on stimulated human and mouse T cells: The kinetics of expression of T cell activation markers.

T cell activation is a fascinating, yet tightly regulated cascade of events that lead to the induction of cytokine and expression of activation molecules that eventually result in divergent immune responses. Analyzing the qualitative and quantitative nature of T cell activation in different immunological conditions provides valuable information about the immune responses mediated by different agents or vaccinations. We evaluated the kinetics of CD4(+) and CD8(+) T cell activation markers such as CD25, CD38, CD69, CD71 and Ki67 following anti-CD3/CD28 stimulation over a time course. Our data show that the kinetics of expression of these activation markers follows a precise and consistent time-course with some differences between mouse and human T cells. Percentage of human T cells expressing CD69 and CD25 reached >90% at 24h stimulation, whereas higher percentage of cells co-expressing CD71 and Ki67 was evident for CD8(+) T cells compared with CD4(+) T cells at 24h. Similar to human T cells, percentage of CD8(+)CD38(+) cells was delayed but reached to >90% on mouse CD8(+) T cells at 48h and on mouse CD4(+) T cells at 72h. After 72h of stimulation all tested activation markers remained at the maximum levels in mouse T cells but interestingly percentages of cells expressing CD69 was significantly reduced in human T cells. Furthermore, these data demonstrate a positive correlation between CD71 and Ki67 expression on both mouse and human T cells from 12h post stimulation. Thus our results define the kinetics of activation markers/proliferation in human and mouse T cells; and may serve a reference for monitoring T cell function in clinical study and vaccinology.