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Simple Summary: Cutaneous T-cell lymphomas (CTCLs) represent a heterogeneous group of rare extranodal non-Hodgkin lymphomas with variable clinical presentation. In the Middle East and North Africa (MENA region), where darker skin colors are more common than in the West, CTCL generally presents at a younger age and with distinct clinical features that necessitate special expertise and management across disciplines: rare forms of CTCL are more common (hypo- and hyperpigmented mycosis fungoides (MF)) and a higher prevalence of pediatric MF is noticed. The high cancer burden in the Middle East and North Africa (MENA region) is coupled with an increasing cancer incidence. While the MENA region constitutes 6% of the world's population, it remains underrepresented in clinical trials. Cutaneous T-cell lymphomas (CTCLs) represent a heterogeneous group of rare extranodal non-Hodgkin lymphomas with variable clinical presentation. In the MENA region, where darker skin colors are more common than in the West, CTCL generally presents at a younger age and with distinct clinical features that necessitate special expertise and management across disciplines: rare forms of CTCL are more common (hypo- and hyperpigmented MF) and a higher prevalence of pediatric MF is noticed. The multidisciplinary approach to cancer management is growing worldwide and is necessary for the comprehensive management of CTCL. The MENA CTCL group was established with the aim of creating a collaborative environment for the diagnosis and treatment of CTCL in the region. Its first meeting was held in May 2023. The group plans to increase the global representation of the MENA region and establish CTCL registries and patient advocacy groups in the region. [ABSTRACT FROM AUTHOR]

Simple Summary: The combination of JAK/HDAC inhibitors shows beneficial effects in hematological malignancies and a promising therapeutic potential in CTCL. Recent in vitro and in vivo data have shown that the combination of Resminostat (HDACi) with Ruxolitinib (Jaki) acts synergistically and inhibits tumorigenesis and metastasis in CTCL experimental models. Angiogenesis is the most critical process for tumor growth and metastasis and plays an essential role in cutaneous lymphoma development and progression. The vascular microenvironment of lymphomas accelerates angiogenesis via the paracrine activity of tumor-derived mediators. However, few studies have investigated the role of either ruxolitinib or resminostat in the angiogenesis of hematological malignancies and solid tumors. Although precise mechanisms of angiogenesis in CTCL remain unclear, the chick embryo chorioallantoic membrane (CAM) has been used, among other in vivo models, to implant several tumor types as well as malignant cell lines to study their growth rate, angiogenic potential, and metastatic capability. The aim of this study was to investigate the effects of combinational therapies of JAKi/HDACi in CTCL angiogenesis by using a CTCL-specific chick embryo model. Angiogenesis plays a pivotal role in the growth and metastasis of tumors, including the development and progression of cutaneous lymphomas. The chick embryo CAM model has been utilized in various studies to assess the growth rate, angiogenic potential, and metastatic capability of different tumor types and malignant cell lines. However, the precise mechanisms of angiogenesis in CTCL and the influence of Ruxolitinib or Resminostat on angiogenesis in hematological malignancies and solid tumors are not well understood. Recent in vitro and in vivo data have demonstrated the synergistic inhibition of tumorigenesis and metastasis in experimental models of CTCL when using the combination of Resminostat (HDACi) with Ruxolitinib (JAKi). The present work aims to elucidate the effects of this combination on the tumor microenvironment's vascular components. We investigated the effects of Ruxolitinib (JAKi) in combination with Resminostat (HDACi) treatment in transendothelial migration of CTCL cells (106 MyLa and SeAx) by using a transwell-based transendothelial migration assay and tumor angiogenesis in vivo. We used the CTCL chick embryo CAM model with xenografted tumors derived from implanted MyLa and SeAx cells and administered topically 15 μM ruxolitinib and 5 μM Resminostat every two days during a 5-day period. JAKi and HDACi inhibited CTCL cell transendothelial migration by 75% and 82% (p < 0.05) in both CTCL engrafted cells (MyLa and SeAx, respectively) compared to the untreated group. Moreover, the combination of ruxolitinib with resminostat blocked angiogenesis by significantly reducing the number of blood vessel formation by 49% and 34% in both MyLa and SeAx, respectively (p < 0.05), indicating that the proposed combination exerted significant anti-angiogenic effects in the CAM CTCL model. Overall, these data provide valuable insights into potential therapeutic strategies targeting angiogenesis in CTCL, paving the way for more effective treatment approaches in the future. [ABSTRACT FROM AUTHOR]

Patients with advanced-stage mycosis fungoides (MF IIB–IVB) and Sézary syndrome (SS) have poor prognoses, with survival ranging from 4.7 to 1.4 years depending on the disease stage. There is a need for therapeutic approaches that lead to long-lasting responses and improved quality of life and survival. Mogamulizumab, a humanized antibody against the CCR4 molecule, and low-dose total skin electron beam therapy (TSEBT) are two known established treatments for MF and SS as a monotherapy. However, little is known about the potential additive effect on the combination of both treatments. We report here for the first time the concurrent use of low-dose hypofractionated TSEBT (2 × 4 Gy) with mogamulizumab. Based on two relapsed/refractory and advanced-stage CTCL patients, we show that this combination may be well tolerated in advanced-stage MF or SS and may potentially lead to an additive treatment effect on response times, particularly in the skin and blood within two weeks. We propose that this combination may be a treatment option for patients with SS. Further research is needed to understand the efficacy and tolerability profile of this therapeutic combination and to determine if there is an additive effect of the combination on the response rates when compared with the monotherapy. [ABSTRACT FROM AUTHOR]

Mogamulizumab is an anti-C–C chemokine receptor 4 antibody that is increasingly being used to treat T-cell malignancies such as cutaneous T-cell lymphoma, adult T-cell leukemia-lymphoma, and peripheral T-cell lymphoma. Because CCR4 is expressed on both malignant T-cells and regulatory T-cells (Tregs), mogamulizumab can be associated with increased immune-related adverse events (irAEs). While there is abundant literature on mogamulizumab-associated rash (MAR) and graft-versus-host disease (GVHD), other reported irAEs have not been collated into a single review. This narrative review covers irAEs associated with mogamulizumab in patients with T-cell lymphomas, focusing on events other than MAR and GVHD. We searched PubMed and Google Scholar for case reports, case series, chart reviews, and clinical trials published from inception to March 2024. Identified events include alopecia, vitiligo, arthritis, psoriasis, myocarditis, myositis/polymyositis, hepatitis, and others. Mogamulizumab's ability to augment the host immune response through Treg depletion adds to its efficacy but has wide-ranging implications for autoimmunity across multiple organ systems, similar to immune checkpoint inhibitor therapy. Occurrence of irAEs may be associated with improved overall clinical response, although long-term follow-up studies are needed. [ABSTRACT FROM AUTHOR]

Background: Mycosis fungoides (MF) is the most common subtype of cutaneous T-cell lymphoma (CTCL). Comprehensive analysis of MF cells in situ and ex vivo is complicated by the fact that is challenging to distinguish malignant from reactive T cells with certainty. Methods: To overcome this limitation, we performed combined single-cell RNA (scRNAseq) and T-cell receptor TCR sequencing (scTCRseq) of skin lesions of cutaneous MF lesions from 12 patients. A sufficient quantity of living T cells was obtained from 9 patients, but 2 had to be excluded due to unclear diagnoses (coexisting CLL or revision to a fixed toxic drug eruption). Results: From the remaining patients we established single-cell mRNA expression profiles and the corresponding TCR repertoire of 18,630 T cells. TCR clonality unequivocally identified 13,592 malignant T cells. Reactive T cells of all patients clustered together, while malignant cells of each patient formed a unique cluster expressing genes typical of naive/memory, such as CD27, CCR7 and IL7R, or cytotoxic T cells, e.g., GZMA, NKG7 and GNLY. Genes encoding classic CTCL markers were not detected in all clusters, consistent with the fact that mRNA expression does not correlate linearly with protein expression. Nevertheless, we successfully pinpointed distinctive gene signatures differentiating reactive malignant from malignant T cells: keratins (KRT81, KRT86), galectins (LGALS1, LGALS3) and S100 genes (S100A4, S100A6) being overexpressed in malignant cells. Conclusions: Combined scRNAseq and scTCRseq not only allows unambiguous identification of MF cells, but also revealed marked heterogeneity between and within patients with unexpected functional phenotypes. While the correlation between mRNA and protein abundance was limited with respect to established MF markers, we were able to identify a single-cell gene expression signature that distinguishes malignant from reactive T cells. [ABSTRACT FROM AUTHOR]

Primary cutaneous T cell lymphomas (CTCL) are a heterogenous group of non-Hodgkin lymphomas derived from skin-homing T cells. These include mycosis fungoides and its leukemic variant Sezary syndrome, as well as the CD30+ lymphoproliferative disorders. In this review, we provide a summary of the current literature on CTCL, with a focus on the immunopathogenesis and treatment of mycosis fungoides and Sezary syndrome. Recent advances in immunology have provided new insights into the biology of malignant T cells. This in turn has led to the development of new therapies that modulate the immune system to facilitate tumor clearance or target specific aspects of tumor biology. [ABSTRACT FROM AUTHOR]

Patients with advanced-stage mycosis fungoides (MF IIB–IVB) and Sézary syndrome (SS) have poor prognoses, with survival ranging from 4.7 to 1.4 years depending on the disease stage. There is a need for therapeutic approaches that lead to long-lasting responses and improved quality of life and survival. Mogamulizumab, a humanized antibody against the CCR4 molecule, and low-dose total skin electron beam therapy (TSEBT) are two known established treatments for MF and SS as a monotherapy. However, little is known about the potential additive effect on the combination of both treatments. We report here for the first time the concurrent use of low-dose hypofractionated TSEBT (2 × 4 Gy) with mogamulizumab. Based on two relapsed/refractory and advanced-stage CTCL patients, we show that this combination may be well tolerated in advanced-stage MF or SS and may potentially lead to an additive treatment effect on response times, particularly in the skin and blood within two weeks. We propose that this combination may be a treatment option for patients with SS. Further research is needed to understand the efficacy and tolerability profile of this therapeutic combination and to determine if there is an additive effect of the combination on the response rates when compared with the monotherapy.

Abstract Background HyBryteTM is a photodynamic therapy of topical hypericin that has recently been shown to be safe and efficacious in early stage cutaneous T‐cell lymphoma (CTCL). However, its efficacy, absorption, and effect on heart function parameters in patients who require greater HyBryteTM exposure is unknown. Objectives The primary objectives in this study were to assess hypericin blood levels using a validated detection method with a cut‐off value of 0.05 ng/mL and to determine if topical HyBryteTM induces any electrocardiogram (EKG) changes during 8 weeks of treatment. A secondary endpoint of this study was to assess the effectiveness of HyBryteTM in this patient population as well as assessing a different additional light device than the one used in the Phase 3 HPN‐CTCL‐01/fluorescent light activated synthetic hypericin trial also entitled “A phase 3 multicenter randomised placebo‐controlled study to determine the efficacy of topical hypericin and light irradiation for the treatment of cutaneous T‐cell lymphoma”. Methods A confirmatory, prospective, open‐label, single‐centre, interventional study focused on stage IB and IIA mycosis fungoides with more than 10% of their body surface areas involved was performed. Results Hypericin concentration in K2EDTA whole blood samples collected before and after light activation at Weeks 4, 6 and 8 showed an average blood concentration of 0.13 ng/mL and achieved steady state by Week 4. EKGs were examined for clinical changes at each study visit, including changes in QT intervals and correction of heart rates. No significant clinical changes in EKGs were observed. Conclusions Hypericin does not appear to be significantly absorbed through the skin nor cause significant cardiac changes overall or prolong the QT interval when applied topically. A larger study is necessary to clearly define these results.

AbstractThere are no established maintenance protocols for cutaneous lymphomas. We aim to determine patient treatments and outcomes during the COVID-19 pandemic in order to uncover the most effective maintenance protocols for cutaneous lymphomas and impact of treatment interruption. Data was collected retrospectively from nine international institutions, including 149 patients. Younger patients had earlier stages of disease and were most frequently treated with skin-directed therapies including topical steroids, mechlorethamine gel, and phototherapy. Treatment interruption varied by treatment type and stage, with patients on topical therapies and earlier stages of disease being least likely to experience interruption. Treatment interruption was significantly associated with progression of disease and worse outcomes, with twice as many patients progressing who had interruption compared to those without interruption. This study may demonstrate the significance of continuous maintenance therapies, even in younger patients with early stages of disease. [ABSTRACT FROM AUTHOR]

The CCR4 receptor is a pivotal target in cutaneous T-cell lymphoma (CTCL) therapy due to its role in impairing immune responses against malignant T-cells and expression profiles. Monoclonal antibodies like mogamulizumab effectively bind to CCR4, reducing tumour burden and enhancing patient outcomes by inhibiting the receptor's interaction with ligands, thereby hindering malignant T-cell migration and survival. Combining CCR4 antibodies with chemotherapy, radiation, and other drugs is being explored for synergistic effects. Additionally, small-molecular inhibitors, old pharmacological agents interacting with CCR4, and CAR-T therapies are under investigation. Challenges include drug resistance, off-target effects, and patient selection, addressed through ongoing trials refining protocols and identifying biomarkers. Despite advancements, real-life data for most of the emerging treatments are needed to temper expectations. In conclusion, CCR4-targeted therapies show promise for CTCL management, but challenges persist. Continued research aims to optimise treatments, enhance outcomes, and transform CTCL management. This review aims to elucidate the biological rationale and the several agents under various stages of development and clinical evaluation with the actual known data. [ABSTRACT FROM AUTHOR]

Background: Interstitial mycosis fungoides (IMF) is a rare subtype of mycosis fungoides (MF) characterized by atypical lymphocytes infiltrating the reticular dermis between collagen bundles with limited epidermotropism and variable granulomatous features. Methods: Retrospective single institution review of 31 cases of IMF including clinical characteristics, disease course and pathological features. Results: Our cohort was predominately male (19; 61%, M:F 1.6:1) with a mean age at diagnosis of 43 years (range 11–85), mean signs/symptoms duration of 7 years prior to diagnosis, and 6 years mean follow‐up duration. Clinically, patients often exhibited symmetric ill‐defined patches/plaques involving intertriginous regions with tan‐yellow hyperpigmentation and follicular‐based papules, wrinkling, and alopecia. Lymphadenopathy was noted in seven patients. Fifteen (52%) patients were in near or complete clinical remission at the latest follow‐up. T‐cell receptor gene rearrangement was positive in 23/24 (96%) cases. Histopathologically, atypical cells were small–medium, CD4+ (29; 94%) or rarely CD4+/CD8+ (1; 3%) lymphocytes infiltrating the reticular dermis with thickened collagen bundles (27; 87%), multinucleated giant cells (12; 39%), and often tracing along adnexa with subtle folliculotropism (12/20; 60%). Conclusions: Our study demonstrates IMF is an indolent subtype of MF with distinct features, including frequent granulomatous and subtle follicular involvement resulting in alopecia. [ABSTRACT FROM AUTHOR]

Physiotherapy is a treatment that may be required permanently by many patients. As a result, a robot that can execute physiotherapy exercises for the legs like a professional therapist with adequate performance and acceptable safety may be efficient and widely used. In this study, a robust control system for a Stewart platform with six degrees of freedom is provided. First, the Newton-Euler approach is used in conjunction with a methodology and some simplification tools to achieve explicit dynamics formulation for the Stewart platform. For the primary application of this research, which is to follow the specified trajectory of ankle rehabilitation, computed torque control law (CTCL) and polynomial chaos expansion (PCE) were used to examine and consider any uncertainty in geometric and physical parameters. In fact, this strategy integrated the uncertainties with CTCL using PCE. The suggested PCE-based CTCL eliminates the system's nonlinearity by applying feedback linearization to evaluate generalized driving forces; hence, the nondeterministic multi-body system follows the desired direction. Uncertainties in the patient's foot as well as the main diameter parameters of the moment of inertia of the upper platform of the Stewart robot with various uniform, beta, and normal distributions, have been analyzed. The PCE technique's results were compared to the Monte Carlo method's outcomes, and the strengths and weaknesses of each method were investigated. In brief, the PCE method operated far better than the Monte Carlo (MC) method in speed, accuracy, and numerical volume. [ABSTRACT FROM AUTHOR]

Current treatment guidelines for cutaneous T cell lymphoma (CTCL) advocate a stage-driven approach, considering clinical presentation, symptom burden, and patient comorbidities. Therapy selection hinges on factors like disease subtype, severity, and treatment availability. The primary goal is to enhance the quality of life by mitigating symptoms, as achieving lasting complete remission is infrequent. Over the past decade (2013–2023), the therapeutic landscape of CTCL has experienced substantial transformation with the introduction of innovative therapies. This review explores the main pivotal developments in traditional treatment schedules and recently introduced drugs, aiming to offer clinicians and researchers a thorough perspective on the decade's progress in the field. Despite the progress made in CTCL therapeutics, ranging from topical chemotherapeutics to immunomodulatory agents, several unmet needs persist. Firstly, there is a pressing need for the incorporation of readily available predictors for treatment response, encompassing clinical, pathological, and molecular features. Secondly, a more profound comprehension of the tumor microenvironment is imperative to optimize the landscape of targetable molecules. Lastly, the undertaking of studies on combination regimens should be encouraged as it enhances therapy efficacies by synergistically combining agents with diverse modes of action. [ABSTRACT FROM AUTHOR]

Purpose: Current monoclonal antibody-based treatment approaches for cutaneous T cell lymphoma (CTCL) rely heavily on the ability to identify a tumor specific target that is essentially absent on normal cells. Herein, we propose tumor associated glycoprotein-72 (TAG-72) as one such target. TAG-72 is a mucin-associated, truncated O-glycan that has been identified as a chimeric antigen receptor (CAR)-T cell target in solid tumor indications. To date, TAG-72 targeting has not been considered in the setting of hematological malignancies. Experimental design: CD3+ cells from patients with CTCL were analyzed for TAG-72 expression by flow cytometry. Immunohistochemistry was used to assess TAG-72 expression in CTCL patient skin lesions and a TAG-72 ELISA was employed to assess soluble TAG-72 (CA 72-4) in patient plasma. TAG-72 CAR transduction was performed on healthy donor (HD) and CTCL T cells and characterized by flow cytometry. In vitro CAR-T cell function was assessed by flow cytometry and xCELLigence® using patient peripheral blood mononuclear cells and proof-of-concept ovarian cancer cell lines. In vivo CAR-T cell function was assessed in a proof-of-concept, TAG-72+ ovarian cancer xenograft mouse model. Results: TAG-72 expression was significantly higher on total CD3+ T cells and CD4+ subsets in CTCL donors across disease stages, compared to that of HDs. TAG-72 was also present in CTCL patient skin lesions, whereas CA 72-4 was detected at low levels in both CTCL patient and HD plasma with no differences between the two groups. In vitro cytotoxicity assays showed that anti-TAG-72 CAR-T cells significantly, and specifically reduced CD3+TAG-72+ expressing CTCL cells, compared to culture with unedited T cells (no CAR). CTCL CAR-T cells had comparable function to HD CAR-T cells in vitro and CAR-T cells derived from CTCL patients eradicated cancer cells in vivo. Conclusion: This study shows the first evidence of TAG-72 as a possible target for the treatment of CTCL.

BackgroundMycosis fungoides (MF) is the most common subtype of cutaneous T-cell lymphoma (CTCL). Comprehensive analysis of MF cells in situ and ex vivo is complicated by the fact that is challenging to distinguish malignant from reactive T cells with certainty.MethodsTo overcome this limitation, we performed combined single-cell RNA (scRNAseq) and T-cell receptor TCR sequencing (scTCRseq) of skin lesions of cutaneous MF lesions from 12 patients. A sufficient quantity of living T cells was obtained from 9 patients, but 2 had to be excluded due to unclear diagnoses (coexisting CLL or revision to a fixed toxic drug eruption).ResultsFrom the remaining patients we established single-cell mRNA expression profiles and the corresponding TCR repertoire of 18,630 T cells. TCR clonality unequivocally identified 13,592 malignant T cells. Reactive T cells of all patients clustered together, while malignant cells of each patient formed a unique cluster expressing genes typical of naive/memory, such as CD27, CCR7 and IL7R, or cytotoxic T cells, e.g., GZMA, NKG7 and GNLY. Genes encoding classic CTCL markers were not detected in all clusters, consistent with the fact that mRNA expression does not correlate linearly with protein expression. Nevertheless, we successfully pinpointed distinctive gene signatures differentiating reactive malignant from malignant T cells: keratins (KRT81, KRT86), galectins (LGALS1, LGALS3) and S100 genes (S100A4, S100A6) being overexpressed in malignant cells.ConclusionsCombined scRNAseq and scTCRseq not only allows unambiguous identification of MF cells, but also revealed marked heterogeneity between and within patients with unexpected functional phenotypes. While the correlation between mRNA and protein abundance was limited with respect to established MF markers, we were able to identify a single-cell gene expression signature that distinguishes malignant from reactive T cells.

Cutaneous T cell lymphomas (CTCLs), encompassing mycosis fungoides (MF) and Sézary syndrome (SS), present a complex landscape influenced by cytokines and cellular responses. In this work, the intricate relationship between these inflammatory proteins and disease pathogenesis is examined, focusing on what is known at the clinical and therapeutic levels regarding the most well-known inflammatory mediators. An in-depth look is given to their possible alterations caused by novel immunomodulatory drugs and how they may alter disease progression. From this narrative review of the actual scientific landscape, Interferon-gamma (IFN-γ) emerges as a central player, demonstrating a dual role in both promoting and inhibiting cancer immunity, but the work navigates through all the major interleukins known in inflammatory environments. Immunotherapeutic perspectives are elucidated, highlighting the crucial role of the cutaneous microenvironment in shaping dysfunctional cell trafficking, antitumor immunity, and angiogenesis in MF, showcasing advancements in understanding and targeting the immune phenotype in CTCL. In summary, this manuscript aims to comprehensively explore the multifaceted aspects of CTCL, from the immunopathogenesis and cytokine dynamics centred around TNF-α and IFN-γ to evolving therapeutic modalities. Including all the major known and studied cytokines in this analysis broadens our understanding of the intricate interplay influencing CTCL, paving the way for improved management of this complex lymphoma. [ABSTRACT FROM AUTHOR]

Cutaneous T-cell lymphoma (CTCL) poses a challenge in terms of diagnosis and assessment of disease progression. High-frequency ultrasound (HFUS) is a non-invasive imaging modality used for evaluating dermal changes, including the assessment of infiltrative intensity in CTCL. HFUS encompasses the assessment of infiltrative intensity, visualization of tumor characteristics, and monitoring of disease progression and treatment response. By providing detailed and precise information regarding the affected skin layers, HFUS contributes to the diagnostic process and aids in the management of this complex disease. Herein, we present the case of a 79-year-old male diagnosed with mycosis fungoides (MF), whose disease was confirmed by HFUS examination during PUVA therapy. [ABSTRACT FROM AUTHOR]

Cutaneous T-cell lymphoma (CTCL) is characterized by the proliferation of malignant T cells in inflamed skin lesions. Mycosis fungoides (MF)—the most common variant of CTCL—often presents with skin lesions around the abdomen and buttocks ("bathing suit" distribution), i.e., in skin areas devoid of sun-induced vitamin D. For decades, sunlight and vitamin D have been connected to CTCL. Thus, vitamin D induces apoptosis and inhibits the expression of cytokines in malignant T cells. Furthermore, CTCL patients often display vitamin D deficiency, whereas phototherapy induces vitamin D and has beneficial effects in CTCL, suggesting that light and vitamin D have beneficial/protective effects in CTCL. Inversely, vitamin D promotes T helper 2 (Th2) cell specific cytokine production, regulatory T cells, tolerogenic dendritic cells, as well as the expression of immune checkpoint molecules, all of which may have disease-promoting effects by stimulating malignant T-cell proliferation and inhibiting anticancer immunity. Studies on vitamin D treatment in CTCL patients showed conflicting results. Some studies found positive effects, others negative effects, while the largest study showed no apparent clinical effect. Taken together, vitamin D may have both pro- and anticancer effects in CTCL. The balance between the opposing effects of vitamin D in CTCL is likely influenced by treatment and may change during the disease course. Therefore, it remains to be discovered whether and how the effect of vitamin D can be tilted toward an anticancer response in CTCL. [ABSTRACT FROM AUTHOR]

Simple Summary: Cutaneous T-cell lymphomas (CTCLs) are a rare kind of skin cancer that currently has no curative treatment except allogeneic stem cell transplantation. The aim of this systematic review is to investigate the effectiveness of Janus kinase inhibitor drugs as a treatment for CTCLs. This study showed that Janus kinase inhibitors can be effective in the treatment of CTCLswith acceptable adverse effects. Adverse events have been reported especially in patients with immunosuppression or an underlying autoimmune disease. We recommend conducting more studies, especially clinical trials, to investigate the benefits of these drugs for the treatment of cutaneous T-cell lymphomas. Cutaneous T-cell lymphomas (CTCLs) are a group of lymphoid neoplasms with high relapse rates and no curative treatment other than allogeneic stem cell transplantation (allo-SCT). CTCL is significantly influenced by disruption of JAK/STAT signaling. Therefore, Janus kinase (JAK) inhibitors may be promising for CTCL treatment. This study is a systematic review aiming to investigate the role of JAK inhibitors in the treatment of CTCL, including their efficacy and safety. Out of 438 initially searched articles, we present 13 eligible ones. The overall response rate (ORR) in the treatment with JAK inhibitors in clinical trials was 11–35%, although different subtypes of CTCL showed different ORRs. Mycosis fungoides showed an ORR of 14–45%, while subcutaneous-panniculitis-like T-cell lymphoma (SPTCL) displayed an ORR ranging from 75% to 100%. Five cases were reported having a relapse/incident of CTCL after using JAK inhibitors; of these, three cases were de novo CTCLs in patients under treatment with a JAK inhibitor due to refractory arthritis, and two cases were relapsed disease after graft-versus-host disease treatment following allo-SCT. In conclusion, using JAK inhibitors for CTCL treatment seems promising with acceptable side effects, especially in patients with SPTCL. Some biomarkers, like pS6, showed an association with better responses. Caution should be taken when treating patients with an underlying autoimmune disease and prior immunosuppression. [ABSTRACT FROM AUTHOR]

Aim: Cutaneous T-cell lymphomas (CTCL) can be described as chronic skin inflammation lesions with the content of malignant T cells and they are considered to be T-cell-mediated skin diseases. CD147 is recognized as a 58-kDa cell surface glycoprotein of the immunoglobulin superfamily; it can induce the synthesis of MMPs (matrix metalloproteinases) on the surface of tumor cells where it was originally identified. It can also function in adjacent tumor fibroblasts using CD147–CD147 interactions. The polymorphism rs8259 T/A is situated in the untranslated region (3′UTR) of the CD147 gene. HLA DRB1*1501 takes part in the process of presentation and recognition of different antigens to T cells. It can be expressed by antigen-presenting cells—macrophages, dendritic cells, and B cells. The aim of the study is to test genotype–phenotype associations of both polymorphisms including therapy in a large cohort of CTCL patients. Materials and Methods: A final total of 104 CTCL patients were enrolled in the study. For the first remission at the clinic department, they were treated by means of local skin-directed therapy, phototherapy, and systemic therapy. Genomic DNA was isolated from peripheral blood leukocytes. A standard technique using proteinase K was applied. The polymorphisms rs8259 T/A (CD147 gene) and rs3135388 (HLA DRB1*1501) were detected through standard PCR-restriction fragment length polymorphism methods. Results: The severity of the disease (patients with parapsoriasis, stages IA and IB, vs patients with stages IIB, IIIA, and IIIB) was associated with the CD147 genotype: the AA variant was 3.38 times more frequent in more severe cases, which reflects the decision on systemic therapy (p = 0.02, specificity 0.965). The AA genotype in the CD147 polymorphism was 12 times more frequent in patients who underwent systemic therapy of CTCL compared to those not treated with this therapy (p = 0.009, specificity 0.976). The same genotype was also associated with radiotherapy—it was observed 14 times more frequently in patients treated with radiotherapy (p = 0.009, specificity 0.959). In patients treated with interferon α therapy, the AA genotype was observed to be 5.85 times more frequent compared to the patients not treated with interferon therapy (p = 0.03, specificity 0.963). The HLA DRB1*1501 polymorphism was associated with local skin-directed therapy of CTCL. The CC genotype of the polymorphism was observed to be 3.57 times more frequent in patients treated with local therapy (p = 0.008, specificity 0.948). When both polymorphisms had been calculated together, even better results were obtained: the AACC double genotype was 11 times more frequent in patients with severe CTCL (p = 0.009, specificity 0.977). The TACT double genotype was associated with local skin-directed therapy (0.09 times lower frequency, p = 0.007, sensitivity 0.982). The AACC genotype was 8.9 times more frequent in patients treated by means of systemic therapy (p = 0.02, specificity 0.976) and as many as 18.8 times more frequent in patients treated with radiotherapy (p = 0.005, specificity 0.969). Thus, the AACC double genotype of CD147 and DRB1*1501 polymorphisms seems to be a clinically highly specific marker of severity, systemic therapy and radiotherapy of patients with T-cell lymphoma. Conclusion: Although genotyping results were not known during the treatment decision and could not modify it, the clinical decision on severity and therapy reflected some aspects of the genetic background of this complicated T-cell-associated disease very well. [ABSTRACT FROM AUTHOR]

Abstract is missing (Short communication)

Abstract Background The risk of developing cutaneous T cell lymphoma (CTCL) in patients using psoriasis biologics has not been well characterized. The goals of this review were to investigate the incidence of CTCL in patients with psoriasis receiving biologic therapy in clinical trials and psoriasis registries, and to review cases of CTCL and biologic use reported in scientific publications. Methods The US National Library of Medicine clinical trials database (clinicaltrials.gov) was queried to identify phase 3 and 4 clinical trials of the 12 biologic agents currently FDA approved for psoriatic disease. The incidence of CTCL in these trials was examined and summarized. To examine the incidence of CTCL in psoriasis registries, a Medline search was conducted. Finally, we performed a systematic review of CTCL cases reported in the literature. Results Only two cases of CTCL were reported in 35,801 subjects with psoriasis receiving a biologic agent in the active arm of 108 psoriasis phase 3 clinical trials. One of these CTCL cases was determined by the investigator to be CTCL misdiagnosed as psoriasis prior to randomization. No cases of CTCL were reported in 5440 subjects with psoriasis in 34 phase 4 clinical trials. Only one case of CTCL was identified in 34,111 registry subjects. In the literature, tumor necrosis factor (TNF) inhibitors had the highest number of reported cases of CTCL (34 cases), followed by interleukin (IL)-17 inhibitors (7 cases), and IL-12/23 inhibitors (6 cases). No cases of CTCL were found to be reported with IL-23 inhibitors. Conclusion Our findings indicate that the development of CTCL is rare in the setting of psoriasis biologic use. Of the limited number of cases of CTCL found, most were in the setting of TNF inhibitor use and no cases of CTCL were reported in the setting of IL-23 inhibitor use.

Simple Summary: Cutaneous T-cell lymphomas (CTCLs) constitute a group of rare lymphoproliferative malignancies primarily manifesting in the skin. This study aimed to assess a combined treatment approach utilizing mogamulizumab and extracorporeal photopheresis for a subset of patients in an advanced stage of this disease, which typically challenges therapy and carries an unfavorable prognosis. The present study aimed to understand the impact of this novel treatment combination on skin- and blood-related symptoms and its associated side effects. This retrospective study included 11 patients with Sézary syndrome (SS) or mycosis fungoides (MF). Encouragingly, three-fourths of the patients showed positive responses, with improvements in skin-related symptoms, a decrease in malignant cells in the blood, and a minimum progression-free survival of 7.2 in the skin and 7.6 months in the blood. Overall, the treatment demonstrated good tolerance. If confirmed through larger-scale studies, this combined therapy could potentially establish a new therapeutic option for patients with advanced-stage cutaneous T-cell lymphoma. Background: Primary cutaneous T-cell lymphomas (CTCLs) are rare lymphoproliferative malignancies characterized by significant morbidity and mortality in advanced disease stages. As curative approaches apart from allogeneic stem cell transplantation are lacking, establishing new treatment options, especially combination therapies, is crucial. Methods: This retrospective study included 11 patients with SS or MF receiving therapy with mogamulizumab in combination with ECP from four European expert centers. The response rates in the skin and blood as well as treatment use and adverse events (AE) were described. Results: 8/11 patients (73%) showed an overall response (OR) in the skin. The mean mSWAT decreased from 98.2 ± 40.8 to 34.6 ± 23.8. The overall response rate (ORR) in the blood was 64% with two complete responses. During combination therapy, the mean number of Sézary cells decreased from 3365.3 × 106/L before treatment to 1268.6 × 106/L. The mean minimum known period without progress was 7.2 months in the skin and 7.6 months in the blood. The most common AEs were mogamulizumab-associated rash (MAR) (45.5%), anemia (27.3%), lymphocytopenia (27.8%), and infusion related reaction (16.7%). No AE led to treatment discontinuation. Conclusions: Our study presents the combination of mogamulizumab and ECP as an effective therapy in the blood and skin in CTCL with good tolerability, similar to mogamulizumab monotherapy. [ABSTRACT FROM AUTHOR]

Background: The risk of developing cutaneous T cell lymphoma (CTCL) in patients using psoriasis biologics has not been well characterized. The goals of this review were to investigate the incidence of CTCL in patients with psoriasis receiving biologic therapy in clinical trials and psoriasis registries, and to review cases of CTCL and biologic use reported in scientific publications. Methods: The US National Library of Medicine clinical trials database (clinicaltrials.gov) was queried to identify phase 3 and 4 clinical trials of the 12 biologic agents currently FDA approved for psoriatic disease. The incidence of CTCL in these trials was examined and summarized. To examine the incidence of CTCL in psoriasis registries, a Medline search was conducted. Finally, we performed a systematic review of CTCL cases reported in the literature. Results: Only two cases of CTCL were reported in 35,801 subjects with psoriasis receiving a biologic agent in the active arm of 108 psoriasis phase 3 clinical trials. One of these CTCL cases was determined by the investigator to be CTCL misdiagnosed as psoriasis prior to randomization. No cases of CTCL were reported in 5440 subjects with psoriasis in 34 phase 4 clinical trials. Only one case of CTCL was identified in 34,111 registry subjects. In the literature, tumor necrosis factor (TNF) inhibitors had the highest number of reported cases of CTCL (34 cases), followed by interleukin (IL)-17 inhibitors (7 cases), and IL-12/23 inhibitors (6 cases). No cases of CTCL were found to be reported with IL-23 inhibitors. Conclusion: Our findings indicate that the development of CTCL is rare in the setting of psoriasis biologic use. Of the limited number of cases of CTCL found, most were in the setting of TNF inhibitor use and no cases of CTCL were reported in the setting of IL-23 inhibitor use. [ABSTRACT FROM AUTHOR]

Cutaneous T-cell lymphoma (CTCL) is a rare type of non-Hodgkin lymphoma of the skin, where at later stages skin-homing malignant T-cells affect lymph nodes, blood, and visceral organs. Even though early CTCL does not affect survival, it can progress to more advanced stages of disease and have a significant effect on the quality of life of patients. Although expectant management is a treatment consideration in early disease stages, most patients cycle through different skin-directed therapies throughout their lifetime. It can become a challenge to manage the serious and accumulating risk of side effects of these therapies, including various skin cancers and skin damage. Adverse effects from topical therapies limit their long-term utility. Thus, there is an unmet need for well-characterized therapies that have a rapid onset of action and minimal long-term/cumulative side effect profile. Most recently, the results of a Phase 3 study of topical HyBryte™ as a potential treatment for CTCL demonstrated its efficacy and safety profile. This article summarizes what is known about HyBryte™, focuses on its mechanism of action, and highlights its effectiveness, safety, and tolerability in the context of other current FDA-approved topical therapies for CTCL.

Mycoses fungoides (MF) and Sézary syndrome (SS) are cutaneous T-cell lymphomas that are often challenging to manage given the absence of reliably curative therapies, at times high symptom burden with significant detriment to quality of life, and need for ongoing treatment for disease and symptom control. Recent developments in skin-directed treatments include optimizing the use of existing topical therapies, the introduction of known dermatological agents and treatment modalities for the specific treatment of MF/SS (such as mechlorethamine gel, calcineurin inhibitor creams, and photodynamic therapy), and novel local and topical agents. For advanced disease, dedicated clinical trials have translated to exciting progress, leading to the approval of brentuximab vedotin (2017) and mogamulizumab (2018) for relapsed MF/SS. Additional studies of other active systemic agents, including various cellular therapies, represent further attempts to add to the therapeutic armamentarium in treating MF/SS. In this review, we highlight these recent advancements, ranging from optimization of skin-directed therapies to the introduction of novel systemic agents. We focus on therapies approved in the preceding five years or under investigation in advanced-phase clinical trials. [ABSTRACT FROM AUTHOR]

Cutaneous T-cell lymphomas (CTCL) are characterized by focal infiltration of malignant T cell clones in solitary skin lesions. Many CTCL patients experience an indolent disease, but some progress to advanced disease with high fatality. We hypothesized that natural killer (NK) cells participate in local control of tumor growth in CTCL skin. Immunohistochemistry and flow cytometry analysis of the density, localization, phenotype and function of NK cells in twenty-nine fresh or formalin-fixed skin biopsies from twenty-four CTCL patients and twenty-three biopsies from twenty healthy controls highlighted higher numbers of CD56+CD3-NK cells in CTCL skin. A reduced fraction of CTCL skin NK cells expressed the maturation marker CD57, the cytotoxic protein granzyme B and the activation marker CD69, indicating reduced tumor-killing abilities of the NK cells. Retained expression of immune checkpoint proteins or inhibitory proteins including PD1, TIM3, LAG3, CD73 and NKG2A and the activating receptors CD16 and NKp46 indicated maintained effector functions. Indeed, the capacity of NK cells to produce anti-tumor acting IFNg upon PMA+ionomycin stimulation was similar in cells from CTCL and healthy skin. Co-cultures of primary human NK cells or the NK cell line NKL with CTCL cells resulted in reduced levels of granzyme B and CD69, indicating that close cellular interactions with CTCL cells induced the impaired functional NK cell phenotype. In conclusion, increased numbers of NK cells in CTCL skin exhibit a partially impaired phenotype in terms of activity. Enhancing NK cell activity with NK cell activating cytokines such as IL-15 or immune checkpoint blockade therefore represents a potential immunotherapeutic approach in CTCL. [ABSTRACT FROM AUTHOR]

IL-32 is a recently described cytokine that performs a variety of functions under inflammatory conditions. Serum IL-32 has been shown to be elevated in several diseases, including type 2 diabetes, cancer, systemic lupus erythematosus, HIV infection, and atopic diseases including atopic dermatitis. There are nine different isoforms of IL-32, with IL-32γ being the most biologically active one. The following review summarizes the different roles of the various IL-32 isoforms in the context of skin inflammation, with a focus on atopic dermatitis. [ABSTRACT FROM AUTHOR]

The CCR4 receptor is a pivotal target in cutaneous T-cell lymphoma (CTCL) therapy due to its role in impairing immune responses against malignant T-cells and expression profiles. Monoclonal antibodies like mogamulizumab effectively bind to CCR4, reducing tumour burden and enhancing patient outcomes by inhibiting the receptor’s interaction with ligands, thereby hindering malignant T-cell migration and survival. Combining CCR4 antibodies with chemotherapy, radiation, and other drugs is being explored for synergistic effects. Additionally, small-molecular inhibitors, old pharmacological agents interacting with CCR4, and CAR-T therapies are under investigation. Challenges include drug resistance, off-target effects, and patient selection, addressed through ongoing trials refining protocols and identifying biomarkers. Despite advancements, real-life data for most of the emerging treatments are needed to temper expectations. In conclusion, CCR4-targeted therapies show promise for CTCL management, but challenges persist. Continued research aims to optimise treatments, enhance outcomes, and transform CTCL management. This review aims to elucidate the biological rationale and the several agents under various stages of development and clinical evaluation with the actual known data.

Cutaneous T cell lymphomas (CTCLs), encompassing mycosis fungoides (MF) and Sézary syndrome (SS), present a complex landscape influenced by cytokines and cellular responses. In this work, the intricate relationship between these inflammatory proteins and disease pathogenesis is examined, focusing on what is known at the clinical and therapeutic levels regarding the most well-known inflammatory mediators. An in-depth look is given to their possible alterations caused by novel immunomodulatory drugs and how they may alter disease progression. From this narrative review of the actual scientific landscape, Interferon-gamma (IFN-γ) emerges as a central player, demonstrating a dual role in both promoting and inhibiting cancer immunity, but the work navigates through all the major interleukins known in inflammatory environments. Immunotherapeutic perspectives are elucidated, highlighting the crucial role of the cutaneous microenvironment in shaping dysfunctional cell trafficking, antitumor immunity, and angiogenesis in MF, showcasing advancements in understanding and targeting the immune phenotype in CTCL. In summary, this manuscript aims to comprehensively explore the multifaceted aspects of CTCL, from the immunopathogenesis and cytokine dynamics centred around TNF-α and IFN-γ to evolving therapeutic modalities. Including all the major known and studied cytokines in this analysis broadens our understanding of the intricate interplay influencing CTCL, paving the way for improved management of this complex lymphoma.

Cutaneous T-cell lymphoma (CTCL) is characterized by the proliferation of malignant T cells in inflamed skin lesions. Mycosis fungoides (MF)—the most common variant of CTCL—often presents with skin lesions around the abdomen and buttocks (“bathing suit” distribution), i.e., in skin areas devoid of sun-induced vitamin D. For decades, sunlight and vitamin D have been connected to CTCL. Thus, vitamin D induces apoptosis and inhibits the expression of cytokines in malignant T cells. Furthermore, CTCL patients often display vitamin D deficiency, whereas phototherapy induces vitamin D and has beneficial effects in CTCL, suggesting that light and vitamin D have beneficial/protective effects in CTCL. Inversely, vitamin D promotes T helper 2 (Th2) cell specific cytokine production, regulatory T cells, tolerogenic dendritic cells, as well as the expression of immune checkpoint molecules, all of which may have disease-promoting effects by stimulating malignant T-cell proliferation and inhibiting anticancer immunity. Studies on vitamin D treatment in CTCL patients showed conflicting results. Some studies found positive effects, others negative effects, while the largest study showed no apparent clinical effect. Taken together, vitamin D may have both pro- and anticancer effects in CTCL. The balance between the opposing effects of vitamin D in CTCL is likely influenced by treatment and may change during the disease course. Therefore, it remains to be discovered whether and how the effect of vitamin D can be tilted toward an anticancer response in CTCL.

Folliculotropic mycosis fungoides (FMF) is a variant of mycosis fungoides characterized by infiltration of hair follicle epithelium by neoplastic lymphoid cells. Generally, it is usually typified by indurated plaques and tumours mainly on the head and neck. However, a wide range of clinical signs have been noted. The clinical presentation of FMF may include prurigo-like lesions, acneiform lesions, cysts, nodules, areas of scarring alopecia, and hypopigmented plaques or papules with follicular prominences. The average age of diagnosis is 60 years while it is rare in childhood and adolescence. We discuss the case of a 12-year-old boy patient who had an asymptomatic, erythematous, infiltrating plaque across his left nasolabial fold for three months prior to presentation. Histological assessment of lesion showed characteristic findings of follicular mucinosis with predominance of CD4+ lymphocytes and immunohistochemical studies were positive for CD3+ stains. An increased CD4:CD8 ratio and negative CD20 was also shown. ---Continue

Mycoses fungoides (MF) and Sézary syndrome (SS) are cutaneous T-cell lymphomas that are often challenging to manage given the absence of reliably curative therapies, at times high symptom burden with significant detriment to quality of life, and need for ongoing treatment for disease and symptom control. Recent developments in skin-directed treatments include optimizing the use of existing topical therapies, the introduction of known dermatological agents and treatment modalities for the specific treatment of MF/SS (such as mechlorethamine gel, calcineurin inhibitor creams, and photodynamic therapy), and novel local and topical agents. For advanced disease, dedicated clinical trials have translated to exciting progress, leading to the approval of brentuximab vedotin (2017) and mogamulizumab (2018) for relapsed MF/SS. Additional studies of other active systemic agents, including various cellular therapies, represent further attempts to add to the therapeutic armamentarium in treating MF/SS. In this review, we highlight these recent advancements, ranging from optimization of skin-directed therapies to the introduction of novel systemic agents. We focus on therapies approved in the preceding five years or under investigation in advanced-phase clinical trials.

IL-32 is a recently described cytokine that performs a variety of functions under inflammatory conditions. Serum IL-32 has been shown to be elevated in several diseases, including type 2 diabetes, cancer, systemic lupus erythematosus, HIV infection, and atopic diseases including atopic dermatitis. There are nine different isoforms of IL-32, with IL-32γ being the most biologically active one. The following review summarizes the different roles of the various IL-32 isoforms in the context of skin inflammation, with a focus on atopic dermatitis.

Cutaneous T-cell lymphomas (CTCL) are characterized by focal infiltration of malignant T cell clones in solitary skin lesions. Many CTCL patients experience an indolent disease, but some progress to advanced disease with high fatality. We hypothesized that natural killer (NK) cells participate in local control of tumor growth in CTCL skin. Immunohistochemistry and flow cytometry analysis of the density, localization, phenotype and function of NK cells in twenty-nine fresh or formalin-fixed skin biopsies from twenty-four CTCL patients and twenty-three biopsies from twenty healthy controls highlighted higher numbers of CD56+CD3- NK cells in CTCL skin. A reduced fraction of CTCL skin NK cells expressed the maturation marker CD57, the cytotoxic protein granzyme B and the activation marker CD69, indicating reduced tumor-killing abilities of the NK cells. Retained expression of immune checkpoint proteins or inhibitory proteins including PD1, TIM3, LAG3, CD73 and NKG2A and the activating receptors CD16 and NKp46 indicated maintained effector functions. Indeed, the capacity of NK cells to produce anti-tumor acting IFNγ upon PMA+ionomycin stimulation was similar in cells from CTCL and healthy skin. Co-cultures of primary human NK cells or the NK cell line NKL with CTCL cells resulted in reduced levels of granzyme B and CD69, indicating that close cellular interactions with CTCL cells induced the impaired functional NK cell phenotype. In conclusion, increased numbers of NK cells in CTCL skin exhibit a partially impaired phenotype in terms of activity. Enhancing NK cell activity with NK cell activating cytokines such as IL-15 or immune checkpoint blockade therefore represents a potential immunotherapeutic approach in CTCL.

Abstract: Specialized pro-resolving mediators (SPMs) have demonstrated potent analgesic actions in animal models of pathological pain. The actions of SPMs in acute and chronic itch are currently unknown. Recently, n-3 docosapentaenoic acid (DPA) was found to be a substrate for the biosynthesis of several novel families of SPMs; 3-oxa-PD1n-3 DPA (3-oxa-PD1) is an oxidation-resistant metabolic stable analogue of the n-3 DPA-derived protectin D1 (PD1). Herein, we demonstrate that 3-oxa-PD1 effectively reduces both acute and chronic itch in mouse models. Intrathecal injection of 3-oxa-PD1 (100 ng) reduced acute itch induced by either histamine, chloroquine, or morphine. Furthermore, intrathecal 3-oxa-PD1 effectively reduced chronic itch, induced by cutaneous T cell lymphoma (CTCL), allergic contact dermatitis with dinitrofluorobenzene, and psoriasis by imiquimod. Intratumoral injection of 3-oxa-PD1 also suppressed CTCL-induced chronic itch. Strikingly, this anti-pruritic effect lasted for several weeks after 1-week of intrathecal 3-oxa-PD1 treatment. Whole-cell recordings revealed significant increase in excitatory postsynaptic currents in spinal dorsal horn (SDH) neurons of CTCL mice, but this increase was blocked by 3-oxa-PD1. 3-oxa-PD1 further increased inhibitory postsynaptic currents in SDH neurons of CTCL mice. CTCL increased the spinal levels of lipocalin-2 (LCN2), an itch mediator produced by astrocytes. 3-oxa-PD1 suppressed LCN2 production in CTCL mice and LCN2 secretion in astrocytes. Finally, CTCL-induced anxiety was alleviated by intrathecal 3-oxa-PD1. Our findings suggest that 3-oxa-PD1 potently inhibits acute and chronic itch via regulation of excitatory/inhibitory synaptic transmission and astroglial LCN2 production. Therefore, stable SPM analogs such as 3-oxa-PD1 could be useful to treat pruritus associated with different skin injuries. [ABSTRACT FROM AUTHOR]

Background: The neutrophil/lymphocyte ratio (NLR) at baseline has been demonstrated to correlate with higher stages of disease and to be a prognostic factor in numerous cancers. However, its function as a prognostic factor for mycosis fungoides (MF) has not been yet clarified. Objective: Our work aimed to assess the association of the NLR with different stages of MF and to outline whether higher values of this marker are related to a more aggressive MF. Methods: We retrospectively calculated the NLRs in 302 MF patients at the moment of diagnosis. The NLR was obtained using the complete blood count values. Results: The median NLR among patients with early stage disease (low-grade IA-IB-IIA) was 1.88, while the median NLR for patients with high-grade MF (IIB-IIIA-IIIB) was 2.64. Statistical analysis showed positive associations of advanced MF stages with NLRs higher than 2.3. Conclusions: Our analysis demonstrates that the NLR represents a cheap and easily available parameter functioning as a marker for advanced MF. This might guide physicians in recognizing patients with advanced stages of disease requiring a strict follow-up or an early treatment. [ABSTRACT FROM AUTHOR]

Primary cutaneous lymphomas are rare non-Hodgkin lymphomas consisting of heterogeneous disease entities. Photodynamic therapy (PDT) utilizing photosensitizers irradiated with a specific wavelength of light in the presence of oxygen exerts promising anti-tumor effects on non-melanoma skin cancer, yet its application in primary cutaneous lymphomas remains less recognized. Despite many in vitro data showing PDT could effectively kill lymphoma cells, clinical evidence of PDT against primary cutaneous lymphomas is limited. Recently, a phase 3 "FLASH" randomized clinical trial demonstrated the efficacy of topical hypericin PDT for early-stage cutaneous T-cell lymphoma. An update on recent advances of photodynamic therapy in primary cutaneous lymphomas is provided. [ABSTRACT FROM AUTHOR]

Dupilumab is a humanized IgG4 monoclonal-antibody that is approved by the United States Food and Drug Administration (FDA) for the treatment of moderate-to-severe atopic dermatitis (AD) in patients aged 12 years and older. In recent years, several case studies have associated the unmasking or progression of cutaneous T-cell lymphomas (CTCL) with dupilumab treatment. To date, all reported cases of dupilumab-associated CTCL have shown a CD4+ T-helper-cell-predominant immunophenotype. Here, we report a case of a 72-year-old man who presented with a 2-year history of a diffuse, pruritic eruption, who was started on dupilumab for 9 weeks. He subsequently developed mycosis fungoides (MF) with a CD8+-predominant immunophenotype. Overall, cases of CD8+ mycosis fungoides are less common and relatively less understood than their CD4+ counterparts, with varied presentations and courses. We present a case of dupilumab-associated CD8+ MF to highlight this presentation for pathologists and providers.

Abstract Background Cutaneous T‐cell lymphomas (CTCLs) often have skin dryness and skin barrier dysfunctions, which are also seen in atopic dermatitis (AD). Expression of keratinocyte proline‐rich protein (KPRP) was decreased in the epidermis of AD, which led to barrier defects and further allergic inflammation. Objectives The aim of this study was to analyze KPRP expression in CTCL. Materials & Methods Skin samples of CTCL and healthy control were collected, and KPRP mRNA expression in the skin tissue was analyzed. We also performed immunohistochemistry of KPRP protein. Results Keratinocyte proline‐rich protein (KPRP) mRNA expression was decreased compared with normal skin. KPRP expression was positively correlated with that of filaggrin and loricrin, and it was negatively correlated with serum interleukin‐2 receptor levels. Immunohistochemistry staining showed that KPRP was detected in upper part of granular layer of epidermis in normal skin and in early‐stage CTCL, but rarely detected in the advanced‐stage CTCL. Conclusion In conclusion, we revealed the decrease in KPRP expression in CTCL.

Abstract Objectives Although the prognosis of Sézary syndrome (SS) is highly unfavorable, the prognostic factors have not been fully understood. In this study, we tried to investigate the prognostic factors in Japanese SS patients for the first time. Methods We performed a retrospective cohort study of 19 SS patients who visited our hospital between January 1, 1999, and December 31, 2019. The collected clinical findings were age, gender, performance status (PS), and TNMB staging at diagnosis. TNMB staging was determined according to the International Society for Cutaneous Lymphomas and the cutaneous task force of the European Organization of Research and Treatment of Cancer criteria. The collected hematological findings were serum levels of soluble IL‐2 receptor (sIL‐2R), lactate dehydrogenase (LDH), thymus and activation‐regulated chemokine (TARC), and immunoglobulin E (IgE), Sézary cell count, Sézary cell ratio among white blood cells, and eosinophil count in peripheral blood at diagnosis. Results We analyzed the correlations between overall survival and various clinical and hematological findings. In the log‐rank test, PS1‐3, N2‐3 stage, higher serum levels of LDH (≥355 IU/L), sIL‐2R (≥1729 U/ml) and TARC (≥19,867 pg/ml), and higher Sézary cell count (≥7480/μl) and Sézary cell ratio among white blood cells (≥52%) at diagnosis were associated with decreased overall survival. Conclusions This is the first report evaluating prognostic factors in Asian SS patients. This study may contribute to selecting the treatment strategy and improving survival and quality of life of Asian SS patients.