Search Results (120)

Background/Objectives: We examined the in vivo effects of successive treatments with the histone deacetylase (HDAC) inhibitor romidepsin in patients with cutaneous T-cell lymphoma (CTCL), using changes in gene expression in peripheral blood mononuclear cells (PBMCs). Methods: Exploiting data from a highly responsive CTCL patient through 12 months of treatment, we identified a malignant cell predictor (MCP), a gene signature associated with the diminishing numbers of circulating malignant cells. Results: The MCP was successfully validated in the patient’s relapse sample 9 months after treatment was terminated and via an independent set of CTCL patient samples. Conclusions: The MCP set of genes contained novel CTCL markers, including membrane-associated proteins not normally expressed in lymphocytes. A subclass of those markers was also detectable in residual malignant cells undetected by flow cytometry in remission samples from a patient who relapsed 10 months later. We identified a subset of transcriptional regulators, miRNAs and methylation patterns associated with the effect of progressive treatments revealing potential mechanisms of transcriptional dysregulation and functional effects in the malignant cells. We demonstrate a role for transcriptional activator HLF, over-expressed in malignant cells, and downregulated transcriptional-suppressor and immune-modulator NFIL3, as regulators of CTCL-specific genes. Full article

Mogamulizumab is a humanized monoclonal antibody that targets C-C chemokine receptor 4 (CCR4) present on certain T cells in lymphomas and leukemias. This antibody-based therapy has demonstrated efficacy in treating various cutaneous T cell lymphomas (CTCLs), including mycosis fungoides and Sézary syndrome, through the depletion of CCR4-expressing T cells by antibody-dependent cellular cytotoxicity (ADCC). However, the precise epitope and binding mode of mogamulizumab responsible for its augmented ADCC activity remain undisclosed. Here, X-ray crystallographic studies of mogamulizumab in complex with a 28-residue N-terminal peptide indicated that SIYSNYYLYES (residues 14–24) would constitute the antibody epitope. Another high-resolution structure, using a short core peptide of these 11 residues, has elucidated unambiguous electron density for the bound peptide, confirming consistent binding for both peptides. This linear epitope is located in the membrane-proximal region of CCR4, facilitating the Fc-mediated effector functions, including ADCC. The structures also provide insights into the molecular basis for the resistance of the CCR4 L21V variant to mogamulizumab, which is due to a lack of structural complementarity with mogamulizumab binding. Understanding the structural basis for the mechanism of action of mogamulizumab is crucial for optimizing anti-CCR4 therapeutics to improve treatment outcomes for patients with these challenging diseases. Full article

Non-Hodgkin lymphomas (NHLs) encompass a diverse group of neoplasms arising from the clonal proliferation of B-cell progenitors, T-cell progenitors, mature B-cells, mature T-cells, and natural killer (NK) cells. These malignancies account for over 90% of lymphoid neoplasms. The link between the gut microbiome and neoplasms has been extensively studied in recent years. Growing evidence suggests that the gut microbiome may be involved not only in the development of the disease, but also in modulating the efficacy of implemented therapies. In this review, we summarize the current knowledge on the potential involvement of the gut microbiome in the development of diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), mucosa-associated lymphoid tissue (MALT) lymphoma, and NK/T-cell lymphoma, including cutaneous T-cell lymphoma (CTCL). Moreover, we discuss the relationship between gut microbiome changes before and after treatment and their association with treatment outcomes, focusing on chemotherapy and CAR T-cell therapy. Full article

Mycosis fungoides (MF) and Sézary syndrome (SS) are the most prevalent forms of cutaneous T-cell lymphoma (CTCL) and are characterized by the proliferation of CD4⁺ T-helper cells. The pathogenesis of CTCLs involves a critical interaction between neoplastic cells and the tumor microenvironment. This interaction is driven not only by cytokines but also by surface proteins that mediate cell–cell contact. One such protein, OX40 (also known as CD134), is a member of the TNF receptor superfamily and serves as an induced costimulatory molecule that facilitates the interaction between T-cells and antigen-presenting cells. In this narrative review, we explore the literature surrounding the OX40–OX40L interaction in CTCLs, highlighting its pathogenic and prognostic significance. Additionally, we compare the expression and function of OX40–OX40L in chronic inflammatory skin diseases, such as atopic dermatitis and psoriasis, with their role in CTCLs. Finally, we provide an overview of the current state of therapeutic research, discussing the potential of targeting the OX40–OX40L axis in CTCL treatment. Full article

Background: Dermoscopy, a non-invasive diagnostic technique, is being increasingly used to evaluate cutaneous T-cell lymphomas such as mycosis fungoides (MF) and Sézary syndrome (SS). However, its diagnostic accuracy and role in staging remain underexplored. Objective: This study aimed to assess the dermoscopic patterns in MF and SS, correlating the findings with the disease stage and lesion type to evaluate dermoscopy’s diagnostic utility. Methods: A retrospective, monocentric analysis was conducted on patients with histologically confirmed MF or SS. Dermoscopic images were evaluated for vascular patterns, pigmentation, scaling, and keratin plugs. The statistical analysis assessed the correlations between these dermoscopic features and the TNMB staging and lesion type. A literature review was also performed to contextualize the findings, focusing on studies describing dermoscopic features in MF based on retrospective, prospective, and cross-sectional data. Results: The study included 30 patients with histologically confirmed MF or SS (19 males and 11 females; mean age: 64.5 years). The dermoscopic evaluation revealed that all the lesions were pigment-free, with vascular structures as the predominant feature. Linear vessels (40%) and serpentine vessels (13.3%) were the most frequently observed, along with dotted vessels (36.7%) and clods (10%). The vessel distribution was diffuse (40%) or perifollicular (36.7%), with a predominant red (56.7%) or orange (40%) background. Scaling was present in 76.7% of cases, either diffuse (40%) or perifollicular (36.7%), and keratin plugs were detected in 40% of the lesions. No statistically significant correlations were found between dermoscopic features and the TNMB stage or lesion type (p > 0.05). A cluster analysis identified two patient groups with differing vascular and scaling features but no clear association with disease stage. The literature review identified studies that commonly reported features in MF dermoscopy, including fine, short linear vessels and an orange-yellow background, particularly in early-stage MF. Spermatozoa-like structures have been marked as highly specific for diagnosing MF. Some studies also suggested a transition in vascular morphology from linear vessels in early disease to branched vessels and ulceration in advanced stages. Conclusions: Our results showed some vascular patterns have some potential but lack sensitivity for staging MF and SS. The terminology used and the reproducibility of our results compared to those reported in the literature showed little consistency, with none of our cases showing spermatozoa-like structures. Moreover, the same issues with the use of non-reproducible terminology were noted across the studies because it is not standardized and due to different incongruent dermoscopic patterns. More significant prospective studies with standardized descriptors and larger groups are needed to refine its diagnostic and staging utility. Full article

Background/Objectives: Primary cutaneous lymphomas (CLs) are a group of skin-limited lymphoproliferative disorders, including cutaneous T-cell (CTCLs) and B-cell lymphomas (CBCLs). Photodynamic therapy (PDT), a non-invasive, light-activated treatment, has gained attention as a skin-directed therapy for early-stage CLs due to its selectivity and favorable safety profile. This systematic review evaluates the current evidence on the clinical use of PDT in managing CLs. Methods: A systematic literature search was conducted in PubMed, Scopus, and Embase through 1 September 2024 following PRISMA guidelines. Search terms included “primary cutaneous skin lymphoma”, “CTCL”, “CBCL”, “mycosis fungoides”, “lymphomatoid papulosis”, and “photodynamic therapy”. After screening 1033 records, 30 studies were included. Data were extracted and categorized by lymphoma subtype and clinical outcomes. Results: Of the included studies, 23 focused on mycosis fungoides (MF), 5 on lymphomatoid papulosis (LyP), and 2 on CBCL. PDT demonstrated notable clinical efficacy in early-stage and localized disease, particularly MF, using methyl aminolevulinate (MAL) or 5-aminolevulinic acid (5-ALA) as photosensitizers. Adjunctive techniques like microneedling and laser-assisted delivery improved treatment outcomes. PDT was generally well tolerated, with mild, transient side effects; rare complications such as localized neuropathy were reported. Conclusions: PDT is a promising, non-invasive treatment for early-stage CLs, especially MF and indolent CBCL variants. While current evidence supports its safety and effectiveness, further comparative and prospective studies are needed to refine protocols, evaluate long-term efficacy, and compare different photosensitizers. Full article

Recent studies have identified N6-methyladenosine (m6A) RNA methylation as a key regulatory mechanism in tumor progression. This study aimed to elucidate the biological function and clinical relevance of the m6A methyltransferase METTL3 in cutaneous T-cell lymphoma (CTCL). Our findings demonstrated that METTL3 expression is upregulated in CTCL, and its knockdown suppresses CTCL progression. Mechanistically, the downregulation of METTL3-mediated m6A modification on ARHGEF12 mRNA accelerated its degradation, a process that is closely associated with tumor behaviors. These results suggest that METTL3 may serve as a potential therapeutic target in CTCL. Full article

Background/Objectives: Brentuximab vedotin (BV) has been shown to be effective in the treatment of classical Hodgkin’s lymphoma (cHL), systemic anaplastic large cell lymphoma (sALCL), and CD30-positive cutaneous T-cell lymphoma (CTCL). This study aimed to evaluate the effectiveness and safety of BV retreatment in patients with relapsed/refractory cHL, sALCL, and CD30-positive CTCL. Methods: This multicenter, non-interventional, retrospective medical chart review study analyzed medical records from 43 patients retreated with BV in Spain. Patients were included if they had relapsed or refractory cHL, sALCL, or CD30-positive CTCL and were previously treated with BV. Demographic characteristics, disease stage, response to treatment, survival outcomes, and adverse events were analyzed. Results: The study population included 16 patients with cHL, 13 with sALCL, and 14 with CTCL. The majority were male (58.1%) with a mean age of 46.2 years and baseline ECOG scores of 0–1. Among cHL and sALCL patients, disease stage, according to the Ann Arbor classification, ranged from I to IVB, while in CTCL, EORTC clinical stages ranged from IA to IVB. The overall response rate to BV retreatment was 76.7%, with the highest response observed in sALCL (92.3%). Complete remission was achieved in 60.5% of patients. Median progression-free survival was 25.4 months, and overall survival reached 50 months. Treatment failure occurred in 37.2% of patients. BV was generally well tolerated, with peripheral neuropathy being the most frequently reported adverse event. Conclusions: The BELIEVE study is the largest study to date demonstrating that retreatment with BV is an effective and well-tolerated option for patients with relapsed or refractory CD30-positive malignancies. Full article

Cutaneous T-cell lymphoma (CTCL), characterized by malignant T-cell proliferation primarily in the skin, includes subtypes such as mycosis fungoides (MF) and Sézary syndrome (SS). The tumor microenvironment (TME) is central to their pathogenesis, with flow cytometry and histology being the gold standards for detecting malignant T cells within the TME. Alongside emerging molecular markers, particularly clonality analysis, these tools are indispensable for accurate diagnosis and treatment planning. Of note, adenosine signaling within the TME has been shown to suppress immune responses, affecting various cell types. The expression of CD39, CD73, and CD38, enzymes involved in adenosine production, can be elevated in MF and SS, contributing to immune suppression. Conversely, the expression of CD26, part of the adenosine deaminase/CD26 complex, that degrades adenosine, is often lost by circulating tumoral cells. Flow cytometry has demonstrated increased levels of CD39 and CD73 on Sézary cells, correlating with disease progression and prognosis, while CD38 shows a variable expression, with its prognostic significance remaining under investigation. Understanding these markers’ roles in the complexity of TME-mediated immune evasion mechanisms might enhance diagnostic precision and offer new therapeutic targets in CTCL. Full article

Background/Objectives: Cutaneous T-cell lymphoma (CTCL) is a rare group of non-Hodgkin lymphomas characterized by the clonal expansion of malignant T cells. While current treatments can alleviate symptoms and significant progress has been made in treating leukemic CTCL, a definitive cure remains elusive. Dysregulation of the Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling pathway is a key driver of CTCL pathogenesis. As a result, therapeutic strategies targeting JAK/STAT signaling have gained momentum, with the increasing use of JAK inhibitors and other agents that effectively suppress this pathway. These immune-modulating therapies have broad effects on physiological processes, inflammation, and the pathological changes associated with both inflammatory diseases and cancers. Several JAK inhibitors, originally FDA-approved for inflammatory conditions, are now being investigated for cancer treatment. Methods: In this paper, a brief review of the literature on JAK/STAT pathway dysregulation in CTCL is provided, highlighting both clinical and preclinical studies involving JAK inhibitors and other agents that target this pathway. Results: Specifically, we focus on six JAK inhibitors currently under clinical investigation—golidocitinib, ruxolitinib, cerdulatinib, tofacitinib, upadacitinib, and abrocitinib. Additionally, we discuss preclinical studies that explore the mechanisms underlying JAK/STAT pathway inhibition in CTCL. Furthermore, we review reported cases in which CTCL relapsed or emerged following JAK inhibitor treatment. Conclusions: Collectively, these findings support the potential clinical utility of targeting the JAK/STAT pathway in CTCL. However, further research is needed to evaluate safety risks, minimize adverse effects, and optimize these therapeutic strategies. Full article

Mycosis fungoides (MF), the most common form of cutaneous T-cell lymphoma, poses significant diagnostic challenges due to its overlap with benign inflammatory skin diseases and the absence of specific symptoms. Accurate early diagnosis and stratification of patients by progression risk are essential for effective treatment. This study proposes a proof-of-concept for integrating T-cell receptor (TCR) clonality analysis with somatic mutation profiling to enhance diagnostic confidence and prognostic accuracy in early-stage MF. This study’s methodology comprised the analysis of nine patients with early MF (stages IA/IB) using whole-exome sequencing and TCR repertoire profiling. The analysis revealed the presence of clonal TCR rearrangements in seven patients, while somatic mutations were identified in two. A notable finding was a recurrent chromosome 7 trisomy in these two cases. The patients were stratified into three molecular profiles: (1) somatic mutations with clonal TCR rearrangement (n = 2), (2) clonal TCR rearrangement without somatic mutations (n = 4), and (3) neither somatic mutations nor clonal TCR rearrangement (n = 3). These findings emphasise the heterogeneity of MF and underscore the limitations of relying solely on TCR clonality or mutation burden for diagnosis. This study underscores the potential of somatic mutations as diagnostic markers to distinguish MF from benign conditions and as prognostic indicators for disease progression. A combined genetic approach may refine treatment decisions, particularly for patients with higher tumor cell fractions and pronounced genetic alterations. Despite the limited size of the cohort, the results advocate for larger, multi-center studies to validate these findings and integrate genetic analyses into routine MF management. Full article

CD30 is overexpressed in many T-cell lymphoma (TCL) entities, including subsets of peripheral T-cell lymphomas (PTCL) and cutaneous T-cell lymphomas (CTCL). The antibody–drug conjugate brentuximab vedotin (BV), targeting CD30-positive cells, has been approved for the treatment of relapsed or refractory (R/R) systemic anaplastic large cell lymphoma (sALCL), and primary cutaneous anaplastic large cell lymphoma or mycosis fungoides in patients who have received previous systemic therapy. However, many patients still experience disease progression after BV monotherapy. Extensive efforts have been dedicated to investigating effective combinations of BV. A phase III clinical study demonstrated that the combination of BV with cyclophosphamide, doxorubicin, and prednisone (CHP) is superior to cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) for CD30-positive PTCL. This study led to the approval of BV with CHP as the first-line therapy for CD30-positive PTCL (sALCL in Europe). We summarize the encouraging combination applications of BV in this review. Ongoing studies on combination therapies of BV are also listed, highlighting potential directions for the future application of BV. We focus on dissecting the underlying mechanisms of BV, discussing its effects on both tumor cells and the tumor microenvironment. Exploring resistance mechanisms in TCL provide valuable insights for optimizing BV-based therapies in the future. Full article

Background: Cutaneous T-cell lymphoma (CTCL) is a type of non-Hodgkin’s lymphoma that primarily affects the skin, rich in hyaluronic acid (HA). HA is a component of the extracellular matrix in the dermis and likely affects the development of CTCL, but the mechanism is poorly understood. Here we show that low-molecular-weight HA (LMWHA) possibly exacerbates CTCL, and bexarotene, already used in CTCL treatment, decreases HA production. Methods: We conducted immunohistochemistry, qRT-PCR, immunoblotting, and HA quantification using both mouse and human specimens to evaluate the impact of HA on CTCL. Additionally, we assessed the effect of bexarotene, which is already used for CTCL treatment, on HA metabolism. Results: HA expression was higher in patients’ serum and skin sections than in healthy controls. HA extracted from the skin of mice inoculated with tumors showed an increase in LMWHA. LMWHA increased lymphoma cell proliferation in vitro and accelerated tumor formation in mice in vivo. LMWHA also created a favorable environment for tumor cells by affecting fibroblasts, vascular endothelial cells, and tumor-associated macrophages. Thus, increased levels of HA, mainly LMWHA, exacerbate CTCL progression by affecting tumor cells and their microenvironment. Bexarotene treatment reduced the amount of total HA in murine tumor-inoculated skin, as well as the supernatant of cultured normal human dermal fibroblasts (NHDFs) and HuT78 cells. Detailed in vitro analyses showed that bexarotene treatment decreased HA synthase (HAS)1 and HAS2 expression in NHDFs and HAS1 and HAS3, and CEMIP expression in HuT78 cells. Chromatin immunoprecipitation assays revealed that bexarotene reduced retinoid X receptor-α binding to the HAS1 and HAS2 promoters in NHDFs. Conclusions: Bexarotene potentially exerts its anti-tumor effect by reducing HA levels through decreased expression of HAS. These findings provide new insights into the process of CTCL development and additional insights regarding bexarotene treatment. Full article

Cutaneous T-cell lymphoma (CTCL) is a rare T-cell malignancy characterized by inflamed and painful rash-like skin lesions that may affect large portions of the body’s surface. Patients experience recurrent infections due to a compromised skin barrier and generalized immunodeficiency resulting from a dominant Th2 immune phenotype of CTCL cells. Given the role of the unfolded protein response (UPR) in normal and malignant T-cell development, we investigated the impact of UPR-inducing drugs on the viability, transcriptional networks, and Th2 phenotype of CTCL. We found that CTCL cells were >5-fold more sensitive to the proteasome inhibitor bortezomib (Btz) and exhibited a distinct signaling and transcriptional response compared to normal CD4+ cells. The CTCL response was dominated by the induction of the HSP70 family member HSPA6 (HSP70B’) and, to a lesser extent, HSPA5 (BiP/GRP78). To understand the significance of these two factors, we used a novel isoform selective small-molecule inhibitor of HSPA5/6 (JG-023). JG-023 induced pro-apoptotic UPR signaling and enhanced the cytotoxic effects of proteasome inhibitors and other UPR-inducing drugs in CTCL but not normal T cells. Interestingly, JG-023 also selectively suppressed the production of Th2 cytokines in CTCL and normal CD4+ T cells. Conditioned media (CM) from CTCL were immunosuppressive to normal T cells through an IL-10-dependent mechanism. This immunosuppression could be reversed by JG-023, other HSP70 inhibitors, Btz, and combinations of these UPR-targeted drugs. Our study points to the importance of the UPR in the pathology of CTCL and demonstrates the potential of proteasome and targeted HSPA5/6 inhibitors for therapy. Full article

Background/Objectives: Cutaneous T-cell lymphoma (CTCL), including Mycosis fungoides (MF) and Sézary syndrome (SS), is a challenging-to-diagnose lymphoproliferative malignancy characterized by T-cell dysfunction and progressive cutaneous and extra cutaneous involvement. Disease severity assessment in CTCL is crucial for guiding treatment. This study aims to evaluate the interrater agreement and interrater reliability of mSWAT among dermatology residents and identify lesion types most prone to scoring variability. Methods: Sixteen dermatology residents with varied experience levels assessed 14 patients with confirmed MF/SS diagnoses. Using mSWAT, residents independently scored lesions severity on a standardized set of patient’s photos. The results were compared with reference mSWAT scores provided by an experienced clinician. Descriptive statistics and the Shapiro–Wilk test were applied to evaluate data distributions, while Student’s t-test assessed score deviations from reference values. Furthemore, we conducted a pilot the high frequency ultrasound (HFUS) study on a single patient, whose mSWAT score and photographs are also presented in the manuscript. Results: Significant discrepancies were observed in 64.29% of cases (9/14), with tumors and infiltrative lesions in erythrodermic SS patients posing particular scoring challenges. Misclassification of tumors as patches or plaques was a frequent issue, leading to underestimations in mSWAT scores. Residents’ assessments of infiltrative lesions were also notably inconsistent. Conclusions: This study highlights significant interobserver variability in mSWAT scoring among less experienced dermatology residents, particularly with tumor and erythrodermic lesions. Findings underscore the need for enhanced training and standardized scoring protocols to improve mSWAT reliability. Similar to other comparable indices, such as PASI, the mSWAT should be employed consistently by the same physician during each assessment to systematically monitor and evaluate the skin condition of a patient under observation. However, broader application requires the acquisition of sufficient experience. The study suggests the use of the HFUS as an objective method of assessment of the skin lesion infiltration in MF/SS patients. Full article