Maintenance therapy for CTCL: importance for prevention of disease progression.

There 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.

A Rare Case of a Primary Cutaneous Collision Tumor Comprising Malignant Melanoma and Rhabdomyosarcoma.

This case reports a 35-year-old man who presented with a painful erythematous nodule on his right posterior calf. He first noticed this nodule several years ago and it often bled upon contact with clothing. An excisional biopsy of the skin lesion revealed two distinct populations of cells. One population of epithelioid cells stained positive for Mart-1, HMB45, and SOX-10, confirming the diagnosis of malignant melanoma. The second population of cells stained positive for desmin and calponin, confirming the diagnosis of sarcoma with muscular differentiation. Subsequently, these unusual findings led to the diagnosis of a collision tumor comprising malignant melanoma and rhabdomyosarcoma. Follow-up PET/CT and brain MRI revealed no metastasis from the primary skin lesion. This case highlights a rare combination of cell types found within a collision tumor in addition to providing details on how to diagnose this skin lesion.

The mycosis fungoides cutaneous microenvironment shapes dysfunctional cell trafficking, antitumor immunity, matrix interactions, and angiogenesis.

Malignant T lymphocyte proliferation in mycosis fungoides (MF) is largely restricted to the skin, implying that malignant cells are dependent on their specific cutaneous tumor microenvironment (TME), including interactions with non-malignant immune and stromal cells, cytokines, and other immunomodulatory factors. To explore these interactions, we performed a comprehensive transcriptome analysis of the TME in advanced-stage MF skin tumors by single-cell RNA sequencing. Our analysis identified cell-type compositions, cellular functions, and cell-to-cell interactions in the MF TME that were distinct from those from healthy skin and benign dermatoses. While patterns of gene expression were common among patient samples, high transcriptional diversity was also observed in immune and stromal cells, with dynamic interactions and crosstalk between these cells and malignant T lymphocytes. This heterogeneity mapped to processes such as cell trafficking, matrix interactions, angiogenesis, immune functions, and metabolism that affect cancer cell growth, migration, and invasion, as well as antitumor immunity. By comprehensively characterizing the transcriptomes of immune and stromal cells within the cutaneous microenvironment of individual MF tumors, we have identified patterns of dysfunction common to all tumors that represent a resource for identifying candidates with therapeutic potential as well as patient-specific heterogeneity that has important implications for personalized disease management.

The Robust Tumoricidal Effects of Combined BET/HDAC Inhibition in Cutaneous T-Cell Lymphoma Can Be Reproduced by ΔNp73 Depletion.

Combined BET inhibitor/histone deacetylase inhibitor treatment induces marked apoptosis of cutaneous T-cell lymphoma (CTCL) with minimal normal T-cell toxicity. At 96 hours when apoptosis was extensive, a majority of CTCL lines showed ≥2-fold suppression of T-cell survival factors (e.g., AKT1, BCL2 antiapoptotic factors, BIRC5, CD40, CD70, GADD45A, PRKCA, TNFRSF1B, ΔNp73) and ≥2-fold upregulation of proapoptotic factors and tumor suppressors (e.g., ATM, BAK, BIM, multiple caspases, FHIT, HIC1, MGMT, NOD1) (P < 0.05). The largest alterations were in TP73 isoform expression, resulting in increased TAp73/ΔNp73 ratios in CTCL lines and leukemic Sézary cells. Targeted ΔNp73 inhibition by small interfering RNA knockdown resulted in robust CTCL apoptosis comparable with that induced by BET inhibitor/histone deacetylase inhibitor with minimal normal T-cell toxicity. Chromatin immunoprecipitation analysis showed that BET inhibitor/histone deacetylase inhibitor treatment reduced RNA polymerase II binding to ΔNp73, MYC, and AKT1 while increasing its binding to TAp73. CTCL skin lesions expressed both TAp73 and ΔNp73 isoforms in situ. In aggregate, these findings implicate TAp73/ΔNp73 balance as a major factor governing CTCL survival, show that the expression of p73 isoforms can be altered by molecular biological and pharmaceutical means, show that p73 isoforms are expressed across the entire CTCL clinical spectrum, and identify the p73 pathway as a potential target for therapeutics.

Single-Cell RNA Sequencing Unveils the Clonal and Transcriptional Landscape of Cutaneous T-Cell Lymphomas.

PURPOSE: Clonal malignant T lymphocytes constitute only a fraction of T cells in mycosis fungoides skin tumors and in the leukemic blood of Sézary syndrome, the classic types of cutaneous T-cell lymphomas. However, lack of markers specific for malignant lymphocytes prevents distinguishing them from benign T cells, thus delaying diagnosis and the development of targeted treatments. Here we applied single-cell methods to assess the transcriptional profiles of both malignant T-cell clones and reactive T lymphocytes directly in mycosis fungoides/Sézary syndrome patient samples. EXPERIMENTAL DESIGN: Single-cell RNA sequencing was used to profile the T-cell immune repertoire simultaneously with gene expression in CD3+ lymphocytes from mycosis fungoides and healthy skin biopsies as well as from Sézary syndrome and control blood samples. Transcriptional data were validated in additional advanced-stage mycosis fungoides/Sézary syndrome skin and blood samples by immunofluorescence microscopy. RESULTS: Several nonoverlapping clonotypes are expanded in the skin and blood of individual advanced-stage mycosis fungoides/Sézary syndrome patient samples, including a dominant malignant clone as well as additional minor malignant and reactive clones. While we detected upregulation of patient-specific as well as mycosis fungoides- and Sézary syndrome-specific oncogenic pathways within individual malignant clones, we also detected upregulation of several common pathways that included genes associated with cancer cell metabolism, cell-cycle regulation, de novo nucleotide biosynthesis, and invasion. CONCLUSIONS: Our analysis unveils new insights into mycosis fungoides/Sézary syndrome pathogenesis by providing an unprecedented report of the transcriptional profile of malignant T-cell clones in the skin and blood of individual patients and offers novel prospective targets for personalized therapy.

CD8+ Lymphogranulomatous Dermatitis as a Manifestation of Malignancy-Associated Immunodeficiency: Rethinking Paraneoplastic Granulomas.

ABSTRACT: Paraneoplastic granulomatous disease occurs in approximately 7.3% of patients with non-Hodgkin lymphoma, most commonly among patients with chronic lymphocytic leukemia (CLL). These lesions are often reported to appear similar to sarcoidosis in clinical presentation and under light microscopy. However, comprehensive descriptions of the cytomorphologic characteristics of these paraneoplastic granulomas are lacking, and the mechanisms involved in their formation remain ill-defined. Noninfectious dermal granulomatous reactions have also been reported in many primary immunodeficiencies, including common variable immune deficiency and ataxia-telangiectasia. We present a case of noninfectious CD8+ predominant granulomatous dermatitis with ocular involvement occurring in the setting of CLL and marked hypogammaglobulinemia. Based on the analysis of shared factors in patients with primary immunodeficiencies and CLL, we conclude that the presence of pan-humoral immunodeficiency could itself be a risk factor for developing a CD8+ lymphogranulomatous reaction. This report and associated discussion evince that CD8+ predominant granulomatous reactions, distinct from sarcoidosis, may represent a previously unappreciated segment of the paraneoplastic granulomas observed in hematologic malignancies.

Etiologies of Melanoma Development and Prevention Measures: A Review of the Current Evidence.

(1) Melanoma is the most aggressive dermatologic malignancy, with an estimated 106,110 new cases to be diagnosed in 2021. The annual incidence rates continue to climb, which underscores the critical importance of improving the methods to prevent this disease. The interventions to assist with melanoma prevention vary and typically include measures such as UV avoidance and the use of protective clothing, sunscreen, and other chemopreventive agents. However, the evidence is mixed surrounding the use of these and other interventions. This review discusses the heritable etiologies underlying melanoma development before delving into the data surrounding the preventive methods highlighted above. (2) A comprehensive literature review was performed to identify the clinical trials, observational studies, and meta-analyses pertinent to melanoma prevention and incidence. Online resources were queried to identify epidemiologic and clinical trial information. (3) Evidence exists to support population-wide screening programs, the proper use of sunscreen, and community-targeted measures in the prevention of melanoma. Clinical evidence for the majority of the proposed preventive chemotherapeutics is presently minimal but continues to evolve. (4) Further study of these chemotherapeutics, as well as improvement of techniques in artificial intelligence and imaging techniques for melanoma screening, is warranted for continued improvement of melanoma prevention.

Management of Mycosis Fungoides with Topical Chlormethine/Mechlorethamine Gel: A Columbia University Cutaneous Lymphoma Center Experience.

Mycosis fungoides is a type of cutaneous T-cell lymphoma, which accounts for the majority of cases of cutaneous T-cell lymphoma. Mycosis fungoides can be classified as early-stage (IA-IIA) or late-stage (IIB or greater) disease. In early-stage mycosis fungoides, skin-directed therapies are commonly used to manage the disease. Chlormethine, or mechlorethamine, is a topical chemotherapeutic, which has been in use for over 60 years. In 2013, the US Food and Drug Administration approved chlormethine/mechlorethamine gel (Valchlor®) for treatment of stage IA and IB mycosis fungoides. Chlormethine/mechlorethamine gel is an effective therapy; however, its use may be limited by the development of adverse cutaneous reactions. Off-label dosing modifications, as well as co-administration of topical steroids and an aggressive moisturization regimen, can be used to reduce these side-effects. We report here 4 cases of mycosis fungoides treated with chlormethine/mechlorethamine gel at the Comprehensive Skin Cancer Center at Columbia University Irving Medical Center, which provide insights into the use of this therapy in clinical practice.

Cutaneous T cell lymphoma.

Primary cutaneous T cell lymphomas (CTCLs) are a heterogeneous group of lymphomas that present in the skin with no evidence of extracutaneous disease at the time of diagnosis. CTCL subtypes demonstrate a variety of clinical, histological, and molecular features, and can follow an indolent or a very aggressive course. The underlying pathogenetic mechanisms are not yet entirely understood. The pathophysiology of CTCL is complex and a single initiating factor has not yet been identified. Diagnosis is based on clinicopathological correlation and requires an interdisciplinary team. Treatment decision is made based on short-term and long-term goals. Therapy options comprise skin-directed therapies, such as topical steroids or phototherapy, and systemic therapies, such as monoclonal antibodies or chemotherapy. So far, the only curative treatment approach is allogeneic haematopoietic stem cell transplantation. Novel therapies, such as chimeric antigen receptor T cells, monoclonal antibodies or small molecules, are being investigated in clinical trials. Patients with CTCL have reduced quality of life and a lack of effective treatment options. Further research is needed to better identify the underlying mechanisms of CTCL development and course as well as to better tailor treatment strategies to individual patients.

Improving smoking cessation referrals among elective surgery clinics through electronic clinical decision support.

INTRODUCTION: Preoperative visits are an exceptional opportunity to encourage smoking cessation, as studies demonstrate the experience of scheduling elective surgery produces an actionable incentive to quit. However, studies suggest surgeons do not regularly assess smoking behavior or offer cessation therapies. Clinical decision support (CDS) is a system in which providers are presented with clinically integrated tools to enhance decision-making. METHODS: A CDS tool was designed to facilitate treatment referrals for smoking cessation services among patients seeking elective surgery. Two clinics were selected: the plastic and vascular surgeries. The study objectives were to assess the utilization rate and effectiveness of this system. RESULTS: No smoking cessation referrals had been submitted by the plastic surgery or vascular surgery clinics in the year before CDS tool implementation. Providers at the plastic surgery clinic utilized the CDS tool in 95.0% (191 of 201) eligible patient encounters. Of these patients, 16.3% were identified as active smokers, and 16.1% of these smokers accepted treatment referrals. Providers at the vascular surgery clinic utilized the CDS tool in 50.3% (98 of 195) eligible patient encounters. Of these patients, 10.2% were identified as active smokers, and 30.0% of these smokers accepted treatment referrals. CONCLUSIONS: The CDS tool improved the incidence of smoking cessation referrals in two surgical clinics from pretest baselines and achieved satisfactory utilization rates. This report demonstrates the feasibility of CDS tools to actualize the preoperative visit as an opportunity to promote smoking cessation.

Immune Checkpoint Inhibition in Non-Melanoma Skin Cancer: A Review of Current Evidence.

Immuno-oncology is a rapidly evolving field with growing relevance in the treatment of numerous malignancies. The prior study of immunotherapy in dermatologic oncology has largely focused on cutaneous melanoma. However, recent focus has shifted to the use of immunotherapy to treat non-melanoma skin cancers (NMSCs), such as basal cell carcinoma (BCC), cutaneous squamous cell carcinoma (cSCC), and Merkel cell carcinoma (MCC). NMSCs represent the most ubiquitous cancers globally and, while they have a lower propensity to develop into advanced disease than cutaneous melanoma, their absolute mortality burden has recently surpassed that of melanoma. Patients with advanced NMSC are now benefiting from the successes of immunotherapy, including checkpoint inhibition with anti-CTLA-4 and anti-PD-1 monoclonal antibodies. In this review, we discuss the existing clinical evidence for immunotherapy in the treatment of NMSCs, with an emphasis on checkpoint inhibitor therapies. We highlight key studies in the field and provide up-to-date clinical evidence regarding ongoing clinical trials, as well as future study directions. Our review demonstrates that checkpoint inhibitors are positioned to provide unparalleled results in the previously challenging landscape of advanced NMSC treatment.

Stem cell therapy for abrogating stroke-induced neuroinflammation and relevant secondary cell death mechanisms.

Ischemic stroke is a leading cause of death worldwide. A key secondary cell death mechanism mediating neurological damage following the initial episode of ischemic stroke is the upregulation of endogenous neuroinflammatory processes to levels that destroy hypoxic tissue local to the area of insult, induce apoptosis, and initiate a feedback loop of inflammatory cascades that can expand the region of damage. Stem cell therapy has emerged as an experimental treatment for stroke, and accumulating evidence supports the therapeutic efficacy of stem cells to abrogate stroke-induced inflammation. In this review, we investigate clinically relevant stem cell types, such as hematopoietic stem cells (HSCs), mesenchymal stem cells (MSCs), endothelial progenitor cells (EPCs), very small embryonic-like stem cells (VSELs), neural stem cells (NSCs), extraembryonic stem cells, adipose tissue-derived stem cells, breast milk-derived stem cells, menstrual blood-derived stem cells, dental tissue-derived stem cells, induced pluripotent stem cells (iPSCs), teratocarcinoma-derived Ntera2/D1 neuron-like cells (NT2N), c-mycER(TAM) modified NSCs (CTX0E03), and notch-transfected mesenchymal stromal cells (SB623), comparing their potential efficacy to sequester stroke-induced neuroinflammation and their feasibility as translational clinical cell sources. To this end, we highlight that MSCs, with a proven track record of safety and efficacy as a transplantable cell for hematologic diseases, stand as an attractive cell type that confers superior anti-inflammatory effects in stroke both in vitro and in vivo. That stem cells can mount a robust anti-inflammatory action against stroke complements the regenerative processes of cell replacement and neurotrophic factor secretion conventionally ascribed to cell-based therapy in neurological disorders.