Skin in the game: a review of single-cell and spatial transcriptomics in dermatological research.

Single-cell RNA sequencing (scRNA-seq) and spatial transcriptomics (ST) are two emerging research technologies that uniquely characterize gene expression microenvironments on a cellular or subcellular level. The skin, a clinically accessible tissue composed of diverse, essential cell populations, serves as an ideal target for these high-resolution investigative approaches. Using these tools, researchers are assembling a compendium of data and discoveries in healthy skin as well as a range of dermatologic pathophysiologies, including atopic dermatitis, psoriasis, and cutaneous malignancies. The ongoing advancement of single-cell approaches, coupled with anticipated decreases in cost with increased adoption, will reshape dermatologic research, profoundly influencing disease characterization, prognosis, and ultimately clinical practice.

Coexistence of large cell transformed mycosis fungoides and diffuse large B-cell lymphoma in one patient.

Diffuse large B-cell lymphoma (DLBCL) is the most common and aggressive subtype of non-Hodgkin lymphoma. The overall risk of developing DLBCL is increased in patients with other lymphomas, such as mycosis fungoides (MF). In this report, we present an 81-year-old female with early-stage MF who simultaneously progressed to tumor stage, large-cell transformed (LCT) MF and developed a primary DLBCL in a lymph node (LN). She presented with a tumor on her leg and new lymphadenopathy in her right axilla. Skin biopsy of the tumor revealed infiltration of large atypical CD3+, CD4+, and CD30+ cells, and a smaller portion of CD8+ cells in the dermis, consistent with LCT MF. Biopsy of the axillary LN revealed diffuse sheets of CD20+, BCL-2+, c-MYC+, and CD10- cells, highly suggestive of double expressor DLBCL. High-throughput sequencing revealed monoclonal T cells in the skin tumor and a monoclonal B-cell population in the LN. The above findings led to simultaneous diagnoses of LCT MF and nodal double expressor DLBCL. Our case demonstrates the importance of performing a full pathological workup in cutaneous T-cell lymphoma patients presenting with lymphadenopathy.

Anaplastic Large Cell Transformation of Mycosis Fungoides: Case Report and Review of the Literature.

ABSTRACT: We report a 48-year-old man with CD30+ large cell transformation of mycosis fungoides (tMF) with distinctive anaplastic morphology. The patient initially presented with folliculotropic and syringotropic mycosis fungoides (MF) manifested as occipital scalp plaque and trunk and extremities patches. Six years later, he progressed to the tumor stage from his scalp lesion and developed cervical lymphadenopathy. Lymph node and scalp biopsies showed diffuse infiltration of CD30+ anaplastic cells with multinucleated, hallmark-like, Hodgkin-Reed-Sternberg-like, histiocytoid forms, indistinguishable from anaplastic large cell lymphoma (ALCL). T-cell receptor gamma gene (TCRg) rearrangement studies revealed identical clones in the initial MF scalp lesion and nodal anaplastic lesion, confirming the transformation. Ancillary studies showed absence of IRF4/DUSP22 and ALK rearrangements and positive RB1, SMARCA4, SOCS1, and TP53 mutations. The patient achieved partial response with systemic chemotherapy. Our case is an example of tMF presenting as the morphology and phenotype of ALCL. Because clinical behavior and therapeutic options of tMF and primary cutaneous ALCL may be different, it is clinically relevant to differentiate these 2 entities. The proof of clonal relationship may be useful in diagnostically challenging cases with features overlapping between tMF and primary cutaneous ALCL.

Omaveloxolone attenuates squamous cell carcinoma growth and disease severity in an Epidermolysis Bullosa mouse model.

Patients with epidermolysis bullosa (EB) are susceptible to development of squamous cell carcinomas (SCC) at sites of chronic inflammation and fibrosis. While triterpenoids such as RTA 408 (Omaveloxolone) have been shown to reduce inflammation and inhibit tumour growth in various cancer models, the utility of this class of drugs in the treatment of SCC has not been investigated. Given the dual anti-inflammatory and anti-neoplastic properties of triterpenoids, we hypothesized RTA 408 would be an effective treatment for SCCs that arise in the chronic inflammatory setting in EB. We tested the effects of topical RTA 408 on a mouse model of non-Herlitz, junctional EB. RTA 408 significantly reduced phenotypic severity in the affected ears of Lamc2jeb mice. In cultures, RTA 408 reduced cell viability in EB-associated SCC cell lines and normal human epidermal keratinocytes. When administered in vivo, RTA 408 inhibited SCC tumour growth in mice without cutaneous or systemic toxicity. These results suggest that RTA 408 can be a promising new therapy to reduce inflammation and inhibit SCC growth in patients with EB.

Disease characteristics, prognosis, and response to therapy in patients with large-cell transformed mycosis fungoides: A single-center retrospective study.

BACKGROUND: Mycosis fungoides with large-cell transformation (MF-LCT) is associated with an aggressive clinical course, yet data comparing treatment outcomes in MF-LCT are sparse. OBJECTIVE: To compare treatment outcomes and to determine disease prevalence and characteristics associated with survival in MF-LCT. METHODS: A retrospective review was conducted of mycosis fungoides patients from 2012 to 2020 treated at Thomas Jefferson University. Patients with histopathologic diagnosis of MF-LCT were included. Treatment outcomes were assessed by mean changes in the modified Severity Weighted Assessment Tool (mSWAT) and stage. RESULTS: Of 171 patients with mycosis fungoides, 23 (13.4%) had histologic diagnosis of MF-LCT. The overall 5-year survival rate for MF-LCT was 74% and was not significantly associated with sex, age, or initial stage at the time of MF-LCT diagnosis. Brentuximab vedotin showed the greatest mean decrease in mSWAT (-20.53) and stage progression (change in Δ stage: -0.4) in MF-LCT compared to oral bexarotene (ΔmSWAT: +4.51; Δstage: +0.27), skin-directed therapy (ΔmSWAT: -5.93; Δstage: -0.08), and chemotherapy (ΔmSWAT: +4.97; Δstage: +0.85). LIMITATIONS: Single-center retrospective design, and patients often on multiple treatment modalities. CONCLUSIONS: We report superior treatment outcomes for brentuximab vedotin compared to oral bexarotene, skin-directed therapy, and chemotherapy in MF-LCT in both early and advanced disease.

Application of the current diagnostic algorithm for early mycosis fungoides to a single center cohort: Identification of challenges and suggestions for modification.

BACKGROUND: Diagnosing early-stage mycosis fungoides (MF) remains a significant challenge. The International Society for Cutaneous Lymphomas (ISCL) proposed an algorithm for diagnosing early MF incorporating clinical and histopathologic characteristics, as well as immunohistochemistry and molecular studies. Here we aim to examine the diagnostic utility of the ISCL algorithm. METHODS: In this single-center retrospective review, the ISCL algorithm was applied to 28 patients diagnosed with early-stage MF. Immunohistochemistry and molecular studies were not performed for all patients, so a subgroup analysis was conducted including 18 patients in whom both studies had been performed. We calculated the diagnostic sensitivity of the algorithm. Subsequently, we examined how modifying the algorithm's histopathologic criterion from epidermotropism without spongiosis to epidermotropism influenced its sensitivity. RESULTS: Forty-three percent (12/28) of the cohort and 50% (9/18) of the subgroup met the algorithm's diagnostic threshold. When the algorithm was modified, 71% of the cohort and 89% of the subgroup met the algorithm's threshold. CONCLUSION: While the ISCL algorithm is useful in diagnosing early-stage MF, its sensitivity remains suboptimal. Further refinement of the algorithm to capture spongiotic subtypes of MF may improve its diagnostic value.

An unexpected case of non-uremic calciphylaxis in a patient with multiple risk factors.

A 58-year-old woman with a history of morbid obesity, asthma, and prior warfarin use presented to the hospital with shortness of breath and a three-month history of painful, ulcerated ulcers with retiform purpura of her bilateral distal extremities. A punch biopsy specimen demonstrated focal necrosis and hyalinization of the adipose tissue with subtle arteriolar calcium deposition, findings consistent with calciphylaxis. We discuss the presentation of non-uremic calciphylaxis and review the risk factors, pathophysiology, and interdisciplinary management approach of this rare disease.

Response to topical corticosteroid monotherapy in mycosis fungoides.

BACKGROUND: Topical corticosteroids alone or in combination with other therapies are widely used to treat mycosis fungoides (MF), but data on response rates to their use as monotherapy in MF are limited. OBJECTIVE: To evaluate the efficacy of topical corticosteroid monotherapy in MF; compare sex, age, stage distributions, and histopathologic features between responders and nonresponders. METHODS: A retrospective cross-sectional review of patients with MF from 2013 to 2019 treated at Thomas Jefferson University was conducted. Patients with biopsy-proven MF, all stages, who received topical corticosteroid monotherapy were included. Response rates were determined by percent change in body surface area (BSA) involvement and modified Severity-Weighted Assessment Tool (mSWAT). RESULTS: Of the 163 patients with MF in our database, 23% (37/163) initially received topical steroid monotherapy. Of these, 73% (27/37) improved, with an average 65% decrease in BSA (67% in mSWAT); 27% (10/37) did not respond/progressed, with an average 51.6% increase in BSA (57% in mSWAT); and 33% (12/37) had a complete response (BSA, 0%) with prolonged topical steroid use. Early-stage MF and female sex were more represented in responders. LIMITATIONS: Single-center retrospective design. CONCLUSIONS: Topical steroid monotherapy in early-stage MF can produce measurable improvements in BSA and mSWAT scores and achieve complete remission in a limited subset of patients.

Linear basal cell nevus with a novel mosaic PTCH1 mutation.

The patched tumor suppressor gene (PTCH1) encodes a receptor, which is a key component of the hedgehog signalling pathway. Mutations in PTCH1 are implicated in the development of sporadic basal cell carcinomas (BCC), as well as those in Gorlin Syndrome. Rarely, BCCs may develop in a linear pattern along lines of Blaschko due to cutaneous mosaicism. In cases in which there are other features of Gorlin syndrome, genomic analysis has demonstrated lesional mutations in the Hedgehog signalling pathway. Causative mutations, however, have not been firmly demonstrated in the cases of linear and segmental BCCs in otherwise healthy individuals. Herein, we report a case of a 31 year-old Caucasian woman with linear development of multiple superficial BCCs in a Blaschkoid distribution without other characteristic findings of Gorlin syndrome. Genomic analysis of lesional skin by whole-exome sequencing identified a novel heterozygous mutation PTCH1: NM_000264.3, Exon 15, c.2336-2337insGGTAGGA, p.Asp779Glufs*13 in PTCH1, shared by two discrete samples within the lesion, while no mutations were found in the non-lesional skin or peripheral blood. Given the young age of our patient and linear distribution of BCCs on non-sun exposed skin, our findings suggest segmental mosaicism. The patient was treated with topical 5% imiquimod with histologically confirmed clearance of BCCs in 2 months.

A prospective cohort study of condensed low-dose total skin electron beam therapy for mycosis fungoides: Reduction of disease burden and improvement in quality of life.

BACKGROUND: Low-dose total skin electron beam therapy (TSEBT) for mycosis fungoides is popular because of reduced toxicity with effective palliation. We condensed TSEBT, reducing visits by half and overall treatment length by one third. OBJECTIVE: To determine the efficacy and safety of a novel condensed low-dose TSEBT for mycosis fungoides. METHODS: We conducted a cohort study (2014-2018) with a median follow-up of 22.8 months. We delivered 12 Gy per 6 fractions with the modified Stanford technique, 3 fractions per week, with boosts to shadowed sites at risk between treatments, completing in 2 weeks. Primary outcomes included clinical response, duration of and time to response, and toxicity. Secondary outcomes included patient-reported quality of life (pain, pruritus, and Dermatology Life Quality Index) and physician-scored disease burden (body surface area involvement and Modified Skin Weighted Assessment Tool). RESULTS: Of 25 patients, stage IB was most common at the time of TSEBT (36%). The overall response rate was 88%. Most common was a near complete response (36%), and complete response was achieved in 6 (24%) patients. The median duration of response was 17.5 months (3.5-44.2), and the median time to response was 2 months (range, 0.9-4.1). No patients had toxicity of grade 3 or greater. QOL and disease burden showed significant benefit after TSEBT (P < .001). LIMITATIONS: Cohort study with limited sample size. CONCLUSIONS: Condensed, low-dose TSEBT has favorable outcomes and toxicity with logistical convenience.

Inherited Interleukin 2-Inducible T-Cell (ITK) Kinase Deficiency in Siblings With Epidermodysplasia Verruciformis and Hodgkin Lymphoma.

Biallelic mutations in the ITK gene cause a T-cell primary immunodeficiency with Epstein-Barr virus (EBV)-lymphoproliferative disorders. We describe a novel association of a homozygous ITK mutation with ß-human papillomavirus (HPV)-positive epidermodysplasia verruciformis. Thus, loss of function in ITK can result in broad dysregulation of T-cell responses to oncogenic viruses, including ß-HPV and EBV.

Molluscum contagiosum infection with features of primary cutaneous anaplastic large cell lymphoma.

CD30+ T cell pseudolymphomas (CD30+ PSL) are a group of benign inflammatory cutaneous disorders that can develop in settings of viral infections or drug reactions. Owing to their histological similarities to malignant lymphomas, these benign infiltrates are occasionally misdiagnosed as malignant, causing significant concerns for patients and physicians. Herein, we report a patient with CD30+ PSL associated with molluscum contagiosum whose initial biopsy revealed atypical large CD30-expressing cells, leading to a misdiagnosis of primary cutaneous anaplastic large cell lymphoma and referral to our cutaneous lymphoma clinic. We report this case to demonstrate that reactive CD30+ infiltrate associated with molluscum contagiosum can be mistaken for T-cell lymphomas and patients should be reassured in these cases.

Impaired wound healing secondary to bevacizumab.

Bevacizumab is a monoclonal antibody that exerts its antitumor activity by inhibiting vascular endothelial growth factor. Consequently, it suppresses endothelial cell proliferation, vascular permeability, and angiogenesis. This inhibitory effect contributes to tumour size reduction but causes wound-healing delay, specifically during the proliferative phase, in patients receiving bevacizumab. Although surgical wound-healing complications (WHC) associated with bevacizumab have been extensively reported, there is limited literature on peripheral WHC. More importantly, the histopathology of bevacizumab-associated WHC has not been described. We present the histopathology findings of a non-healing ulcer in a patient receiving bevacizumab, providing insight into the possible aetiology of this drug's adverse reaction. Furthermore, our patient's positive response to hyperbaric oxygen suggests its possible use for treatment of bevacizumab-associated non-healing wounds.

Cutting edge: Macrophages are required for localization of antigen-activated B cells to the follicular perimeter and the subsequent germinal center response.

We demonstrated recently that, after accumulation of Ag-engaged B cells at the T cell zone boundaries in the spleen, these B cells migrate to the perimeter of follicles adjacent to the marginal zone. They undergo rapid proliferation at this site prior to coalescence into germinal centers (GCs). In this article, we report that this phase of migration and expansion of activated Ag-specific B cells, as well as subsequent formation of GCs, does not take place in the absence of splenic macrophages. Our data suggest a previously unappreciated function for macrophages in orchestrating the early phases of T cell-dependent B cell responses and formation of GCs distinct from their potential role in Ag presentation to T cells.

Evaluating Response Trends of Chlormethine/Mechlorethamine Gel in Patients With Stage I-IIA Mycosis Fungoides: Analysis of Individual Patient Data From a Randomized Controlled Phase II Study to Facilitate Optimal Treatment Experiences.

INTRODUCTION: Chlormethine (CL) gel was approved for treatment of mycosis fungoides based on the pivotal 201 trial (NCT00168064). Data visualization from individual patients is a powerful tool for discovery of hidden treatment trends. Here, we present a post hoc analysis of individual patient data from the pivotal trial to provide a more granular depiction of treatment and response changes over time, with an emphasis on end of treatment status. MATERIALS AND METHODS: Individual patient response data were plotted over a 12-month treatment period to visualize patient experiences while using CL gel. Responder status was assigned according to end-of-treatment Composite Assessment of Index Lesion Severity (CAILS) score, and patients were classified as early (≤4 months) or late responders based on timing of response. Baseline and active treatment characteristics were compared between early and late responders, and baseline body surface area (BSA) was compared between responders and patients with stable or progressive disease. RESULTS: Data from 123 patients with baseline and postbaseline results were included. At the end of treatment, 64.2%/55.3% were responders, 30.9%/34.1% had stable disease, and 4.9%/10.6% had progressive disease by CAILS and mSWAT, respectively. Among patients who responded to treatment, 64.6% and 35.4% were early and late responders, respectively. Response pattern analysis also identified patients with an intermittent response or initial progressive disease. Baseline BSA was not associated with responder status. Late responders had longer treatment duration and higher postbaseline plaque elevation, while early responders had a higher frequency of dermatitis. CONCLUSIONS: Results presented here can facilitate optimal treatment experiences for patients starting CL gel.

Investigating the relationship between physical, cognitive, and environmental factors of ergonomics with the prevalence of musculoskeletal disorders: A case study in a car-parts manufacturing industry.

BACKGROUND: Work-related musculoskeletal disorders (WRMSDs) is a multi-factorial disorder in most occupational setting and it has increased significantly in recent years. OBJECTIVE: This study aimed to investigate the relationship between physical, cognitive, and environmental factors of ergonomics with the prevalence of WRMSDs in a car-parts manufacturing industry. METHODS: This cross-sectional study was performed among 220 workers in a milling unit of a car parts manufacturing company in 2021-2022. The prevalence of WRMSDs was assessed using the Extended Version of the Nordic Musculoskeletal Questionnaire. Noise exposure was evaluated using dosimetry method. Mental and physical workload were evaluated by the NASA-TLX and key index methods (KIM-MHO and KIM-LHC), respectively. Data analysis was performed using SPSS version 25.0. RESULTS: The subjects' mean age and work experience were 36.3±6.5 and 8.35±6.41 years, respectively. Eighty-five percent of the subjects reported WRMSDs in at least one area of the body. The results of mental workload assessment revealed a high workload mean range (73.23±14.89) in all of the subjects. Mean score of KIM-LHC and KIM-MHO were 738.18±336.42 and 201.86±36.41, respectively with odds ratio of 1.32 for KIM-LHC in creating the WRMSDs. There was a significant relationship between the noise exposure, mental and physical workload and the prevalence of WRMSDs (p-value <  0.05). CONCLUSION: The results of the present study revealed that environmental, physical and cognitive factors can simultaneously be effective in the prevalence of WRMSDs. Therefore, performing effective control measures requires comprehensive attention to physical, environmental, and cognitive ergonomics in the algorithm of ergonomics management in the workplace.