Bowen's Disease Research Articles

Abstract B015: Targeting CX3CL1 transforms a cold tumor microenvironment into a hot one by enhancing T cells and DCs locally and systemically

Abstract Intratumoral heterogeneity (ITH) is associated with immunotherapy failure and a weaker anti- tumor immune response. Using a series of carcinogen-induced tumor (CIT) squamous cell skin carcinoma cell lines, our lab has sought to identify tumor-intrinsic factors—particularly chemokines and cytokines—which can have a “dominant negative” effect on the immune microenvironment when present within a heterogeneous tumor. We identified CX3CL1 as a one such critical mediator of a cold (T cell low) immune microenvironment and found that tumors containing as few as 10% CX3CL1high tumor cells exhibit a diminished T cell response compared to tumors which lack CX3CL1high tumor cells. We predicted that targeting CX3CL1 could therefore transform a cold tumor microenvironment (TME) into an inflammatory hot (T cell high) TME. Supporting this, we found that CRISPR-Cas9-mediated deletion of CX3CL1 in a tumor cell line that typically gives rise to cold tumors led to higher T cell infiltration and fewer immunosuppressive macrophages in the TME of CX3CL1-/- tumors. Building on this, we further explored T cell populations in the TME and found that CX3CL1-/- tumors had significantly increased activation and decreased exhaustion markers on T cells. Flow cytometry analysis showed higher expression of CD44 on effector CD4 T cells and an increase in the number of activated CD44+ PD1low CD4 T cells. By contrast, the frequency of CD4 T cells which were PD1High TIM3+ and PD1High TIM3+ TIGIT+ which represent a likely exhausted effector CD4 population was lower in CX3CL1-/- tumors than in counterpart control tumors. An interrogation of DC subsets in the TME further revealed a higher number of cDC1 and cDC2 populations in CX3CL1−/− tumors. To determine the effect of tumor-produced CX3CL1 on immune activity in lymphoid organs, we investigated T cell and DC markers in the spleen and tumor-draining lymph nodes during early tumor development. Spleens harvested 10 days after tumor injection showed higher infiltration of cDC1 CCR7+ and cDC2 CCR7+ mature DCs in CX3CL1-/- tumor-bearing mice. Thus, in the absence of tumor-produced CX3CL1, both cDC1 and cDC2 dendritic cell subsets attain more mature phenotypes in both the TME and the spleen. At the same time point, tumor-draining lymph nodes also exhibited a shift in immune cell composition characterized by an increased frequency of T cells, particularly CD4+ T cells, and a decreased frequency of B cells. Moreover, the percentage of PD1+ CD8 cells was also higher, indicating better priming and activation of CD8 T cells via DCs in tumor-draining lymph nodes. These findings indicate that tumor-produced CX3CL1 drives a cold immune microenvironment through both tumor-localized and systemic effects. These studies suggest therapeutically targeting CX3CL1 particularly in tumors where tumor cells produce high levels of CX3CL1 holds promise to transform a cold TME into a hot immune inflammatory TME and potentiate better anti-tumor immunity. Citation Format: Piyush Chaudhary, Savannah Hughes, Joshua Tay, Robert Letchworth, Miho Tanaka, Melissa Reeves. Targeting CX3CL1 transforms a cold tumor microenvironment into a hot one by enhancing T cells and DCs locally and systemically [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor-body Interactions: The Roles of Micro- and Macroenvironment in Cancer; 2024 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(22_Suppl):Abstract nr B015.

Abstract B007: Unlocking antiviral immunity against endogenous retroviruses in skin squamous cell carcinomas

Abstract Known as molecular parasites that invaded our genome through ancestors, transposons (mainly retrotransposons) are interspersed genomic repeats that constitute ∼40% of the mammalian genome. Primarily residing in the heterochromatin, retrotransposons exhibit dynamic expressions to orchestrate embryonic development and shape adult functions. Although rare, a cohort of evolutionarily young retrotransposons resisted extinction, whose selfish activities underlie polymorphic variations and genetic diseases including cancer. While the extraordinary molecular and functional heterogeneity of retrotransposons has been long recognized, mechanistic dissection remains challenging. To tackle this challenge, we use murine skin as our model, given its well-characterized, abundant, and highly accessible adult stem cells, not only mediating postnatal remodeling and tissue repair, but also serving as cell of origin for squamous cell carcinomas. By analyzing a genetic model lacking a known retrotransposon suppressor, histone methyltransferase Setdb1, which we found to be essential in the adult skin, we saw hair loss and hair follicle stem cell exhaustion phenotype, accompanied by a robust and selective surge of endogenous retroviruses (ERVs). When combined with squamous cell carcinoma drivers, Setdb1 loss significantly blocked tumor progression in vivo. We detected abundant retroviral peptides originated from its full-length copies through mass spectrometry and viral-like particles through transmission electron microscopy that are immunoreactive to previously reported ERV surface envelope (env) antibody. Similar viral-like particles were broadly evident across several epithelial tissues beyond skin, implicating its conserved function across squamous cancers. Mechanistically, epithelial originated ERVs elicit tissue wide inflammatory response, and can be ameliorated by pharmacological or genetic inhibition of retroviral activity. Moreover, ERV reactivation induced replication stress functionally accounts for stem cell exhaustion, therefore serving as a specific therapeutic vulnerability in squamous cancers. As an evolutionary conundrum, viral-coding ERVs pose a threat to host fitness and yet, they’ve resisted extinction persisting in the mammalian genome. Our findings suggest ERVs wrestle with the host surveillance programs to regulate adult tissue physiology and pathology, thus providing a key target in eliciting innate immunity in squamous cell carcinomas. Citation Format: Ying Lyu, Yejing Ge. Unlocking antiviral immunity against endogenous retroviruses in skin squamous cell carcinomas [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: RNAs as Drivers, Targets, and Therapeutics in Cancer; 2024 Nov 14-17; Bellevue, Washington. Philadelphia (PA): AACR; Mol Cancer Ther 2024;23(11_Suppl):Abstract nr B007.

Risks of malignancies related to disease-modifying antirheumatic drugs in rheumatoid arthritis: a pharmacovigilance analysis using the FAERS database

ObjectivesOver the years when disease-modifying antirheumatic drugs (DMARDs) have been used in rheumatoid arthritis patients, reports of malignancies have emerged. This study aims to investigate the association between malignancies and DMARDs by using data extracted from the Food and Drug Administration Adverse Event Reporting System (FAERS).MethodsFAERS data (January 2019 to December 2023) were reviewed. For each drug-event pair, the disproportionality analysis was conducted to evaluate the risk of malignancy. Multivariate logistic regression was implemented to mitigate potential biases. Moreover, the time to onset of malignancy was also evaluated.ResultsWe conducted a detailed search for rheumatoid arthritis indications and identified a total of 17,412 adverse event reports associated with malignancies, with selective DMARDs designated as the role code “primary suspect”. At the preferred term level, there were 198 positive signals, among which the lower limit of the 95% confidence interval for the information component is 3.55 for squamous cell carcinoma of the skin, 2.39 for breast cancer, and 2.27 for lymphoproliferative disorder. In comparison to other DMARDs, targeted synthetic DMARDs were associated with a broader range of malignancies at both preferred term and Standardized MedDRA Queries levels. The number of adverse events reported in female patients is approximately 2–3 times higher than men, and the median age across the population was approximately 62 years. In terms of onset time, the conventional synthetic DMRADs exhibited a relatively longer median time, ranging from 3.58 to 7.08 years, while the targeted synthetic DMARDs demonstrated a shorter median time of 0.83–1.67 years.ConclusionOur study uncovers varying degrees of malignancy risks related to DMARDs, with a significantly higher risk observed in targeted synthetic DMARDs. Additionally, novel malignancy signals, not documented in product labels, have been detected. In the future, further research will be necessary to validate our findings.

5-fluorouracil 5% cream for squamous cell carcinoma in situ: Factors impacting treatment response

Complete clinical response (CCR) rates for squamous cell carcinoma in situ (SCCis) treated with 5-fluorouracil (5-FU) 5% cream range from 27-85%. Factors associated with CCR are not well-established. Retrospective review of biopsy-proven primary SCCis diagnosed between 5/1/2019-4/30/2020 and treated with 5-FU 5% cream. Disease status at follow-up was recorded, with treatment failure defined as persistent or recurrent disease. The study included 149 SCCis cases, including 33.6% (50/149) arising in the context of immunosuppression. Eighteen cases failed treatment (10 persistent disease, 8 recurrent disease). By tumor size, CCR was noted in 128/144 (88.9%) tumors measuring <2 centimeters in diameter and 3/5 tumors ≥2 centimeters (60.0%, p=0.051). By treatment duration, CCR was observed in 4/7 (57.1%) tumors treated for <2 weeks, 72/83 (86.7%), tumors treated for 2 to <4 weeks, and 55/59 (93.2%) tumors treated for ≥4 weeks (p=0.019). On multivariate analysis, treatment failure was significantly associated with shorter treatment durations (OR 0.26; p=0.007) and increasing tumor size (OR 2.40; p=0.037). Shorter treatment duration and larger lesion size were significantly associated with failure of 5-FU in SCCis. Immunosuppression and anatomic location were not significant factors, supporting 5-FU use for SCCis in the immunosuppressed population and highlighting its versatility irrespective of anatomic location.

Nuclear versus cytoplasmic IKKα signaling in keratinocytes leads to opposite skin phenotypes and inflammatory responses, and a different predisposition to cancer.

IKKα is known as an essential protein for skin homeostasis. However, the lack of suitable models to investigate its functions in the skin has led to IKKα being mistakenly considered as a suppressor of non-melanoma skin cancer (NMSC) development. In this study, using our previously generated transgenic mouse models expressing exogenous IKKα in the cytoplasm (C-IKKα mice) or in the nucleus (N-IKKα mice) of basal keratinocytes, we demonstrate that at each subcellular localization, IKKα differently regulates signaling pathways important for maintaining the balance between keratinocyte proliferation and differentiation, and for the cutaneous inflammatory response. In addition, each type of IKKα-transgenic mice shows different predisposition to the development of spontaneous NMSC. Specifically, N-IKKα mice display an atrophic epidermis with exacerbated terminal differentiation, signs of premature skin aging, premalignant lesions, and develop squamous cell carcinomas (SCCs). Conversely, C-IKKα mice, whose keratinocytes are nearly devoid of endogenous nuclear IKKα, do not develop skin SCCs, although they exhibit hyperplastic skin with deficiencies in terminal epidermal differentiation, chronic cutaneous inflammation, and constitutive activation of STAT-3 and NF-κB signaling pathways. Altogether, our data demonstrate that alterations in the localization of IKKα in the nucleus or cytoplasm of keratinocytes cause opposite skin changes and differentially predispose to the growth of skin SCCs.

Mohs Micrographic Surgery: A Brief Overview

AbstractMohs micrographic surgery (MMS) is a tissue-sparing skin cancer resection technique that involves 100% margin analysis. This procedure is performed in the outpatient setting under local anesthesia by dermatologic surgeons who act as both the surgeon and the pathologist. The technique allows for prompt reconstruction immediately after cancer clearance and offers the highest cure rate for many skin malignancies, including basal and squamous cell carcinoma, as well as more rare tumors. Mohs surgery effectively ensures cancer clearance while minimizing defect size and optimizing cosmetic and functional outcomes for patients. Herein we will discuss the evolution, procedure, and indications of MMS.

Disabled 2 (Dab2) Regulates Tumour Progression in Skin Squamous Cell Carcinoma.

Dab2 is an endocytic adaptor protein involved in various physiological processes and signaling pathways. Dab2 is deregulated in various cancers; however, its role in skin squamous cell carcinoma ( SCC) has not been elucidated yet. In the present study, we used the DMBA/TPA induced murine skin carcinogenesis model to examine the role of Dab2 in skin tumour progression. We generated tamoxifen inducible Dab2 conditional knockout system for our study. Loss of Dab2 led to delayed papilloma initiation and reduced papilloma burden. Delayed papilloma initiation was due to reduce proliferative potential of the papillomas due to Dab2 loss. Furthermore, while the WT papillomas progressed to SCC, the papillomas formed in Dab2 cKO mice failed to undergo malignant conversion to SCC. Dab2 cKO tumours showed reduced expression of K8, a marker for aggressive tumour. Moreover, Dab2 ckO tumours failed to undergo EMT as shown by reduced expression of Vimentin and Twist1. Dab2 cKO tumours also showed reduced expression of Sox2, a stem cell marker. Furthermore, qPCR analysis showed upregulation of Dab2 expression in the human skin cancer cell lines as compared to normal human skin keratinocytes. In patients, TCGA data analysis of skin cancer melanoma (SKCM) showed a trend where high levels of Dab2 correlated with poor overall survival. The present study shows that Dab2 promotes tumour progression in skin SCC.

Potential Antitumor Mechanism of Propolis Against Skin Squamous Cell Carcinoma A431 Cells Based on Untargeted Metabolomics.

Propolis is a sticky substance produced by honeybees (Apis mellifera) through the collection of plant resins, which they mix with secretions from their palate and wax glands. Propolis can inhibit tumor invasion and metastasis, thereby reducing the proliferation of tumor cells and inducing cell apoptosis. Previous research has shown that propolis has an inhibitory effect on skin squamous cell carcinoma A431 cells. Nevertheless, its inhibitory mechanism is unclear because of many significantly different Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways between the ethanol extract of the propolis (EEP) group and the control group of cells. In this study, the main components of EEP and the antitumor mechanism at an IC50 of 29.04 μg/mL EEP were determined via untargeted metabolomics determined using ultra high-performance liquid chromatography tandem mass spectrometry (UHPLC‒MS/MS), respectively. The results revealed 43 polyphenolic components in the EEP and 1052 metabolites, with 160 significantly upregulated and 143 significantly downregulated metabolites between cells treated with EEP and solvent. The KEGG enrichment results revealed that EEP significantly inhibited A431 cell proliferation via the steroid hormone biosynthesis and linoleic acid metabolism pathways. These findings may provide valuable insights for the development of targeted therapies for the treatment of cutaneous squamous cell carcinoma.

Abstract A033: Pro-inflammatory tumor cells drive CD4+ T cell localization within heterogeneous tumors

Abstract Immunotherapies such as immune checkpoint inhibitors (ICIs) have greatly improved patient outcomes in multiple tumor types, but ICIs have failed to achieve responses in many patients. Meta-analyses of patient cohorts treated with ICIs have observed that worse clinical outcomes are strongly correlated with high levels of intratumoral genetic heterogeneity (ITH). ITH occurs when tumor cells mutate as they divide, typically due to oxidative stress or DNA damage from rapid proliferation and continued carcinogenic insults, generating tumor subclones. However, the mechanisms by which ITH impairs the anti-tumor immune response are not fully understood. We propose a novel mechanism for how ITH in highly T cell-infiltrated inflamed tumors can adversely affect T cell behavior. We hypothesize that strongly pro-inflammatory tumor subclones secreting robust pro-inflammatory chemokine profiles can dominate T cell trafficking within the tumor, resulting in a weakened immune response against other tumor subclones. Using a murine squamous cell skin carcinoma (SCC) model, we have demonstrated that in immune-inflamed tumors, the spatial distribution and behavior of tumor-infiltrating T cells is influenced by ITH. A strongly pro-inflammatory tumor line expressing an endogenous RFP fluorophore was mixed with a weakly pro-inflammatory tumor line expressing an endogenous YFP fluorophore at a 1:1 ratio. The resulting tumors contained distinct RFP+ and YFP+ regions. These were analyzed by immunofluorescence (IF) and by manually dissecting the tumors and analyzing each region by flow cytometry. Flow cytometry analysis determined that the strongly pro-inflammatory RFP+ regions contained significantly more total T cells and CD4+ T cells than YFP+ regions. Furthermore, FoxP3- “conventional” CD4+ T cells were significantly more likely to be “terminal effector-like” CD44+CD62L- in RFP+ regions, and significantly more likely to be “naïve-like” CD62L+CD44- in YFP+ regions. IF analysis confirmed the preferential distribution of CD4+ T cells in RFP+ regions, and observed that this spatial pattern was evident as early as 11 days after subcutaneous injection. Notably, this localization trend did not occur with CD8+ T cells, which were evenly dispersed throughout the tumors. ELISA analysis of lysates of both tumor cell lines determined that the pro-inflammatory RFP+ cell line secretes significantly higher levels of the chemokine CCL5, which has been observed by other studies to selectively mediate CD4+ T cell chemotaxis. These results demonstrate that intratumoral CD4+ trafficking is shaped by the spatial distribution of specific tumor subclones, and suggest tumor cell chemokine signaling may directly mediate T cell spatial localization and behavior within tumors. Citation Format: Robert Letchworth, Savannah Hughes, Abigail Keku, Melissa Reeves. Pro-inflammatory tumor cells drive CD4+ T cell localization within heterogeneous tumors [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor Immunology and Immunotherapy; 2024 Oct 18-21; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2024;12(10 Suppl):Abstract nr A033.

CK20-negative Merkel Cell Carcinoma with Concomitant Squamous Cell Carcinoma In-Situ and Metastasis to the Parotid Gland

Abstract Introduction/Objective This report presents a patient with an aggressive CK20-negative neuroendocrine tumor of the dermis with metastasis to the parotid gland and a concomitant squamous cell carcinoma in-situ (SCCIS) and highlights diagnostic challenges of CK20-negative tumors. Methods/Case Report A centennial female with a history of non-melanoma skin cancer and leukemia presented to the dermatology clinic with a one-year history of an enlarging skin lesion on her right cheek and a subcutaneous mass on the right central lateral neck. On examination, the lesion appeared as a rough and raised red papule with a central crust. On CT, a large heterogeneously enhancing right parotid mass with surrounding satellite nodules, adjacent necrotic adenopathy, and an ulcerating subcutaneous mass in the adjacent right face. An incidental 3 mm right upper lobe nodule was identified. The pathology report noted two distinct malignant neoplasms within the specimen. Microscopy revealed ulceration with acanthosis and full thickness keratinocyte atypia, suggesting Bowen’s disease. On microscopic examination of the separate dermal tumor, there were sheets of uniform small cells with a high nuclear to cytoplasmic ratio and scant cytoplasm. IHC staining was positive for the neuroendocrine markers AE1/AE3, CAM5.2, synaptophysin, and CD56. CK20, CK7, and TTF-1 were negative. As some MCC may be negative for CK20, CK20 was performed twice. Differential diagnoses included SCCIS with CK20-negative MCC versus a metastatic neuroendocrine carcinoma of parotid gland to the skin. The patient transitioned to hospice care soon after the diagnosis. Results (if a Case Study enter NA) NA. Conclusion Our patient presents with an interesting case of a CK20-negative MCC with metastasis to the parotid gland. Since CK20 was stained negative twice, it complicated the diagnosis of MCC vs. small cell carcinoma. We suspected a more likely diagnosis of MCC metastasis to the parotid gland due to multiple reported cases (Day et al. 2016). Our patient also had an identifiable Bowen’s disease borderline to the neuroendocrine carcinoma. It is well known of the coexistence of MCC and squamous cell carcinoma in a cutaneous lesion (Suaiti et al. 2019). Thus, a metastatic MCC to the parotid gland is more likely in this case. As MCC is an aggressive cancer that metastasizes quickly, accurate diagnosis is crucial. With recent literature reporting the association of CK20-negativity with VN-MCC, and the presence of UV signature mutations in CK20- negative MCC, genomic screening would be a useful diagnostic tool.

12564 A Rare Case Of Pembrolizumab Induced Secondary Adrenal Insufficiency

Abstract Disclosure: L. Escano Volquez: None. P. Desai: None. Pembrolizumab is an immune check-point inhibitor that blocks the PD1 receptor and is currently used in the treatment of a vast variety of malignancies. Despite adrenal insufficiency (AI) already being documented as a rare but potential side effect, its diagnosis is usually delayed due to vague presentation, increasing the risk of deleterious outcomes. We present a case of secondary AI while on pembrolizumab in which diagnosis was delayed due to unspecific clinical picture.This is a 66-year-old male who presented to the hospital with decreased appetite, nausea and generalized weakness. Patient was seen a month prior with similar symptoms which were thought to be secondary to poor oral intake in the setting of underlying malignancy. Medical history remarkable for squamous cell carcinoma of the skin with recent lung metastasis for which he was started on pembrolizumab a year ago. On arrival to the emergency department, patient was hypertensive with BP 144/68 mmHg, HR 88, and RR 15. Orthostatic vitals were positive. Physical examination otherwise unremarkable. Laboratory tests revealed mild hypernatremia of 147, potassium of 4.7, chloride 108, HCO3 18, anion gap 21, BUN 33, elevated creatinine 1.62 and elevated beta-hydroxybutyrate 5.4. EKG revealed sinus rhythm. Patient was admitted for further evaluation of orthostasis and starvation ketosis. Initial management included IV fluids and Midodrine. However, patient continued to have episodes of orthostatic hypotension. Lack of improvement of symptoms led to further workup which revealed low AM cortisol of 1.0 and a low ACTH level &amp;lt;3.0 pg/ml, concerning for secondary adrenal insufficiency. Patient was administered Solu-Medrol 40 mg IV before being transitioned to a daily hydrocortisone regimen with subsequent improvement of symptoms. Pembrolizumab induced AI is a very rare event. It is estimated that the incidence approaches 1% and symptoms can develop at any time throughout treatment. Despite its low incidence, it can be life-threatening if not diagnosed and treated promptly. However, given its very heterogeneous and vague clinical presentation, a prompt diagnosis can be difficult. The clinical course of our patient and subsequent resolution of symptoms after appropriate treatment was started, supports the diagnosis of pembrolizumab induced adrenal insufficiency after a year of initiating treatment. This patient had prior hospitalizations and office visits with symptoms that are usually already present in individuals with underlying malignancy, which resulted in underestimation of his symptoms. This case highlights the importance of always considering AI as a potential adverse effect of immune check-point inhibitors. This will ensure a prompt diagnosis and treatment of an endocrine disorder that could otherwise lead to deleterious outcomes if left untreated. Presentation: 6/1/2024

Transcriptomic analysis of genes associated with vitamin D receptor signalling reveals differences between skin cancers.

Vitamin D activates the vitamin D receptor (VDR), which dimerizes preferentially with the retinoid X receptor-α (RXRα). This heterodimer connects with genetic elements responsive to vitamin D, inhibiting or stimulating gene activity. We performed Nanostring® analysis of VDR/RXRα to compare the mRNA expression of this heterodimer and their correlated transcriptomes in non-melanoma skin cancer (basal cell carcinomas (BCC) and squamous cell carcinomas (SCC)) and melanocytic lesions (intradermal nevi (IN), and melanomas (MM)) with control skin. To evaluate VDR, RXRα and other 22 correlated genes in BCC, SCC, IN and MM, paraffin samples had their transcriptomes analysed using Nanostring®, a platform that allows multiple mRNA analyses. There were 46 samples, including 11 BCC, 10 SCC, 10 IN, 12 MM and 3 pools of control skins. Most mRNAs differed between the lesion groups and the control group. BCC and SCC NCOR2 were upregulated; in MM and IN, RXRγ was higher than in the control group. TP53, FOXO3 and MED1 showed a significant difference when we compared the BCC group to the SCC group. Melanoma and intradermal nevi differed only in AhR. VDR and RXRα were lower than the control in all groups. The panel shows a clear difference between the non-melanocytic cancers and, on the other hand, a slight difference between the melanocytic lesions. The study of vitamin D's influence through its receptor and RXRα is an exciting issue for understanding the importance of this pathway, and the present study can impact the prevention and treatment strategies, mainly in non-melanocytic tumours.

ZEB2 drives intra-tumor heterogeneity and skin squamous cell carcinoma formation with distinct EMP transition states

ZEB2 drives intra-tumor heterogeneity and skin squamous cell carcinoma formation with distinct EMP transition states

Photogallery. HIV infection and neoplastic skin diseases

Malignant neoplasms constitute a group of the most important secondary diseases that develop in people infected with the human immunodeficiency virus (HIV). The first neoplastic disease described in HIV-infected patients is Kaposi's sarcoma. In contrast to other types of Kaposi's sarcoma, its epidemic (AIDS-associated) type is more common in young and middle-aged HIV-positive individuals, especially among men who have same-sex sex. Epidemic Kaposi's sarcoma does not have a favourite localisation. However, there is a tendency to lesions of the scalp (face, ear flaps), upper extremities, anogenital area, oral mucosa. On the trunk, the pathological process spreads along the Langer lines. Skin rashes are represented by spotty, papular, nodular elements of red-brown or purple colour. The aggressive course is characteristic: rapid dissemination and generalisation of rashes. Plasmoblastic lymphoma is associated with immunodeficiency states and is rare. The tumour lesion is usually located in the oral cavity. Few cases of plasmoblastic lymphoma with skin and soft tissue involvement have been described in the literature. Squamous cell skin cancer in the context of HIV infection is a dangerous disease. In people living with HIV, it manifests at a significantly earlier age and is associated with a high risk of local recurrence. The extent of invasion and the likelihood of metastasis are influenced by HIV-associated immunodeficiency. In the vast majority of cases, risk factors and clinical manifestations of basal cell skin cancer do not differ from those in immunocompetent individuals. Basal cell carcinomas rarely metastasise. Nevertheless, metastatic forms lead to unfavourable outcome. Here is a photo gallery of cases of neoplastic skin lesions developed in HIV-positive patients.

Comment on ‘Efficacy of interventions for cutaneous squamous cell carcinoma in situ (Bowen's disease): A systematic review and meta‐analysis of proportions’

Comment on ‘Efficacy of interventions for cutaneous squamous cell carcinoma in situ (Bowen's disease): A systematic review and meta‐analysis of proportions’

Multimodal contrastive learning for spatial gene expression prediction using histology images.

In recent years, the advent of spatial transcriptomics (ST) technology has unlocked unprecedented opportunities for delving into the complexities of gene expression patterns within intricate biological systems. Despite its transformative potential, the prohibitive cost of ST technology remains a significant barrier to its widespread adoption in large-scale studies. An alternative, more cost-effective strategy involves employing artificial intelligence to predict gene expression levels using readily accessible whole-slide images stained with Hematoxylin and Eosin (H&E). However, existing methods have yet to fully capitalize on multimodal information provided by H&E images and ST data with spatial location. In this paper, we propose mclSTExp, a multimodal contrastive learning with Transformer and Densenet-121 encoder for Spatial Transcriptomics Expression prediction. We conceptualize each spot as a "word", integrating its intrinsic features with spatial context through the self-attention mechanism of a Transformer encoder. This integration is further enriched by incorporating image features via contrastive learning, thereby enhancing the predictive capability of our model. We conducted an extensive evaluation of highly variable genes in two breast cancer datasets and a skin squamous cell carcinoma dataset, and the results demonstrate that mclSTExp exhibits superior performance in predicting spatial gene expression. Moreover, mclSTExp has shown promise in interpreting cancer-specific overexpressed genes, elucidating immune-related genes, and identifying specialized spatial domains annotated by pathologists. Our source code is available at https://github.com/shizhiceng/mclSTExp.

Novel copper complex inhibits the proteasome in skin squamous cell carcinoma induced by DMBA in mice

The proteasomal system is becoming a target for the treatment of several diseases, especially in cancer therapy. The present study aims to develop a novel copper complex that inhibits the proteasome in skin squamous cell carcinoma. New molecules based on the copper complex were synthesized for the first time to assess their potential as proteasome inhibitors, specifically targeting squamous cell carcinoma induced by 7,12-dimethylbenz(a)anthracene (DMBA) in mouse models. Fourier Transform Infrared (FTIR), X-ray diffraction (XRD), scanning electron microscopy (SEM), nuclear magnetic resonance (NMR), and energy dispersive X-ray analysis (EDX) were carried out to characterize this new copper complex. Notably, the presence of a papilloma (skin tumor) was confirmed by histopathological analysis. Subsequent investigation included the quantification of proteasome levels using a sandwich ELISA test, and the catalytic activity of the 20S proteasome was determined by measuring the fluorescence emitted after the cleavage of 7-amino-4-methylcoumarin (AMC). Hence, X-ray crystallography indicates that all Cu atoms are five-coordinated in a square-pyramidal configuration and biological activity of copper Schiff base complex, which exhibits high proteasome inhibitory activities with particular selectivity of β5 subunit. The pharmacokinetic properties (ADMET) of the copper complex named Cu(L1) showed encouraging results with very low toxicity, distribution, and absorption. Structure–activity relationship (SAR) information obtained from Cu(L1) demonstrated its selectivity and potent inhibition for β5 subunit. In this regard, this copper complex has emerged as a novel therapy for skin cancer.

Photodynamic therapy in dermatology: established and new indications.

Photodynamic therapy (PDT) is internationally established as an approved treatment option for in situ forms of keratinocytic skin cancer (actinic keratoses, Bowen's disease, basal cell carcinoma). For these indications, there are standardized treatment protocols using narrow-spectrum light sources or (artificial) daylight, the use of which is associated with successful healing, a low rate of lesion recurrence, and a very good cosmetic result. Daylight PDT is superior to conventional PDT in terms of significantly less pain and associated higher patient acceptance. Newer indications, for which no approval has yet been granted, but which nevertheless have sufficient evidence of efficacy according to the study situation, are inflammatory (lichen sclerosus, acne) and infectious dermatoses (viral warts, cutaneous leishmaniasis, atypical mycobacteriosis). In addition, PDT is increasingly being used in aesthetic dermatology with the aim of skin rejuvenation.

53021 Clinical Characteristics of Invasive Squamous Cell Carcinoma in Skin of Color Patients

53021 Clinical Characteristics of Invasive Squamous Cell Carcinoma in Skin of Color Patients

Arsenical keratosis in China: A case report and review of the literature.

Arsenical keratosis is a precancerous dermatosis which could be induced by long-term exposure to arsenic poisoning. Arsenic is often added to traditional Chinese medicine in a non-compliant manner to increase the effectiveness of psoriasis treatment, which is often the main cause of arsenic poisoning in Chinese patients with psoriasis. We performed a systemic review of arsenic keratosis during the past 32 years to better understand the sources, treatment, and prognosis of arsenic keratosis in China. We searched Medline/PubMed, Embase, CNKI, and Wanfang databases for research studies published between 1992 and 2024. A total of 64 papers with 78 individual Chinese of arsenical keratosis were included in this analysis. Of the patients included in the analysis, 92.21% of arsenic poisoning was due to iatrogenic factors: Chinese traditional medicine. Seventy-six patients (98.70%) had skin manifestation of hyperkeratotic papules and plaques, 68 patients (88.31%) had hyperpigmentation, 43 cases (55.84%) had hypopigmentation, and only 4 had a clear indication of Mees' lines in nails. A total of 52.63% of patients presented with tumors, including squamous cell carcinoma, Bowen's disease, and basal cell carcinoma. For patients with tumors, 20 opted for surgery, 6 for radiotherapy, and 3 for PDT. All patients with only cutaneous tumors are currently well-controlled. Death occurred in one patient with metastatic squamous cell carcinoma. Keratinizing papules improved significantly in 70.59% of patients treated with Acitretin Capsules. In this study, arsenic sources in Chinese patients were mainly from traditional Chinese medicine, and there were no reports of exposure to water sources or occupational sources in the past 32 years. Most of the patients showed keratinizing papules and pigmentation, and more than 1/2 of the patients showed skin tumors, mainly squamous cell carcinoma. The treatments of tumors are mainly surgical treatment, PDT and radiotherapy can also be selected. The improvement in keratinizing rash was greater than 70% with acitretin capsules. Patients with this disease should be regularly followed up for early detection and timely treatment of potential malignant tumors.