G protein-coupled estrogen receptor 1 and collagen XVII endodomain expression in human cutaneous melanomas: can they serve as prognostic factors?

Melanoma incidence is increasing globally. Although novel therapies have improved the survival of primary melanoma patients over the past decade, the overall survival rate for metastatic melanoma remains low. In addition to traditional prognostic factors such as Breslow thickness, ulceration, and mitotic rate, novel genetic and molecular markers have been investigated. In our study, we analyzed the expression of G-protein coupled estrogen receptor 1 (GPER1) and the endodomain of collagen XVII (COL17) in relation to clinicopathological factors in primary cutaneous melanomas with known lymph node status in both sexes, using immunohistochemistry. We found, that GPER1 expression correlated with favorable clinicopathological factors, including lower Breslow thickness, lower mitotic rate and absence of ulceration. In contrast, COL17 expression was associated with poor prognostic features, such as higher tumor thickness, higher mitotic rate, presence of ulceration and presence of regression. Melanomas positive for both GPER1 and COL17 had significantly lower mean Breslow thickness and mitotic rate compared to cases positive for COL17 only. Our data indicate that GPER1 and COL17 proteins may be of potential prognostic value in primary cutaneous melanomas.

Predicting immune checkpoint therapy response in three independent metastatic melanoma cohorts.

Introduction: While Immune checkpoint inhibition (ICI) therapy shows significant efficacy in metastatic melanoma, only about 50% respond, lacking reliable predictive methods. We introduce a panel of six proteins aimed at predicting response to ICI therapy. Methods: Evaluating previously reported proteins in two untreated melanoma cohorts, we used a published predictive model (EaSIeR score) to identify potential proteins distinguishing responders and non-responders. Results: Six proteins initially identified in the ICI cohort correlated with predicted response in the untreated cohort. Additionally, three proteins correlated with patient survival, both at the protein, and at the transcript levels, in an independent immunotherapy treated cohort. Discussion: Our study identifies predictive biomarkers across three melanoma cohorts, suggesting their use in therapeutic decision-making.

Predicting immune checkpoint therapy response in three independent metastatic melanoma cohorts.

While Immune checkpoint inhibition (ICI) therapy shows significant efficacy in metastatic melanoma, only about 50% respond, lacking reliable predictive methods. We introduce a panel of six proteins aimed at predicting response to ICI therapy. Evaluating previously reported proteins in two untreated melanoma cohorts, we used a published predictive model (EaSIeR score) to identify potential proteins distinguishing responders and non-responders. Six proteins initially identified in the ICI cohort correlated with predicted response in the untreated cohort. Additionally, three proteins correlated with patient survival, both at the protein, and at the transcript levels, in an independent immunotherapy treated cohort. Our study identifies predictive biomarkers across three melanoma cohorts, suggesting their use in therapeutic decision-making.

Consensus statement on the diagnosis and treatment of sclerosing diseases of the skin, Part 2: Scleromyxoedema and scleroedema.

The term 'sclerosing diseases of the skin' comprises specific dermatological entities, which have fibrotic changes of the skin in common. These diseases mostly manifest in different clinical subtypes according to cutaneous and extracutaneous involvement and can sometimes be difficult to distinguish from each other. The present consensus provides an update to the 2017 European Dermatology Forum Guidelines, focusing on characteristic clinical and histopathological features, diagnostic scores and the serum autoantibodies most useful for differential diagnosis. In addition, updated strategies for the first- and advanced-line therapy of sclerosing skin diseases are addressed in detail. Part 2 of this consensus provides clinicians with an overview of the diagnosis and treatment of scleromyxoedema and scleroedema (of Buschke).

Identifying Ferroptosis Inducers, HDAC, and RTK Inhibitor Sensitivity in Melanoma Subtypes through Unbiased Drug Target Prediction.

The utilization of PD1 and CTLA4 inhibitors has revolutionized the treatment of malignant melanoma (MM). However, resistance to targeted and immune-checkpoint-based therapies still poses a significant problem. Here we mine large scale MM proteogenomic data integrating it with MM cell line dependency screen, and drug sensitivity data to identify druggable targets and forecast treatment efficacy and resistance. Leveraging protein profiles from established MM subtypes and molecular structures of 82 cancer treatment drugs, we identified nine candidate hub proteins, mTOR, FYN, PIK3CB, EGFR, MAPK3, MAP4K1, MAP2K1, SRC and AKT1, across five distinct MM subtypes. These proteins serve as potential drug targets applicable to one or multiple MM subtypes. By analyzing transcriptomic data from 48 publicly accessible melanoma cell lines sourced from Achilles and CRISPR dependency screens, we forecasted 162 potentially targetable genes. We also identified genetic resistance in 260 genes across at least one melanoma subtype. In addition, we employed publicly available compound sensitivity data (Cancer Therapeutics Response Portal, CTRPv2) on the cell lines to assess the correlation of compound effectiveness within each subtype. We have identified 20 compounds exhibiting potential drug impact in at least one melanoma subtype. Remarkably, employing this unbiased approach, we have uncovered compounds targeting ferroptosis, that demonstrate a striking 30x fold difference in sensitivity among different subtypes. This implies that the proteogenomic classification of melanoma has the potential to predict sensitivity to ferroptosis compounds. Our results suggest innovative and novel therapeutic strategies by stratifying melanoma samples through proteomic profiling, offering a spectrum of novel therapeutic interventions and prospects for combination therapy. Highlights: (1) Proteogenomic subtype classification can define the landscape of genetic dependencies in melanoma (2) Nine proteins from molecular subtypes were identified as potential drug targets for specified MM patients (3) 20 compounds identified that show potential effectiveness in at least one melanoma subtype (4) Proteogenomics can predict specific ferroptosis inducers, HDAC, and RTK Inhibitor sensitivity in melanoma subtypes.

Targeting Melanoma-Associated Fibroblasts (MAFs) with Activated γδ (Vδ2) T Cells: An In Vitro Cytotoxicity Model.

The tumor microenvironment (TME) has gained considerable scientific attention by playing a role in immunosuppression and tumorigenesis. Besides tumor cells, TME is composed of various other cell types, including cancer-associated fibroblasts (CAFs or MAFs when referring to melanoma-derived CAFs) and tumor-infiltrating lymphocytes (TILs), a subpopulation of which is labeled as γδ T cells. Since the current anti-cancer therapies using γδ T cells in various cancers have exhibited mixed treatment responses, to better understand the γδ T cell biology in melanoma, our research group aimed to investigate whether activated γδ T cells are capable of killing MAFs. To answer this question, we set up an in vitro platform using freshly isolated Vδ2-type γδ T cells and cultured MAFs that were biobanked from our melanoma patients. This study proved that the addition of zoledronic acid (1-2.5 µM) to the γδ T cells was necessary to drive MAFs into apoptosis. The MAF cytotoxicity of γδ T cells was further enhanced by using the stimulatory clone 20.1 of anti-BTN3A1 antibody but was reduced when anti-TCR γδ or anti-BTN2A1 antibodies were used. Since the administration of zoledronic acid is safe and tolerable in humans, our results provide further data for future clinical studies on the treatment of melanoma.

Cutaneous malignancies in patients with Parkinson's disease at a dermato-oncological university centre in Hungary.

Background: The possible correlation between melanoma and Parkinson's disease (PD) has been intensively studied. In this work, we aimed to assess the coincidence of skin malignancies and PD at a dermato-oncological university centre in Central-Eastern Europe, Hungary. Methods: From 2004 to 2017, a retrospective analysis of the centre's database was performed based on International Statistical Classification of Diseases-10 codes. Results: Out of the patients who visited the clinic during the study period, 20,658 were treated for malignant skin tumours. Over the 14 years, 205 dermatological patients had PD simultaneously, 111 (54%) of whom had at least one type of skin malignancy: melanoma (n=22), basal cell carcinoma (BCC) (n=82), or squamous cell carcinoma (SCC) (n=36) (in some patients, multiple skin tumours were identified). Compared to the age- and sex-matched control group, patients with PD had a significantly lower risk for basal cell carcinoma (OR, 0.65; 95% CI, 0.47-0.89, p=0.0076) and for all skin tumours (OR, 0.74; 95% CI, 0.56-0.98, p=0.0392) but not for melanoma. Conclusions: We found a decreased risk of all skin tumours and basal cell carcinoma and an unchanged risk of melanoma among patients with PD. However, it should be kept in mind that some large-scale meta-analyses suggest a higher incidence of melanoma after a diagnosis of PD, indicating the importance of skin examination in this vulnerable population.

The Driverless Triple-Wild-Type (BRAF, RAS, KIT) Cutaneous Melanoma: Whole Genome Sequencing Discoveries.

The genetic makeup of the triple-wild-type melanoma (BRAF, NRAS and NF1) has been known for some time, but those studies grouped together rare histopathological versions with common ones, as well as mucosal and even uveal ones. Here we used whole genome sequencing to genetically characterize the triple-wild-type melanoma (TWM), termed here as BRAF, RAS and KIT wild type (the most frequent oncogenic drivers of skin melanoma), using the most common histological forms and excluding rare ones. All these tumors except one were clearly induced by UV based on the mutational signature. The tumor mutational burden was low in TWM, except in the NF1 mutant forms, and a relatively high frequency of elevated LOH scores suggested frequent homologue recombination deficiency, but this was only confirmed by the mutation signature in one case. Furthermore, all these TWMs were microsatellite-stabile. In this driverless setting, we revealed rare oncogenic drivers known from melanoma or other cancer types and identified rare actionable tyrosine kinase mutations in NTRK1, RET and VEGFR1. Mutations of TWM identified genes involved in antitumor immunity (negative and positive predictors of immunotherapy), Ca++ and BMP signaling. The two regressed melanomas of this cohort shared a 17-gene mutation signature, containing genes involved in antitumor immunity and several cell surface receptors. Even with this comprehensive genomic approach, a few cases remained driverless, suggesting that unrecognized drivers are hiding among passenger mutations.

Differences in the detection of circulating Hsp90 alpha between patients with atopic dermatitis and dermatitis herpetiformis.

Heat shock protein 90 alpha (Hsp90α) is one of the key intra- and extracellular chaperones responsible for the biological activity of various signaling molecules that are involved in (auto)immune-mediated inflammatory diseases. Recent epidemiologic data suggest that patients with atopic dermatitis (AD) are at risk for several autoimmune diseases, including dermatitis herpetiformis (DH), an extraintestinal manifestation of celiac disease (CD). In addition, pruritic diseases such as AD may be confused clinically with DH. In this study, we aimed to determine the role of circulating Hsp90α in patients with AD in relation to patients with DH, CD, and healthy controls. Using an enzyme-linked immunosorbent assay, levels of circulating Hsp90α were determined in serum samples derived from patients with AD (n = 31), DH (n = 26), CD (n = 15), and healthy controls (n = 55). Although serum concentrations of Hsp90α were similar between patients with DH, CD, and healthy controls, we found that serum levels of Hsp90α were significantly higher (mean value of 5.08-fold; p < 0.0001) in patients with AD when compared to patients with DH. A cutoff value calculated as 2 × standard deviation above the mean concentration of Hsp90α in DH patients revealed that 83.9% (26/31) of AD patients were Hsp90α positive, whereas none of the DH patients (0/26) displayed such a positivity. This preliminary study suggests a distinct role for extracellular Hsp90α in the pathogenesis of AD compared to DH and its potential use in distinguishing AD from DH. Nevertheless, the potential role of the evaluation of extracellular Hsp90α for distinguishing between AD and DH is at present speculative and requires further and careful observations.

Ocular paraneoplastic pemphigoid / Szemészeti érintettséggel járó paraneoplasiás pemphigoid

Paraneoplastic mucous membrane pemphigoid, a rare pemphigoid variant is associated with primary malignancy, and characterised by fulminant progression and frequent ineffectivity of classical systemic immunosuppression. In this paper, the clinical features, diagnostic and therapeutical challenges are presented through three cases. Detailed history and analysis of the immunofluorescent samples help the diagnosis. The therapeutic goal is to prevent the progression with systemic immunosuppressive treatment, which can be contraindicated during the ongoing oncological therapy. In absence of consent in the exact diagnostic criteria and management protocol of this rare condition, consultation with other specialists (ophthalmologist, dermatologist, dentist, ear-nose-throat specialist, immunologist) has high importance in early diagnosis and treatment.

Mesenchymal-Stromal Cell-like Melanoma-Associated Fibroblasts Increase IL-10 Production by Macrophages in a Cyclooxygenase/Indoleamine 2,3-Dioxygenase-Dependent Manner.

Melanoma-associated fibroblasts (MAFs) are integral parts of melanoma, providing a protective network for melanoma cells. The phenotypical and functional similarities between MAFs and mesenchymal stromal cells (MSCs) prompted us to investigate if, similarly to MSCs, MAFs are capable of modulating macrophage functions. Using immunohistochemistry, we showed that MAFs and macrophages are in intimate contact within the tumor stroma. We then demonstrated that MAFs indeed are potent inducers of IL-10 production in various macrophage types in vitro, and this process is greatly augmented by the presence of treatment-naïve and chemotherapy-treated melanoma cells. MAFs derived from thick melanomas appear to be more immunosuppressive than those cultured from thin melanomas. The IL-10 increasing effect is mediated, at least in part, by cyclooxygenase and indoleamine 2,3-dioxygenase. Our data indicate that MAF-induced IL-10 production in macrophages may contribute to melanoma aggressiveness, and targeting the cyclooxygenase and indoleamine 2,3-dioxygenase pathways may abolish MAF-macrophage interactions.

Mapping the Melanoma Plasma Proteome (MPP) Using Single-Shot Proteomics Interfaced with the WiMT Database.

Plasma analysis by mass spectrometry-based proteomics remains a challenge due to its large dynamic range of 10 orders in magnitude. We created a methodology for protein identification known as Wise MS Transfer (WiMT). Melanoma plasma samples from biobank archives were directly analyzed using simple sample preparation. WiMT is based on MS1 features between several MS runs together with custom protein databases for ID generation. This entails a multi-level dynamic protein database with different immunodepletion strategies by applying single-shot proteomics. The highest number of melanoma plasma proteins from undepleted and unfractionated plasma was reported, mapping >1200 proteins from >10,000 protein sequences with confirmed significance scoring. Of these, more than 660 proteins were annotated by WiMT from the resulting ~5800 protein sequences. We could verify 4000 proteins by MS1t analysis from HeLA extracts. The WiMT platform provided an output in which 12 previously well-known candidate markers were identified. We also identified low-abundant proteins with functions related to (i) cell signaling, (ii) immune system regulators, and (iii) proteins regulating folding, sorting, and degradation, as well as (iv) vesicular transport proteins. WiMT holds the potential for use in large-scale screening studies with simple sample preparation, and can lead to the discovery of novel proteins with key melanoma disease functions.

Organ Specific Copy Number Variations in Visceral Metastases of Human Melanoma.

Malignant melanoma is one of the most aggressive skin cancers with high potential of visceral dissemination. Since the information about melanoma genomics is mainly based on primary tumors and lymphatic or skin metastases, an autopsy-based visceral metastasis biobank was established. We used copy number variation arrays (N = 38 samples) to reveal organ specific alterations. Results were partly completed by proteomic analysis. A significant increase of high-copy number gains was found in an organ-specific manner, whereas copy number losses were predominant in brain metastases, including the loss of numerous DNA damage response genes. Amplification of many immune genes was also observed, several of them are novel in melanoma, suggesting that their ectopic expression is possibly underestimated. This "immunogenic mimicry" was exclusive for lung metastasis. We also provided evidence for the possible autocrine activation of c-MET, especially in brain and lung metastases. Furthermore, frequent loss of 9p21 locus in brain metastases may predict higher metastatic potential to this organ. Finally, a significant correlation was observed between BRAF gene copy number and mutant allele frequency, mainly in lung metastases. All of these events may influence therapy efficacy in an organ specific manner, which knowledge may help in alleviating difficulties caused by resistance.

An Observational Study on the Molecular Profiling of Primary Melanomas Reveals a Progression Dependence on Mitochondrial Activation.

Melanoma in advanced stages is one of the most aggressive tumors and the deadliest of skin cancers. To date, the histopathological staging focuses on tumor thickness, and clinical staging is a major estimate of the clinical behavior of primary melanoma. Here we report on an observational study with in-depth molecular profiling at the protein level including post-translational modifications (PTMs) on eleven primary tumors from melanoma patients. Global proteomics, phosphoproteomics, and acetylomics were performed on each sample. We observed an up-regulation of key mitochondrial functions, including the mitochondrial translation machinery and the down-regulation of structural proteins involved in cell adhesion, the cytoskeleton organization, and epidermis development, which dictates the progression of the disease. Additionally, the PTM level pathways related to RNA processing and transport, as well as chromatin organization, were dysregulated in relation to the progression of melanoma. Most of the pathways dysregulated in this cohort were enriched in genes differentially expressed at the transcript level when similar groups are compared or metastasis to primary melanomas. At the genome level, we found significant differences in the mutation profiles between metastatic and primary melanomas. Our findings also highlighted sex-related differences in the molecular profiles. Remarkably, primary melanomas in women showed higher levels of antigen processing and presentation, and activation of the immune system response. Our results provide novel insights, relevant for developing personalized precision treatments for melanoma patients.

The many-faced gluten sensitivity: Gluten-induced autoimmunity from dermatological point of view / A sokarcú gluténérzékenység: gluténindukált autoimmunitás a borgyógyász szemével.

Összefoglaló. A glutén, alimentáris környezeti antigénként, különbözo szervrendszereket érinto autoimmun betegségeket tud kiváltani. A kórképek hátterében a gluténtolerancia veleszületett hiánya vagy az élet során bekövetkezo elvesztése áll. A gluténindukált autoimmun betegségek között a leggyakoribb a coeliakia, melyet különbözo súlyosságú enteropátia jellemez, és melynek a szöveti, 2-es típusú transzglutamináz az autoantigénje. A coeliakia extraintestinalis tünetei között azonban néha olyan bor- és idegrendszeri kórképek jellegzetességei is megtalálhatók, melyek hátterében további transzglutamináz-autoimmunitás kialakulása áll. Idesorolható a hevesen viszketo, polimorf autoimmun borbetegség, a dermatitis herpetiformis (transzglutamináz-3-autoimmunitás) és a centrális és/vagy perifériás neurológiai károsodások egy jellegzetes csoportja (transzglutamináz-6-autoimmunitás). Az indukált autoimmunitás reverzibilis, a szigorúan tartott gluténmentes diéta mellett a coeliakia és a bortünetek elmúlnak, de az idegrendszeri tünetek egy része maradandó. Az elmúlt évtizedben beszámoltak gluténérzékeny, transzglutamináz-6-pozitív, nem coeliakiás (transzglutamináz-2-negatív) betegekrol is. A gluténszenzitivitás sokféle megjelenését ma is erosen kutatják. Fontos a korai felismerés és a kórképek interdiszciplináris szemléletu kezelése. A coeliakia családi szurovizsgálatokkal való korai felismerése és a tünetmentes egyének diétás kezelése is nagy jelentoségu a gluténérzékenység által kiváltott hiányállapotok és a társuló egyéb betegségek kialakulásának megelozésében. Orv Hetil. 2021; 162(28): 1107-1118. Summary. Autoimmune diseases induced by digestion of gluten, an environmental antigen, can affect different organ systems. The diseases develop in individuals with congenital or acquired loss of gluten tolerance for life. Amongst the gluten-induced autoimmune diseases, celiac disease is the most common one, characterized by an enteropathy of varying severity. Here the target autoantigen is tissue (type 2) transglutaminase. While the extraintestinal manifestations of celiac disease are complex, they may include characteristics of certain skin and nervous system disorders that develop due to additional transglutaminase autoimmunities. Such diseases are the severely pruritic, polymorphic autoimmune skin disease, dermatitis herpetiformis due to epidermal (type 3) transglutaminase autoimmunity, and a distinctive group of gluten-sensitive neuropathies with central and/or peripheral neurological involvement caused by type 6 transglutaminase autoimmunity. While the celiac and skin autoimmune diseases gradually get into remission under a strict gluten-free diet, some neurological symptoms may persist. In the last decade, gluten-induced transglutaminase 6 positive but non-celiac (transglutaminase 2 negative) patients were reported. Today, various manifestations of gluten sensitivity are under extensive research. Early detection and interdisciplinary treatment of these disorders are important. Family screenings are of particular relevance in early recognition and dietary treatment of latent disease forms in order to prevent enteropathy-induced, malabsorption-related and other associated co-morbidities. Orv Hetil. 2021; 162(28): 1107-1118.

The Human Melanoma Proteome Atlas-Complementing the melanoma transcriptome.

The MM500 meta-study aims to establish a knowledge basis of the tumor proteome to serve as a complement to genome and transcriptome studies. Somatic mutations and their effect on the transcriptome have been extensively characterized in melanoma. However, the effects of these genetic changes on the proteomic landscape and the impact on cellular processes in melanoma remain poorly understood. In this study, the quantitative mass-spectrometry-based proteomic analysis is interfaced with pathological tumor characterization, and associated with clinical data. The melanoma proteome landscape, obtained by the analysis of 505 well-annotated melanoma tumor samples, is defined based on almost 16 000 proteins, including mutated proteoforms of driver genes. More than 50 million MS/MS spectra were analyzed, resulting in approximately 13,6 million peptide spectrum matches (PSMs). Altogether 13 176 protein-coding genes, represented by 366 172 peptides, in addition to 52 000 phosphorylation sites, and 4 400 acetylation sites were successfully annotated. This data covers 65% and 74% of the predicted and identified human proteome, respectively. A high degree of correlation (Pearson, up to 0.54) with the melanoma transcriptome of the TCGA repository, with an overlap of 12 751 gene products, was found. Mapping of the expressed proteins with quantitation, spatiotemporal localization, mutations, splice isoforms, and PTM variants was proven not to be predicted by genome sequencing alone. The melanoma tumor molecular map was complemented by analysis of blood protein expression, including data on proteins regulated after immunotherapy. By adding these key proteomic pillars, the MM500 study expands the knowledge on melanoma disease.

A Rasch model analysis of two interpretations of 'not relevant' responses on the Dermatology Life Quality Index (DLQI).

PURPOSE: Eight of the ten items of the Dermatology Life Quality Index (DLQI) have a 'not relevant' response (NRR) option. There are two possible ways to interpret NRRs: they may be considered 'not at all' or missing responses. We aim to compare the measurement performance of the DLQI in psoriasis patients when NRRs are scored as '0' (hereafter zero-scoring) and 'missing' (hereafter missing-scoring) using Rasch model analysis. METHODS: Data of 425 patients with psoriasis from two earlier cross-sectional surveys were re-analysed. All patients completed the paper-based Hungarian version of the DLQI. A partial credit model was applied. The following model assumptions and measurement properties were tested: dimensionality, item fit, person reliability, order of response options and differential item functioning (DIF). RESULTS: Principal component analysis of the residuals of the Rasch model confirmed the unidimensional structure of the DLQI. Person separation reliability indices were similar with zero-scoring (0.910) and missing-scoring (0.914) NRRs. With zero-scoring, items 6 (sport), 7 (working/studying) and 9 (sexual difficulties) suffered from item misfit and item-level disordering. With missing-scoring, no misfit was observed and only item 7 was illogically ordered. Six and three items showed DIF for gender and age, respectively, that were reduced to four and three by missing-scoring. CONCLUSIONS: Missing-scoring NRRs resulted in an improved measurement performance of the scale. DLQI scores of patients with at least one vs. no NRRs cannot be directly compared. Our findings provide further empirical support to the DLQI-R scoring modification that treats NRRs as missing and replaces them with the average score of the relevant items.

Melanoma-associated fibroblasts impair CD8+ T cell function and modify expression of immune checkpoint regulators via increased arginase activity.

This study shows that melanoma-associated fibroblasts (MAFs) suppress cytotoxic T lymphocyte (CTL) activity and reveals a pivotal role played by arginase in this phenomenon. MAFs and normal dermal fibroblasts (DFs) were isolated from surgically resected melanomas and identified as Melan-A-/gp100-/FAP+ cells. CTLs of healthy blood donors were activated in the presence of MAF- and DF-conditioned media (CM). Markers of successful CTL activation, cytotoxic degranulation, killing activity and immune checkpoint regulation were evaluated by flow cytometry, ELISPOT, and redirected killing assays. Soluble mediators responsible for MAF-mediated effects were identified by ELISA, flow cytometry, inhibitor assays, and knock-in experiments. In the presence of MAF-CM, activated/non-naïve CTLs displayed dysregulated ERK1/2 and NF-κB signaling, impeded CD69 and granzyme B production, impaired killing activity, and upregulated expression of the negative immune checkpoint receptors TIGIT and BTLA. Compared to DFs, MAFs displayed increased amounts of VISTA and HVEM, a known ligand of BTLA on T cells, increased L-arginase activity and CXCL12 release. Transgenic arginase over-expression further increased, while selective arginase inhibition neutralized MAF-induced TIGIT and BTLA expression on CTLs. Our data indicate that MAF interfere with intracellular CTL signaling via soluble mediators leading to CTL anergy and modify immune checkpoint receptor availability via L-arginine depletion.

Efficiency of long-term high-dose intravenous ascorbic acid therapy in locally advanced basal cell carcinoma - a pilot study.

INTRODUCTION: The anti-cancer properties of high-dose intravenous ascorbic acid have been demonstrated in various malignancies. In our recent study, we tested topically applied ascorbic acid to treat basal cell carcinoma (BCC), and achieved a good clinical response. AIM: Based on these results, we decided to examine the efficacy and tolerability of high-dose intravenous ascorbic acid (IVA) for locally advanced BCC. MATERIAL AND METHODS: In this pilot study, patients diagnosed with locally advanced BCC who were not amenable to radiation, surgical or local therapy (no other treatment option was available at the time) received intravenous ascorbic acid (1-1.8 g/kg), in an outpatient setting, 1-3 times per week for a mean duration of 42 ±23.6 weeks. This therapy was generally well tolerated. RESULTS: Among 4 patients who had a total of 165 (mean: 41 ±51, range: 1-114) skin lesions, 3 patients achieved stable disease and one had progressive disease. There was substantial variability in individual tumor response to therapy. With the aid of two-photon microscopy and second harmonic generation imaging techniques, alterations in collagen structure were observed between tumor nests during IVA therapy. CONCLUSIONS: Our results suggest that IVA is well tolerated in a small group of patients with extensive BCCs. However, in the era of smoothened (Smo) receptor inhibitors, it may only be considered as an adjuvant therapy in treatment-resistant cases.