Multiple Skin Cancers Research Articles

Multiple non-melanoma skin cancers during 43-years long therapy with azathioprine in renal transplant recipient

Multiple non-melanoma skin cancers during 43-years long therapy with azathioprine in renal transplant recipient

Minimally Invasive Plasma Device Management of Multiple Benign Skin Cancers Associated with Rare Genodermatoses-Case Series and Review of the Therapeutic Methods.

Background: Non-melanocytic benign skin tumours encompass a diverse group of lesions, classified based on their cellular origin, such as epidermal, vascular, fibrous, neural, muscle, and adnexal tumours. Though they often reveal solitary lesions, multiple skin tumours focus on genodermatoses. Each syndrome exhibits distinct clinical characteristics and potential complications, including cutaneous and extra-cutaneous malignancies, some of which are potentially life-threatening. Diagnosing genetic syndromes is complex and requires numerous histopathological and immunohistochemistry tests due to similarities between the adnexal tumours and basal cell carcinoma upon pathology. Methods: To illustrate the clinical practice, we conducted a retrospective case study that included eleven patients with genodermatoses referred to a tertiary dermatology clinic from September 2018 to April 2024. We have also conducted a research study on available treatment modalities in this setting. Results: Five patients with excellent aesthetic results were treated using a recently approved FDA plasma device. After searching SCOPUS and PubMed database records, we assessed 96 original articles to present current knowledge regarding the dermato-surgical approach. Conclusions: Multiple skin tumours, especially on the face, may significantly affect patients' quality of life and have psychological consequences. An appropriate treatment selection tailored to the patient's needs should be provided. There is no standardised treatment for multiple benign tumours in genodermatoses, and selected methods with varying efficacy are employed. We presented the utility of a new plasma device in these settings.

Analysis of Prevalence, Socioeconomic and Disease Trends of Non-Melanoma Skin Cancer in New Zealand from 2008 to 2022

BackgroundSkin cancer shows geographic and ethnic variation. New Zealand—with a predominantly fair-skinned populations, high UV indices and outdoor lifestyles—has high rates of skin cancer. However, population prevalence data is lacking. This study aimed to determine the demographics and socioeconomic disease trends of non-melanoma skin cancer prevalence in New Zealand from a large targeted-screening study.MethodsA targeted screening programme was conducted among 32,839 individuals, Fitzpatrick Skin Types I to IV in Auckland, New Zealand during the 2008–2022 period. This data was analyzed retrospectively. Linear regression models were used to assess statistical trends of skin cancer prevalence over time, along with associated factors that included demographics, disease trends and overall prevalence.ResultsA total of 32,839 individuals were screened and 11,625 skin cancers were detected. 16,784 individuals were females who had 4,378 skin cancers. 16,055 individuals were males who had 5,777 skin cancers. 54 males and 65 females had multiple skin cancers. The article presents detailed descriptions of tumour types and subtypes detected, age groups, demographic and socioeconomic information. regarding the non-melanoma skin cancers detected.ConclusionOverall men have more non-melanoma skin cancer (NMSC) than females; however females develop more BCC on the lips. BCC is three times more common in the 31-50 age group, whereas SCC are significantly more prevalent after age 80. Prevalence of BCC has not changed over the 15-year timeframe of the study but SCC has increased. Older ages and higher incomes are associated with higher rates of NMSC in New Zealand.

Surgical treatment of extensive and multiple skin cancers via excision and reconstruction using multiple flaps: a case report

A 47-year-old male patient presented with multiple squamous and basal cell carcinomas on the anterior chest, back, and left cheek. The patient experienced odorous discharge from the tumors. Surgical excision was planned, beginning with the anterior chest squamous cell carcinoma. An extensive 32×30 cm cutaneous defect was created, which was covered by a bilateral deep inferior epigastric perforator and pedicled latissimus dorsi myocutaneous flaps. The basal cell carcinomas on the back and squamous cell carcinoma on the left cheek were serially excised, after which the left cheek wound required flap coverage. Postoperative complications such as venous thrombosis and infection led to several reoperations, yet the extensive defect was successfully reconstructed. No local recurrence developed during 31 months of follow-up. We report this case to demonstrate that although the wide excision of very large skin cancers may result in extensive and challenging defects as large as 5.8% of the total body surface area, coverage with appropriate flaps may lead to successful oncologic outcomes and improve the patient’s quality of life.

MICIL: Multiple-Instance Class-Incremental Learning for skin cancer whole slide images

Artificial intelligence (AI) agents encounter the problem of catastrophic forgetting when they are trained in sequentially with new data batches. This issue poses a barrier to the implementation of AI-based models in tasks that involve ongoing evolution, such as cancer prediction. Moreover, whole slide images (WSI) play a crucial role in cancer management, and their automated analysis has become increasingly popular in assisting pathologists during the diagnosis process. Incremental learning (IL) techniques aim to develop algorithms capable of retaining previously acquired information while also acquiring new insights to predict future data. Deep IL techniques need to address the challenges posed by the gigapixel scale of WSIs, which often necessitates the use of multiple instance learning (MIL) frameworks. In this paper, we introduce an IL algorithm tailored for analyzing WSIs within a MIL paradigm. The proposed Multiple Instance Class-Incremental Learning (MICIL) algorithm combines MIL with class-IL for the first time, allowing for the incremental prediction of multiple skin cancer subtypes from WSIs within a class-IL scenario. Our framework incorporates knowledge distillation and data rehearsal, along with a novel embedding-level distillation, aiming to preserve the latent space at the aggregated WSI level. Results demonstrate the algorithm’s effectiveness in addressing the challenge of balancing IL-specific metrics, such as intransigence and forgetting, and solving the plasticity-stability dilemma.

Abstract 6988: TP53RK regulates DNA replication by CDC7-mediated MCM helicase phosphorylation in colorectal cancer

Abstract Background: We identify TP53 regulating kinase (TP53RK), which showed the highest cell growth inhibition efficiency in six colon cancer cell lines. TP53RK is overexpressed in various cancer types, including multiple myeloma and skin cancer, but the mechanism for its tumorigenesis in colon cancer is unknown. Therefore, this study aims to reveal the tumorigenesis mechanism of TP53RK, which is overexpressed in Colorectal Cancer (CRC), through global and phospho-proteomics. Method: A total 5 CRC cell lines (HT29, SW480, HCT116, H508 and CaCO2), colon normal fibroblast CRL1459, HCT116 p53 null cell and patient-derived normal organoid were used. Immunoblotting, MTT assay, Colony formation assay, Annexin-V assay and cell cycle analysis were performed for evaluation of TP53RK loss-of-function. With kinase-substrate enrichment analysis with phospho-proteome analysis, MCM2 was found to be a substrate for the kinase regulated by TP53RK. Results: High-throughput genetic screening approach have been widely applied to the study the gene function and molecular mechanism associated with tumorigenesis. By using genome-wide CRISPR/Cas9 library screening, we identify TP53RK, the first committed negative-selected gene, as a tyrosine kinase in the colorectal cancer(CRC) specific biomarker. Through proteome analysis, we found that depletion of TP53RK can hypo-phosphorylate the DNA helicase complex, MCM2 (minichromosome maintenance protein2). According to previous studies, the phosphorylation of MCM2 is regulated by CDC7 (cell division cycle7), and the abnormal states of CDC7 and MCM2 cause DNA replication disorder. Our results show that TP53RK expression is upregulated in CRC and its depletion results in decreased CDC7 expression and hypo-phosphorylation of the MCM complex. Decreased CDC7 expression due to its instability after TP53RK depletion can lead to DNA replication errors. DNA replication errors can lead cancer cells to apoptosis, suggesting that they may be a strategy for cancer treatment. In summary, we provide TP53RK as a novel prognostic and therapeutic target in CRC. Conclusion: To recapitulate briefly, our findings suggest that the interaction of TP53RK with CDC7 can regulate CDC7 protein stability and stabilized CDC7 can phosphorylate MCM2 to initiate DNA replication. In other words, because overexpression of TP53RK acts as an oncogene that promotes tumor progression in CRC, depletion of TP53RK can degrade CDC7 and induce colon cancer cells to death or regression. Citation Format: Younghee Choi, Ji-won Park, Jun-kyu Kang, Eun-ju Kim, Sang-Hyun Song, Eugene C. Yi, Tae-You Kim. TP53RK regulates DNA replication by CDC7-mediated MCM helicase phosphorylation in colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6988.

Abstract 4484: Discovery of a potential first-in-class Za targeted small molecule inhibitor of ADAR1 p150 which demonstrates strong anti-tumor efficacy

Abstract Background: Adenosine deaminase, RNA specific (ADAR1), catalyzes the hydrolytic deamination of adenosine (A) to inosine (I) in double-stranded (ds) RNAs. ADAR1 has two isoforms: p110 in the nucleus and p150 in the cytoplasm. Both isoforms alter the coding and non-coding sections of self-dsRNA. The ADAR1 p150 isoform is expressed from an interferon (IFN)-response promoter and has a Z-DNA/Z-RNA binding domain at the N-terminus. ADAR1 has been implicated in promoting cell survival and resistance to immune response in several cancer types like multiple myeloma, breast, lung, liver, and skin cancer. Inhibition of ADAR1 p150 has the potential to enhance anti-tumor efficacy as monotherapy and in combination with other therapeutic modalities. The Zα domain of ADAR1 p150 provides exclusivity to p150 compared to the other isoforms. Herein, we outline the discovery of a potential first-in-class Zα targeted ADAR1 p150 inhibitor and degrader for cancer immunotherapy. Methods: AVA-ADR-001 was identified through a high throughput p110 knockout cell-based assay. The ability of AVA-ADR-001 to induce interferons was confirmed in various cell lines. The anti-tumor efficacy of AVA-ADR-001 was evaluated in B16F10 syngeneic melanoma mice model as monotherapy and in combination with anti-PD-1. PROTAC AVA-ADR-703 was used to demonstrate selective degradation of the ADAR1 p150 protein. Results: We have discovered AVA-ADR-001, a novel small molecule inhibitor of ADAR1 which significantly increases the IFN response in vitro in an MDA5-dependent manner. In vitro binding studies confirm that AVA-ADR-001 binds to the Zα domain of ADAR1 with low nM potency. AVA-ADR-001 demonstrates anti-tumor efficacy 1.5X superior to anti-PD1 ICB non-responsive tumor models. In addition, the AVA-ADR-001 monotherapy and combination groups showed a significant upregulation of numerous interferon-stimulated genes, including IFIH1, IFN-β, and CXCL-10. Finally, targeted protein degradation of ADAR1 p150 while sparing ADAR1 p110 was confirmed when cells were treated with AVA-ADR-703 with nM DC50, the PROTAC variant of AVA-ADR-001. Conclusions: To our knowledge, AVA-ADR-001 and AVA-ADR-703 are the first selective Zα-targeted small molecule inhibitor and degrader of ADAR1 p150 respectively to be disclosed. As a powerful and targeted first-in-class ADAR1 inhibitor, AVA-ADR-001 has demonstrated a strong induction of interferon (IFN) in a number of cancer cell lines and in vivo. AVA-ADR-001 has also demonstrated strong in vivo anti-tumor efficacy as monotherapy and in combination with anti-PD1. Furthermore, AVA-ADR-703 demonstrates selective and highly efficient degradation of ADAR1 p150 while sparing ADAR1 p110. Given that ADAR1 has a pro-metastatic and immune-suppressive role, AVA-ADR-001 and AVA-ADR-703 have significant potential to emerge as strong cancer immunotherapy candidates. Citation Format: Avijit Goswami, Sandeep Goyal, Kawaljit Singh, Princy Khurana, Barnali Deb, Aditya Kulkarni. Discovery of a potential first-in-class Za targeted small molecule inhibitor of ADAR1 p150 which demonstrates strong anti-tumor efficacy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4484.

Familial Melanoma Phenotype With Xeroderma Pigmentosum Group C (XP-C) Genotype - The Putative Role of MC1R Polymorphism as Modifier.

Xeroderma pigmentosum (XP), a rare inherited condition, hallmarked by extreme sensitivity to sun exposure resulting in multiple skin cancers and non-malignant skin alterations is attributed to homozygous inactivating pathogenic variants (PVs) in DNA repair genes, predominantly the XPC gene. Report a unique phenotypic expression of mutant XPC allele that may be compatible with a putative modifier role for MC1R polymorphism. A family of 13 siblings, seven of whom were diagnosed with at least one cutaneous melanoma (N = 53) and non-melanoma skin cancers (N = 9) was studied. Of seven melanoma-affected cases, five consented for genetic analysis. CDKN2A revealed no PV in any case and subsequent whole-exome sequencing (WES) identified a rare homozygous missense PV (c.919C>T; p.Arg307Trp) in exon 8 of the XPC gene in all affected individuals. Notably, XPC PV carriers who co-harbored the p.I155T MC1R variant (N = 3) exhibited larger number of tumors, deeper Breslow indexes, higher rates of invasive melanomas and earlier age at diagnosis compared with non MC1R variant carriers (N = 2). Familial malignant melanoma phenotype may, in fact, be an unusual clinical presentation of XPC, and MC1R may be a genetic modifier of penetrance and phenotype of mutant XPC alleles.

MSCDNet-based multi-class classification of skin cancer using dermoscopy images.

Skin cancer is a life-threatening disease, and early detection of skin cancer improves the chances of recovery. Skin cancer detection based on deep learning algorithms has recently grown popular. In this research, a new deep learning-based network model for the multiple skin cancer classification including melanoma, benign keratosis, melanocytic nevi, and basal cell carcinoma is presented. We propose an automatic Multi-class Skin Cancer Detection Network (MSCD-Net) model in this research. The study proposes an efficient semantic segmentation deep learning model "DenseUNet" for skin lesion segmentation. The semantic skin lesions are segmented by using the DenseUNet model with a substantially deeper network and fewer trainable parameters. Some of the most relevant features are selected using Binary Dragonfly Algorithm (BDA). SqueezeNet-based classification can be made in the selected features. The performance of the proposed model is evaluated using the ISIC 2019 dataset. The DenseNet connections and UNet links are used by the proposed DenseUNet segmentation model, which produces low-level features and provides better segmentation results. The performance results of the proposed MSCD-Net model are superior to previous research in terms of effectiveness and efficiency on the standard ISIC 2019 dataset.

Efficient Harris Hawk Optimization (HHO)-Based Framework for Accurate Skin Cancer Prediction

The prediction of skin cancer poses a number of challenges due to the differences in visual characteristics between melanoma, basal cell carcinomas, and squamous cell carcinomas. These visual differences pose difficulties for models in discerning subtle features and patterns accurately. However, a remarkable breakthrough in image analysis using convolutional neural networks (CNNs) has emerged, specifically in the identification of skin cancer from images. Unfortunately, manually designing such neural architectures is prone to errors and consumes substantial time. It has become increasingly popular to design and fine-tune neural networks by using metaheuristic algorithms that are based on natural phenomena. A nature-inspired algorithm is a powerful alternative to traditional algorithms for solving problems, particularly in complex optimization tasks. One such algorithm, the Harris hawk optimization (HHO), has demonstrated promise in automatically identifying the most appropriate solution across a wide range of possibilities, making it suitable for solving complex optimization problems. The purpose of this study is to introduce a novel automated architecture called “HHOForSkin” that combines the power of convolutional neural networks with meta-heuristic optimization techniques. The HHOForSkin framework uses an innovative custom CNN architecture with 26 layers for the analysis of medical images. In addition, a Harris hawk optimization algorithm (HHO) is used to fine-tune the developed model for multiple skin cancer classification problems. The developed model achieves an average accuracy of 99.1% and 98.93% F1 score using a publicly available skin cancer dataset. These results position the developed optimization-based skin cancer detection strategy at the forefront, offering the highest accuracy for seven-class classification problems compared to related works.

Patients’ willingness to accept adverse event and cost tradeoffs from oral nicotinamide for reduced risk of non-melanoma skin cancer

BackgroundNon-immunosuppressed patients with a history of multiple non-melanoma skin cancers (NMSCs) taking oral nicotinamide supplementation experienced a 23% decrease in annual NMSC risk in a randomized clinical trial. Patient preferences for risks and costs associated with nicotinamide are unknown.ObjectivesTo understand how patients prioritize NMSC reduction, infection risk, and cost.MethodsA sample of adults with history of ≥2 NMSC within the past five years undergoing Mohs procedure completed a discrete-choice experiment comprising two hypothetical treatments—characterized by varying reductions in NMSC incidence, increased severe infection risk, and cost—and no treatment. The data were analyzed with random-parameters logit models.ResultsA total of 203 subjects (mean age 71.5 years, 65.5% males) participated. For a 23% annual reduction in NMSC incidence, a 26% [95% CI: 8%–45%] annual increase in severe infection risk and $8 [95% CI: $2–14] monthly cost was acceptable. Outcomes across analyzed subgroups (before vs. during COVID pandemic, site of interview, less vs. more prior NMSCs) were similar.ConclusionsPatients were unwilling to accept high severe infection risks to obtain the reduction in NMSC incidence observed in a nicotinamide trial, suggesting that routinely recommending nicotinamide may run counter to some patients’ preferences.

Squamous cell carcinoma of the skin after cardiac transplantation: a clinical case

Background. Solid organ transplantation recipients have a high risk of non-melanoma skin tumors. Patients after heart transplantation are prone to a higher incidence of malignant skin tumors due to intensive immunosuppressive therapy. The most common histological type is squamous cell carcinoma, followed by basal cell carcinoma. These tumors have a more aggressive clinical course, including the frequency of recurrence and metastasis, and a tendency to multifocal lesions.
 Materials and methods. We present a clinical case of primary multiple squamous cell carcinoma with metastatic lesions of regional lymph nodes in a patient after heart transplantation.
 Results. A 67-year-old patient underwent an orthotopic heart transplant in September 2018 for ischemic cardiomyopathy. Subsequently, triple immunosuppressive therapy was administered, including tacrolimus combined with mycophenolate mofetil and prednisolone. In May 2022, a solid tumor with ulceration occurred on the skin of the right scapular region. After some time, similar tumors appeared on the skin of the temporal region on the left, the posterior surface of the auricle and the parietal region on the left. The patient later found a solid, painless tumor on the left jaw angle. As a part of the examination in the oncology dispensary, a biopsy of the scapular skin tumor, scrapings from tumors, and aspiration biopsy of the submandibular lymph nodes were performed. Histological and cytological studies of all neoplasms showed squamous cell keratinizing cancer with metastases to the submandibular lymph nodes. Additional examination methods showed no signs of progression. The diagnosis was made: primary multiple synchronous skin cancer: right scapular area, stage III, cT3N0M0; left parietal area, stage II, cT2N0M0; occipital area, stage I, cT1N0M0; left auricle, stage IV, cT1N2M0. Considering the localization of tumors, surgical treatment was performed, including of excision of tumors in the scapular and parietal regions. Radiation therapy was performed on lymph nodes with metastases. After 6 months, a tumor recurrence was detected in the irradiation area.
 Conclusion. After heart transplantation, squamous cell carcinoma of the skin is common. Usually, it affects the scalp and neck with metastases to the regional lymph nodes and is prone to recurrence. The primary treatment method is surgical and radiation therapy.

Health utilities and health‐related quality of life of patients with keratinocyte skin cancers

AbstractBackgroundHealth utilities and health‐related quality of life (HRQoL) have not been adequately examined in patients with basal and squamous cell carcinomas (or keratinocyte skin cancers KCs) repeatedly treated for multiple skin cancers and who require ongoing medical surveillance.ObjectivesOur aim was to assess whether health utilities and HRQoL in an Australian population‐based sample of patients recently treated for multiple KCs were poorer compared to patients with single or no KCs.MethodsSelected from the QSkin Study, a cross‐sectional analysis of 680 patients was undertaken involving data linkage of survey and administrative claims data. Health utility was measured using the EuroQol‐5D 5‐level (EQ‐5D‐5L) while HRQoL was assessed using the Basal and Squamous Cell Carcinoma Quality of Life (BaSQoL) instrument. Scores were summarised by sociodemographic and skin cancer profiles and stratified by skin cancer group (i.e., naïve or zero, single, multiple KCs). Generalised linear models with Poisson family and log link functions were used for multivariate analyses.ResultsThe mean EQ‐5D‐5L score was slightly worse for people with multiple KCs (mean: 0.88, SD: 0.14) versus single KCs (mean: 0.90, SD: 0.16) versus none (mean: 0.91, SD: 0.11). Mean scores were not significantly different across skin cancer group after adjustment for number of comorbidities and self‐reported health. BaSQoL domain scores indicated having KCs had little impact on quality of life with mean total scores ranging from 0.27 for the ‘appearance’ domain to 1.15 for the ‘other people’ domain out of a maximum (worst) score of 3.ConclusionsEven among persons chronically afflicted with multiple KCs and ongoing surgical and nonsurgical treatments, health utility and HRQoL losses were minimal and similar to those people without KCs.

Cancer risks in a population-based study of agricultural workers: results from the Taiwan's Farmers and Health Cohort study.

The purpose of this study was to assess cancer risk among agricultural workers compared to the general population. The study utilized data from Farmers' Health Insurance (FHI) in Taiwan, which enrolled agricultural workers (N=1 175 149). The enrolled workers were matched to a general population (N=1 175 149) of the same age, gender, township, and enrollment year. The study population was linked to the National Cancer Registry to identify new cancer cases between 2000 and 2018. The Cox proportional hazards model was used to estimate the hazard ratio and 95% confidence interval for outcomes. During the study period, 136 913 new cancers among agricultural workers were identified. The study found that male farmers had an increased cancer risk, including lymphocytic leukemia, chronic myelogenous leukemia, non-Hodgkin's lymphoma (NHL), oral cancer, lip cancer, esophagus cancer, rectum and rectosigmoid junction cancer, liver and intrahepatic bile duct cancer, lung cancer, trachea and bronchi cancer, and other non-melanoma skin cancer, even when considering the latency period. Female farmers had an elevated risk of multiple myeloma and other non-melanoma skin cancer. Moreover, only lymphoma, NHL, other lymphoid, and multiple myeloma, were both found to occur at different insurance periods. This study provides farmer cancer patterns and risk, adding to the evidence that farmers are at increased risk of certain types of cancer, especially for hematological cancers. As exposure varies by farm operation type, individual farmer exposure may vary widely. Further understanding of the complex relationship between occupational exposure, environmental factors, and lifestyle factors is needed.

Temporal correlation between the first melanoma and the first noncutaneous tumor in CKDN2A genotyped patients.

CDKN2A pathogenic variants are well known to be associated with cutaneous melanoma and noncutaneous tumors (NCTs). Herein, we investigated the temporal correlation between the first cutaneous melanoma and NCT both in CDKN2A mutation carriers (MUT) and in wild-type melanoma patients, a poorly explored issue to date. Two hundred forty-five cutaneous melanoma patients were genotyped for the CDKN2A gene and divided into 51 MUT and 189 wild-type; the remaining five variant carriers were excluded from the analyses. MUT developed a significantly higher number of cutaneous melanoma than wild-type, while 13.7% in both genotyped groups received a diagnosis of at least one malignant NCT, without statistically significant differences. The onset of the first cutaneous melanoma preceded that of the first malignant or benign NCT in both MUT and wild-type patients by an average of 4.5 and 3.02 years, respectively. Considering only malignant tumors, the diagnosis of melanoma preceded that of the first NCT on an average of 8 and 4.34 years, in MUT and wild-type patients respectively. We emphasize the relevance to adopt a global vision for the primary and secondary surveillance of patients affected by cutaneous melanoma, not only limited to high-risk for multiple primary skin cancers but also to NCT that may develop several years after the diagnosis of the first cutaneous melanoma.

Abstract 5885: A pathway-centric approach to characterising tumour heterogeneity and cell diversity across multiple cancer types

Abstract Biological tissues are composed of heterogeneous populations intricately organized in 3D architectures, yet cell type composition and spatial organization remain largely unknown for most tissue types. Single-cell sequencing analysis provides a systematic and quantitative approach to identify cell types and determine their composition in tissues. However, the spatial organization of cells and cell-cell interactions that are critical for tissue function are lost when cells are dissociated from tissue. This is especially important when working with the complex microenvironment of a tumour where such information is needed to fully understand patient prognosis. Complex diseases such as cancer can be better understood from the perspective of dysregulated pathways, rather than as a disease resulting from alterations of individual genes. Recently, spatially resolved, single-cell imaging platforms have provided a necessary solution to bridge the spatial information gap evident in previous transcriptomic methodologies. Vizgen’s MERSCOPE platform, built on multiplexed error robust in situ hybridisation (MERFISH) technology, enables the direct profiling of the spatial organisation of intact tissue with subcellular resolution. Here, we present a Pan-Cancer approach to characterise various cancers in human clinical samples with MERSCOPE. Using a 500-gene panel that includes the canonical signalling pathways of cancer, cancer type-specific genes, key immune genes, proto-oncogenes, and tumour-suppressor genes we demonstrate MERSCOPE’s ability to spatially profile gene expression across multiple tumour samples, including breast, colon, prostate, ovarian, lung, and skin cancer. To confirm the specificity and sensitivity of our pathway-focused gene panel, we assessed how tumour cell clusters in each dataset expressed different cancer type-specific markers. As expected, we found specific cancer types enriched in corresponding marker genes. To further evaluate how individual cell types in each tumour are dysregulated by cancer, we compared non-tumour cell clusters to similarly annotated clusters derived from single-cell RNA-sequencing data of normal tissue. Notably, the non-tumour cells in these datasets exhibit higher expression of stress and inflammation pathways, while immune cell clusters demonstrate higher immune activity and higher immune exhaustion compared to those in normal tissue. These results demonstrate the power of the MERSCOPE platform to generate individualised, accurate cell atlases from patient-derived tumours and to enable further insights into the relationship between genomic profiles, dysregulated pathways, and disease phenotype. Such network-centric approaches are critical for identifying genotypic causes of diseases, classifying disease subtypes, and identifying drug targets. Citation Format: Leiam Colbert, Benjamin Patterson, Cheng Yi Chen, Nicolas Fernandez, Jiang He. A pathway-centric approach to characterising tumour heterogeneity and cell diversity across multiple cancer types [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5885.

Abstract 3095: Development of a novel ADAR1 inhibitor as a potent immunomodulator for the treatment of solid tumors

Abstract Background: Adenosine deaminase, RNA specific (ADAR1), catalyzes the hydrolytic deamination of adenosine (A) to inosine (I) in double-stranded (ds) RNAs. There are 2 isoforms of ADAR1 (p110 in the nucleus; p150 in cytoplasm) and both modify self dsRNA in coding and non-coding regions​. The ADAR1 p150 isoform is expressed from an interferon (IFN)-response promoter and has a Z-DNA/Z-RNA binding domain at the N-terminus. ADAR1 p150 edits 3′-untranslated region dsRNAs comprising of inverted Alu repeats and thereby suppresses MDA5-MAVS-IFN signaling. ADAR1 is commonly overexpressed in multiple myeloma, breast, lung, liver, skin and esophageal cancer where it promotes cancer progression. Inhibition of ADAR1 has promising anti-tumor efficacy as monotherapy and in combination with checkpoint inhibitors, radiotherapy and chemotherapeutic modalities. Herein, we outline the discovery of a potential first-in-class ADAR1 inhibitor for cancer immunotherapy. Methods: AVA-ADR-001 was identified through a high throughput p110 knockout cell-based assay. The ability of AVA-ADR-001 to induce interferons was confirmed in various cell lines like A549 p110 KO, HCT116 and B16F10. Finally, the anti-tumor efficacy of AVA-ADR-001 was evaluated in B16F10 syngeneic melanoma mice model as monotherapy and in combination with anti-PD-1. Results: We have identified a first-in-class small molecule inhibitor of ADAR1, which shows significant IFN response in vitro in an MDA5 dependent manner. In vitro binding studies have confirmed direct binding of AVA-ADR-001 with the Zα domain of ADAR1 thus confirming its selectivity to the p150 isoform. AVA-ADR-001 demonstrates micromolar EC50 and anti-tumor efficacy against B16F10 melanoma syngeneic mouse model. 100 µg of AVA-ADR-001 treatment resulted in 45% tumor growth inhibition (TGI), 1.5x superior to Anti-PD1 treatment. Combining AVA-ADR-001 with Anti-PD1 demonstrated a synergistic effect 2x superior to Anti-PD1 alone. Additionally, several interferon stimulated genes like IFIH1, IFN-β and CXCL-10 were significantly upregulated in the tumor samples of the AVA-ADR-001 monotherapy and combination groups. Conclusions: To our knowledge no selective small molecule inhibitors of ADAR1 have been reported so far and AVA-ADR-001 is the first disclosure of such an inhibitor. AVA-ADR-001 is a potent and selective first-in-class ADAR1 inhibitor which has shown significant IFN induction in various cancer cell lines and in vivo in the tumor microenvironment resulting in substantial tumor growth inhibition as monotherapy and synergistically in combination with Anti-PD1. Considering the immune-suppressive and pro-metastatic role of ADAR1, AVA-ADR-001 serves as a promising starting point for novel ADAR1 inhibitors as therapeutic modalities in cancer immunotherapy. Keywords: Cancer immunotherapy, small molecule inhibitors, ADAR1, innate immunity Citation Format: Aditya Kulkarni, Avijit Goswami, Sandeep Goyal, Kawaljit Singh, Princy Khurana, Ishani Ghoshal. Development of a novel ADAR1 inhibitor as a potent immunomodulator for the treatment of solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3095.

Actinic keratosis as a predictor of primary multiple synchronous squamous cell skin cancer: a clinical case

We present a clinical case of a primary multiple synchronous highly differentiated keratinizing squamous cell skin cancer in an 84-year old patient with multiple actinic keratosis and actinic cheilitis. The clinical case is unique for the simultaneous development of primary multiple squamous cell carcinoma of the tip of the nose and the vermilion zone of the lower lip in a patient with a past occupational and solar burden, a light phenotype, and signs of chronic photo injury the skin. Clinical, dermatoscopic and sonographic signs of keratotic actinic keratosis were identified in the patient and confirmed by pathomorphological examination. The risk factors for malignant transformation of actinic keratosis were found, such as multiple efflorescences and a long disease history. The malignant transformation of the actinic areas manifested as rapidly progressive ulceration zones more than 1 cm in diameter, pronounced hyperkeratosis, inflammation and infiltration of the underlying tissues, increased bleeding and pain. It is to be underlined that definitive and differential diagnosis requires pathomorphological assessment of the skin biopsy sample. This clinical case indicates that patients with multiple foci of actinic keratosis should be under a lifelong follow-up by dermatovenereologists, with mandatory treatment and prevention measure.

Risk Factors Associated With First and Second Primary Melanomas in a High-Incidence Population

An increasing number of people develop more than 1 primary melanoma, yet to date, no population-based prospective cohort studies have reported on risk factors for developing first vs second primary melanomas. To compare the clinical characteristics of first and second melanomas and then to estimate the relative risks of developing 1 vs multiple melanomas associated with demographic, phenotypic, sun exposure, and genetic factors. This population-based prospective cohort study included men and women aged 40 to 69 years recruited in 2011 and followed up until December 2018 in Queensland, Australia. Data analysis was performed from February to July 2022. Self-reported information about demographic, phenotypic, and sun exposure measures captured using a survey completed at baseline, and polygenic risk score for melanoma. Incident first or second primary melanoma diagnosis, and histologic and clinical characteristics thereof. The Wei-Lin-Weissfeld model for recurrent events was used to estimate the association of each factor with the risks of first and second primary melanoma. A total of 38 845 patients (mean [SD] age at baseline, 56.1 [8.2] years; 17 775 men and 21 070 women) were included in the study. During a median follow-up period of 7.4 years, 1212 (3.1%) participants had a single primary melanoma diagnosis, and 245 (0.6%) had a second primary melanoma diagnosis. Second melanomas were more likely than first melanomas to be in situ; for invasive tumors, second melanomas were more likely to be thin (ie, ≤1 mm) than first melanomas. Having many moles at age 21 years (self-reported using visual scoring tool) was more strongly associated with second (hazard ratio [HR], 6.36; 95% CI, 3.77-10.75) than first primary melanoma (HR, 3.46; 95% CI, 2.72-4.40) (P value for difference between the HRs = .01). A high genetic predisposition (ie, polygenic risk score in tertile 3) was also more strongly associated with second (HR, 3.28; 95% CI, 2.06-5.23) than first melanoma (HR, 2.06; 95% CI, 1.71-2.49; P = .03). Second melanomas were more strongly associated with a history of multiple skin cancer excisions (HR, 2.63; 95% CI, 1.80-3.83) than first melanomas (HR, 1.86; 95% CI, 1.61-2.16; P = .05). For all other phenotypic characteristics and sun exposure measures, similarly elevated associations with first vs second melanomas were observed. Findings of this cohort study suggest that within the general population, the presence of many nevi and having a high genetic predisposition to melanoma were associated with the highest risks of developing second primary melanomas.

Eruptive Non-melanoma Skin Cancers/Squamous Atypia Following Skin Surgery. Report of Two New Cases, Concise Review of the Literature With Special Emphasis on Treatment Options.

Eruptive cutaneous squamous cell carcinomas (ESCC), eruptive squamous atypia (ESA) and eruptive keratoacanthomas (EKA) are different terms used to describe the occurrence of multiple cutaneous squamous neoplasms after skin surgery, laser treatment, traumas, such as tattoos, and local or systemic medical treatments. ESCC have been reported to arise at the sites of skin surgery, including the area affected by the primary tumor and split thickness skin graft (STSG) donor and recipient sites. The aim of this study is to report 2 additional cases of ESCC after skin surgery and make a critical revision of the literature, analyzing the clinical, histological features and outcomes of ESCC after cutaneous surgery. Up to August 2021, according to our systematic review of the literature, we have collected 19 published articles and a total of 34 patients, including our 2 cases. The results of this review highlight five red flags that clinicians should consider: (i) lower and upper limbs represent the cutaneous site with the highest risk, representing 83,78% of the cases in the literature; (ii) the median time to onset of ESCC is approximately 6 weeks; (iii) primary cutaneous squamous cell carcinomas were completely excised with free margins on histologic examination in the totality of the cases of the literature, and therefore ESCC should not be considered recurrences; (iv) any surgical technique involves a risk to promote ESCC; (v) treatment of ESCC includes medical treatment, surgery or combined surgical and medical treatment. This review highlights 5 red flags which could support clinicians in the diagnosis and management of ESCC after skin surgery.