Tumor Type Research Articles

Abstract A018: Endothelial pyrimidine synthesis deficiency promotes tumor growth

Abstract The tumor microenvironment plays a crucial role in cancer progression and treatment response. Systemically administered metabolic cancer therapies target not only malignant but also stromal cells, including immune cells - the only stromal population previously addressed in this context. However, how such treatments impact other non-malignant cell types in tumors remains poorly understood. Here we show that inhibition of de novo pyrimidine synthesis in endothelial cells accelerates tumor growth and alters tumor immune repertoire. We found that whole-body de novo pyrimidine synthesis deficiency in mice, caused by the inducible whole-body ablation of DHODH, accelerates the growth rate of orthotopic lung tumors. Single-cell transcriptomic analysis of tumor-bearing lungs revealed that DHODH deficiency in the stroma impacts multiple cell populations, including immune and, surprisingly, endothelial cells. To explore the endothelial-specific effects, we generated a mouse model with inducible DHODH deficiency restricted to endothelial cells. The endothelium-specific model recapitulates the accelerated lung tumor growth observed in the whole-body DHODH deficiency model. Single-cell transcriptomics analysis of tumor-bearing lungs in the endothelium-specific model pointed to changes in the immune repertoire, particularly an enrichment of monocytes. We confirmed these results on the protein level using spectral flow cytometry, and we are currently in the process of uncovering the mechanism by which endothelial deficiency of pyrimidine synthesis affects the immune landscape of tumors. Inhibitors of pyrimidine de novo synthesis have been tested in clinical trials but failed due to their low efficiency. Our findings indicate that systemic treatment targeting pyrimidine synthesis may be hampered by its pro-tumorigenic effects in the endothelium, highlighting the unexpected role of endothelial metabolism in this context. Citation Format: Petra Hyrossova, Isidora Milisav, Silvia Novais, Mirko Milosevic, Jakub Rohlena, Katerina Rohlenova. Endothelial pyrimidine synthesis deficiency promotes tumor growth [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 A018.

Abstract PR012: KRAS mutation-specific effects on the tumor immune microenvironment drive tumor progression in pancreatic cancer

Abstract Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive malignancy with abysmal survival rates. The highly immunosuppressive microenvironment of PDAC poses a major barrier to effective therapy. KRAS mutations are near-ubiquitous in PDAC, and studies indicate clinical outcomes vary depending on the specific KRAS genotype. Given that tumor genotype can shape the immune cell composition of tumors, we examined the immune cell composition of pancreatic tumors with specific KRAS mutations, focusing on KRASG12D mutations (representing 40% of PDAC cases which have the worst prognosis) and KRASG12R mutations (which make up 20% of PDAC cases and have a better prognosis). Orthotopically implanted Kras G12R/+ ;Trp53 KO mouse pancreatic tumors have a distinct immune profile in comparison to Kras G12D/+ ;Trp53 KO tumors, characterized by an influx of intratumoral CD3+ T cells and mature dendritic cells. Selective depletion of CD4+ T cells induces a rapid progression in KRASG12R, but not KRASG12D mouse tumors. RNA sequencing of KRASG12R tumor cells revealed enrichment of Type I interferon (IFN) pathways accompanied by related chemokines, CXCL9 and CXCL10 in comparison to KRASG12D tumors. Analysis of publicly available and real-world human PDAC datasets and enrichment of dendritic cells and other immune related cell types in KRASG12R tumors. Collectively, these data link the KRASG12R mutation to a unique immunogenic role. Citation Format: Andrew Wenger, Tal Baron, Erika Hissong, Rohit Chandiwani, Lukas Dow, Despina Siolas, Katherine Bacchi, Huanhuan Sun, Erika Hissong, Adrian Vega, Whitney Sisso, and Kawther Abdilleh. KRAS mutation-specific effects on the tumor immune microenvironment drive tumor progression in pancreatic cancer [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 PR012.

Abstract B043: BDNF-TrkB.T1 signaling increases neutrophil recruitment and epithelial-to- mesenchymal transition in gliomas

Abstract Gliomas are the most common type of brain tumor in both children and adults. Communication between glioma cells and the brain tumor microenvironment (TME) is a fundamental aspect of brain cancer pathophysiology. Glioma cells secrete factors that act as chemoattractants, influencing the TME. In addition, neuronal activity within the TME drives the proliferation and growth of gliomas through paracrine signaling, with brain-derived neurotrophic factor (BDNF) being a key mediator. BDNF binds with high affinity to the tropomyosin receptor kinase B (TrkB). Recent work from our group has demonstrated that the TrkB.T1 splice variant is upregulated in human gliomas. Furthermore, TrkB.T1 overexpression enhances tumor aggressiveness in vivo and is associated with the downregulation of genes involved in tumor cell recognition and elimination. However, the role of the TrkB.T1 splice variant in the bidirectional communication between glioma cells and the surrounding microenvironment remains unexplored. Our aim was to investigate whether the increased levels of TrkB.T1 observed in gliomas contribute to modulating immune responses. We investigated the immune cell heterogeneity associated with elevated TrkB.T1 levels in vivo using a glioma mouse model engineered with RCAS/tv-a technology. Tumors overexpressing TrkB.T1 exhibited increased neutrophil recruitment, a phenomenon linked to tumor growth, metastasis and therapeutic resistance. To further dissect the signaling mechanisms underlying the BDNF-TrkB.T1 axis, we conducted in vitro studies using glioma stem cells (GSCs) that express high levels of TrkB.T1. GSCs were treated with BDNF, after which the conditioned media was analyzed using a cytokine multiplex assay, and cell lysates were subjected to proteomic analysis. Our findings revealed that TrkB.T1 significantly upregulates key chemokines previously implicated in neutrophil recruitment. Moreover, BDNF signaling increased the expression of N-cadherin, β- catenin, and Snail, markers indicative of the epithelial-to-mesenchymal transition (EMT) phenotype. To further explore the role of TrkB.T1, we used CRISPR/Cas9-based genome editing to knock down TrkB.T1 in GSCs. In conclusion, our findings suggest that the highly expressed TrkB.T1 receptor in gliomas contributes to creating an immunosuppressive microenvironment by recruiting neutrophils and promoting EMT. These insights highlight TrkB.T1 as a potential therapeutic target for modulating glioma-immune cell interactions, which could be crucial in curbing disease progression. Citation Format: Leyre Merino-Galan, Sergio Ortiz-Espinosa, Hawa L. Jagana, John M. Hemenway, Ashmitha Rajendran, Taylor S. Jackson, Daniel A. Kuppers, Sonali Arora, Patrick J. Paddison, Siobhan S. Pattwell. BDNF-TrkB.T1 signaling increases neutrophil recruitment and epithelial-to- mesenchymal transition in gliomas [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 B043.

Misdiagnosis in breast imaging: a statement paper from European Society Breast Imaging (EUSOBI)-Part 2: Main causes of errors in breast imaging and recommendations from European Society of Breast Imaging to limit misdiagnosis.

Breast cancer is one of the leading causes of negligence claims in radiology. The objective of this document is to describe the specific main causes of errors in breast imaging and provide European Society of Breast Imaging (EUSOBI) recommendations to try to minimize these. Technical failures represent 17% of all mammographic diagnostic negligence claims. Mammography quality control protocol and dedicated training for technologists and radiologists are essential. Lack of consideration of the clinical context is a second critical issue, as a clinical abnormality is found in 80% of malpractice claims. EUSOBI emphasizes the importance of communication and clinical examination before the diagnostic investigation. Detection errors or misapplications of the lexicon or Breast Imaging Reporting Data System (BI-RADS) score account for 5% of malpractice claims and should be reduced by limiting radiologists' distraction or fatigue, and being aware of satisfaction of search errors and the importance of a personal systematic review. Errors related to pathological concordance and MDT review can be limited by the use of markers after biopsy and the use of standardized reports, which can aid communication with other specialities. Finally, errors related to tumor or patient factors should be discussed, considering the use of contrast-enhanced mammography and magnetic resonance imaging. Several factors are responsible for misdiagnosis in breast cancer, including errors in the practice of the technician and/or radiologist (technical failures, lack of consideration of the clinical context, incorrect application of the BI-RADS score, false reassurances), lack of communication with other specialists or with the patient, and the type of tumor and breast parenchyma. Question What factors most contribute to and what implications stem from misdiagnosis in breast imaging? Findings Ongoing training and education for radiologists and other healthcare providers, as well as interdisciplinary collaboration and communication is paramount. Clinical relevance Misdiagnosis in breast imaging can have significant implications for patients, healthcare providers, and the entire healthcare system.

Endothelin-1 receptor blockade impairs invasion patterns in engineered 3D high-grade serous ovarian cancer tumouroids.

High-grade serous ovarian cancer (HG-SOC), accounting for 70-80% of ovarian cancer deaths, is characterized by a widespread and rapid metastatic nature, influenced by diverse cell types, cell-cell interactions, and acellular components of the tumour microenvironment (TME). Within this tumour type, autocrine and paracrine activation of the endothelin-1 receptors (ET-1R), expressed in tumour cells and stromal elements, drives metastatic progression. The lack of three-dimensional models that faithfully recapitulate the unique HG-SOC TME has been the bottleneck in performing drug screening for personalized medicine. Herein, we developed HG-SOC tumouroids by engineering a dense central artificial cancer mass (ACM) containing HG-SOC cells, nested within a compressed hydrogel recapitulating the stromal compartment comprising type I collagen, laminin, fibronectin, and stromal cells (fibroblasts and endothelial cells). ET-1-stimulated HG-SOC cells in the tumouroids showed an altered migration pattern and formed cellular aggregates, mimicking micrometastases that invaded the stroma. Compared with control cells, ET-1-stimulated tumouroids showed a higher number of invasive bodies, which were reduced by treatment with the dual ET-1 receptor (ET-1R) antagonist macitentan. In addition, ET-1 increased the size of the invading aggregates compared with control cells. This study establishes an experimental 3D multicellular model eligible for mechanical research, investigating the impact of matrix stiffness and TME interactions, which will aid drug screening to guide therapeutic decisions in HG-SOC patients.

Benign but troublesome: A case study of irritational fibroma in the oral cavity

In the oral cavity, fibroma is the most common type of connective tissue tumor. The size of these proliferative benign connective tissue tumors varies from tiny to large, contingent upon the degree of presence of one or more components of the inflammatory response. They are usually asymptomatic.It is a locally confined hyperplasia of fibrous connective tissue brought on by persistent inflammation or local trauma. This lesion is more typically observed in men, with a preference for buccal mucosa, labial mucosa, and tongue . This lesion preferentially affects the tongue, buccal mucosa, and labial mucosa. A traumatic or irritating fibroma develops from an inflammatory hyperplastic lesion that can occur at any age and in almost any soft tissue location.

Prospects of anti-GD2 immunotherapy for retinoblastoma

Retinoblastoma is the most common type of eye tumor in infants and children. Current treatments for retinoblastoma include intravenous chemotherapy, intra-arterial chemotherapy, intravitreal chemotherapy, cryotherapy, radiotherapy, and surgery. However, these treatments come accompanied by adverse effects such as the toxic side effects of chemotherapeutic drugs, post-operative complications including blindness after surgery, or other complications caused by radiotherapy. Immunotherapy is more promising for its low toxicity on normal cells and effectively improves the quality of life of patients. Disialoganglioside (GD2), a sphingolipid expressed on the surface of retinoblastoma, is a potential therapeutic target for retinoblastoma. We summarized immunotherapeutic approaches for both preclinical studies and clinical trials of GD2. An anti-GD2 monoclonal antibody (Dinutuximab), which has been approved for the treatment of high-risk neuroblastomas, has shown promising efficacy in improving patients’ prognosis. Additionally, chimeric antigen receptors (CAR)-T therapy, GD2 vaccines and nanoparticles are also potential therapeutics. Finally, we discuss the prospects and current limitations of these immunotherapeutic approaches for treating retinoblastoma, as well as how to address these problems.

Precise Genotyping Via Surface‐Enhanced Raman Spectroscopy‐Based Optical Sensing Chip for Guiding Targeted Therapy in Lung Cancer

AbstractThe emergence of “precision medicine” marks a notable shift in cancer treatment, moving from a tumor type–oriented approach to a more targeted, gene‐oriented approach. Detecting low‐abundance mutant genes in blood is challenging but crucial for personalized treatment plans. Herein, a novel platform combining catalytic hairpin self‐assembly (CHA)‐mediated self‐calibrating surface‐enhanced Raman spectroscopy (SERS) with a high‐throughput Raman system (CCSPS) was designed. This platform enables ultrasensitive and rapid genotype analysis of gene mutations. The development of CCSPS specifically targets EGFR mutations, which serve as crucial therapeutic targets for precision therapy in lung cancer. This system shows excellent sensitivity and selectivity, capable of detecting multiple EGFR mutations (Del‐19, L858R, and T790M) with a detection limit as low as attomolar levels. Additionally, precise genotyping analysis was successfully conducted on 42 clinical samples using the CCSPS, yielding results consistent with those obtained through next‐generation sequencing. These results underscore the efficacy of the CCSPS in noninvasively identifying circulating tumor DNA (ctDNA) mutations, facilitating immediate therapeutic decision making at the bedside. In summary, the CCSPS is a fast, accurate, versatile, and compact testing system capable of precisely screening individuals who stand to benefit from targeted therapy, thus promoting personalized and precise healthcare.

Chondroblastic Osteosarcoma of the Mandible: An Uncommon Site for Osteosarcoma

Osteosarcoma is one of the most common types of malignant bone tumors, typically involving long bones such as the femur, tibia, and humerus. However, osteosarcomas occurring in the jaws are exceptionally rare, accounting for approximately 7% of all osteosarcoma cases and just 1% of malignancies in the head and neck region. This type of tumor usually affects individuals in their second and third decades of life. The subtypes of osteosarcoma include osteoblastic, chondroblastic, fibroblastic, small cell, and epithelioid. Chondroblastic osteosarcoma is associated with a poor prognosis, marked by a high recurrence rate, metastatic potential, and poor long-term survival outcomes. Here, we present the case of a 65-year-old woman with a painless swelling over the left cheek for 1 year, which significantly increased in size over the past 3 months, accompanied by trismus, reduced oral intake, and weight loss. Examination revealed a non-tender, hard swelling on the left cheek measuring 20x20cm, with prominent dilated veins. The left external auditory canal was collapsed due to the mass effect. Histopathological examination resulted as chondroblastic osteosarcoma of the left mandible. Computer tomography showed a large lobulated enhancing mass occupying the left cheek, associated with bone erosion and an aggressive periosteal reaction resembling a 'sunburst' pattern involving the ramus extending to the angle of the left mandible. The patient undergone open tracheostomy, left temporary tarsorrhaphy, wide local excision of tumor, left hemimandibulectomy, left partial maxillectomy and anterolateral thigh free flap reconstruction as patient unable to tolerate neoadjuvant chemotherapy.

CHALLENGES IN BRAIN METASTASES DIAGNOSIS AND TREATMENT

Although brain metastases are the most frequent type of intracranial tumors, their diagnosis and treatment is still challenging. They have poor prognosis and life expectancy is short, as brain metastases appear in advanced stage cancers. In U.S., the rate of recently discovered cancer that will evolve with brain metastases is considered to be 6-14%. Left untreated, brain metastases become lethal in less than 2 months. The most common primary cancers that develop brain metastases are lung, breast, melanoma and colorectal. In our department, approximately 60 patients with brain tumors were diagnosed after surgery with brain metastases in the last 10 years. The most common cancer to metastasize by far was lung cancer, with a mean age at diagnosis 60 years old, affecting mostly smoking men. The majority of patients presented with multiple metastases, unaware of the primary disease and without conducting any oncological treatment prior to admission in our departement. We observed that COVID-19 pandemic period highly affected patients with cancer. The number of patients with brain metastases operated on in our department has drastically decreased in that period. There were a lot of reasons why cancer patients among which being the imposibility to reach emergency rooms without having COVID-19 symptoms and difficulty of reaching radiology centers for early imaging. Most of the patients presented in the Emergency Department with multiple brain metastases, comatose or with focal neurological deficits installed long before presentation, regardless of their primary cancer, thus making neurosurgery an impractical option for most of these cases. Although there have been significant advances in systemic oncological treatment and radiotherapy, surgery remains an essential method of managing brain metastases, even in cases presenting with multiple lesions. Careful patient selection is essential in obtaining the best outcome.

Abstract PR010: DICER1 cancer predisposition tumor promotion mediated non-cell autonomously via neutrophils and NETosis

Abstract DICER1 cancer predisposition syndrome is a heritable condition where affected patients have increased risk of neoplasms including fusion-negative rhabdomyosarcoma (FN-RMS). The syndrome is defined by germline heterozygous loss of function mutations in DICER1, but it remains unclear exactly how these mutations predispose children to cancer. To gain insight into the role of Dicer1 loss in DICER1 cancer predisposition, we deleted the Dicer1 gene both in the germline or conditionally within the tumor cell in our previously established mouse model of FN-RMS. One would expect the germline loss of one allele to provide a sensitized background in the tumor cell to acquire a second hit mutation. However, we observed faster tumor onset and increased penetrance in mice with germline heterozygous Dicer1 loss (Dicer1 +/- ) but not in mice when Dicer1 loss was restricted to the tumor cells (Dicer1 Flox/+ ), demonstrating that haploinsufficient tumor suppressor activity of Dicer1 loss requires non-cell autonomous cell types. Single cell RNA sequencing (scRNA-Seq) revealed significant expansion of immature neutrophils in Dicer1 +/- tumors, which were enriched for proteases associated with neutrophil extracellular traps (NETs). NETs are webs of chromatin and proteases released when neutrophils in response to inflammatory stimuli in process termed NETosis. We show Dicer1 +/- murine and human tumors are enriched for neutrophils and tumor-bearing mice had abundant circulating NETs. NETs cause significant damage to the local extracellular matrix (ECM) and have been implicated in tumor promotion. In addition, neutrophil enrichment, we found that Dicer1 +/- tumors show significant ECM remodeling and are increased C5a, a potent neutrophil chemoattractant and NET-priming factor. These results suggest NETosis is upregulated in Dicer1 +/- FN-RMS tumors. Ligand-receptor pair analysis (iTALK) on the scRNA- Seq data revealed a putative interaction between a NET-derived ligand and EGFR and IGF1R on tumor cells, suggesting direct tumor promoting signaling from NET-to-tumor. We validated this novel FN-RMS promotion mechanism in vitro using human FN-RMS cell lines and observed that this NET-derived ligand promoted FN-RMS growth through both EGFR and IGF1R signaling. NET release requires citrullination of histone H3 mediated by peptidyl arginine deiminase 4 (PADI4) to facilitate decondensation of chromatin. We intercrossed the Padi4 -/- allele into our tumor model to genetically block NETosis and observed complete rescue of the accelerated tumor onset and increased penetrance observed in Dicer1 +/- mice. These results demonstrate that NETosis promotes the growth of Dicer1 +/- FN-RMS tumors and is required for Dicer1 +/- haploinsufficiency. These findings may be applicable to many DICER1 syndrome- associated cancers, as neutrophils which get converted to tumor promoters by heterozygous DICER1 loss are present in DICER1 syndrome patients regardless of tumor type and suggest targeting neutrophils/NET-release may reduce cancer risk in DICER1 +/- individuals. Citation Format: Randolph K Larsen, Jason A Hanna, Hongjian Jin, Kristen B Reed, Darden W Kimbrough, Kyna Voung, Myron K Evans, Casey G Langdon, Catherine J Drummond, Matthew R Garcia, David Finkelstein, Patrick A Schreiner, Jerold E Rehg, Kris Ann P Schultz, Mark E Hatley. DICER1 cancer predisposition tumor promotion mediated non-cell autonomously via neutrophils and NETosis [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 PR010.

Abstract A060: Identification of tumour-specific variants from pleural effusion cell-free DNA as diagnostic markers of cancers affecting the lungs

Abstract Background: Pleural mesothelioma (PM) can be difficult to diagnose due to a combination of the growth pattern of the tumour, the invasive nature of the biopsy procedure and the frailty of the patient. Some patients with PM develop a build-up of fluid around their lungs as their first clinical symptom. This fluid can make breathing difficult and is routinely drained as part of standard care. Currently, a cytological test can be performed to identify if PM cells are present in the fluid, however, while this is a specific test, it lacks sensitivity. We examined if (a) cell-free DNA (cfDNA) originating from tumours affecting the lung could be detected in this fluid and (b) if this cfDNA could be determined as coming from PM compared to non-small cell lung cancer (NSCLC), due to changes in genes that only occur in these types of tumours. Methods: Using the QIAamp MinElute ccfDNA Kit, we were able to isolate sufficient concentrations of cfDNA from pleural effusions (n=80) derived from patient samples procured by our colleagues at Southmead Hospital with either PM or NSCLC to perform gene panel sequencing. Using the QIAseq Targeted DNA Pro Human Lung Cancer Research Panel, with additional booster primers covering BAP1 and SETD2, we performed the library preparation in-house. Data analysis was carried out using the QIAGEN CLC Genomics Workbench, with the specific workflows for the gene panels and results were filtered by QC, proportion of variant reads and variant read count. Data were compared to expected variant frequencies published in TCGA. Results: Tumour-specific cfDNA was isolated from pleural effusions in the majority of samples tested. In a proportion of these, variants indicative of a specific type of tumour (PM or NSCLC) were readily detectable, at slightly lower than the expected frequencies than reported in TCGA. Conclusions and future work: This approach can act as a 'rule-in' clinically diagnostic test for the presence of PM or NSCLC in a higher proportion of people that can currently be identified through cytology testing. These individuals could be spared from receiving an invasive biopsy to diagnose their tumour. We are currently working on (i) increasing the sensitivity of this approach to identify more cases and (ii) if a bioinformatic method can identify tumour-specific copy number alterations from the gene panel sequencing data. Citation Format: Connie MacKinnon, Dr Colette Mustard, Dr Nicole Brace, Dr Beth Sage, Jenny Symonds, Colin Nixon, Dr Anna Bibby, A/Prof Antonia Pritchard. Identification of tumour-specific variants from pleural effusion cell-free DNA as diagnostic markers of cancers affecting the lungs [abstract]. In: Proceedings of the AACR Special Conference: Liquid Biopsy: From Discovery to Clinical Implementation; 2024 Nov 13-16; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2024;30(21_Suppl):Abstract nr A060.

Abstract B053: NucAE: Autoencoder-based enhancement of nucleosome occupancy signals from low-coverage cfDNA sequencing

Abstract Introduction: Cell-free DNA (cfDNA) is emerging as a valuable cancer biomarker, enabling both the detection and epigenetic characterization of malignancies through sequencing. cfDNA sequencing can reveal cancer-specific nucleosome occupancy patterns, which provide insights into tumor type and differentiation status, which define prognosis and therapy recommendations. Low-coverage whole-genome cfDNA sequencing is a cost-efficient approach to assay multiple cfDNA samples, however, the low coverage limits its sensitivity. We developed NucAE, a denoising autoencoder model, to enhance nucleosome occupancy signals from low-coverage cfDNA-sequencing. Methods: We designed NucAE to estimate nucleosome occupancy genome- wide from low-coverage sequencing data. To train the model, we undersampled high-coverage cfDNA-sequencing data and produced high- and low-coverage sample pairs at varying coverages (1x-90x). Inputs to NucAE include cfDNA fragment data and the corresponding genomic nucleotide sequence, with the model leveraging a symmetrical architecture comprising two convolutional layers in both the encoder and decoder, connected by ReLU activations. Mean squared error relative to the high-coverage signal was employed as the loss function. To evaluate the model independently, we performed peak detection from the nucleosome occupancy signals. We conducted a grid search to optimize hyperparameters. Results: We found that NucAE enhances the signal to noise ratio by detecting periodicities in nucleosome occupancy data. Denoising was improved by supplementing the cfDNA fragment signals with the genomic nucleotide sequences as input, which demonstrates that the model learned the nucleotide- sequence dependence of nucleosome positioning. Independent validation through peak detection on previously unseen samples demonstrated a significant improvement (p<0.001) in accuracy compared to raw signals across all tested coverages (1x-45x). Remarkably, at extremely low coverages (1x-2x), denoised signals allowed for more accurate peak detection than raw signals from 10-20x deeper sequencing. Conclusions: By using advanced machine-learning, we were able to enhance low-coverage cfDNA sequencing data to assay nucleosome positions at a nucleotide resolution. NucAE achieves an order of magnitude improvement over the low- coverage signals and greatly improves the utility of cfDNA-sequencing data to identify cancer- specific nucleosome occupancy, while preserving its low cost. Our model is the first to use autoencoders for genome-wide signal enhancement with potential use cases in many other areas of genomics. Citation Format: Zsolt Balázs, Jean Radig, Noah Wolford, Manuel Schürch, Michael Krauthammer. NucAE: Autoencoder-based enhancement of nucleosome occupancy signals from low-coverage cfDNA sequencing [abstract]. In: Proceedings of the AACR Special Conference: Liquid Biopsy: From Discovery to Clinical Implementation; 2024 Nov 13-16; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2024;30(21_Suppl):Abstract nr B053.

Analysis of Circulating Plasma MicroRNA Profile in Low-Grade and High-Grade Glioma – A Cross-Sectional Study

Background Glioma is the second most common type of brain tumor, accounting for 24% of all brain tumor cases. The current diagnostic procedure is through an invasive tissue sampling to obtain histopathological analysis, however, not all patients are able to undergo a high-risk procedure. Circulating microRNAs (miRNAs) are considered as promising biomarkers for glioma due to their sensitivity, specificity, and non-invasive properties. There is currently no defined miRNA profile that contributes to determining the grade of glioma. This study aims to find the answer for “Is there any significant miRNA that able to distinguish different grades of glioma?”. Methods This study was conducted to compare the expression of miRNAs between low-grade glioma (LGG) and high-grade glioma (HGG). Eighteen blood plasma samples from glioma patients and 6 healthy controls were analyzed for 798 human miRNA profiles using NanoString nCounter Human v3 miRNA Expression Assay. The differential expressions of miRNAs were then analyzed to identify the differences in miRNA expression between LGG and HGG. Results Analyses showed significant expressions in 12 miRNAs between LGG and HGG, where all of them were downregulated. Out of these significant miRNAs, miR-518b, miR-1271-3p, and miR-598-3p showed the highest potential for distinguishing HGG from LGG, with area under curve (AUC) values of 0.912, 0.889, and 0.991, respectively. Conclusion miR-518b, miR-1271-3p, and miR-598-3p demonstrate significant potentials in distinguishing LGG and HGG.

OGC O01 - Stomach Cancer Elective Surgery Morbidity and Mortality at 90-Days (HOLD Study): A Prospective, International Collaborative Cohort Study

Abstract Background Data on multinational 90-day mortality and morbidity rates after surgery for gastric cancer is limited in the literature. This study aimed to understand the 90-day mortality and morbidity outcomes according to GASTRODATA Registry for elective gastric cancer surgery patients and identify risk factors. Method We conducted an international prospective study on ≥18 years patients undergoing elective surgery for gastric cancer with curative intent from 01 April 2022 to 30 September 2022. Known metastatic disease, concurrent secondary cancers, gastrointestinal stromal tumour (GIST) and Siewert type I/II oesophagogastric junction malignancies were excluded. Univariate and multivariate logistic regression was used to identify variables associated to 90-day outcome. Results 380 collaborators from 47 countries submitted data on 1538 patients. Mean age was 64.2 years and 58.5% were males. 90-day morbidity rate was 38.2% (n=587) and mortality rate was 2.9% (n=45). Pre-operative higher CCI or ASA score, pre-operative weight loss >10%, and surgical determinants such as type of gastric resection, positive specimen margin, number of harvested lymph nodes, longer surgery duration and post operative pathological IV staging (p value<0.05) were identified as predictors of postoperative severe complications and mortality. Conclusion Elective gastric cancer surgery has a 90-day morbidity of 38.2% and 90-day mortality of 2.9%, globally. This study identified several factors associated with higher morbidity and exemplified the importance of a unified language on surgical morbidity, pre-habilitation and ongoing audits to enhance patient outcomes.

A case of ovarian mesothelioma with VHL mutation diagnosed by immunohistochemistry and literature review

The malignant mesothelioma mainly develops in the pleura and peritoneum, while primary ovarian mesothelioma is very rare. Here, we report the first case of primary ovarian mesothelioma (clear cell variant) with VHL mutations in the world based on the results of histomorphology, immunohistochemistry, and genetic testing. This is an extremely rare type of tumor that has not been reported so far. Through the literature search, we reviewed primary ovarian mesothelioma, focusing on its differential diagnosis and molecular genetics. The purpose of this paper is to deepen the flexible selection and application of immunohistochemical markers in mesothelioma, so as to reduce missed diagnosis and misdiagnosis.

Abstract B024: Personalized tumor-informed circulating tumor (ct) DNA for advanced thyroid carcinoma

Abstract Background: Clinical adoption of personalized tumor-informed ctDNA testing is increasing with clinical validation in monitoring for recurrence for colorectal, breast, bladder, & ovarian tumors, as well as treatment response for immune-checkpoint inhibitors regardless of tumor type. However, few studies have evaluated tumor-informed ctDNA testing in patients (pts) with advanced thyroid carcinoma (TC). Methods: This retrospective cohort study identified pts with advanced TC, with any histology, treated at an academic institution with ctDNA testing (Signatera™, Natera Inc.) performed during routine clinical care at any point during the disease natural history after requiring referral to medical oncology. The goal was to investigate the feasibility of personalized, tumor-informed ctDNA testing in advanced TC, and characteristics associated with ctDNA detectability & values. Results: Between 1/1/24 & 8/20/24, ctDNA testing was obtained in 45 pts with advanced TC (median age: 63y, 58% male). Testing could not be performed in 4 (9%) pts due to inadequate tumor tissue. Initial tests were in progress for 7 (16%) pts at data cutoff. Thirty-four pts had available results for at least 1 blood draw, including 19 (56%) with radioiodine refractory (RAIR) differentiated TC (DTC), 10 (29%) with anaplastic TC (ATC), & 5 (15%) with medullary TC (MTC). ctDNA was detected in 16/34 (47%) pts with advanced TC. These included 8/19 (42%) pts with RAIR DTC (range: 0.05–346.26 mean tumor molecules, MTM/mL), including 4/4 (100%) about to initiate new systemic Rx, 1/4 (25%) on ongoing systemic Rx, & 3/11 (27.3%) on active surveillance not requiring systemic Rx. 4/10 (40%) with ATC had detectable ctDNA (range: 3.57–80.55 MTM/mL), including 4/4 (100%) about to initiate new systemic Rx, & 0/6 in those with disease control on ongoing Rx or on active surveillance after completion of Rx. 4/5 (80%) with MTC (range: 0.04–94.72 MTM/mL), including 4/4 (100%) on ongoing systemic Rx & 0/1 on active surveillance. Radiographic evidence of disease was observed in 28/34 (82%) pts, with ctDNA detection in 16/28 (57%). For all cases, there was a significant association between anatomic tumor burden represented by the no. of organ sites involved by advanced TC (median:2.5, range:0-6) & ctDNA detectability (Mann-Whitney, p=0.003). In pts with a ctDNA-positive result (n=16), there was a modest correlation between ctDNA quantitative values & no. of involved organ sites (Spearman’s rho=0.48), but was not statistically significant (p=0.06). Similarly, modest correlation with serum biomarkers was observed but not statistically significant in RAIR DTC (with serum thyroglobulin, n=8, rho=0.52, p=0.18), & MTC (with serum calcitonin, n=4, rho=0.8, p=0.2). Conclusions: Personalized ctDNA testing is feasible and often detectable in pts with advanced TC. Further research is warranted to ascertain factors associated with ctDNA test performance, and understand whether ctDNA monitoring can guide optimal timing for initiation of systemic Rx in advanced TC, as well as the dynamics of ctDNA on systemic Rx. Citation Format: Kartik Sehgal, Theodora Pappa, Michael J. Dennis, Nicole J. Scarfo, Michelle S. Mullin, Tura Coombs, Roy B. Tishler, Danielle N. Margalit, Ravindra Uppaluri, Rosh K. Sethi, Jonathan D. Schoenfeld, Justine A. Barletta, Gerard M. Doherty, Erik K. Alexander, Laura A. Goguen, Eleni M. Rettig, Robert I. Haddad, Glenn J. Hanna. Personalized tumor-informed circulating tumor (ct) DNA for advanced thyroid carcinoma [abstract]. In: Proceedings of the AACR Special Conference: Liquid Biopsy: From Discovery to Clinical Implementation; 2024 Nov 13-16; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2024;30(21_Suppl):Abstract nr B024.

HPB SO38 - Assessing current pancreatic cancer reporting practice against the PACT-UK Synoptic Reporting Template: An initial clinical audit

Abstract Background In the last decade, the incidence of pancreatic cancer has increased by 9% in the UK. The gold standard for initial assessment of pancreatic cancer (or even peri-ampullary cancer) resectability is pancreatic-protocol CT scan. The PACT-UK project introduced a synoptic template for pancreatic cancer to standardise CT reporting practice across UK and enable consistent reporting of pertinent aspects of resectability status such as vascular involvement of the tumour. The aim of this audit is to assess the quality of current CT reports received by a tertiary hepato-pancreato-biliary (HPB) unit against the standards set out by PACT-UK. Method A retrospective analysis of 66 patients who underwent pancreatic resection between September 2023 and May 2024 at a tertiary HPB centre was undertaken. Patients were excluded from the analysis if they underwent resection for benign pancreatic pathology, were diagnosed with pathology other than peri-ampullary cancer or did not have a formal report of their CT scan. Initial CT scans performed at presentation and if available, subsequent up-to-date staging scan prior to surgery were assessed against the PACT-UK reporting template, in accordance with their guidance. The audit was registered with our clinical audit team (no. 11643). Results In total, 42 patients with peri-ampullary cancers were included in this audit. All patients had a reported CT scan on presentation. Additionally, 24 patients had a reported staging CT scan. The compliance (i.e. more than 90% information available) with PACT-UK reporting standards was 0% for initial presentation scans and 4.2% (n=1) for staging scans. The only staging scan with >90% compliance was reported using the PACT-UK template. Majority (more than 80%) of CT scan reports lacked information on aspects such as pancreatic duct size, predicted tumour type and radiological stage, variant vascular anomalies, and arterial/venous involvement. Conclusion This audit highlights the substandard quality of current CT reporting for peri-ampullary cancer. There is an urgent need to adopt a structured and dedicated reporting template to address the issue. Utilising a template such as the one developed by PACT-UK will help ensure that relevant information is formally reported to facilitate optimal decision-making at MDT meetings, and assist surgeons in operative planning and oncologists in assessing treatment response.

Somatic and psychiatric symptoms of brain tumors - a review of the literature

Introduction and Purpose Brain tumors cause a variety of somatic and psychiatric symptoms, which vary depending on the age of the patient and the location and type of tumor. Symptomatology includes both physical symptoms, such as headache, nausea, seizures and weakness, and psychiatric symptoms, including mood, personality and cognitive dysfunction. In children, the clinical picture is more complex and includes specific developmental difficulties. The purpose of this paper is to analyze the various symptoms accompanying brain tumors in order to detect them early and enable faster diagnosis. Material and Methods A comprehensive literature review was conducted using the PubMed database, focusing on articles published until the end of 2023.The search included the keywords: "brain tumors" "symptoms" "headache" and "psychiatric" in various combinations. Relevant studies were selected based on criteria such as somatic and psychiatric symptoms and early diagnosis of brain tumors. Results Accumulating data show the diversity of symptoms associated with brain tumors. Somatic symptoms such as headache, optic disc swelling, nausea, and seizures depend on intracranial pressure and tumor location. Psychiatric symptoms, including personality changes, mood disorders, and cognitive impairment, pose a significant diagnostic challenge in adult patients. In children, brain tumors can cause developmental delay and atypical neurological symptoms. Conclusions The symptoms of brain tumors are highly variable and difficult to diagnose, which significantly delays proper diagnosis of the disease. Its early detection is crucial as it improves the prognosis of patients, significantly improves their quality of life, and allows for the introduction of effective therapeutic interventions.

GAMMA KNIFE AND QUALITY OF LIFE: A REVIEW ON THE USE OF RADIOSURGERY IN BRAIN TUMORS

INTRODUCTION: Considering the quality of life of patients with brain tumors, several treatment alternatives have been developed over time, aiming at a less invasive potential and providing a permanent functional capacity for the individual. In this regard, in recent decades there has been debate about radiosurgery for the treatment of brain tumors. OBJECTIVE: The objective of this study was to evaluate the feasibility of Gamma Knife radiosurgery, considering patient safety. METHODS: This article is characterized as an integrative literature review of an exploratory nature, in the PubMED and Cochrane databases, the search was restricted to observational studies and randomized clinical trials as primary data to contemplate the outcomes Quality of life, neurological preservation, recurrence, cerebral complications and overall survival. RESULTS: The analysis of the collected data demonstrated that, in general, radiosurgery by the Gamma Knife platform preserves quality of life in several cases, mainly in smaller benign brain tumors. The disease recurrence rate after 3 years of radiosurgery ranged from 20 to 40%, depending on the type of tumor and treatment, with the highest recurrence rate in grade III meningiomas and high-grade gliomas. The 5-year recurrence rate ranged from 60 to 80%, and was therefore higher than that of more invasive treatments. CONCLUSION: The qualitative synthesis of these data proves the efficacy of radiosurgery and may suggest to neurosurgeons the possibility of treating brain tumors in patients who are not eligible for conventional surgery or in patients with non-bulky tumors.