Primary Pancreatic Adenocarcinoma Research Articles

Predictive genomic and transcriptomic analysis on endoscopic ultrasound-guided fine needle aspiration materials from primary pancreatic adenocarcinoma: a prospective multicentre study

We apply endoscopic ultrasound-guided fine needle aspiration biopsy to cytopathologically diagnose and sample nucleic acids from primary tumours regardless of the disease stage. 397 patients with proven pancreatic adenocarcinoma were included and followed up in a multicentre prospective study. DNA and mRNA were extracted from materials of primary tumours obtained by endoscopic ultrasound-guided fine needle aspiration biopsy and analysed using targeted deep sequencing and RNAseq respectively. The variant allele frequency of the KRAS mutation was used to evaluate the tumour cellularity, ranging from 15 to 20% in all cells, regardless of the tumour stage. The molecular profile of metastatic primary tumours significantly differed from other types of tumours, more frequently having TP53 mutations (p=0.0002), less frequently having RNF43 mutations, and possessing more basal-like mRNA component (p=0.001). Molecular markers associated with improved overall survival were: mutations in homologous recombination deficiency genes in patients who received first-line platinum-based chemotherapy (p=0.025) and wild-type TP53 gene in patients with locally advanced tumours who received radio-chemotherapy (p=0.01). The GemPred transcriptomic profile was associated with a significantly better overall survival in patients with locally advanced or metastatic pancreatic cancer who received a gemcitabine-based first-line treatment (p=0.019). The combination of genomic and transcriptomic analyses of primary pancreatic tumours enables us to distinguish metastatic tumours from other tumour types. Our molecular strategy may assist in predicting overall survival outcomes for platinum or gemcitabine-based chemotherapies, as well as radio-chemotherapy. Institut National Du Cancer (BCB INCa_7294), CHU of Toulouse, Inserm and Ligue Nationale Contre le Cancer (CIT program).

Metástasis cerebral múltiple de adenocarcinoma pancreático. Reporte de caso

Introduction: Brain metastases are the most common malignant lesions in the central nervous system. Brain metastases from pancreatic cancer are very rare, with poor prognosis. The present paper aims to describe a rare pathology and the work carried out for the patient's care. Case report: 49-year-old man with personality changes, depression, and apathy. Five days before admission, he presented dysarthria, added left hemiparesis, and disorientation that progressed to sudden neurological deterioration that required advanced airway management. A computed tomography study was seen with cerebral cystic lesions. A decompressive craniectomy and drainage of the larger lesión was performed, with subsequent resection. The study protocol with immunohistochemistry reports CK 19, compatible with pancreatic adenocarcinoma. Conclusions: A rare case of multiple brain metastases and suspected lung metastasis, both secondary to primary pancreatic adenocarcinoma was presented. The patient began with symptoms associated with brain lesions. The incidence of brain metastases with a primary pancreatic tumor is very low, and this is an exceptional case when presenting with neurological symptoms. Surgical resection of the brain lesion had a limited role in the clinical improvement of the patient since the progression of the disease was rapid. Still, it was useful to establish a diagnosis by immunohistochemistry. Since there are no screening tests for pancreatic tumors, it is difficult to identify them in early stages and without gastrointestinal symptoms. Keywords: Pancreatic adenocarcinoma; brain tumors; brain metastases; cytokeratin 19; immunohistochemistry.

Association of overexpression of PLD6, CHRAC1 and PDCD5 with type 2 diabetes mellitus.

Diabetes type 2 (DT2) is a metabolic disease characterized by high blood sugar caused by insulin resistance and/or insufficient insulin production. The pathogenesis of DT2 is complicated by both genetic predisposition and environmental and lifestyle variables. At least 150 genetic variants have been linked to the probability of having DT2. The aim of this study was to determine the expression of PLD6, CHRAC1, and PDCD5 genes in type 2 diabetic patients. Information on 12 DT2 patients was obtained from the Gene Expression Omnibus (GEO) using the series identification (ID) (GSE34008). The analysis tools GEO2R, String Utils (STRING), University of Alabama at Birmingham Cancer data analysis (UAL-CAN), and the Cancer Genome Atlas (TCGA) were used. The human protein atlas provided details on gene cancer. Only ten genes with expression differences ranging from low to high were selected. PLD6, CHRAC1, and PDCD5 were detected to have higher expression in patients compared to controls. The number of patients with primary pancreatic adenocarcinoma for SLC16A4, DERK2, and CHRAC1 was greater than that of healthy controls. Concerning the severity of cancer, all chosen genes demonstrated a greater proportion of affected individuals compared to the control group. There are multiple genes whose increased expression is linked to type 2 diabetes.

Identifying a gene signature of metastatic potential by linking pre-metastatic state to ultimate metastatic fate.

Identifying the key molecular pathways that enable metastasis by analyzing the eventual metastatic tumor is challenging because the state of the founder subclone likely changes following metastatic colonization. To address this challenge, we labeled primary mouse pancreatic ductal adenocarcinoma (PDAC) subclones with DNA barcodes to characterize their pre-metastatic state using ATAC-seq and RNA-seq and determine their relative in vivo metastatic potential prospectively. We identified a gene signature separating metastasis-high and metastasis-low subclones orthogonal to the normal-to-PDAC and classical-to-basal axes. The metastasis-high subclones feature activation of IL-1 pathway genes and high NF-κB and Zeb/Snail family activity and the metastasis-low subclones feature activation of neuroendocrine, motility, and Wnt pathway genes and high CDX2 and HOXA13 activity. In a functional screen, we validated novel mediators of PDAC metastasis in the IL-1 pathway, including the NF-κB targets Fos and Il23a, and beyond the IL-1 pathway including Myo1b and Tmem40. We scored human PDAC tumors for our signature of metastatic potential from mouse and found that metastases have higher scores than primary tumors. Moreover, primary tumors with higher scores are associated with worse prognosis. We also found that our metastatic potential signature is enriched in other human carcinomas, suggesting that it is conserved across epithelial malignancies. This work establishes a strategy for linking cancer cell state to future behavior, reveals novel functional regulators of PDAC metastasis, and establishes a method for scoring human carcinomas based on metastatic potential.

A Reliable System for Quantitative G-Protein Activation Imaging in Cancer Cells.

Fluorescence resonance energy transfer (FRET) biosensors have proven to be an indispensable tool in cell biology and, more specifically, in the study of G-protein signalling. The best method of measuring the activation status or FRET state of a biosensor is often fluorescence lifetime imaging microscopy (FLIM), as it does away with many disadvantages inherent to fluorescence intensity-based methods and is easily quantitated. Despite the significant potential, there is a lack of reliable FLIM-FRET biosensors, and the data processing and analysis workflows reported previously face reproducibility challenges. Here, we established a system in live primary mouse pancreatic ductal adenocarcinoma cells, where we can detect the activation of an mNeonGreen-Gαi3-mCherry-Gγ2 biosensor through the lysophosphatidic acid receptor (LPAR) with 2-photon time-correlated single-photon counting (TCSPC) FLIM. This combination gave a superior signal to the commonly used mTurquoise2-mVenus G-protein biosensor. This system has potential as a platform for drug screening, or to answer basic cell biology questions in the field of G-protein signalling.

Single-cell transcriptome reveals the heterogeneity of malignant ductal cells and the prognostic value of REG4 and SPINK1 in primary pancreatic ductal adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) is one of the leading causes of cancer-related deaths, with very limited therapeutic options available. This study aims to comprehensively depict the heterogeneity and identify prognostic targets for PDAC with single-cell RNA sequencing (scRNA-seq) analysis. ScRNA-seq analysis was performed on 16 primary PDAC and three adjacent lesions. A series of analytical methods were applied for analysis in cell clustering, gene profiling, lineage trajectory analysis and cell-to-cell interactions. In vitro experiments including colony formation, wound healing and sphere formation assay were performed to assess the role of makers. A total of 32,480 cells were clustered into six major populations, among which the ductal cell cluster expressing high copy number variants (CNVs) was defined as malignant cells. Malignant cells were further subtyped into five subgroups which exhibited specific features in immunologic and metabolic activities. Pseudotime trajectory analysis indicated that components of various oncogenic pathways were differentially expressed along tumor progression. Furthermore, intensive substantial crosstalk between ductal cells and stromal cells was identified. Finally, genes (REG4 and SPINK1) screened out of differentially expressed genes (DEGs) were upregulated in PDAC cell lines. Silencing either of them significantly impaired proliferation, invasion, migration and stemness of PDAC cells. Our findings offer a valuable resource for deciphering the heterogeneity of malignant ductal cells in PDAC. REG4 and SPINK1 are expected to be promising targets for PDAC therapy.

Oncological Outcomes and Patterns of Recurrence after the Surgical Resection of an Invasive Intraductal Papillary Mucinous Neoplasm versus Primary Pancreatic Ductal Adenocarcinoma: An Analysis from the German Cancer Registry Group of the Society of German Tumor Centers.

Intraductal papillary mucinous neoplasms (IPMNs) are premalignant cystic neoplasms of the pancreas (CNPs), which can progress to invasive IPMN and pancreatic cancer. The available literature has shown controversial results regarding prognosis and clinical outcomes after the resection of invasive IPMN. This study aims to characterize the oncologic outcomes and metastatic progression pattern after the resection of non-metastatic invasive IPMN. Data were obtained from 24 clinical cancer registries participating in the German Cancer Registry Group of the Society of German Tumor Centers (ADT). Patients with invasive IPMN (n = 217) as well as PDAC (n = 5794) between 2000 and 2021 were included and compared regarding oncological outcomes. Invasive IPMN was significantly smaller in size (p < 0.001) and of a lower tumor grade (p < 0.001), with fewer lymph node metastases (p < 0.001), lymphangiosis (p < 0.001), and consequently a higher R0 resection rate (88 vs. 74%) compared to PDAC. Moreover, invasive IPMN was associated with fewer local (11 vs. 15%) and distant recurrences (29 vs. 46%) and metastasized more frequently in the lungs only (26% vs. 14%). Invasive IPMN was associated with a longer median OS (29 vs. 19 months) and DFS (31 vs. 15 months) compared to PDAC and stayed independently prognostic in multivariable analyses. These survival differences were most pronounced in early tumor stages. Interestingly, postoperative chemotherapy was not associated with improved overall survival in surgically resected invasive IPMN. Invasive IPMN is a rare pancreatic entity with increasing incidence in Germany. It is associated with favorable histopathological features at the time of resection and longer OS and DFS compared to PDAC, particularly before the locoregional spread has occurred. Invasive IPMNs are associated with lung-only metastasis. The benefit of postoperative chemotherapy after the resection of invasive IPMN remains uncertain.

Establishment, characterization, and biobanking of 36 pancreatic cancer organoids: prediction of metastasis in resectable pancreatic cancer

PurposeEarly dissemination of primary pancreatic ductal adenocarcinoma (PDAC) is the main cause of dismal prognosis as it highly limits possible treatment options. A number of PDAC patients experience distant metastasis even after treatment due to the metastatic clones. We aimed to demonstrate the molecular architecture of borderline resectable PDAC manifests cancer dissemination of PDAC.MethodsHere, 36 organoids isolated from primary tumor masses of PDAC patients with diverse metastatic statues are presented. Whole-exome sequencing and RNA sequencing were performed and drug responses to clinically relevant 18 compounds were assessed.ResultsOur results revealed that borderline resectable PDAC organoids exhibited distinct patterns according to their metastatic potency highlighted by multiple genetic and transcriptional factors and strong variances in drug responses.ConclusionsThese data suggest that the presence of metastatic PDAC can be identified by integrating molecular compositions and drug responses of borderline resectable PDAC.

Abstract 6903: Treatment efficacy of transcatheter hepatic arterial infusion chemotherapy with cisplatin in a severe immunodeficient rat model with patient-derived primary pancreatic ductal adenocarcinoma xenografted into the liver

Abstract Purpose: Liver metastases of pancreatic ductal adenocarcinoma (PDAC) is a highly fatal disease; most patients die within 5 years. There is a critical need to identify appropriate anticancer treatments for these patients. A patient-derived tumor xenograft (PDX) model in severe immunodeficient rat with primary PDAC xenografted into the liver is suitable for evaluating transcatheter hepatic arterial infusion chemotherapy. Materials and Methods: The purpose of this study was to develop a severe immunodeficient rat model with patient-derived primary PDAC xenografted into the liver, and to assess the treatment efficacy of hepatic arterial infusion chemotherapy with cisplatin in this model. Three patient-derived tumors of PDAC were transplanted into the liver of 21 rats each, totaling 63 rats. Four weeks after transplantation, the 21 rats were randomly assigned into three treatment groups of seven rats each: hepatic arterial infusion, systemic venous infusion, and control group. Tumor volumes were evaluated on CT twice at pre-treatment and 4-weeks post-treatment. Following euthanasia of the rats, resected tumor specimens were pathologically analyzed. Results: The liver-implanted PDAC PDX rat model was established in all 63 rats. hepatic arterial infusion chemotherapy and systemic venous infusion chemotherapy with cisplatin were able to be performed in the assigned rats. The hepatic arterial infusion group significantly inhibited tumor growth and reduced Ki67 expression, indicating lower cell proliferation, compared to the control group in three PDX tumors. Conclusion: A rat-based preclinical platform was established by liver-implanted PDAC PDX rat model. Arterial cisplatin infusion chemotherapy would be one of potential therapies for PDAC liver metastases. Citation Format: Ken Kageyama, Akira Yamamoto, Masanori Ozaki, Kenjiro Kimura, Shinpei Eguchi, Ryota Tanaka, Mizue Terai, Takami Sato, Yukio Miki. Treatment efficacy of transcatheter hepatic arterial infusion chemotherapy with cisplatin in a severe immunodeficient rat model with patient-derived primary pancreatic ductal adenocarcinoma xenografted into the liver [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 6903.

Abstract C012: TIGIT expression correlates to worse overall survival in primary and metastatic pancreatic ductal adenocarcinoma

Abstract Pancreatic Cancer has a 12% 5-year survival rate due to late-stage detection and lack of many chemotherapy or targeted therapy options. TIGIT is an immune checkpoint inhibitor being explored in clinical trials in pancreatic cancer due to the implications of its ligand (CD155) promoting immune evasion. TIGIT is a marker of T cell exhaustion and plays a key role in the inhibition of anti-tumor immune responses. We hypothesize that targeted anti-TIGIT therapy, in conjunction with other therapies targeting the tumor microenvironment, could reverse immune suppression that is characteristic of pancreatic ductal adenocarcinoma (PDAC). As such, here we aim to quantify TIGIT expression using automated RNAscope technology and to correlate it with overall patient survival. We performed RNAscope in situ hybridization and immunohistochemistry on 25 primary and 4 metastatic (liver) formalin-fixed paraffin-embedded (FFPE) tissue sections from patients with histologically confirmed PDAC. A nuclear counterstain combined with an RNAscope probe specific for the human TIGIT mRNA was utilized. Slides were scanned at 40X magnification with an automated slide scanner and quantified using the ISH-IHC module of the HALO-v3.5 software. After cells were segmented based on nuclear recognition, the presence of TIGIT probe within the cytoplasm of each cell was determined and quantified. Percent positive cell values were then exported for statistical analysis in SPSS. De-identified clinical metadata was obtained from REDCap, a cloud-based HIPAA-compliant database used to compile patient data for research purposes. Gender, survival months, ethnicity, race, tumor histology, stage, cancer history, treatment status, and comorbidities were evaluated. We analyzed a cohort of 29 histologically-confirmed surgically resected PDACs, comprised of 25 primary pancreatic tumor samples and 4 metastatic liver core biopsies. The mean percentage of TIGIT positive cells was 63%. From this, the TIGIT high versus low threshold was determined to be 70%. High TIGIT was associated with significantly lower overall survival (p=.013), suggesting that expression of TIGIT and T cell exhaustion may predict overall worse survival. The median overall survival months for the TIGIT low group was 321 months versus 106 months for the TIGIT high group. This data leads us to hypothesize that expression of TIGIT and T cell exhaustion may predict worse overall survival. Anti-TIGIT medications are currently in clinical trials for metastatic PDAC. Here we demonstrate that high TIGIT expression is associated with an overall worse prognosis and present a novel, automated TIGIT detection protocol that may be used to determine if patients are candidates for anti-TIGIT therapy. In a clinical setting, this novel, automated biomarker TIGIT detection protocol could be used to select candidates for anti-TIGIT therapy. This may lead to improved overall patient survival. Citation Format: Madison George, Julie Clark, Kendyll Gartrelle, Georges Nassif, Donald Rempinski, Daniel Long, Hui-Ju Wen, Simone Benitz, Samuel Zwernik, Rupen Shah, Hakmin Park, David Kwon, Philip Philip, Gazala Khan, Howard Crawford, Brian Theisen, Nina Steele. TIGIT expression correlates to worse overall survival in primary and metastatic pancreatic ductal adenocarcinoma [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr C012.

Multifocal Primary Pancreatic Adenocarcinoma With No Precursor Lesion: A Report of Two Cases

Multifocal Primary Pancreatic Adenocarcinoma With No Precursor Lesion: A Report of Two Cases

Characteristics Associated With Survival in Surgically Nonresected Pancreatic Adenocarcinoma in the Military Health System.

Pancreatic cancer is often diagnosed at advanced stages with high-case fatality. Many tumors are not surgically resectable. We aimed to identify features associated with survival in patients with surgically nonresected pancreatic cancer in the Military Health System. We used the Military Cancer Epidemiology database to identify the Department of Defense beneficiaries aged 18 and older diagnosed with a primary pancreatic adenocarcinoma between January 1998 and December 2014 who did not receive oncologic surgery as treatment. We used Cox Proportional Hazard regression with stepwise procedures to select the sociodemographic and clinical characteristics related to 2-year overall survival, expressed as adjusted hazard ratios (aHR) and 95% CIs. Among 1148 patients with surgically nonresected pancreatic cancer, sex, race-ethnicity, marital status, and socioeconomic indicators were not selected in association with survival. A higher comorbidity count (aHR 1.30, 95% CI: 1.06-1.59 for 5 vs. 0), jaundice at diagnosis (aHR 1.57, 95% CI: 1.33-1.85 vs. no), tumor grade G3 or G4 (aHR 1.32, 95% CI: 1.05-1.67 vs. G1/G2), tumor location in pancreas tail (aHR 1.49, 95% CI: 1.22-1.83 vs. head) or body (aHR 1.30, 95% CI: 1.04-1.62 vs. head), and metastases were associated with survival. Patients receiving chemotherapy (aHR 0.66, 95% CI: 0.57-0.76) had better survival compared with no treatment. In a comprehensive health system, sociodemographic characteristics were not related to survival in surgically nonresected pancreatic cancer. This implicates access to care in reducing survival disparities in advanced pancreatic cancer and emphasizes the importance of treating patients based on clinical features.

Primary Pancreatic Lymphoma: A Rare Clinical Entity

Pancreatic adenocarcinoma is one of the most aggressive malignant diseases, rarely, pancreatic lymphomas are diagnosed. The final diagnosis of primary pancreatic lymphoma demands histopathology of the lesion; however, radiological features and tumor markers can help to give an idea about the disease. The most important difference between primary pancreatic lymphomas and pancreatic adenocarcinoma is the different treatment modalities the response to treatment and finally good prognosis in primary pancreatic lymphoma cases. Clinically it is difficult to differentiate the symptoms of primary pancreatic lymphomas from other carcinomas of the pancreas. Rarely patients may experience B- symptoms of lymphomas that are night sweats and fever in the case of primary pancreatic lymphomas.

Intercellular Mechanisms of Therapeutic Resistance at the Tumor-Stromal Interface Using Ultra High-Plex Single-Cell Spatial Transcriptomics and Genetically-Engineered Tumoroids

There is a major gap in knowledge regarding how intercellular interactions in the tumor microenvironment (TME) mediate therapeutic resistance. Achievement of this goal has been limited by a lack of (1) spatial context in dissociated single-cell methods; (2) single-cell resolution in spatial profiling approaches; (3) high quality data and yield with FFPE patient specimens; and (4) computational methods for ligand-receptor analyses that consider both gene expression and spatial coordinates. We developed an innovative spatial biology paradigm that combines cutting-edge experimental and computational methods to enable high-resolution, spatially-guided discovery of critical mediators of therapeutic resistance. We applied this approach to dissect the single-cell spatial transcriptomic landscape of untreated vs. chemoradiotherapy-treated primary human pancreatic ductal adenocarcinoma (PDAC; n = 21) using ultra-high plex spatial molecular imaging (SMI) optimized for high-sensitivity, subcellular detection of up to 6000 gene transcripts in FFPE sections-an order of magnitude greater than contemporary methods. We recovered over 1,000,000 high-quality single cells in situ representing more than 20 distinct cell types, including epithelial, immune, endothelial, endocrine, and diverse stromal cells. We developed an optimal transport-based computational method to infer cell-cell communication at the cancer-stromal interface. Treatment with chemoradiotherapy was associated with the largest increase in fibroblast-malignant interactions. Comparing the SMI data with orthogonal single-nucleus RNA-sequencing and digital spatial profiling data, we identified CLCF1-CNTFR as the fibroblast-malignant interaction most associated with resistance to chemoradiotherapy in PDAC. CLCF1 is a gp130-family cytokine that activates Jak-STAT signaling and acts as a potent neurotrophic factor. Notably, the CLCF1-CNTRF (fibroblast-malignant) interaction has prominent pro-oncogenic effects in lung adenocarcinoma and an engineered CNTFR decoy receptor with therapeutic potential has been developed. To functionally validate the role of the CLCF1-CNTFR (fibroblast-malignant) interaction in mediating resistance to cytotoxic therapy, we created CRISPR-engineered cancer-fibroblast tumoroids and modulated expression of this ligand-receptor pair. Pancreatic cancer cell viability in the presence of 5-fluorouracil was better maintained with increased CLCF1-CNTFR signaling. In this study, we integrated ultra high-plex single-cell spatial transcriptomics, optimal transport ligand-receptor predictions, and genetically-engineered stromal tumoroids to identify and validate CLCF1-CNTFR as an important intercellular mechanism of resistance to chemoradiotherapy in PDAC-pioneering a paradigm for translating single-cell spatial biology to clinical oncology.

Comparison of gemcitabine plus oxaliplatin versus gemcitabine plus nab-paclitaxel as first-line chemotherapy for advanced pancreatic adenocarcinoma: A single-center retrospective analysis.

Pancreatic cancer is mostly diagnosed in an advanced stage and treated with systemic therapy with palliative intent. Nowadays, the doublet chemotherapy of Gemcitabine and nab-paclitaxel (Gem-Nab) is one of the most frequently used regimens worldwide, but is not ubiquitarily available or reimbursed. Therefore, we compared the clinical efficacy of Gem-Nab to a historical control of patients treated with gemcitabine and oxaliplatin (Gem-Ox) at our tertiary cancer center, which was the standard treatment prior to the introduction of FOLFIRINOX. This single-center retrospective real world study includes 121 patients diagnosed with locally advanced or primary metastatic pancreatic adenocarcinoma who were treated with chemotherapy doublet, with either Gem-Nab or Gem-Ox in palliative first-line. Survival rates were analyzed using the Kaplan-Meier method, and comparisons were made with log-rank tests. Gem-Ox was considered as standard first line therapy at our institution for patients who were deemed fit for doublet chemotherapy between the years 2006 to 2012. These patients were compared to a cohort of patients treated with the new standard first-line therapy of Gem-Nab between 2013 and 2020. A total of 554 patients with pancreatic cancer of all stages were screened, and 73 patients treated with Gem-Nab and 48 patients treated with Gem-Ox in the palliative first-line setting were identified and included in this analysis. Patients receiving Gem-Ox had a statistically significantly better performance score (ECOG PS) when compared to the Gem-Nab group (Odds ratio (OR) 0.28, 95% CI 0.12-0.65, p = 0.005), more often suffered from locally advanced than metastatic disease (OR 3.10, 95% CI 1.27-7.91, p = 0.019) and were younger in age (OR 0.95, 95% CI 0.91-0.99, p = 0.013). Median overall survival (OS) of the whole study cohort was 10.3 months (95% CI 8.5-11.6). No statistically significant difference in OS could be observed between the Gem-Nab and the Gem-Ox cohort (median OS: 8.9 months (95% CI 6.4-13.5) versus 10.9 months (95% CI 9.5-13.87, p = 0.794, HR 1.27, 95% CI 0.85-1.91)). Median progression-free survival (PFS) was 6.8 months in the entire cohort (95% CI 4.9-8.4). No statistically significant difference in PFS could be observed between the Gem-Nab and the Gem-Ox cohort (median PFS: 5.8 months (95% CI 4.3-8.2) versus 7.9 months (95% CI 5.4-9.5) p = 0.536, HR 1.11, 95% CI 0.74-1.67). Zero-truncated negative binomial regressions on OS and PFS adjusting for gender, age, performance status (ECOG PS), and CA19-9 levels yielded no significant difference between Gem-Nab or Gem-Ox. From our analysis, we could evidence no difference in outcome parameters in this retrospective analysis despite the worse prognostic pattern for GemOX. Therefore, we suggest Gem-Ox as potential first line treatment option for inoperable locally advanced or metastatic pancreatic cancer, especially if Gem-Nab is not available.

Optimization of laser dosimetry based on patient-specific anatomical models for the ablation of pancreatic ductal adenocarcinoma tumor

Laser-induced thermotherapy has shown promising potential for the treatment of unresectable primary pancreatic ductal adenocarcinoma tumors. Nevertheless, heterogeneous tumor environment and complex thermal interaction phenomena that are established under hyperthermic conditions can lead to under/over estimation of laser thermotherapy efficacy. Using numerical modeling, this paper presents an optimized laser setting for Nd:YAG laser delivered by a bare optical fiber (300 µm in diameter) at 1064 nm working in continuous mode within a power range of 2–10 W. For the thermal analysis, patient-specific 3D models were used, consisting of tumors in different portions of the pancreas. The optimized laser power and time for ablating the tumor completely and producing thermal toxic effects on the possible residual tumor cells beyond the tumor margins were found to be 5 W for 550 s, 7 W for 550 s, and 8 W for 550 s for the pancreatic tail, body, and head tumors, respectively. Based on the results, during the laser irradiation at the optimized doses, thermal injury was not evident either in the 15 mm lateral distances from the optical fiber or in the nearby healthy organs. The present computational-based predictions are also in line with the previous ex vivo and in vivo studies, hence, they can assist in the estimation of the therapeutic outcome of laser ablation for pancreatic neoplasms prior to clinical trials.

Prediction of synchronous distant metastasis of primary pancreatic ductal adenocarcinoma using the radiomics features derived from 18F-FDG PET and MRI

To explore the potential of the joint radiomics analysis of positron-emission tomography (PET) and magnetic resonance imaging (MRI) of primary tumours for predicting the risk of synchronous distant metastasis (SDM) in patients with pancreatic ductal adenocarcinoma (PDAC). 18F-FDG PET and MRI images of PDAC patients from January 2011 to December 2020 were collected retrospectively. Patients (n=66) who received 18F-FDG PET/CT and MRI were included in a development group. Patients (n=25) scanned with hybrid PET/MRI were incorporated in an external test group. A radiomics signature was constructed using the least absolute shrinkage and selection operator algorithm to select PET-MRI radiomics features of primary PDAC tumours. A radiomics nomogram was developed by combining the radiomics signature and important clinical indicators using univariate and multivariate analysis to assess patients' metastasis risk. The nomogram was verified with the employment of an external test group. Regarding the development cohort, the radiomics nomogram was found to be better for predicting the risk of distant metastasis (area under the curve [AUC]: 0.93, sensitivity: 87%, specificity: 85%) than the clinical model (AUC: 0.70, p<0.001; sensitivity:70%, specificity: 65%) and the radiomics signature (AUC: 0.89, p>0.05; sensitivity: 65%, specificity:100%). Concerning the external test cohort, the radiomics nomogram yielded an AUC of 0.85. PET-MRI based radiomics analysis exhibited effective prediction of the risk of SDM for preoperative PDAC patients and may offer complementary information and provide hints for cancer staging.

The diagnostic value of 18F-FAPI-74 PET/CT in detecting primary pancreatic ductal adenocarcinoma lesion and metastatic lymph node compared to 18F-FDG-PET/CT

The diagnostic value of 18F-FAPI-74 PET/CT in detecting primary pancreatic ductal adenocarcinoma lesion and metastatic lymph node compared to 18F-FDG-PET/CT

Tumor cell-free DNA detection-based liquid biopsy of plasma and bile in pancreatic ductal adenocarcinoma: a pilot study

INTRODUCTION: Plasma liquid biopsy with tumor cell-free DNA detection is one of the most promising technologies in pancreatic ductal adenocarcinoma diagnosis. Due to low levels of this biomarker in plasma its detectability turns out to be lower than expected. However, some patients with this disease present with biliary obstruction, which enables collection of bile for tumor cell-free DNA analysis.&#x0D; THE AIM: To comparison of diagnostic potential of cell-free tumor DNA detection-based liquid biopsy of plasma and bile in pancreatic ductal adenocarcinoma patients.&#x0D; MATERIAL AND METHODS: The pilot study included 15 primary untreated pancreatic ductal adenocarcinoma patients with biliary obstruction. Cell-free DNA was isolated from 5 mL of plasma and 5 mL of bile. Tumor cell-free DNA detection was performed using digital droplet PCR with KRAS gene mutations analysis: G12A, G12C, G12D, G12R, G12S, G12V, G13D и Q61H (183AC), Q61H (183AT), Q61K, Q61L, Q61R. False-positive droplets threshold was established during the analysis of plasma cell-free DNA samples from 15 healthy volunteers.&#x0D; RESULTS: Tumor cell-free DNA was detected in 13 out of 15 bile samples, whereas among paired plasma samples only 9 were positive. All plasma positive samples had a paired positive bile sample. Tumor cell-free DNA levels were statistically significantly higher in bile than in plasma: 538.0 (4.11960.0) vs. 4.4 (027.6) copies/mL (p=0.005).&#x0D; CONCLUSION: Bile liquid biopsy in pancreatic ductal adenocarcinoma patients with biliary obstruction is a promising alternative to plasma analysis, due to higher concentrations of tumor cell-free DNA.

Abstract 665: Repetitive elements and viral mimicry co-evolve with the immune microenvironment in pancreatic ductal adenocarcinoma

Abstract Overexpression of repetitive RNA is an emerging hallmark of human cancers. These diverse repetitive elements, including SINEs (Short Interspersed Nuclear Elements) and LINEs (Long Interspersed Nuclear Elements), can mimic viruses by replicating in the genome through retrotransposition and displaying pathogen-associated molecular patterns, potentially triggering inflammatory responses. However, our knowledge of how specific repeats affect tumor evolution and shape the tumor immune microenvironment in a pro- or anti-tumorigenic manner remains incomplete. We integrated evolutionary analysis on whole genome and total RNA sequencing data from a unique cohort of multiregion-sampled human primary and metastatic pancreatic ductal adenocarcinoma (PDAC). We find that the more recently evolved SINEs are more likely to form double-strand RNAs (dsRNAs), a structure known to stimulate innate immune response. Consistently, these younger SINEs are highly associated with a RIG-I associated type-I interferon signature. LINE-1 (L1) retrotransposition activity in these samples tracks with tumor phylogenetic branching and is depended on the status of TP53 mutations, supporting active differential surveillance of L1 mobility by mutant TP53 during tumor evolution. Lastly, we discovered that immunostimulatory SINE expression is anti-correlated with both ADAR1 expressions, exonuclease DIS3 expression, and L1 retrotransposons activity, suggesting a cooperative relationship between ADAR1 and L1 activity in regulating immunogenic SINE expression. We propose that pancreatic tumors modulate immunogenic SINE abundance to their pro-tumorigenic inflammatory advantage through hyperactive L1 activity via accelerated exonuclease degradation when ADAR1 is not activated. Our analysis illustrates for the first time the evolutionary role of dark matter genomic repeats in allowing tumors to actively leverage viral-like innate immune responses to manipulate their immune microenvironment for selective advantage. Citation Format: Siyu Sun. Repetitive elements and viral mimicry co-evolve with the immune microenvironment in pancreatic ductal adenocarcinoma [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 665.