Diagnosis Of Pancreatic Ductal Adenocarcinoma Research Articles

Hidden in plain sight: commonly missed early signs of pancreatic cancer on CT.

Pancreatic ductal adenocarcinoma (PDAC) has poor prognosis mostly due to the advanced stage at which disease is diagnosed. Early detection of disease at a resectable stage is, therefore, critical for improving outcomes of patients. Prior studies have demonstrated that pancreatic abnormalities may be detected on CT in up to 38% of CT studies 5years before clinical diagnosis of PDAC. In this review, we highlight commonly missed signs of early PDAC on CT. Broadly, these commonly missed signs consist of small isoattenuating PDAC without contour deformity, isolated pancreatic duct dilatation and cutoff, focal pancreatic enhancement and focalparenchymal atrophy, pancreatitis with underlying PDAC, and vascular encasement. Through providing commentary on demonstrative examples of these signs, we demonstrate how to reduce the risk of missing or misinterpreting radiological features of early PDAC.

Temporal Trends in Body Composition and Metabolic Markers Prior to Diagnosis of Pancreatic Ductal Adenocarcinoma

Changes in body composition and metabolic factors may serve as biomarkers for the early detection of pancreatic ductal adenocarcinoma (PDAC). The aim of this study was to capture the longitudinal changes in body composition and metabolic factors prior to diagnosis of PDAC. We performed a retrospective cohort study in which all patients (≥18 years) diagnosed with PDAC from 2002 to 2021 were identified. We collected all abdominal CT scans and 10 different blood-based biomarkers up to 36 months prior to diagnosis. We applied a fully automated abdominal segmentation algorithm previously developed by our group for three-dimensional quantification of body composition on CT scans. Longitudinal trends of body composition and blood-based biomarkers prior to PDAC diagnosis were estimated using linear mixed models, compared across different time windows, and visualized using spline regression. We included 1,690 patients in body composition analysis, of whom 516 (30.5%) had ≥ 2 prediagnostic CT scans. For analysis of longitudinal trends of blood-based biomarkers, 3,332 individuals were included. As an early manifestation of PDAC, we observed a significant decrease in visceral and subcutaneous adipose tissue (β =-1.94 (95% CI, -2.39, -1.48) and β = -2.59 (95% CI, -3.17, -2.02 in area (cm2)/height (m2) per 6 months closer to diagnosis, accompanied by a decrease in serum lipids (e.g., LDL; β = -2.83; 95% CI, -3.31, -2.34, total cholesterol; β = -2.69; 95% CI, -3.18, -2.20, and triglycerides; β = -1.86; 95% CI, -2.61, -1.11), and an increase in blood glucose levels. Loss of muscle tissue and bone volume was predominantly observed in the last 6 months prior to diagnosis. This study identified significant alterations in a variety of soft tissue and metabolic markers that occur in the development of PDAC. Early recognition of these metabolic changes may provide an opportunity for early detection.

Investigating the influence of taurochenodeoxycholic acid (TCDCA) on pancreatic cancer cell behavior: An RNA Sequencing Approach

Pancreatic cancer (PC) poses a substantial global health challenge, ranking as the fourth leading cause of cancer-related deaths due to its high mortality rate. Late-stage diagnoses are common due to the absence of specific symptoms. Pancreatic ductal adenocarcinoma (PDAC) accounts for the majority of PC cases. Recent research has suggested a potential link between elevated serum levels of bile acids (BAs) and tumorigenesis of PDAC. This study aims to understand how taurochenodeoxycholic acid (TCDCA), a secondary BA, influences PDAC using RNA sequencing techniques on the Capan-1 cell line. We identified 2,950 differentially expressed genes (DEGs) following TCDCA treatment, with 1,597 upregulated and 1,353 downregulated genes. These DEGs were associated with critical PDAC pathways, including coagulation, angiogenesis, cell migration, and signaling regulation.Furthermore, we reviewed relevant literature highlighting genes like DKK-1, KRT80, UPLA, and SerpinB2, known for their roles in PDAC tumorigenesis and metastasis. Our study sheds light on the complex relationship between BAs and PDAC, offering insights into potential diagnostic markers and therapeutic targets. Further research is needed to unravel these findings' precise mechanisms and clinical implications, potentially improving PDAC diagnosis and treatment.

Leveraging genomic signatures of oral microbiome-associated antibiotic resistance genes for diagnosing pancreatic cancer.

Growing evidence has increasingly suggested a potential linkage between the oral microbiome and various diseases, including pancreatic ductal adenocarcinoma (PDAC). However, the utilization of gene-level information derived from the oral microbiome for diagnosing PDAC remains unexplored. In this study, we sought to investigate the novel potential of leveraging genomic signatures associated with antibiotic resistance genes (ARGs) within the oral microbiome for the diagnosis of PDAC. By conducting an analysis of oral microbiome samples obtained from PDAC patients, we successfully identified specific ARGs that displayed distinct sequence abundance profiles correlated with the presence of PDAC. In the healthy group, three ARGs were found to be enriched, whereas 21 ARGs were enriched in PDAC patients. Remarkably, these ARGs from oral microbiome exhibited promising diagnostic capabilities for PDAC (AUROC = 0.79), providing a non-invasive and early detection method. Our findings not only provide novel modal data for diagnosing PDAC but also shed light on the intricate interplay between the oral microbiome and PDAC.

Abstract CT214: Paricalcitol addition to chemotherapy in patients with previously untreated metastatic pancreatic ductal adenocarcinoma (PINBALL)

Abstract Background Vitamin D agonism has been shown in preclinical studies to decrease the production of collagen, decrease myeloid derived suppressor cells, and decrease regulatory T cells in pancreatic ductal adenocarcinoma (PDAC). Paricalcitol is a vitamin D analog used for vitamin D replacement for those with secondary hyperparathyroidism. Two individuals with PDAC who had been developed resistance gemcitabine based combination therapy had shown clinical benefit with the addition of paricalcitol. This clinical study was done to study the effect of adding paricalcitol to individuals with metastatic PDAC receiving gemcitabine based combination therapy (NCT04054362, NCT03415854) . Methods Adults with a histologically- or cytologically-confirmed diagnosis of metastatic PDAC and who were previously untreated were eligible. Individuals received gemcitabine based combination- either gemcitabine plus nab-paclitaxel or gemcitabine plus nab-paclitaxel and cisplatin and had to either demonstrate progressive or stable disease. Paricalcitol was given at a fixed dose of 25 mcg IV three days a week. The combination continued until either disease progression or poor tolerance. The primary objective was to determine the clinical benefit of adding paricalcitol to gemcitabine based combination therapy for metastatic PDAC. Secondary objectives included assessing safety and pharmacodynamic through patient biopsies. Results A total of 34 patients were enrolled across two sites. 16 patients received paricalcitol. The overall response rate was 0% ( CR, PR). Disease control rate at 9 weeks was 21.4% (CR+PR+ SD). PFS upon addition of paricalcitol was 1.6 months. OS upon addition of paricalcitol was 4.8 months. Grade 3/4 AE's attributed to paricalcitol include 13% thrombocytopenia; 19% anemia; 6% transaminitis; 6% pleural effusion; 6% ascites- all grade 3. Conclusions The addition of paricalcitol demonstrated evidence of limited clinical benefit in individuals with metastatic PDAC receiving front-line gemcitabine based therapy. Paricalcitol was generally well tolerated. Tumor analysis is ongoing. Addition studies utilizing prospective treatment of paricalcitol for front line treatment of mPDAC are ongoing (NCT03520790). Trial funding provided by SU2C, CRUK, Lustgarten Foundation, and AACR. Citation Format: David Propper, Gayle Jameson, Denise Roe, Betsy Wertheim, Dan Von Hoff, Erkut H. Borazanci. Paricalcitol addition to chemotherapy in patients with previously untreated metastatic pancreatic ductal adenocarcinoma (PINBALL) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT214.

Circulating cell-free DNA methylation-based multi-omics analysis allows early diagnosis of pancreatic ductal adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive cancer with a 5-year survival rate of 7.2% in China. However, effective approaches for diagnosis of PDAC are limited. Tumor-originating genomic and epigenomic aberration in circulating free DNA (cfDNA) have potential as liquid biopsy biomarkers for cancer diagnosis. Our study aims to assess the feasibility of cfDNA-based liquid biopsy assay for PDAC diagnosis. In this study, we performed parallel genomic and epigenomic profiling of plasma cfDNA from Chinese PDAC patients and healthy individuals. Diagnostic models were built to distinguish PDAC patients from healthy individuals. Cancer-specific changes in cfDNA methylation landscape were identified, and a diagnostic model based on six methylation markers achieved high sensitivity (88.7% for overall cases and 78.0% for stage I patients) and specificity (96.8%), outperforming the mutation-based model significantly. Moreover, the combination of the methylation-based model with carbohydrate antigen 19-9 (CA19-9) levels further improved the performance (sensitivity: 95.7% for overall cases and 95.5% for stage I patients; specificity: 93.3%). In conclusion, our findings suggest that both methylation-based and integrated liquid biopsy assays hold promise as non-invasive tools for detection of PDAC.

Carboxylesterase-mediated imaging tool for diagnosis of liver injury and surgical resection navigation of pancreatic cancer

The liver and pancreas are both very important digestive and metabolic organs. Once a patient's liver and pancreas show lesions, such as accompanied by tumor proliferation or acute inflammation, their digestive function will be significantly damaged. The malfunction of carboxylesterase (CE) would indicate various metabolic diseases. Monitoring and utilizing the activity changes of CE of liver and pancreas related metabolic diseases will help to discover the pathological mechanisms and interaction between different organs, which would further provide indications for diagnosis and treatment. In this work, we developed a turn-on red fluorescent probe MG-CE with lysosome targeting for CE sensing in vitro and in vivo imaging showed a decrease of CE level in a hepatitis cell model and in non-alcoholic steatohepatitis (NASH) mouse. The fluorescence intensity was higher in pancreatic ductal adenocarcinoma (PDAC) than that in both cancerous and normal cells. Our results show that CE could promote the prodrug irinotecan activation and cause more significant damage to PDAC cells. Therefore, this work would provide a new molecular tool for the diagnostic imaging of NASH and PDAC, which is helpful in understanding the pathogenesis of NASH and the early diagnosis of NASH and PDAC.

Chronological pattern of venous thromboembolism (VTE) occurrence impacts in survival of pancreatic ductal adenocarcinoma (PDAC).

Limited data exist on the prognostic significance of the chronology of VTE in patients with PDAC. Medical data and survival characteristics of patients treated for PDAC from 2019 to 2021 were retrospectively reviewed. Early VTE was defined as occurring within the three months of PDAC diagnosis. 197 patients were included, 54 (27.4%) developed a VTE. Early appearanceof VTE was associated with worse prognosis: median overall survival (mOS) VTE < 3months 8.5months (HR 1.65, 95% CI 1.11-2.46; p = 0.014), mOS VTE > 3months 12.8months (HR 0.78, 95% CI 0.39-1.54; p = 0.5) and mOS patients without VTE 11.4months (95% CI 10.1-15.4). There was no significant association between the patient's VTE risk according to the Khorana risk score (KRS) (chi2 test p-value = 0.9). Early VTE is a prognostic factor in PDAC, which may identify a more aggressive subtype.

Metabolic responses to the occurrence and chemotherapy of pancreatic cancer: biomarker identification and prognosis prediction

As the most malignant tumor, the prognosis of pancreatic cancer is not ideal even in the small number of patients who can undergo radical surgery. As a highly heterogeneous tumor, chemotherapy resistance is a major factor leading to decreased efficacy and postoperative recurrence of pancreatic cancer. In this study, nuclear magnetic resonance (NMR)-based metabolomics was applied to identify serum metabolic characteristics of pancreatic ductal adenocarcinoma (PDAC) and screen the potential biomarkers for its diagnosis. Metabolic changes of patients with different CA19-9 levels during postoperative chemotherapy were also monitored and compared to identify the differential metabolites that may affect the efficacy of chemotherapy. Finally, 19 potential serum biomarkers were screened to serve the diagnosis of PDAC, and significant metabolic differences between the two CA19-9 stratifications of PDAC were involved in energy metabolism, lipid metabolism, amino acid metabolism, and citric acid metabolism. Enrichment analysis of metabolic pathways revealed six shared pathways by PDAC and chemotherapy such as alanine, aspartate and glutamate metabolism, arginine biosynthesis, glutamine and glutamate metabolism, citrate cycle, pyruvate metabolism, and glycogolysis/gluconeogeneis. The similarity between the metabolic characteristics of PDAC and the metabolic responses to chemotherapy provided a reference for clinical prediction of benefits of postoperative chemotherapy in PDAC patients.

Abstract 3794: Clinical impact of high-quality liquid biopsy for peritoneal lavage cytology in resectable pancreatic cancer

Abstract Despite the general trends towards increased cancer survival, pancreatic ductal adenocarcinoma (PDAC) still has a dismal prognosis. Peritoneal recurrence is a major recurrence pattern after pancreatectomy. Peritoneal lavage cytology (CY) is employed widely in the diagnosis and staging of PDAC to rule out patients with occult peritoneal metastasis. However, the importance of CY status both as a sign of irresectability and as a prognostic factor for PDAC remains controversial. The purposes of this study were to determine whether CY+ status precludes radical resection and to propose novel liquid biopsy using peritoneal lavage fluid to detect viable peritoneal tumor cells (v-PTCs). We conducted this study to evaluate use of a new genetically modified telomerase-specific replication-selective adenovirus, expressing GFP (TelomeScan F35) in rapid detection of v-PTC dissemination (Telo-CY). We assessed the clinical utility of high-quality testing of Telo-CY in PDAC patients in comparison with the findings of conventional CY (Conv-CY). This study was approved by the IRB in our Hospital. Patients with resectable cytologically or histologically proven PDAC were enrolled. 100 ml of saline as peritoneal lavage fluid was harvested just after a laparotomy. Half of the fluid was examined by conv-CY, based on Papanicolaou staining and MOC-31 immunostaining, and the remaining half was analyzed to detect v-PTCs by Telo-CY. To distinguish between leucocyte and cells with epithelial origin, cells were stained with anti-CD45 mAb. To further distinguish cells with primary tumor origin, cells were labeled with anti-CEA, anti-CA19-9 and Ep-CAM mAbs. GFP(+) and CD45(-), and either CEA-, CA19-9- or Ep-CAM-(+) cells were counted as v-PTCs. Patients were followed to evaluate its clinical significance. Among 53 patients aged 53-87 years (30 males, 23 females), 5 were conv-CY(+), other 12 were Telo-CY(+). All 53 patients underwent surgical resection (PD/DP/TP=32/14/7). 2 patients were double-CY-(+) [conv-CY(+) and Telo-CY(+)], and peritoneal recurrence occurred at 7-9 months after surgery, despite adjuvant chemotherapy. 3 were conv-CY(+) alone, but Telo-CY(-), and no peritoneal recurrences were observed (0%). Conversely, 10 were Telo-CY(+) alone, but conv-CY(-), and 6 out of 10 patients were relapsed with peritoneal dissemination (60%). Remaining 38 patients were double-CY-negative (conv-CY- and Telo-CY-, conv-CY±), peritoneal recurrence was observed in 3 patients (8.3%). Although CY-positive status predicts poor prognosis and a higher risk of peritoneal dissemination after resection, it is not sufficient to preclude pancreatectomy by conv-CY alone. Combined CY examination with conv-CY and Telo-CY may open the window of opportunity for leading true results, accurately predicting peritoneal recurrence in PDAC patients. The CY status should be confirmed by staging laparoscopy prior to resection. Citation Format: Masahiro Tanemura, Kenta Furukawa, Tadafumi Asaoka, Daiki Marukawa, Hironao Yasuoka, Yasuo Urata, Daisaku Yamada, Shogo Kobayashi, Hidetoshi Eguchi. Clinical impact of high-quality liquid biopsy for peritoneal lavage cytology in resectable pancreatic 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 3794.

Novel serum protein biomarker panel for early diagnosis of pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest cancers. Late presentation of disease at the time of diagnosis is one of the major reasons for dismal prognostic outcomes for PDAC patients. Currently, there is a lack of clinical biomarkers, which can be used to diagnose PDAC patients at an early resectable stage. This study performed proteomic mass spectrometry to identify novel blood-based biomarkers for early diagnosis of PDAC. Serum specimens from 88 PDAC patients and 88 healthy controls (60 discovery cohort and 28 validation cohort) were analyzed using data independent acquisition high resolution mass spectrometry to identify candidate biomarker proteins. A total of 249 proteins were identified and quantified by the mass spectrometric analysis. Six proteins were markedly (>1.5 fold) and significantly (p < .05; q < 0.1) increased in PDAC patients compared to healthy controls in discovery cohort. Notably, four of these six proteins were significantly upregulated in an independent validation cohort. The top three upregulated proteins (i.e., Polymeric Immunoglobulin Receptor [PIGR], von Willebrand Factor [vWF], and Fibrinogen) were validated using enzyme linked immunosorbent assay, which led to selection of PIGR and vWF as a diagnostic biomarker panel for PDAC. The panel showed high ability to diagnose early stage (stage I and II) PDAC patients (area under the curve [AUC]: 0.8926), which was further improved after the addition of clinically used prognostic biomarker (Ca 19-9) to the panel (AUC: 0.9798). In conclusion, a novel serum protein biomarker panel for early diagnosis of PDAC was identified.

Identification of breath volatile organic compounds to distinguish pancreatic adenocarcinoma, pancreatic cystic neoplasm, and patients without pancreatic lesions.

Volatile organic compounds (VOCs) are a promising potential biomarker that may be able to identify the presence of cancers. To identify exhaled breath VOCs that distinguish pancreatic ductal adenocarcinoma (PDAC) from intraductal papillary mucinous neoplasm (IPMN) and healthy volunteers. We collected exhaled breath from histologically proven PDAC patients, radiological diagnosis IPMN, and healthy volunteers using the ReCIVA® device between 10/2021-11/2022. VOCs were identified by thermal desorption-gas chromatography/field-asymmetric ion mobility spectrometry and compared between groups. A total of 156 participants (44% male, mean age 62.6 ± 10.6) were enrolled (54 PDAC, 42 IPMN, and 60 controls). Among the nine VOCs identified, two VOCs that showed differences between groups were dimethyl sulfide [0.73 vs 0.74 vs 0.94 arbitrary units (AU), respectively; P = 0.008] and acetone dimers (3.95 vs 4.49 vs 5.19 AU, respectively; P < 0.001). After adjusting for the imbalance parameters, PDAC showed higher dimethyl sulfide levels than the control and IPMN groups, with adjusted odds ratio (aOR) of 6.98 (95%CI: 1.15-42.17) and 4.56 (1.03-20.20), respectively (P < 0.05 both). Acetone dimer levels were also higher in PDAC compared to controls and IPMN (aOR: 5.12 (1.80-14.57) and aOR: 3.35 (1.47-7.63), respectively (P < 0.05 both). Acetone dimer, but not dimethyl sulfide, performed better than CA19-9 in PDAC diagnosis (AUROC 0.910 vs 0.796). The AUROC of acetone dimer increased to 0.936 when combined with CA19-9, which was better than CA19-9 alone (P < 0.05). Dimethyl sulfide and acetone dimer are VOCs that potentially distinguish PDAC from IPMN and healthy participants. Additional prospective studies are required to validate these findings.

Serum and tissue metallome of pancreatic ductal adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) patients have late presentation at the time of diagnosis and a poor prognosis. Metal dyshomeostasis is known to play a role in cancer progression. However, the blood and tissue metallome of PDAC patients has not been assessed. This study aimed to determine the levels of essential and toxic metals in the serum and pancreatic tissue from PDAC patients. Serum samples were obtained from PDAC patients before surgical resection. Tissue (tumor and adjacent normal pancreas) were obtained from the surgically resected specimen. Inductively coupled plasma-mass spectrometry (ICP-MS) analysis was performed to quantify the levels of 10 essential and 3 toxic metals in these samples. Statistical analysis was performed to identify dysregulated metals in PDAC and their role as potential diagnostic and prognostic biomarkers. Significantly decreased serum levels of magnesium, potassium, calcium, iron, zinc, selenium, arsenic, and mercury and increased levels of molybdenum were shown to be associated with PDAC. There were significantly decreased levels of zinc, manganese and molybdenum, and increased levels of calcium and selenium in the pancreatic tumor tissue compared with the adjacent normal pancreas. Notably, lower serum levels of calcium, iron, and selenium, and higher levels of manganese, were significantly associated with a poor prognosis (i.e., overall survival) in PDAC patients. In conclusion, this is the first study to comprehensively assess the serum and tissue metallome of PDAC patients. It identified the association of metals with PDAC diagnosis and prognosis.

MicroRNA-20a in extracellular vesicles derived from duodenal fluid is a possible biomarker for pancreatic ductal adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) has a high mortality rate owing to its late diagnosis and aggression. In addition, there are relatively few minimally invasive screening methods for the early detection of PDAC, making the identification of biomarkers for this disease a critical priority. Recent studies have reported that microRNAs in extracellular vesicles (EV-miRs) from bodily fluids can be useful for the diagnosis of PDACs. Given this, we designed this study to evaluate the utility of cancer EVs extracted from duodenal fluid (DF) and their resident EV-miRs as potential biomarkers for the detection of PDAC. EV-miRs were evaluated and identified in the supernatants of various pancreatic cancer cell lines (Panc-1, SUIT2, and MIAPaca2), human pancreatic duct epithelial cells, and the DF from patients with PDAC and healthy controls. EVs were extracted using ultracentrifugation and the relative expression of EV-miR-20a was quantified. We collected a total of 34 DF samples (27 PDAC patients and seven controls) for evaluation and our data suggest that the relative expression levels of EV-miR-20a were significantly higher in patients with PDAC than in controls (p = 0.0025). In addition, EV-miR-20a expression could discriminate PDAC from control patients regardless of the location of the tumor with an area under the curve values of 0.88 and 0.88, respectively. We confirmed the presence of EVs in the DF and suggest that the expression of EV-miR-20a in these samples may act as a potential diagnostic biomarker for PDAC.

Prevención y detección precoz del cáncer de páncreas

In western countries, pancreatic ductal adenocarcinoma (PDAC) has shown a rising incidence and is currently one of the leading causes of cancer related mortality. Due to its aggressive biology, most patients diagnosed with PDAC present with advanced disease not suitable for curative treatment. An early detection strategy could potentially improve results by detecting more PDAC patients within the initial stages of the disease.Currently, diagnosis of PDAC is mostly based in cross sectional imaging, including computed tomography and magnetic resonance imaging (MRI) as well as biomarkers such as CA 19-9. Selected cases might be further studied using endoscopic ultrasound (EUS) with the option of EUS guided biopsy if histology is needed to confirm diagnosis.Due to its low incidence, screening general population for PDAC has been shown to be an ineffective and expensive approach. For this reason, efforts have shifted towards surveillance of specific groups of patients known to be at risk for development of PDAC. In these groups, screening has shown to have a higher yield for early cases and improved results in terms of resection rates and survival. These groups include carriers of certain oncogenic germline mutations, patients with strong family history for PDAC, and patients diagnosed with mucinous cystic neoplasms of the pancreas. Patients over 50 years old diagnosed with new-onset diabetes and patients living with chronic pancreatitis are also considered to be at risk for PDAC development. Patients selected for surveillance should be included in screening protocols including periodic imaging with MRI or EUS.Development of biomarkers is an area of active research in the field of pancreatic cancer. New genetic or molecular biomarkers, to be measured in an isolated or combined manner, are an interesting approach looking to improve current diagnostic capabilities and to provide new tools for effective screening in wider groups of patients.The aim of this article is to describe strategies currently available for early detection of PDAC, including promising research areas for the near future.

JS-K Combined with a Melanin-Based Theranostic Agent: A Novel Sequential Delivery Strategy to Enhance the Near-Infrared Fluorescence Imaging of Pancreatic Ductal Adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy with a 5 year survival rate less than 12%. This malignancy is closely related to the unique tumor microenvironment (TME), which is characterized by a hypovascular and hyperdense extracellular matrix, making it difficult for drugs to permeate the tumor center. Near-infrared fluorescence (NIRF) imaging, which has high sensitivity and resolution, may improve the survival rate of PDAC patients. In this study, we first used JS-K (O2-(2,4-dinitrophenyl) 1-[(4-ethoxycarbonyl) piperazine-1-yl] diazene-1-ium-1,2-diolate) to specifically dilate blood vessels within the TME of PDAC patients and subsequently injected IR820-PEG-MNPs (IPM NPs) to diagnose and treat orthotopic PDAC. We found that JS-K promoted the accumulation of IPM NPs in orthotopic Pan02 tumor-bearing mice and was able to increase the tumor signal-to-background ratio (SBR) in the orthotopic PDAC area by 41.5%. In addition, surgical navigation in orthotopic Pan02 tumor-bearing mice and complete tumor resection based on fluorescence imaging were achieved with a detection sensitivity of 81.0%. Moreover, we verified the feasibility of the combination of laparoscopy and photothermal ablation (PTA) for the treatment of PDAC. Finally, we demonstrated that IPM NPs had greater affinity for human PDAC tissues than for normal pancreatic tissues ex vivo, preliminarily highlighting the potential for clinical translation of these NPs. In conclusion, we developed and validated a novel sequential delivery strategy that promotes the accumulation of nanoagents in the tumor area and can be used for the diagnosis and treatment of PDAC.

Liquid Biopsy for Pancreatic Cancer by Serum Extracellular Vesicle-Encapsulated Long Noncoding RNA HEVEPA.

The role of long noncoding RNAs (lncRNAs) in pancreatic ductal adenocarcinoma (PDAC) remain unclear. Extracellular vesicle (EV)-encapsulated RNAs could be effective targets for liquid biopsy. We aimed to identify previously unknown EV-encapsulated lncRNAs in PDAC and establish highly accurate methods for isolating EVs. Extracellular vesicles were isolated using existing and newly developed methods, namely, PEViA-UC and PEViA-IP, from serum samples of 20 patients with PDAC, 22 patients with intraductal papillary mucinous neoplasms, and 21 healthy individuals. Extracellular vesicle lncRNA expression was analyzed using digital PCR. Gene expression analysis using cDNA microarray revealed a highly expressed lncRNA, HEVEPA , in serum EVs from patients with PDAC. We established PEViA-UC and PEViA-IP using PEViA reagent, ultracentrifugation, and immunoprecipitation. Although detection of EV-encapsulated HEVEPA using existing methods is challenging, PEViA-UC and PEViA-IP detected EV HEVEPA , which was highly expressed in patients with PDAC compared with non-PDAC patients. The detection sensitivity for discriminating PDAC from non-PDAC using the combination of HEVEPA and HULC , which are highly expressed lncRNAs in PDAC, and carbohydrate antigen 19-9 (CA19-9), was higher than that of HEVEPA , HULC , or CA19-9 alone. Extracellular vesicle lncRNAs isolated using PEViA-IP and CA19-9 together could be effective targets in liquid biopsy for PDAC diagnosis.

Clinical Evaluation of the Pancreatic Cancer Microenvironment: Opportunities and Challenges.

Advances in our understanding of pancreatic ductal adenocarcinoma (PDAC) and its tumor microenvironment (TME) have the potential to transform treatment for the hundreds of thousands of patients who are diagnosed each year. Whereas the clinical assessment of cancer cell genetics has grown increasingly sophisticated and personalized, current protocols to evaluate the TME have lagged, despite evidence that the TME can be heterogeneous within and between patients. Here, we outline current protocols for PDAC diagnosis and management, review novel biomarkers, and highlight potential opportunities and challenges when evaluating the PDAC TME as we prepare to translate emerging TME-directed therapies to the clinic.

Improving timeliness and equity in germline genetic testing for pancreatic ductal adenocarcinoma patients: A comparative analysis and future strategies.

611 Background: Germline genetic testing is recommended for patients with pancreatic ductal adenocarcinoma (PDAC). Our previous study identified delays in germline testing for socioeconomically disadvantaged patients. We aimed to compare delays before and after implementing recommendations for same-day germline testing and identify reasons why germline testing was not performed. Methods: Using an IRB-approved protocol, PDAC patients were identified from Jan 2022 to Dec 2022 in our EMR system. Median income was estimated by zip code. Delays were calculated as the difference between diagnosis and germline test date. Social work needs were assessed through EMR review. An in-depth chart review was conducted to identify why tests were not performed. Results: An additional 100 patients were found with tests performed. Compared to our previous 135-patient study with a median delay of 27 days (d) in testing, our recent data showed a median delay of 15d (p=0.0215). In our previous study, 50 out of 135 patients (37%) received testing within two weeks of their PDAC diagnosis, whereas our recent data showed that 49 out of 100 patients (49%) received testing within two weeks (c2=3.372, p=0.0663), a 32% relative increase. The negative correlation between median income and delays in testing (r=-0.2578, p=0.0025) found in our previous study no longer existed in our recent analysis (r=0.0419, p=0.6802). Compared to our previous study in underserved minority (UM) patients (African American and Hispanic), our recent data showed a significant decrease in the delays for testing in UM patients (66d vs 19d, p=0.0041). We did not identify a difference in delays for testing between UM and not UM patients in the recent dataset (UM: 19d vs not UM: 15d, p=0.8075). In addition, compared to our previous study in patients with social work (SW) needs, our recent data showed a significant decrease in the delays for patients with SW needs (104d vs 13d, p=0.0004). We did not detect a significant difference between patients with SW needs and without SW needs in our recent data (SW: 13d vs no SW: 15d, p=0.8041). Finally, in our analysis of 87 patients without documented tests, 51 (59%) received care elsewhere, 25 (29%) were never offered tests, 5 (6%) refused tests, and 6 (7%) pursued a palliative approach. Conclusions: Our recent analysis showed a significant decrease in delays of testing, as more patients received prompt testing after PDAC diagnosis. Socioeconomically disadvantaged patients and those with social work needs no longer experienced significant delays in testing. To further mitigate delays, we plan to initiate germline testing during the first visit by providing introductory videos to increase understanding of consent. Furthermore, the substantial number of patients who were not offered tests will raise physician awareness regarding the necessity of offering germline tests.

Prognosis and clinical and molecular characteristics of patients with brain metastasis secondary to pancreatic ductal adenocarcinoma.

635 Background: Pancreatic ductal adenocarcinoma (PDAC) is a disease of poor prognosis, while secondary brain metastasis (Br-M) is reported to occur in less than 1% of patients with PDAC, with only limited data available suggesting that patients with Br-M have even worse prognosis. We sought to evaluate the prognosis, clinical, and molecular characters of patients with Br-M secondary to PDAC. Methods: The Foundry software platform was used to retrospectively query the electronic health records to identify patients diagnosed with Br-M secondary to PDAC from 2005 to 2023; clinical, molecular, and oncologic outcome data were collected. Results: Br-M was diagnosed in 44 patients with PDAC. The median follow-up was 78 months for our cohort while median overall survival (OS) from diagnosis was 47 months (95%CI=34-79 months). The median duration for Br-M detection from PDAC diagnosis was 24 months, while median OS from Br-M diagnosis was only 3 months (95%CI=2-6 months). 48% (n=21) had metastatic disease at diagnosis. Histological grade was assessed for 37 patients of which 51% (n=19) patients had poor differentiation, while 46% had moderate differentiation, and only 1 patient had a well differentiated tumor. Most of our patients received multiple lines of chemotherapy prior to Br-M development, with a median of 4 chemotherapy regimens received. The majority (73%, n=32) had ECOG performance score of 0 or 1 at Br-M diagnosis, also 82% (n=36) patients had elevated CA19-9 prior to Br-M. Metastases to more than one site other than the brain were detected in 73% (n=32), lung metastasis was the most frequently detected, followed by liver then bone (71% n=31, 66% n=29, 39% n=17, respectively). The frontal lobe was the most frequently affected (34%, n=15) followed by cerebellar affection (23%, n=10). Leptomeningeal affection was observed in (18%, n=8) patients. Targeted clinical mutation testing was done for 17 patients, KRAS was mutated in 95% (n=16) of patients, with G12V in 47% (n=8) of patients, G12D in 29% (n=5), and G12R in 18% (n=3), the second most prevalent mutation was TP53, 70% (n=12) then CDKN2A in 18% (n=3) of the patients. Surgical resection for Br-M was performed for 5 patients who had better median OS of 8.6 months followed by patients who underwent stereotactic radiosurgery (n=11) with median OS of 3.3 months, and patients who received whole brain radiation (n=20) with median OS of 2.8 months. Conclusions: This is the largest cohort for patients with Br-M form PDAC reporting thatsecondary Br-M is a late complication, associated with extremely poor prognosis, in patients who received multiple lines of therapy and have widely metastatic disease. The frontal lobe is the most frequently affected site. KRAS was the most frequently detected mutation and G12V subtype was more prevalent. surgical resection for Br-M was associated with better OS.