Early Pancreatic Ductal Adenocarcinoma Research Articles

Abstract PR005: Modulating the immunosuppressive pancreas tumor microenvironment through intratumoral delivery of cytokine-encoding mRNAs

Abstract Pancreatic ductal adenocarcinoma (PDAC) is an extremely aggressive cancer, with a mere 13% average 5-year survival rate. The hallmark desmoplastic stromal response in PDAC leads to poor vascularization, drug delivery challenges, and impaired cytotoxic immune cell infiltration, contributing to de novo therapy resistance. Our previous research has shown therapeutic induction of cellular senescence with RAS pathway targeting therapies can induce cytokine and chemokine production through the senescence-associated secretory phenotype (SASP) that can effectively activate anti-tumor T cell immunity and responses to anti-PD-1 immune checkpoint blockade. To build on these findings as well as overcome limitations associated with senescence-inducing therapy toxicity and induction of pro-tumorigenic SASP cytokines, here we leveraged mRNA technology to deliver specific SASP cytokines and chemokines we have found to stimulate immune responses directly into the suppressive PDAC TME as an immune oncology platform. We created an in vitro transcription pipeline for mRNA production and multiplexing, and demonstrate we can intratumorally deliver multiple mRNAs simultaneously into the TME of transplanted and autochthonous PDAC mouse models, stimulating the local production of cytokines normally absent in PDAC. We further characterized a novel combination of five cytokines and chemokines that can effectively recruit and activate both innate and adaptive immune responses against PDAC. Through repeated bi-weekly dosing, this mRNA combination also promotes tumor destruction and improves survival outcomes. Considering the recent success of off-the-shelf neoantigen mRNA vaccines in early human PDAC patient trials, we have now developed mRNAs that encode PDAC-specific antigens. By integrating our cytokine mRNA platform with antigen mRNAs, we observe a significant increase in intratumoral antigen-presenting dendritic cell populations and a substantially enhanced T-cell mediated anti-tumor immune response in orthotopic transplant models of PDAC. Overall, this study not only unveils pivotal insights into the cytokines absent in PDAC that are crucial for promoting anti-tumor immunity, but also pioneers an innovative immunotherapy approach. This platform has the potential to be integrated with existing immunotherapy modalities, addressing the longstanding challenge of therapy resistance in PDAC. Citation Format: Chaitanya Naimesh Parikh, Kelly De Marco, Boyang Ma, Katherine Murphy, Loretah Chibaya, Lin Zhou, Youwei Qiao, Griffin Kane, Li Li, Wen Xue, Marcus Ruscetti. Modulating the immunosuppressive pancreas tumor microenvironment through intratumoral delivery of cytokine-encoding mRNAs [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 PR005.

Trends and Outcomes of Neoadjuvant Chemotherapy for Clinical Stage T1 Pancreatic Cancer.

Neoadjuvant chemotherapy (NC) for early pancreatic ductal adenocarcinoma (PDAC) remains controversial. We investigate the adoption of NC and its impact on survival in clinical T1 (cT1) PDAC. National Cancer Database (2006-2017) was reviewed for cT1 PDAC. Patients receiving NC and surgery were compared with patients undergoing upfront surgery (US). A total of 5886 patients were included. NC use increased from 4.8% in 2006 to 18.8% in 2017. The NC group (n = 618) versus the US group (n = 5268) had: younger age (66 years vs. 68 years), smaller tumor size (2 cm vs. 2.2 cm), more pancreas head tumors (77% vs. 70.6%), lower lymph-vascular invasion (25.9% vs. 40.6%), and less lymph node positivity (43.6% vs. 54.5%), p < 0.001. Factors associated with receipt of NC were: younger age, recent year of diagnosis, and treatment at an academic program. In the NC group versus the US group, median OS was 35.2 months versus 28.3 months, p < 0.001. Factors associated with improved survival included: well differentiated pathology, R0 surgical margins, and receipt of chemotherapy. In cT1 PDAC, chemotherapy is associated with improved survival. In a surgery-first approach, only 59% of patients receive adjuvant chemotherapy. These data suggest consideration of neoadjuvant therapy for early pancreatic cancer.

Abstract A058: Tumour-associated myeloid cells expressing IL-10R2/IL-22R1 as a potential biomarker for diagnosis and recurrence of pancreatic ductal adenocarcinoma

Abstract Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer with a poor prognosis, largely due to late diagnosis and limited treatment options. The immunosuppressive tumor microenvironment (TME) further exacerbates the situation, hindering the effectiveness of traditional therapies. This study investigates the potential of IL-10R2/IL-22R1 expressing immune cells as novel biomarkers for early PDAC detection and recurrence monitoring, offering a potential avenue for improved patient outcomes. The research revealed a significant increase in the number of IL-10R2/IL-22R1 expressing immune cells in the peripheral blood of PDAC patients compared to healthy controls. These cells were found to infiltrate PDAC tissue and exhibit immunosuppressive functions, contributing to the TME's suppression of the immune response. Further investigation using a mouse model of PDAC demonstrated that early tumor progression was accompanied by a rise in IL-10R2/IL-22R1 expressing immune cells in the blood, highlighting their potential role in tumor development. In post-pancreatectomy patients, the study observed that elevated levels of IL-10R2+ immune cells were associated with earlier recurrence compared to the currently employed biomarker, CA19-9. This finding suggests that IL-10R2/IL-22R1 expressing immune cells could serve as valuable tools for predicting PDAC recurrence and potentially improving treatment outcomes. This research provides compelling evidence for the potential of IL-10R2/IL-22R1 expressing immune cells as promising biomarkers for early PDAC diagnosis and recurrence monitoring. However, further research is crucial to comprehensively understand their generation, function, and clinical utility. Larger-scale studies are needed to validate these findings and translate them into practical clinical applications for improved patient care. Citation Format: Hyung Keun Lee, So Young Kim, Soo-Hyun Chung, Sung Ill Jang, Bongkun Choi, Ji-Eun Kim, Dohee Yoon, Areum Yeo, Hyun Goo Kang, Jusung Lee, Yoon Ha Choi, Joon Seong Park, Yoolim Sung, Jong Kyoung Kim, Eun-Ju Chang, Dong Ki Lee. Tumour-associated myeloid cells expressing IL-10R2/IL-22R1 as a potential biomarker for diagnosis and recurrence of pancreatic ductal adenocarcinoma [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 A058.

Select Endocrine Disorders and Exosomes in Early PDAC Diagnosis

Disturbances in carbohydrate metabolism are suggested to be the early symptoms of pancreatic ductal adenocarcinoma (PDAC). The accumulated data suggests that endocrine function-related biomarkers may represent a breakthrough in the early detection of PDAC. Factors which may predispose one to the development of PDAC are insulin resistance and hyperinsulinemia. Elevated insulin levels induce the onset of carcinogenesis by altering the differentiation and function of islet cells through stimulating growth factors, including insulin-like growth factors (IGFs). Impaired β cell function, along with the impact of PDAC-released factors (e.g., adrenomedullin (ADM), IGF-1, and macrophage inhibitory factor (MIF) on pancreatic islets, may contribute to the induction of diabetes associated with PDAC. Recently, exosomes have attracted worldwide attention due to their role in varied features of cell function, particularly in cancer progression. Exosomes comprise of small extracellular vesicles produced by almost all cells. These vesicles contain a vast array of biomolecules, including proteins and microRNAs. Exosomes participate in cancer growth and promote angiogenesis. They promote tumorigenesis and metastasis, and are associated with the acquisition of cancer cells resistant to chemotherapy. Data have been accumulating recently on the role of exosomes in the rapid recognition, prognosis and potential therapy of pancreatic cancer.

Letrozole-Based Near-Infrared Dynamic Imaging Targeting Ductal-Vascular RhoJ From Pancreatic Intraepithelial Neoplasia to Pancreatic Ductal Adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) relies heavily on neoangiogenesis for its progression, making early detection crucial. Here, LTZi-MHI148 (Letrozole inhibitor bonding with MHI-148 dye), a near-infrared (NIR) fluorescent agent is developed, to target RhoJ (Ras Homolog Family Member J), a protein expressed in neonatal vasculature, for both imaging and therapy of early PDAC. This agent is synthesized by conjugating Letrozole with MHI-148, exhibiting excellent NIR characteristics and photostability. In vitro studies showed that LTZi-MHI148 selectively accumulated within pancreatic cancer cells through Organic Anion Transporting Polypeptide (OATP) transporters and bound to cytoplasmic RhoJ. In vivo, the probe effectively targeted neoangiogenesis and Pancreatic Intraepithelial Neoplasias (PanINs) in various PDAC models, including the orthotopic, ectopic, spontaneous, and tamoxifen-induced tumors. Notably, LTZi-MHI148 detected preneoplastic PanIN lesions with Overexpressed RhoJ and active neoangiogenesis in both spontaneous and tamoxifen-induced PDAC murine models. Longitudinal imaging studies revealed that RhoJ-targeted neoangiogenesis tracks lesion progression, highlighting LTZi-MHI148's utility in monitoring disease progression. Furthermore, multiple LTZi-MHI148 administrations attenuated PanINs to PDAC progression, suggesting its potential as a therapeutic intervention. These findings underscore the translational potential of LTZi-MHI148 for the early detection and targeted therapy of PDAC, utilizing NIR-I/II imaging to monitor RhoJ overexpression in precancerous ductal neoplasia associated with neoangiogenesis.

Association of pancreatic atrophy patterns with intraductal extension of early pancreatic ductal adenocarcinoma: a multicenter retrospective study.

Focal pancreatic parenchymal atrophy (FPPA) and upstream pancreatic atrophy (UPA) may indicate the presence of early pancreatic cancer. In early pancreatic cancer, the tumor occasionally spreads laterally along the main pancreatic duct, presenting challenges in determining the extent of surgical resection. This study aimed to investigate the association of pancreatic atrophy pattern and intraductal cancer extension. Thirty-two patients with early-stage pancreatic cancer who underwent surgery at five participating centers were enrolled. Pancreatic atrophy was defined as the narrowing of parenchyma compared to the surrounding parenchyma and was classified as either FPPA (partial atrophy surrounding the pancreatic duct stenosis) or UPA (global atrophy caudal to the site of duct stenosis). Intraductal cancer extension was defined as an extension exceeding 10mm. Preoperative computed tomography revealed FPPA, UPA, and no parenchymal atrophy in 13, 13, and 6 patients. Cases with FPPA or UPA showed significantly longer cancer extensions than those without atrophy (P = 0.005 and P = 0.03, respectively). Intraductal cancer extension was present in all but one case of FPPA. 69% (9/13) of the cases with UPA showed intraductal cancer extension, whereas cases without atrophy showed no intraductal cancer extension. Importantly, two patients with FPPA or UPA showed positive resection margins during surgery and three patients with FPPA or UPA showed recurrence in the remnant pancreas. The presence of FPPA and UPA indicates lateral cancer extension in early-stage pancreatic cancer. Preoperative assessment of the pancreatic parenchyma may provide valuable insights for determining the extent of surgical resection.

Abstract B059: Modulating the immunosuppressive pancreas tumor microenvironment through intratumoral delivery of cytokine-encoding mRNAs

Abstract Pancreatic ductal adenocarcinoma (PDAC) is an extremely aggressive cancer, with a mere 13% average 5-year survival rate. The hallmark desmoplastic stromal response in PDAC leads to poor vascularization, drug delivery challenges, and impaired cytotoxic immune cell infiltration, contributing to de novo therapy resistance. Our previous research has shown therapeutic induction of cellular senescence with RAS pathway targeting therapies can induce cytokine and chemokine production through the senescence-associated secretory phenotype (SASP) that can effectively activate anti-tumor T cell immunity and responses to anti-PD-1 immune checkpoint blockade. To build on these findings as well as overcome limitations associated with senescence-inducing therapy toxicity and induction of pro-tumorigenic SASP cytokines, here we leveraged mRNA technology to deliver specific SASP cytokines and chemokines we have found to stimulate immune responses directly into the suppressive PDAC TME as an immune oncology platform. We created an in vitro transcription pipeline for mRNA production and multiplexing, and demonstrate we can intratumorally deliver multiple mRNAs simultaneously into the TME of transplanted and autochthonous PDAC mouse models, stimulating the local production of cytokines normally absent in PDAC. We further characterized a novel combination of five cytokines and chemokines that can effectively recruit and activate both innate and adaptive immune responses against PDAC. Through repeated bi-weekly dosing, this mRNA combination also promotes tumor destruction and improves survival outcomes. Considering the recent success of off-the-shelf neoantigen mRNA vaccines in early human PDAC patient trials, we have now developed mRNAs that encode PDAC-specific antigens. By integrating our cytokine mRNA platform with antigen mRNAs, we observe a significant increase in intratumoral antigen-presenting dendritic cell populations and a substantially enhanced T-cell mediated anti- tumor immune response in orthotopic transplant models of PDAC. Overall, this study not only unveils pivotal insights into the cytokines absent in PDAC that are crucial for promoting anti- tumor immunity, but also pioneers an innovative immunotherapy approach. This platform has the potential to be integrated with existing immunotherapy modalities, addressing the longstanding challenge of therapy resistance in PDAC. Citation Format: Chaitanya Naimesh Parikh, Kelly De Marco, Katherine Murphy, Loretah Chibaya, Lin Zhou, Youwei Qiao, Griffin Kane, Li Li, Wen Xue, Marcus Ruscetti. Modulating the immunosuppressive pancreas tumor microenvironment through intratumoral delivery of cytokine-encoding mRNAs [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research; 2024 Sep 15-18; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl_2):Abstract nr B059.

Abstract B084: Comparative functional analysis of TP53 alleles in pancreatic ductal adenocarcinoma in vivo

Abstract TP53 is the second most mutated gene in pancreatic ductal adenocarcinoma (PDAC), bearing both truncal loss-of-function and missense point mutations. TP53 encodes a stress-induced transcription factor (p53) capable of activating tumor suppressive pathways mediating cell cycle arrest, apoptosis, senescence, and metabolic reprogramming. Despite high mutational frequency, how TP53 mutants function to suppress pancreatic tumorigenesis in vivo remains unclear. Previous studies indicate that the most frequent point mutations observed in human PDAC (TP53 R175H and R273H; mouse homologues Trp53 R172H and R270H) exhibit both dominant-negative (e.g., response to radiation in leukemia cells) and gain-of-function (e.g., increased liver metastasis in advanced PDAC models) roles compared to p53 null cells in various contexts. To rigorously explore the differential functions of p53 point and deletion mutants in PDAC progression, we performed an isogenic comparative analysis of Trp53 alleles in vivo using Mosaic Analysis with Double Markers (MADM) in mice. MADM uses stochastic mitotic recombination to induce two genotypically distinct daughter cells – created at 1-to-1 ratios – expressing different Trp53 variants dependent on the genotype of the mouse (+/+ vs. -/-, R172H/R172H vs. +/+, R172H/R172H vs. -/-, R270H/R270H vs. +/+, R270H/R270H vs. -/-) and simultaneously label them with unique genetically encoded fluorescent markers (TdTomato vs. GFP). We integrated MADM into a faithful Kras-driven model of pancreatic tumorigenesis (KC: Kras LSL-G12D/+ ; Pdx1-Cre) and used fluorescence microscopy to trace subclonal populations with various Trp53 alleles within the same mouse. By analyzing the ratio of TdTomato+ to GFP+ cells, we studied the functional differences between alleles in driving tumor initiation and expansion at various stages of progression. Strikingly, we found that Trp53 -/- cells exhibited greater expansion in preinvasive pancreatic intraepithelial neoplasias (PanINs) compared to not only Trp53 +/+ cells but also cells harboring either point mutation (Trp53 R172H/R172H or Trp53 R270H/R270H ). While Trp53 R270H/R270H cells predominated over Trp53 +/+ in PanINs, Trp53 R172H/R172H cells were surprisingly indistinguishable from Trp53 +/+ cells, suggesting that p53R172H retains tumor suppressive properties in early PDAC progression. Conversely, both Trp53 R172H/R172H and Trp53 R270H/R270H cells progressed to advanced PDAC with comparable PDAC incidence and survival as Trp53 -/- , arguing that Trp53 R172H is a separation-of-function mutant concordant with a distinct transcriptional profile relative to Trp53 -/- tumor cells. Together, these studies offer the strongest evidence to date for stage-specific functional differences between TP53 mutant variants in cancer progression in vivo and provide a faithful MADM-based PDAC model to define molecular mechanisms (through ongoing transcriptomic, epigenomic, and metabolomic studies) that govern functional differences amongst these diverse alleles. Citation Format: Sherry S. Agabiti, Andy Tang, Timothy Nottoli, Mandar D. Muzumdar. Comparative functional analysis of TP53 alleles in pancreatic ductal adenocarcinoma in vivo [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research; 2024 Sep 15-18; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl_2):Abstract nr B084.

Multiplexed Glycan Immunofluorescence Identification of Pancreatic Cancer Cell Subpopulations in Both Tumor and Blood Samples.

Pancreatic ductal adenocarcinoma (PDAC) tumor heterogeneity impedes the development of biomarker assays suitable for early disease detection that would improve patient outcomes. The CA19-9 glycan is currently used as a standalone biomarker for PDAC. Furthermore, previous studies have shown that cancer cells may display aberrant membrane-associated glycans. We therefore hypothesized that PDAC cancer cell subpopulations could be distinguished by aberrant glycan signatures. We used multiplexed glycan immunofluorescence combined with pathologist annotation and automated image processing to distinguish between PDAC cancer cell subpopulations within tumor tissue. Using a training-set/test-set approach, we found that PDAC cancer cells may be identified by signatures comprising 4 aberrant glycans (VVL, CA19-9, sTRA, and GM2) and that there are three glycan-defined PDAC tumor types: sTRA type, CA19-9 type, and intermixed. To determine whether the aberrant glycan signatures could be detected in blood samples, we developed hybrid glycan sandwich assays for membrane-associated glycans. In both patient-matched tumor and blood samples, the proportion of aberrant glycans detected was consistent. Furthermore, our multiplexed glycan immunofluorescent approach proved to be more sensitive and more specific than CA19-9 alone. Our results provide proof of concept for a novel methodology to improve early PDAC detection and patient outcomes.

Case Study on Analysing the Early Disease Detection of Pancreatic Ductal Adenocarcinoma in Korean Association for Clinical Oncology.

Pancreatic ductal adenocarcinoma (PDAC) is the most pervasive sort of pancreatic malignant growth. Due to the lack of early symptoms and effective methods for early detection and screening, the majority of patients (80% to 85%) are diagnosed with advanced metastatic or locally advanced disease, resulting in a low 5-year survival rate of 12%. The case study represents a comprehensive investigation into the intricate landscape of pancreatic cancer diagnosis within the Korean population. Grounded in epidemiological bits of knowledge, the review plans to disentangle the particular examples, commonness, and segment attributes of PDAC in Korea. By scrutinizing current diagnostic modalities, including conventional imaging techniques, molecular markers, and emerging technologies, the research seeks to evaluate the strengths and limitations of existing approaches within the Korean clinical context. Central to the study is an exploration of the collaborative initiatives spearheaded by the Association of Clinical Oncology in Korea in the domain of PDAC early detection. Analysing research projects, clinical trials, and interdisciplinary collaborations, the case study sheds light on the association's pivotal role in driving innovation and progress in oncology. The goal is to offer a detailed analysis of how the association helps in furthering knowledge and enhancing results in the management of PDAC. The case study delves into the implications of early PDAC detection for patient outcomes, emphasizing the significance of timely interventions and tailored treatment strategies. By outlining the potential benefits and challenges associated with early diagnosis, the study aims to inform health care policies, shape clinical guidelines, and guide future research priorities. Through a holistic approach, the case study endeavours to offer important experiences into the multifaceted landscape of PDAC early detection within the Korean health care system, contributing to the broader discourse on effective oncological practices and patient care.

Power-Doppler-based NH002 microbubble sonoporation with chemotherapy relieves hypoxia and enhances the efficacy of chemotherapy and immunotherapy for pancreatic tumors

Pancreatic ductal adenocarcinoma (PDAC) poses challenges due to late-stage diagnosis and limited treatment response, often attributed to the hypoxic tumor microenvironment (TME). Sonoporation, combining ultrasound and microbubbles, holds promise for enhancing therapy. However, additional preclinical research utilizing commercially available ultrasound equipment for PDAC treatment while delving into the TME's intricacies is necessary. This study investigated the potential of using a clinically available ultrasound system and phase 2-proven microbubbles to relieve tumor hypoxia and enhance the efficacy of chemotherapy and immunotherapy in a murine PDAC model. This approach enables early PDAC detection and blood-flow-sensitive Power-Doppler sonoporation in combination with chemotherapy. It significantly extended treated mice's median survival compared to chemotherapy alone. Mechanistically, this combination therapy enhanced tumor perfusion and substantially reduced tumor hypoxia (77% and 67%, 1- and 3-days post-treatment). Additionally, cluster of differentiation 8 (CD8) T-cell infiltration increased four-fold afterward. The combined treatment demonstrated a strengthening of the anti-programmed death-ligand 1(αPDL1) therapy against PDAC. Our study illustrates the feasibility of using a clinically available ultrasound system with NH-002 microbubbles for early tumor detection, alleviating hypoxic TME, and improving chemotherapy and immunotherapy. It suggests the development of an adjuvant theragnostic protocol incorporating Power-Doppler sonoporation for pancreatic tumor treatment.

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.

CT-based fully automated artificial intelligence model to predict extrapancreatic perineural invasion in pancreatic ductal adenocarcinoma

Background: Extrapancreatic perineural invasion (EPNI) increases the risk of postoperative recurrence in pancreatic ductal adenocarcinoma (PDAC). This study aimed to develop and validate a computed tomography (CT)-based, fully automated preoperative artificial intelligence (AI) model to predict EPNI in patients with PDAC. Methods: We retrospectively enrolled 1065 patients from two Shanghai hospitals between June 2014 and April 2023. Patients were split into training (n=497), internal validation (n=212), internal test (n=180), and external test (n=176) sets. The AI model used perivascular space and tumor contact for EPNI detection. We evaluated the AI model’s performance based on its discrimination. Kaplan-Meier curves, log-rank tests, and Cox regression were used for survival analysis. Results: The AI model demonstrated superior diagnostic performance for EPNI with 1-pixel expansion. The area under the curve in the training, validation, internal test, and external test sets were 0.87, 0.88, 0.82, and 0.83, respectively. The log-rank test revealed a significantly longer survival in the AI-predicted EPNI-negative group than the AI-predicted EPNI-positive group in the training, validation, and internal test sets (P&lt;0.05). Moreover, the AI model exhibited exceptional prognostic stratification in early PDAC and improved assessment of neoadjuvant therapy’s effectiveness. Conclusion: The AI model presents a robust modality for EPNI diagnosis, risk stratification, and neoadjuvant treatment guidance in PDAC, and can be applied to guide personalized precision therapy.

The Potential of Fecal and Urinary Biomarkers for Early Detection of Pancreatic Ductal Adenocarcinoma: A Systematic Review.

Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal cancer often diagnosed at advanced stages, highlighting the urgent need for early detection strategies. This systematic review explores the potential of fecal and urinary biomarkers for early PDAC detection. A comprehensive search identified eight relevant studies investigating various biomarkers, including proteins, metabolites, microbial profiles, DNA mutations, and non-coding RNAs. Promising findings suggest that urinary biomarkers related to metabolic alterations, inflammatory processes, fecal microbiome profiles, and fecal miRNAs hold diagnostic potential even at early stages of PDAC. Combining biomarkers into panels may enhance diagnostic accuracy. Challenges such as validation in larger cohorts, standardization of protocols, and regulatory approval must be addressed for clinical translation. Despite these hurdles, non-invasive urinary and fecal biomarkers represent a promising avenue for improving PDAC outcomes through early detection.

Hepatic signal transducer and activator of transcription-3 signalling drives early-stage pancreatic cancer cachexia via suppressed ketogenesis.

Patients with pancreatic ductal adenocarcinoma (PDAC) often suffer from cachexia, a wasting syndrome that significantly reduces both quality of life and survival. Although advanced cachexia is associated with inflammatory signalling and elevated muscle catabolism, the early events driving wasting are poorly defined. During periods of nutritional scarcity, the body relies on hepatic ketogenesis to generate ketone bodies, and lipid metabolism via ketogenesis is thought to protect muscle from catabolizing during nutritional scarcity. We developed an orthotopic mouse model of early PDAC cachexia in 12-week-old C57BL/6J mice. Murine pancreatic cancer cells (KPC) were orthotopically implanted into the pancreas of wild-type, IL-6-/-, and hepatocyte STAT3-/- male and female mice. Mice were subject to fasting, 50% food restriction, ad libitum feeding or ketogenic diet interventions. We measured longitudinal body composition by EchoMRI, body mass and food intake. At the endpoint, we measured tissue mass, tissue gene expression by quantitative real-time polymerase chain reaction, whole-body calorimetry, circulating hormone levels, faecal protein and lipid content, hepatic lipid content and ketogenic response to medium-chain fatty acid bolus. We assessed muscle atrophy in vivo and C2C12 myotube atrophy in vitro. Pre-cachectic PDAC mice did not preserve gastrocnemius muscle mass during 3-day food restriction (-13.1±7.7% relative to food-restricted sham, P=0.0117) and displayed impaired fatty acid oxidation during fasting, resulting in a hypoketotic state (ketogenic response to octanoate bolus, -83.0±17.3%, P=0.0328; Hmgcs2 expression, -28.3±7.6%, P=0.0004). PDAC human patients display impaired fasting ketones (-46.9±7.1%, P<0.0001) and elevated circulating interleukin-6 (IL-6) (12.4±16.5-fold increase, P=0.0001). IL-6-/- PDAC mice had improved muscle mass (+35.0±3.9%, P=0.0031) and ketogenic response (+129.4±44.4%, P=0.0033) relative to wild-type PDAC mice. Hepatocyte-specific signal transducer and activator of transcription 3 (STAT3) deletion prevented muscle loss (+9.3±4.0%, P=0.009) and improved fasting ketone levels (+52.0±43.3%, P=0.018) in PDAC mice. Without affecting tumour growth, a carbohydrate-free diet improved tibialis anterior myofibre diameter (+16.5±3.5%, P=0.0089), circulating ketone bodies (+333.0±117.6%, P<0.0001) and Hmgcs2 expression (+106.5±36.1%, P<0.0001) in PDAC mice. Ketone supplementation protected muscle against PDAC-induced atrophy in vitro (+111.0±17.6%, P<0.0001 myofibre diameter). In early PDAC cachexia, muscle vulnerability to wasting is dependent on inflammation-driven metabolic reprogramming in the liver. PDAC suppresses lipid β-oxidation and impairs ketogenesis in the liver, which is reversed in genetically modified mouse models deficient in IL-6/STAT3 signalling or through ketogenic diet supplementation. This work establishes a direct link between skeletal muscle homeostasis and hepatic metabolism. Dietary and anti-inflammatory interventions that restore ketogenesis may be a viable preventative approach for pre-cachectic patients with pancreatic cancer.

Computed tomography-based radiomics diagnostic approach for differential diagnosis between early- and late-stage pancreatic ductal adenocarcinoma.

One of the primary reasons for the dismal survival rates in pancreatic ductal adenocarcinoma (PDAC) is that most patients are usually diagnosed at late stages. There is an urgent unmet clinical need to identify and develop diagnostic methods that could precisely detect PDAC at its earliest stages. To evaluate the potential value of radiomics analysis in the differentiation of early-stage PDAC from late-stage PDAC. A total of 71 patients with pathologically proved PDAC based on surgical resection who underwent contrast-enhanced computed tomography (CT) within 30 d prior to surgery were included in the study. Tumor staging was performed in accordance with the 8th edition of the American Joint Committee on Cancer staging system. Radiomics features were extracted from the region of interest (ROI) for each patient using Analysis Kit software. The most important and predictive radiomics features were selected using Mann-Whitney U test, univariate logistic regression analysis, and minimum redundancy maximum relevance (MRMR) method. Random forest (RF) method was used to construct the radiomics model, and 10-times leave group out cross-validation (LGOCV) method was used to validate the robustness and reproducibility of the model. A total of 792 radiomics features (396 from late arterial phase and 396 from portal venous phase) were extracted from the ROI for each patient using Analysis Kit software. Nine most important and predictive features were selected using Mann-Whitney U test, univariate logistic regression analysis, and MRMR method. RF method was used to construct the radiomics model with the nine most predictive radiomics features, which showed a high discriminative ability with 97.7% accuracy, 97.6% sensitivity, 97.8% specificity, 98.4% positive predictive value, and 96.8% negative predictive value. The radiomics model was proved to be robust and reproducible using 10-times LGOCV method with an average area under the curve of 0.75 by the average performance of the 10 newly built models. The radiomics model based on CT could serve as a promising non-invasive method in differential diagnosis between early and late stage PDAC.

Excavation of gene markers associated with pancreatic ductal adenocarcinoma based on interrelationships of gene expression.

Pancreatic ductal adenocarcinoma (PDAC) accounts for 95% of all pancreatic cancer cases, posing grave challenges to its diagnosis and treatment. Timely diagnosis is pivotal for improving patient survival, necessitating the discovery of precise biomarkers. An innovative approach was introduced to identify gene markers for precision PDAC detection. The core idea of our method is to discover gene pairs that display consistent opposite relative expression and differential co-expression patterns between PDAC and normal samples. Reversal gene pair analysis and differential partial correlation analysis were performed to determine reversal differential partial correlation (RDC) gene pairs. Using incremental feature selection, the authors refined the selected gene set and constructed a machine-learning model for PDAC recognition. As a result, the approach identified 10 RDC gene pairs. And the model could achieve a remarkable accuracy of 96.1% during cross-validation, surpassing gene expression-based models. The experiment on independent validation data confirmed the model's performance. Enrichment analysis revealed the involvement of these genes in essential biological processes and shed light on their potential roles in PDAC pathogenesis. Overall, the findings highlight the potential of these 10 RDC gene pairs as effective diagnostic markers for early PDAC detection, bringing hope for improving patient prognosis and survival.

Temporal progression of pancreatic cancer computed tomography findings until diagnosis: A large-scale multicenter study.

Focal parenchymal atrophy and main pancreatic duct (MPD) dilatation have been identified as early signs of pancreatic ductal adenocarcinoma. However, limited evidence exists regarding their temporal progression due to previous study limitations with restricted case numbers. To ascertain a more precise frequency assessment of suspicious pancreatic ductal adenocarcinoma findings as well as delineate the temporal progression of them. A multicenter retrospective study was conducted on patients diagnosed with pancreatic ductal adenocarcinoma between 2015 and 2021. We included patients who had undergone at least one computed tomography (CT) scan ≥6months before diagnosing pancreatic ductal adenocarcinoma. The temporal progression of suspicious pancreatic ductal adenocarcinoma findings on CT was investigated. Out of 1832 patients diagnosed with pancreatic ductal adenocarcinoma, 320 had a previous CT before their diagnosis. Suspicious pancreatic ductal adenocarcinoma findings were detected in 153 cases (47.8%), with focal parenchymal atrophy (26.6%) being the most common followed by MPD dilatation (11.3%). Focal parenchymal atrophy was the earliest detectable sign among all suspicious findings and became visible on average 2.7years before diagnosis, and the next most common, MPD dilatation, 1.1years before diagnosis. Other findings, such as retention cysts, were less frequent and appeared around 1year before diagnosis. Focal parenchymal atrophy followed by MPD dilatation was observed in 10 patients but not in reverse order. Focal parenchymal atrophy was more frequently detected in the pancreatic body/tail. No significant relationship was found between the pathological pancreatic ductal adenocarcinoma differentiation or tumor stage and the time course of the CT findings. All cases of focal parenchymal atrophy progressed just prior to diagnosis, and the atrophic area was occupied by tumor at diagnosis. Main pancreatic duct dilatation continued to progress until diagnosis. This large-scale study revealed that the temporal progression of focal parenchymal atrophy is the earliest detectable sign indicating pancreatic ductal adenocarcinoma. These results provide crucial insights for early pancreatic ductal adenocarcinoma detection.

Emerging Horizons in the Diagnosis of Pancreatic Cancer: The Role of Circulating microRNAs as Early Detection Biomarkers for Pancreatic Ductal Adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive cancer with a poor prognosis, primarily due to a late diagnosis. Recent studies have focused on identifying non-invasive biomarkers for early detection, with microRNAs (miRNAs) emerging as promising candidates. This systematic review aims to evaluate the potential of circulating miRNAs as biomarkers for the early detection of PDAC, analyzing their diagnostic accuracy, specificity, and sensitivity. Following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, a comprehensive search across PubMed, Embase, and the Cochrane Library was conducted. Studies published from January 2013 to October 2023 focusing on miRNA biomarkers for early PDAC detection were included. Data synthesis was performed through a narrative approach due to the heterogeneity of the studies. Nine studies met the inclusion criteria. Key findings include the elevated levels of specific miRNAs, such as miR-18a, miR-106a, and miR-25, in early-stage PDAC patients compared to controls. The integration of miRNA profiles with traditional biomarkers like CA19-9 showed improved diagnostic performance. However, challenges in the standardization of miRNA evaluation methodologies were noted. Circulating miRNAs demonstrate significant potential as non-invasive biomarkers for early PDAC detection. Despite promising results, further research and standardization are necessary for clinical application.

Abstract A014: Combinations of previously reported biomarkers achieve improved sensitivity and specificity of detection of early stage pancreatic ductal adenocarcinoma

Abstract A promising approach to the early detection of pancreatic ductal adenocarcinoma (PDAC) is surveillance among people at elevated risk for the disease using a blood test. Several groups have reported promising biomarkers, but no single biomarker delivers the rate of positively predicting cancers and of negatively predicting non-cancers needed for routine use. We hypothesized that combinations of previously reported PDAC biomarkers could contribute complementary detection across heterogeneous subgroups of patients and consequently improve biomarker performance. Blood plasma specimens from 427 individuals, grouped into a training set (n = 132) and a validation set (n = 295), were distributed to four different laboratories for analysis using their independently developed biomarker assays. We analyzed the training set to identify biomarker combinations that improved upon CA19-9 for identification of early stage PDAC relative to benign disease conditions, both for improved sensitivity while controlling for high specificity and improved specificity while controlling for high sensitivity. We then applied the biomarker combinations to the validation set to determine their performance. The combination of CA19-9 with the glycan biomarker CA199.STRA improved sensitivity from 0.44 sensitivity with 0.98 specificity for CA19-9 to 0.71 sensitivity with 0.94 specificity (p &amp;lt; 0.001, 1000-fold bootstrap), and CA19-9 combined with the protein biomarker LRG1 and CA199.STRA improved specificity from 0.16 specificity and 0.94 sensitivity for CA19-9 to 0.58 specificity and 0.89 sensitivity (p &amp;lt; 0.001, 1000-fold bootstrap). Notably, cross-laboratory biomarker combinations that did not include CA19-9 in the panel significantly improved upon CA19-9. The combination of CA199.STRA with the protein biomarker MUC5AC improved sensitivity over CA19-9 with 0.61 sensitivity and 0.94 specificity (p = 0.0002, 1000-fold bootstrap), and the combination of CA199.STRA and the protein biomarkers MUC5AC, THSP2, and ANG improved specificity over CA19-9 with 0.66 specificity and 0.88 sensitivity (p &amp;lt; 0.0001, 1000-fold bootstrap). By coordinating this biomarker study across independent laboratories, we have identified novel biomarker combinations that significantly increase the sensitivity and specificity of early stage PDAC detection and that demonstrate the future feasibility of surveillance for PDAC using combinations of serum assays. Citation Format: Brian Haab, Lu Qian, Ben Staal, Maneesh Jain, Johannes Fahrmann, Christine Worthington, Denise Prosser, Liudmila Velokokhatnaya, Camden Lopez, Runlong Tang, Mark Hurd, Gopalakrishnan Natarajan, Sushil Kumar, Lynette Smith, Samir Hanash, Surinder Batra, Anirban Maitra, Anna Lokshin, Ying Huang, Randall E. Brand, Liudmila Velokokhatnaya. Combinations of previously reported biomarkers achieve improved sensitivity and specificity of detection of early stage 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 A014.