Diagnosis Of PDAC Research Articles

New Therapeutic Targets in RAS Wild-type Pancreatic Cancer.

The landscape of treatment of advanced PDAC is witnessing significant changes. This is in part due to the advent of molecular profiling, which has highlighted molecularly-distinct subsets of pts, especially those with KRAS wild-type disease. We now know that these pts harbor genomic alterations that not only serve as molecular drivers but also pose as therapeutically relevant markers. In the absence of strong evidence to support the use of targeted therapy in the front-line setting, we continue to offer chemotherapy for treatment-naïve pts. However, an argument can be made for the front-line use of targeted therapy in pts who are not fit for chemotherapy or who are not interested in it. The challenge is ensuring that molecular profiling is done in a timely fashion to prevent significant delays in therapy. In our practice, we offer molecular testing to all pts with a new diagnosis of advanced PDAC. We prefer the utility of targeted therapy in the second line and beyond for pts who have an actionable target, over the use of further chemotherapy, as targeted therapy appears to confer deep and durable responses and longer survival. For pts with MSI-H or MMRd disease, the use of immunotherapy is indicated, although it has to be noted that MSI-H/MMRd PDAC performed worse that other MSI-H/MMRd cancers treated with immunotherapy. Therefore, in the presence of MSI-H/MMRd and an additional actionable target, we prefer treating with targeted therapy and reserving immunotherapy for later lines. Pt preference has to be taken into consideration at all times though.

Prognostic significance of collagen signatures in pancreatic ductal adenocarcinoma obtained from second-harmonic generation imaging

BackgroundPancreatic ductal adenocarcinoma (PDAC) ranks among the deadliest types of cancer, and it will be meaningful to search for new biomarkers with prognostic value to help clinicians tailor therapeutic strategies.MethodsHere we tried to use an advanced optical imaging technique, multiphoton microscopy (MPM) combining second-harmonic generation (SHG) and two-photon excited fluorescence (TPEF) imaging, for the label-free detection of PDAC tissues from a cohort of 149 patients. An automated image processing method was used to extract collagen features from SHG images and the Kaplan-Meier survival analysis and Cox proportional hazards regression were used to assess the prognostic value of collagen signatures.ResultsSHG images clearly show the different characteristics of collagen fibers in tumor microenvironment. We gained eight collagen morphological features, and a Feature-score was derived for each patient by the combination of these features using ridge regression. Statistical analyses reveal that Feature-score is an independent factor, and can predict the overall survival of PDAC patients as well as provide well risk stratification.ConclusionsSHG imaging technique can potentially be a tool for the accurate diagnosis of PDAC, and this optical biomarker (Feature-score) may help clinicians make more approximate treatment decisions.

Droplet digital polymerase chain reaction detection of KRAS mutations in pancreatic FNA samples: Technical and practical aspects for routine clinical implementation.

Pancreatic adenocarcinoma (PDAC) is associated with a 5-year survival rate of less than 6%, and current treatments have limited efficacy. The diagnosis of PDAC is mainly based on a cytologic analysis of endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) samples. However, the collected specimens may prove noncontributory in a significant number of cases, delaying patient management and treatment. The combination of EUS-FNA sample examination and KRAS mutation detection can improve the sensitivity for diagnosis. In this context, the material used for molecular analysis may condition performance. The authors prospectively compared the performance of cytologic analysis combined with a KRAS droplet digital polymerase chain reaction (ddPCR) assay for PDAC diagnosis using either conventional formalin-fixed, paraffin-embedded cytologic samples or needle-rinsing fluids. Molecular testing of formalin-fixed, paraffin-embedded cytologic samples was easier to set up, but the authors observed that the treatment of preanalytic samples, in particular the fixation process, drastically reduced ddPCR sensitivity, increasing the risk of false-negative results. Conversely, the analysis of dedicated, fresh needle-rinsing fluid samples appeared to be ideal for ddPCR analysis; it had greater sensitivity and was easily to implement in clinical use. In particular, fluid collection by the endoscopist, transportation to the laboratory, and subsequent freezing did not affect DNA quantity or quality. Moreover, the addition of KRAS mutation detection to cytologic examination improved diagnosis performance, regardless of the source of the sample. Considering all of these aspects, the authors propose the use of an integrated flowchart for the KRAS molecular testing of EUS-FNA samples in clinical routine.

Clinical impact of KRAS mutations in metastatic pancreatic ductal adenocarcinoma (PDAC).

619 Background: Mutations in the KRAS oncogene occur in most PDAC and lead to the activation of the KRAS protein. Little is known about the differential impact of KRAS mutations on the outcomes of patients receiving standard of care cytotoxic treatments for metastatic disease. KRAS inhibitors are emerging as promising options for this disease and understanding the impact of distinct KRAS mutations in patient outcomes is needed. Methods: This study used the nationwide Flatiron Health electronic health record (EHR)-derived de-identified database from 5,369 patients. Adult patients with diagnosis of metastatic PDAC who received at least one line of systemic therapy and had sufficient data available were included in this analysis. Median time to next treatment (TTNT) and overall survival (OS) time were calculated for three common first-line treatments and KRAS mutations. TTNT and OS were calculated for each permutation of treatment and each KRAS mutation. Hazard ratios (HR) were generated for each KRAS mutation and treatment, accounting for potentially confounding variables. Results: Of the 5,369 patients, 2,472 met the inclusion/exclusion criteria. G12C had the shortest median OS (7.5 mo) and G12R had the longest (9.1 mo). Overall, KRAS mutation-positive patients had a median OS of 8.6 mo, compared to 11.7 mo for KRAS Wild Type (WT) patients. A Cox Proportional Hazard analysis of OS across KRAS mutation status found that G12C, G12V, G12D, and Other Non G12/13 KRAS had significantly higher HR than KRAS WT. A comparison of the three common first-line interventions for metastatic PDAC showed that FOLFIRINOX had the longest median TTNT (5.3 mo) and the longest OS (10.2 mo), while Gemcitabine had the shortest TTNT (2.6 mo) and OS (5.9 mo). A Cox Proportional Hazard analysis of OS across all patients found that Gemcitabine and Gemcitabine with Nabpaclitaxel had significantly higher HR than FOLFIRINOX. FOLFIRINOX had the longest TTNT in the G12C, G12V, G12D, G12R, and other non-G12/G13 KRAS groups (see table). Conclusions: Our data suggest that FOLFIRINOX has a longer TTNT than other first-line regimens for KRAS G12C, G12V, G12D, and G12R. KRAS G12C was associated with the shortest OS among common KRAS mutations.[Table: see text]

A novel early cancer detection approach for pancreatic cancer.

613 Background: Pancreatic adenocarcinoma (PDAC) is commonly diagnosed at advanced stages, leading to high mortality rates. Earlier detection of PDAC is associated with improved long-term survival, but effective population-level screening is not available. There is therefore an urgent need to improve early detection of PDAC. Wholomics has developed a PDAC-specific proprietary early detection test, using cancer-specific molecular signatures in peripheral blood. Methods: We conducted a retrospective analysis of serum samples from the Amsterdam UMC Liquid Biopsy Center. Three cohorts were included in this study: 1) A cohort of healthy control subjects, 2) patients with a histopathologically confirmed diagnosis of PDAC spanning stages I through IV, and 3) patients with a confirmed diagnosis of chronic pancreatitis. Peripheral blood samples of cancer patients were taken before treatment or surgery. Wholomics used its proprietary technology to quantitatively analyse all serum specimens. Disease-specific molecular signatures were identified and used to develop computational biomarkers specific to both pancreatic pathologies (chronic pancreatitis and pancreatic cancer) and to pancreatic cancer individually. A comparative analysis was conducted employing multiple machine learning algorithms, which were subjected to a 10-fold cross-validation procedure. The accuracy, specificity and sensitivity of the best-performing algorithm is reported. Results: This retrospective study included 50 healthy controls, 12 patients with chronic pancreatitis, and 42 patients with pancreatic cancer (12 stage I, 15 stage II, 9 stage III, 6 stage IV). Applying Wholomics´ technology, an accuracy of 99.1% in differentiating the chronic pancreatitis and pancreatic cancer patients from the healthy controls was achieved. A specificity of 98.0% and a sensitivity of 100.0% were reached. Furthermore, pancreatic cancer patients and chronic pancreatitis patients were differentiated with 95.2% accuracy. Wholomics was also capable of differentiating between early stage (stages I and II) and late-stage (stages III and IV) pancreatic cancer with an accuracy of 100%. Conclusions: Taken together, this study demonstrates that disease-specific molecular signatures in peripheral blood can distinguish patients with PDAC from healthy individuals and patients with pancreatitis with very high accuracy. If validated in additional cohorts, this method could be evaluated as a screening test for PDAC to allow for early detection and improve patient outcomes.

VSIG2 promotes malignant progression of pancreatic ductal adenocarcinoma by enhancing LAMTOR2-mediated mTOR activation

BackgroundPancreatic ductal adenocarcinoma (PDAC) is one of the most intractable malignancies to overcome clinically due to its insidious onset as well as rapid progression. It is urgent to seek new diagnostic markers and therapeutic targets in order to furthest ameliorate the prognosis of patients with PDAC. V-set and immunoglobulin domain containing 2 (VSIG2) belongs to immunoglobulin superfamily (IgSF), which function as coinhibitory molecule to mediate immune evasion of tumors. Nevertheless, the role of VSIG2 in PDAC and related mechanism still keep unclear.MethodsDifferent expression of VSIG2 in PDAC tissues and cells were detected by bioinformatic analysis, immunohistochemistry, real-time quantitative PCR as well as western blotting. CCK-8, colony formation, Transwell assay, and scratch experiment were utilized to assess proliferation, invasion and migration properties of PDAC cells. The relationship of VSIG2 with late endosomal/lysosomal adaptor, MAPK and MTOR activator 2 (LAMTOR2) and mechanistic target of rapamycin (mTOR) was identified using mass spectrometry, co-immunoprecipitation and immunofluorescence. GO and KEGG enrichment analysis were performed for further pathway verification using western blotting. Additionally, subcutaneous xenograft tumor model and clinical samples analysis were implemented to further elucidate the oncogenic effect of VSIG2 on PDAC in vivo and clinically.ResultsVSIG2 was highly expressed in PDAC tissues and cells. Overexpression of VSIG2 facilitated the proliferation, invasion and migration abilities of PDAC cells, while VSIG2-inhibition exerted opposite effects. Mechanistically, VSIG2 could simultaneously bind to LAMTOR2 and mTOR, thereby enhancing interaction between two molecules, which resulted in elevated phosphorylation-modificatory activation of mTOR and downstream key molecules. Clinically, up-regulation of VSIG2 was positively associated with advanced stage, overall survival and disease-free survival of PDAC patients.ConclusionsOur study disclosed that VSIG2 was overexpressed in PDAC, which promoted the proliferation, invasion and metastasis. Mechanically, VSIG2 acted as a scaffold to recruit LAMTOR2 and mTOR simultaneously, stabilize the interaction between them, thus enhancing LAMTOR2-mediated mTOR phosphorylated activation. Collectively, VSIG2 could be exploited as a biomarker for diagnosis and prognosis monitor of PDAC in the future, meanwhile, targeting VSIG2 in PDAC management is expected to be a novel strategy. Video .BaES_1bSmDgbiStG2w_JZBVideo

Improved predictability of pancreatic ductal adenocarcinoma diagnosis using a blood immune cell biomarker panel developed from bulk mRNA sequencing and single-cell RNA-sequencing

BackgroundPancreatic ductal adenocarcinoma (PDAC) remains a devastating cancer due to its poor survival rate, early detection, and resectability. This study aimed to determine the peripheral blood mononuclear cell (PBMC) immune biomarkers in patients with PDAC and investigate the PDAC-specific peripheral blood biomarker panel and validate its clinical performance.MethodsIn this prospective, blinded, case–control study, a biomarker panel formula was generated using a development cohort—including healthy controls, patients at high risk of PDAC, and patients with benign pancreatic disease, PDAC, or other gastrointestinal malignancies—and its diagnostic performance was verified using a validation cohort, including patients with ≥ 1 lesion suspected as PDAC on computed tomography (CT).ResultsRNA-sequencing of PBMCs from patients with PDAC identified three novel immune cell markers, IL-7R, PLD4, and ID3, as specific markers for PDAC. Regarding the diagnostic performance of the regression formula for the three biomarker panels, the sensitivity, specificity, positive predictive value, negative predictive value, and accuracy were 84.0%, 78.8%, 47.2%, 95.6%, and 79.8%, respectively. Based on the formula scores for the biomarker panel, the false-negative rate (FNR) of the biomarkers was 8% (95% confidence interval [CI] 3.0–13.0), which was significantly lower than that based on CT in the validation cohort (29.2%, 95% CI 20.8–37.6).ConclusionsThe regression formula constructed using three PBMC biomarkers is an inexpensive, rapid, and convenient method that shows clinically useful performance for the diagnosis of PDAC. It aids diagnoses and differential diagnoses of PDAC from pancreatic disease by lowering the FNR compared to CT.Clinical trial registration Clinical Research Information Service, KCT0004614 (08 January 2020).

Coupling magnetic levitation of graphene oxide–protein complexes with blood levels of glucose for early detection of pancreatic adenocarcinoma

IntroductionPancreatic adenocarcinoma (PDAC) has a poor prognosis since often diagnosed too late. Dyslipidemia and hyperglycemia are considered risk factors, but the presence of the tumor itself can determine the onset of these disorders. Therefore, it is not easy to predict which subjects with diabetes or dyslipidemia will develop or have already developed PDAC. Over the past decade, tests based on the use of nanotechnology, alone or coupled with common laboratory tests (e.g., hemoglobin levels), have proven useful in aiding the diagnosis of PDAC. Tests based on magnetic levitation (MagLev) have demonstrated high diagnostic accuracy in compliance with the REASSURED criteria. Here, we aimed to assess the ability of the MagLev test in detecting PDAC when coupled with the blood levels of glycemia, cholesterol, and triglycerides.MethodsBlood samples from 24 PDAC patients and 22 healthy controls were collected. Human plasma was let to interact with graphene oxide (GO) nanosheets and the emerging coronated systems were put in the MagLev device. Outcomes from Maglev experiments were coupled to glycemia, cholesterol, and triglycerides levels. Linear discriminant analysis (LDA) was carried out to evaluate the classification ability of the test in terms of specificity, sensitivity, and global accuracy. Statistical analysis was performed with Matlab (MathWorks, Natick, MA, USA, Version R2022a) software.ResultsThe positions of the levitating bands were measured at the starting point (i.e., as soon as the cuvette containing the sample was subjected to the magnetic field). Significant variations in the starting position of levitating nanosystems in controls and PDACs were detected. The combination of the MagLev outcomes with the blood glycemic levels returned the best value of global accuracy (91%) if compared to the coupling with those of cholesterol and triglycerides (global accuracy of ~ 77% and 84%, respectively).ConclusionIf confirmed by further studies on larger cohorts, a multiplexed Maglev-based nanotechnology-enabled blood test could be employed as a screening tool for PDAC in populations with hyperglycemia.

HPB P63 Five-year follow-up after pancreatoduodenectomy performed for malignancy: a nine-year experience

Abstract Background Pancreatic ductal adenocarcinoma (PDAC) of the pancreatic head is a leading cause of cancer-related death in the Western world and its incidence is set to rise across the globe. Unfortunately, the majority of patients present with metastatic disease and prognosis is very poor. Ampullary adenocarcinoma (AA) and cholangiocarcinoma (CC) are less common but their prognoses are only marginally better. Patients with one of these cancers may undergo pancreaticoduodenectomy (PD) providing they present with resectable disease and have an appropriate performance status. Whilst this offers some patients the possibility of a cure, it is a high-risk operation and overall morbidity is often quoted at 50%. Additionally, early recurrence rates are high and few patients achieve long-term survival. This study aimed to describe the experience of a typical tertiary hepatopancreatobiliary (HPB) unit in the United Kingdom. We aimed to a compile a complication profile and investigate the impact of selected preoperative variables on short- and long-term outcomes. We also aimed to compare patient outcomes based on their cancer type. Methods Patients were included if they underwent PD for histologically-confirmed PDAC, AA or CC at our institution between 01/09/2006 and 31/05/2015. The end date of 31/05/2015 was chosen to complete five-year follow-up for all included patients. Information was collected on the following: patient demographics, comorbidities, preoperative imaging and staging, NAT (if given), selected preoperative blood results, procedure and intraoperative findings, postoperative management and complications, histology results, adjuvant treatment (if given), cancer recurrence, palliative treatment (if given), and five-year survival. When comparing patients by their histological diagnosis, medians were compared using the Kruskal-Wallis test and other variables were compared using Fisher's exact test. Fisher's exact test was also used to investigate the association of selected preoperative variables on overall morbidity, major morbidity (Clavien-Dindo grade I and II complications excluded), 90-day mortality and five year survival. The Kaplan-Meier method was used to compare survival between patients with PDAC, AA and CC. The Mantel-Cox method was used to test for statistical significance. Fisher's exact test was used to investigate the impact of selected preoperative variables on five-year survival. A p-value of less than 0.05 was considered statistically significant. Results A total of 271 patients were included; 57.9% had a histological diagnosis of PDAC, 25.8% had AA and 16.2% had CC. Ninety-day mortality was 3.3%, 67.9% of patients experienced at least one complication and 17.3% experienced a complication which was Clavien-Dindo grade III or higher. A total of 401 postoperative complications were recorded; 27.2% were CD grade I, 53.2% were grade II, 12.7% were grade III, 4.4% were grade IV and 1.5% were grade V. Rates of CR-POPF, bile leak, gastrojejunal leak, PPH and DGE were 8.1%, 4.1%, 0.0%, 9.2% and 19.9%, respectively. Patients with a preoperative bilirubin ≤29 µmol/L less often experienced morbidity (p=0.03) or major morbidity (p=0.02) but this did not affect 90-day mortality (p=0.7). Similarly, those with a preoperative neutrophil/lymphocyte ratio (NLR) ≤3.1 had lower rates of morbidity (p=0.04) and major morbidity (p=0.01) but the difference in 90-day mortality was not significant (p=0.3). An ASA grade of III or IV correlated with increased overall morbidity (p=0.002) and major morbidity (p=0.009) but the difference in 90-day mortality was not significant (p=0.2). Overall five-year survival was 22.5%; this was not affected by age, BMI, preoperative comorbidities, ASA grade or preoperative blood tests. Conclusions In our series, most patients experienced at least one complication but less than a fifth experienced major morbidity. Rates of CR-POPF, bile leak, gastrojejunal leak, PPH and DGE were 8.1%, 4.1%, 0.0%, 9.2% and 19.9%, respectively. ASA grade III/IV patients and those with a high preoperative bilirubin and/or NLR more commonly experienced overall and major morbidity. Five-year recurrence and survival rates were 68.3% and 22.5%, respectively. The preoperative variables studied did not affect five-year survival. Surgeons who perform PD should have a sound understanding of the figures above as this will guide patient selection and the consenting process. Future research should focus on identifying patients who are likely to achieve poor long-term outcomes, this sub-group may benefit from neoadjuvant chemotherapy.

Abstract A060: Characterizing acinar cell and ductal cell derived PDACs in mouse models

Abstract Understanding the origins of PDAC is critical for developing better clinical interventions. Modeling in mice has revealed that either pancreatic acinar or ductal cells can serve as the cell of origin for PDAC. Using tamoxifen-inducible Ptf1aCreER and Sox9CreER alleles to induce genetic alterations in adult pancreatic acinar and ductal cells, respectively, we showed that oncogenic Kras expression, coupled with p53 inactivation or mutation, can drive PDAC from either pancreatic cell type. PDACs derived from acinar cells resemble the classical subtype of human PDAC, while those derived from ductal cells resemble the basal-like subtype of human PDAC, suggesting that cell of origin is one factor that can influence PDAC subtype. Moreover, the histological lesions preceding cancer are notably different, suggesting that oncogenic events in each cell type result in distinct paths of tumor evolution. Such findings highlight the importance of the earliest events of tumorigenesis in influencing phenotypes and outcomes, and better understanding these different paths of PDAC evolution can therefore be critical for improving early diagnosis and treatment of PDAC. To deepen our understanding of these paths of PDAC development, we have used spatial transcriptomics to characterize the acinar and ductal cell-derived mouse PDACs, to contextualize cell-specific expression programs in cancer cell and stromal cell compartments. The segmentation of transcriptional programs by cell type is of great importance in PDAC due to a characteristically pervasive desmoplastic stroma and low neoplastic cellularity. These studies have validated differences in transcriptomic profiles of the cancer cells in these two types of PDAC, with HIF1 signaling and glycolysis pathway being upregulated in ductal cell-derived PDAC and programs that mirror tissue development and morphogenesis being more prominent in acinar cell-derived PDAC. Our analysis also revealed differences in the fibroblast and immune compartments of acinar and ductal cell-derived tumors, which we are further characterizing, and which will reveal novel strategies for tumor targeting based on the tumor microenvironment. Together, these findings suggest that these two types of PDAC are driven and sustained by distinct pathways and tumor-stromal crosstalk. To help characterize pathways central for cancer cell growth, we also generated cell lines from acinar cell and ductal cell-derived PDACs, and we are characterizing their sensitivity to different agents that modulate pathways specific to each PDAC subtype. Ultimately, this work will help to elucidate how the two major types of human PDAC develop, paving the way in finding subtype-specific vulnerabilities that may be exploited therapeutically. Citation Format: Sofia Ferreira, Brittany M. Flowers, Kathryn J. Hanson, Alberto Gatto, Sohinee Bhattacharyya, Mara H. Sherman, Laura D. Attardi. Characterizing acinar cell and ductal cell derived PDACs in mouse models [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr A060.

Diagnostic Accuracy of Blood-based Biomarkers for Pancreatic Cancer: A Systematic Review and Meta-analysis.

In a systematic review and three-level multivariate meta-analysis, it is shown for the first time that blood-based multi-biomarker panels for the diagnosis of PDAC exhibit superior performance in comparison with single biomarkers. CA19-9 is demonstrated to have limited utility alone, and to perform poorly in patient control cohorts of both healthy and benign individuals. Multi-biomarker panels containing CA19-9 produce the best diagnostic performance overall.

Survival outcomes amongst patients with new onset diabetes preceding the diagnosis of pancreatic adenocarcinoma: Multicenter retrospective study.

e16251 Background: In patients (pts) with new-onset diabetes (NOD) above the age of 50 years, 1% are diagnosed with pancreatic adenocarcinoma (PDAC) within three years. Based on this, NOD has been proposed as an important factor for early diagnosis of PDAC. Research has been directed towards investigating NOD vs Type 2 diabetes and association with PDAC. Limited data exists on its impact on the survival outcomes amongst PDAC pts. Methods: We retrospectively analyzed clinical data of 150 pts diagnosed with a pancreatic mass at three hospitals from 2014 to 2021. NOD group consisted of pts diagnosed with Diabetes or Pre-Diabetes defined as HBA1c > 6.5% and 5.7-6.4%, respectively, within the three years prior to PDAC diagnosis. Primary aim of the study was the characterization of the impact of NOD on clinical outcomes. Results: 83 pts [mean age 68.32 yrs, 58% males, 61% white] were identified with biopsy proven PDAC, out of which, 9 (11%) pts had pre-existing Diabetes, 21 (25%) pts met the criteria for NOD group. In the NOD group whose weight was available (n = 15), 11 pts (79%) had experienced weight loss within one year of the NOD diagnosis with a median age of 68.46 yrs. No significant differences were noted between race (P = 0.36), age (P = 0.9), sex (P = 0.9), tumor location (P = 0.17), and chemotherapy received (P = 0.9) between the two groups. When comparing survival outcomes, no significant differences were noted in the metastatic cohort (n = 42, PFS HR 0.77, P = 0.4, OS HR 0.9 P = 0.7) including in the subgroup analysis for pts receiving FOLFIRINOX n = 20, PFS HR 0.59, P = 0.28, OS HR 0.66 P = 0.4) or Gemcitabine based treatment (n = 9, PFS HR 1.31, P = 0.7, OS HR 0.46 P = 0.3). In the resected cohort (n = 20), pts in the NOD group did worse than pts who did not meet the criteria with PFS 10 months vs. 18.3 months (P = 0.0058, HR 7.78), a similar trend was noticed in the OS 15.2 months vs. 28.2 months (P = 0.08 HR 2.98), but it did not reach statistical significance. Conclusions: Consistent with current literature, NOD preceding PDAC is distinct from Type 2 diabetes associated NOD, characterized by weight loss and occurring at a later age. Pts with NOD preceding PDAC were shown to have worse survival outcomes in the resected cohort. Larger studies need to be conducted in this context as this could have significant implications for PDAC screening and treatment.

Pyroptosis-related genes regulate proliferation and invasion of pancreatic cancer and serve as the prognostic signature for modeling patient survival

ObjectivePancreatic ductal adenocarcinoma (PDAC) has high mortality and poor prognosis. Pyroptosis can influence the prognosis of patients by regulating the proliferation, invasion, and metastasis of cancer cells. However, the role of pyroptosis-related genes (PRGs) in PDAC remains unclear.MethodsIn this study, based on the Cancer Genome Atlas (TCGA) cohort of PDAC samples, univariate Cox analysis and LASSO regression analysis were used to screen the prognostic PRGs and establish the gene signature. To further evaluate the functional significance of CASP4 and NLRP1 in PDAC, we also conducted an in vitro study to explore the mechanism of CASP4 and NLRP1 regulating the occurrence and development of PDAC. Finally, we investigated the relationship between CASP4 and NLRP1 expression levels and drug sensitivity in pancreatic cancer cells.ResultsA risk prediction model based on CASP4 and NLRP1 was established, which can distinguish high-risk patients from low-risk patients (P < 0.001). Both internal validation and external GEO data sets validation demonstrate good predictive capability of the model (AUC = 0.732, AUC = 0.802, AUC = 0.632, P < 0.05). In vitro, CCK8 and Transwell assay suggested that CASP4 may accelerate the progression of PDAC by promoting proliferation and migration of pancreatic cancer cells, while NLRP1 has been found to have tumor suppressive effect. It should be noted that knockdown of CASP4 reduced the level of coke death, the expression levels of acetyl-CoA carboxylase, FASN, SREBP-1 and SREBP-2 were decreased, and the number of lipid droplets was also significantly reduced. Moreover, the enrichment of signaling pathways showed that NLRP1 was significantly correlated with MAPK and RAS/ERK signaling pathways, and knocking down NLRP1 could indeed up-regulate p-ERK expression. Finally, high expression of CASP4 and low expression of NLRP1 increased the sensitivity of pancreatic cancer cells to ERK inhibitors.ConclusionsIn especial, CASP4 can promote tumor progression by promoting the synthesis and accumulation of fatty acids, while NLRP1 acts on RAS/ERK signaling pathway. Both of genes play an important role in the diagnosis and treatment of PDAC, which may also affect the inhibitors of MAPK/ERK efficiency.

Circulating Nucleic Acids as Novel Biomarkers for Pancreatic Ductal Adenocarcinoma

Simple SummaryPancreatic ductal adenocarcinoma (PDAC) is a particularly aggressive and deadly cancer, primarily due to failure to identify early-stage disease. PDAC is often diagnosed at a late stage due to nonspecific symptoms, and a distinct lack of reliable biomarkers for timely diagnosis. Current PDAC biomarkers are inadequate for the monitoring of a patient’s response to treatment. The aim of this review is to highlight the potential use of circulating nucleic acid-based biomarkers, along with technology facilitating their detection, in liquid biopsies. These biomarkers primarily focus on the detection of PDAC-specific genetic mutations, both freely circulating and contained within exosomes.Despite considerable advancements in the clinical management of PDAC it remains a significant cause of mortality. PDAC is often diagnosed at advanced stages due to vague symptoms associated with early-stage disease and a lack of reliable diagnostic biomarkers. Late diagnosis results in a high proportion of cases being ineligible for surgical resection, the only potentially curative therapy for PDAC. Furthermore, a lack of prognostic biomarkers impedes clinician’s ability to properly assess the efficacy of therapeutic interventions. Advances in our ability to detect circulating nucleic acids allows for the advent of novel biomarkers for PDAC. Tumor derived circulating and exosomal nucleic acids allow for the detection of PDAC-specific mutations through a non-invasive blood sample. Such biomarkers could expand upon the currently limited repertoire of tests available. This review outlines recent developments in the use of molecular techniques for the detection of these nucleic acids and their potential roles, alongside current techniques, in the diagnosis, prognosis and therapeutic governance of PDAC.

THSB2 as a prognostic biomarker for patients diagnosed with metastatic pancreatic ductal adenocarcinoma.

Patients newly diagnosed with metastatic pancreatic ductal adenocarcinoma generally have poor survival, with heterogeneous rates of progression. Biomarkers that could predict progression and/or survival would help inform patients and providers as they make care decisions. In a previous retrospective study, we discovered that circulating thrombospondin-2 (THBS2) could, in combination with CA19-9, better distinguish patients with PDAC versus healthy controls. Here we evaluated whether THBS2 levels, previously not known to be prognostic, were associated with outcome in 68 patients at time of diagnosis of metastatic PDAC. Specifically, we interrogated the association of THBS2 level, alone or in combination with CA19-9, with progression by 90 days and/or survival to 180 days. The results indicate that elevated THBS2 levels alone, at the time of a metastatic PDAC diagnosis, can identify patients with a shorter time to death and thus help patients and providers when planning treatment.

Randomized phase II study of gemcitabine and S-1 combination therapy versus gemcitabine and nanoparticle albumin-bound paclitaxel combination therapy as neoadjuvant chemotherapy for resectable/borderline resectable pancreatic ductal adenocarcinoma (PDAC-GS/GA-rP2, CSGO-HBP-015)

BackgroundPancreatic ductal adenocarcinoma (PDAC) is a lethal disease, and multimodal strategies, such as surgery plus neoadjuvant chemotherapy (NAC)/adjuvant chemotherapy, have been attempted to improve survival in patients with localized PDAC. To date, there is one prospective study providing evidence for the superiority of a neoadjuvant strategy over upfront surgery for localized PDAC. However, which NAC regimen is optimal remains unclear.MethodsA randomized, exploratory trial is performed to examine the clinical benefits of two chemotherapy regimens, gemcitabine plus S-1 (GS) and gemcitabine plus nab-paclitaxel (GA), as NAC for patients with planned PDAC resection. Patients are enrolled after the diagnosis of resectable or borderline resectable PDAC. They are randomly assigned to either NAC regimen. Adjuvant chemotherapy after curative resection is highly recommended for 6 months in both arms. The primary endpoint is tumor progression-free survival time, and secondary endpoints include the rate of curative resection, the completion rate of protocol therapy, the recurrence type, the overall survival time, and safety. The target sample size is set as at least 100.DiscussionThis study is the first randomized phase II study comparing GS combination therapy with GA combination therapy as NAC for localized pancreatic cancer.Trial registrationUMIN Clinical Trials Registry UMIN000021484. This trial began in April 2016.

Endoscopic Ultrasound in Borderline &amp; Locally Advanced Pancreatic: Leeds Experience

Introduction: Endoscopic ultrasonography (EUS) is an essential pancreatic cancer investigation which has picked up in the last decade and is commonly used in combination with more traditional cross-sectional imaging techniques. Up to 79% of all pancreatic malignancies are locally advanced (stage 3) or metastatic (stage 4) at initial presentation. Developments in technology, such as contrast enhancement, elastography and fine needle aspiration (EUS-FNA) have further increased EUS diagnostic yield. EUS-FNA is accepted as the optimal method of obtaining tissue for histological diagnosis prior to starting neoadjuvant treatment (NAT) and has a lower incidence of complications such as pancreatitis, bleeding and tumour seeding. The aim of this study was to evaluate the role of EUS in advanced pancreatic cancers. Methods: Patients with borderline and locally advanced pancreatic ductal adenocarcinoma between 2016 and 2020 were retrieved from institutional pancreatic tumour database. Patients with IPMN, MCN, periampullary cancers and metastatic pancreatic cancer were excluded. All patients with BRPC, LAPC received NAT. Data of patients undergoing EUS were retrieved and compared with cross-sectional imaging. Appropriate statistical analysis was performed where applicable. Results: 96 patients underwent EUS and FNB. Diagnosis of PDAC was confirmed in 81.25% (78) cases before starting neoadjuvant treatment. Mean tumour size on EUS was 2.7cm as compared to 3cm on CT. CT confirmed N1 disease was seen in 21.6% (26) patients however, in only 2.5% (3) cases local lymphadenopathy was detected using EUS. Vascular involvement was seen in 50.8% (61) cases on CT and only in 44.1% (53) in the EUS group. EUS induced pancreatitis was seen in 3.12% (3) patients. > 2 attempts to confirm tissue diagnosis was seen in 3.84% of patients. Dysplasia, IPMN, Pancreatitis and Suspicious lesions were detected in 1.04%, 2.08%, 1% and 15.62% is suspected PDAC on imaging. There were no EUS induced bleeding or other complications during the study period. Conclusion: EUS has a role in the evaluation of advanced pancreatic malignancies and in assessment of vascular involvement and local lymphadenopathy. It also provides cytological and histological confirmation prior to commencing NAT. EUS-guided therapeutic interventions also provide effective biliary drainage particularly in individuals where ERCP is not feasible.

Inflammation, Tumoral Markers and Interleukin-17, -10, and -6 Profiles in Pancreatic Adenocarcinoma and Chronic Pancreatitis

Interleukin profiles can be used as biochemical markers regarding the early diagnosis of pancreatic cancer. To assess CRP, CA 19-9, CEA levels, and interleukin-6, -10, and -17 profiles in pancreatic ductal adenocarcinoma, chronic pancreatitis was compared with a control group, and the correlation with pancreatic cancer survival. A total of 87 patients were prospective divided in pancreatic cancer (n = 53), chronic pancreatitis (n = 22) ,and control group (n = 12). The diagnosis of PDAC was made histologically. The diagnosis of chronic pancreatitis was based on medical history, imaging methods, and endoscopic ultrasound. Systemic concentrations of interleukins were measured using ELISA kits. The patients were followed at 1, 3, and 6months. CRP, CA 19-9, and CEA were higher in the pancreatic cancer group (p < 0.001). Interleukin-10 was significantly higher in the pancreatic cancer and chronic pancreatitis groups (p < 0.001). Interleukin-17 was statistically higher in the pancreatic cancer group (p < 0.0001). The cut-off of interleukin-17 of 0.273 had a sensitivity of 90.9 and a specificity of 80.9 with a curve under ROC of 0.80 in order to differentiate between pancreatic cancer and chronic pancreatitis. The serum levels of interleukins are not correlated with the stage of the disease. CRP, CA 19-9, CEA, and interleukin-6, -10, and -17 were lower in patients with survival more than 6months. We detected high levels of interleukin-6, -10, and -17 in chronic pancreatitis and pancreatic cancer. Serum interleukin-17 levels can discriminate between pancreatic cancer and chronic pancreatitis. The prognostic role of interleukins needs to be established.

Comparison of minimal invasive versus open radical antegrade modular pancreatosplenectomy (RAMPS) for pancreatic ductal adenocarcinoma: a single center retrospective study

Radical antegrade modular pancreatosplenectomy (RAMPS) was proposed a decade ago with the aim to achieve higher R0 tangential margin and radical N1 lymph node resection for left-sided pancreatic adenocarcinoma (PDAC), which has been widely accepted worldwide at present. Laparoscopic RAMPS (Lap-RAMPS) has been attempted for PDAC during last several years, however, no outcomes evaluation by comparison between laparoscopic vs open RAMPS has been reported yet. From August, 2012 to March, 2018, patients undergoing open or lap-RAMPS for the diagnosis of left-sided PDAC were reviewed from a prospective database. Patients excluded if they were related with combined organs or vessels resection, systematic metastasis as well as conversion from open RAMPS to lap RAMPS. The surgical and oncologic outcomes were compared. A total of 48 PDAC patients were enrolled (25 underwent lap-RAMPS and 23 underwent open-RAMPS). There were no significant differences in demographic or perioperative morbidity. In the lap-RAMPS group, R0 transection margin and retroperitoneal margin were both achieved in 23 of 25 patients (92%). In the open RAMPS group, R0 transection margin was achieved in 21 of 23 patients (91.3%), R0 retroperitoneal margin was 22 of 23 patients (95.65%). There were no differences in pathological examinations. The number of lymph node (LN) retrieved between lap-RAMPS and open- RAMPS group was not significant difference (15.84 vs 18.22; P = 0.268). Median disease-free survival (DFS) was analogous in two groups (18.11m vs 20.00m, P = 0.999). Median overall survival (OS) was 24.53m in lap-RAMPS group and 28.73m in the open-RAMPS group (P = 0.633). Lap-RAMPS is technically feasible, and has comparable long-term oncological outcome with open-RMAPS.

A PK/PD mathematical model to forecast severe toxicities in pancreatic cancer patients treated with FOLFIRINOX regimen.

e16774 Background: FOLFIRINOX regimen is the most efficient treatment in pancreatic adenocarcinoma. However, this triple-therapy causes significant and dose-limiting toxic effects leading to empirical dose-reduction, postponement of the forthcoming courses and sometimes treatment discontinuation. Dose-limiting toxicities with FOLFIRINOX are mostly oxaliplatin-induced peripheral neuropathy (OIPN) and irinotecan-induced diarrhoea (IID). The first aim of our study was to establish dose-concentration-toxicity relationships for these two main ordinal toxicities. Second, we aimed to perform in silico simulations to define the optimal FOLFIRINOX administration protocol (i.e., dosing, scheduling, sequencing) for a maximal benefit to risk ratio. Methods: We performed a retrospective pharmacometric analysis from clinical data collected in three French institutes. Patients had all confirmed diagnosis of PDAC treated with FOLFIRINOX as first line regimen. Demographic characteristics, toxicity data and dosage modifications were collected. Two mathematical models connecting dose – concentration – toxicity (PKPD Tox model) were developed using Monolix2019 to describe both OIPN and IID. Results: Data from 75 patients (36 females/39 males) treated with FOLFIRINOX regimen between 2015-2018 and representing 566 courses were collected. Median age was 65.4 years (range 29-78). The performance status at the start of treatment was 0-1 for 70% of patients. The most frequent location of the tumor was pancreatic head (50%). 91% of patients were subject to empirical dose reduction during their treatment. Oxaliplatin doses were decreased in 258 courses and stopped in 66 courses. Irinotecan doses were decreased in 257 courses and stopped in 33 courses. Overall, 130 IID and 198 OIPN events were observed. From these data, two different PKPD Tox models were developed. The individual concentrations of SN38 (active metabolite of irinotecan) and oxaliplatin were simulated with population PK models, either home-built or taken from the literature. Concentrations were translated into adequate exposure via an interface model developed by our group. Exposure was finally related to a pharmacodynamic model to predict probabilities assigned to each grade of IID or OIPN. Conclusions: These PKPD Tox models help to predict dose-limiting toxicities upon FOLFIRINOX and are useful to select the administration protocol of FOLFIRINOX minimizing the occurrence probabilities of treatment-related neuropathy and diarrhoea, while maintaining efficacy.