Survival Of Pancreatic Cancer Patients Research Articles

Neoadjuvant chemotherapy is associated with improved disease-free survival in pancreatic cancer patients undergoing pancreaticoduodenectomy with vascular resection.

Neoadjuvant chemotherapy (NAC) is becoming favored for all pancreatic adenocarcinoma (PDAC). Patients with seemingly resectable disease infrequently still display vascular involvement intraoperatively. Outcomes following NAC versus upfront surgery in patients undergoing pancreaticoduodenectomy (PD) with vascular resection are unknown. We performed a retrospective cohort study of PDAC patients who underwent PD with vascular resection between January 1, 2013, to December 31, 2020, within a single academic center. Clinicopathologic characteristics and disease-free survival (DFS) were compared between NAC versus upfront surgery cohorts using the Kaplan-Meier estimate and Cox proportional-hazards regression model. Eighty-one patients who underwent PD with vascular resection for PDAC were included. Forty-six patients (56%) received NAC. The NAC cohort more often had pathologic N0 status (47.8% vs. 8.6%, p < 0.001), had decreased vascular invasion (11% vs. 40%, p = 0.002), and completed chemotherapy (80% vs. 40%, p < 0.01). The NAC cohort demonstrated improved DFS (40.5 vs. 14.3 months, p = 0.007). In multivariable analysis, NAC remained independently associated with increased DFS (HR = 0.48, p = 0.02). NAC was associated with improved clinicopathologic outcomes and DFS in PD with vascular resection. These findings demonstrate the advantage of NAC in PDAC patients undergoing PD with vascular resection.

Bidirectional relationship between pancreatic cancer and diabetes mellitus: a comprehensive literature review

Pancreatic cancer (PC) is a fatal malignant disease. It is well known that the relationship between PC and type 2 diabetes mellitus (T2DM) is a complicated bidirectional relationship. The most important factors causing increased risks of pancreatic cancer are hyperglycemia, hyperinsulinemia, pancreatitis, and dyslipidemia. Genetics and the immune system also play an important role in the relationship between diabetes mellitus and pancreatic cancer. The primary contributors to this association involve insulin resistance and inflammatory processes within the tumor microenvironment. The combination of diabetes and obesity can contribute to PC by inducing hyperinsulinemia and influencing leptin and adiponectin levels. Given the heightened incidence of pancreatic cancer in diabetes patients compared to the general population, early screening for pancreatic cancer is recommended. Diabetes negatively impacts the survival of pancreatic cancer patients. Among patients receiving chemotherapy, it reduced their survival. The implementation of a healthy lifestyle, including weight management, serves as an initial preventive measure to mitigate the risk of disease development. The role of antidiabetic drugs on survival is controversial, however, metformin may have a positive impact, especially in the early stages of cancer, while insulin therapy increases the risk of PC.

Abstract 2802: Enterococcus faecalis-derived X facilitates pancreatic tumor by regulating immune microenvironment

Abstract Previous research in human samples has found a link between the intratumoral microbiome and the development and progression of pancreatic cancer. Nevertheless, the bacterial strains that may have an effect, and the underlying mechanisms, are largely unknown. To identify potential bacterial species, microbiome sequencing was performed on fecal and tumor samples obtained from KPC mice and patients with pancreatic tumors in this study. To identify metabolites associated with bacteria, untargeted metabolomics were analyzed on serum and tumor samples. Furthermore, advanced and high-throughput techniques, such as single-cell RNA sequencing, tumor organoids, engineered bacteria and germ-free mouse models, were used to elucidate the specific influence on the immune microenvironment of pancreatic tumors. Our findings reveal an increased abundance of Enterococcus faecalis (E. faecalis) in the gut during the development of pancreatic cancer, accompanied by its accumulation in the tumor. Patient-derived E. faecalis strain and its metabolite X, facilitated pancreatic tumor growth, reduced the recruitment of CD8+T cells, and caused their dysfunction in the tumor, relying heavily on E. faecalis intratumoral colonization. We found that X inhibits the production of anti-tumor chemokines like CCL21 and CCL8 in tumor cells, reducing peripheral CD8+ T cell infiltration into the tumor. Furthermore, X was found to inhibit glycolysis and compromise the function of tumor-infiltrating CD8+ T cells by decreasing the activity of lactate dehydrogenase (LDH) in CD8+ T cells. Additionally, oral doxycycline, an antibiotic that targets intratumoral E. faecalis, effectively enhanced the therapeutic effect of gemcitabine in pancreatic cancer. Finally, we present evidence that X may predicts efficacy and survival in pancreatic cancer patients. Together, our findings provide new insights into the role of E. faecalis in mediating the immune environment of pancreatic tumors, highlighting E. faecalis and X as potential therapeutic targets for pancreatic cancer patients. Citation Format: Bin Wang, Chao Yang, Yongjie Xie, Tianxing Zhou, Jun Yu, Jihui Hao. Enterococcus faecalis-derived X facilitates pancreatic tumor by regulating immune microenvironment [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 2802.

Abstract 232: Multi-dimensional patient-derived organoid analysis highly correlates with progression-free survival of pancreatic cancer patients in a retrospective clinical trial

Abstract Patient-derived tumor organoids (PDOs) are promising cancer models, since they preserve the clonal heterogeneity, mutational landscape, and histological architecture of the originating patient tumor1-2. Recent studies have even provided first evidence that PDOs responded similarly to the corresponding patient when treated with the same standard of care therapy, but these studies were only able to predict clinical responses in a subset of patients3,4. This restriction was largely due to the limitation of current analysis methods. The gold-standard analysis method for PDO-based research, CellTiter-Glo 3D,5,6 fails to account for the heterogeneity of PDOs by relying on a bulk lysis approach, and thus only extracts a fraction of the clinically-relevant information that PDOs could provide7. Therefore, we hypothesized that using higher-dimensional analysis methods, will further unlock the predictive performance of PDOs and facilitate translation of research. In this study, we developed an artificial intelligence-driven analysis platform for live-PDO imaging. By combining drug screening metrics with dynamic quantification of organoids on a single-organoid resolution, we unraveled patient-specific tumor heterogeneity and PDAC aggressiveness in response to therapies8. Using a fully characterized a PDAC organoid panel (n=8) we matched our PDO analysis with retrospective clinical patient response to standard of care therapies (gemcitabine-paclitaxel and FOLFIRINOX). Our results demonstrated that our PDO analysis method identified patient-specific sensitives to therapy that were in-line with clinical outcomes. Moreover, our PDO readouts highly correlated with progression-free survival of matched patients (R=0.97), which was a significant improvement to the current, conventional drug response readouts. Taken together, our approach increased the clinical translatability of PDOs by more accurately recapitulating and measuring the complexity of human tumors. This work highlights the potential applications (extendable to other tumor types) and clinical translatability of our approach in drug discovery and clinical care, in the emerging era of personalized medicine.

Abstract 7192: Teriflunomide overcomes gemcitabine resistance by inhibiting the GSK3β/mTOR pathway in pancreatic cancer

Abstract Background: Pancreatic cancer (PC) is a lethal malignancy that is partly attributable to the acquisition of chemoresistance to conventional chemotherapies. Hence, developing strategies to overcome such chemoresistance is essential. Teriflunomide, an active metabolite of leflunomide, has been widely utilized in managing autoimmune disorders, and emerging evidence suggests that it can augment the efficacy of chemotherapy in cancer. We investigated the therapeutic effect of teriflunomide in overcoming resistance to Gemcitabine-based therapy in PC. Methods: We performed docking and genomewide transcriptomic profiling analyses to identify therapeutic targets of Teriflunomide associated with Gemcitabine resistance (Gem-R) in PC. Subsequently, we analyzed the TCGA dataset to determine the prognostic significance of candidate genes in PC patients. A series of experiments were performed in PC cells, and the key findings were validated in patient-derived 3D organoids and a Gem-R Mia-PaCa2 xenograft model. Results: Docking and transcriptomic profiling studies identified GSK3β, MAPK8, and MAPK9 as potential targets of Teriflunomide, which were significantly upregulated in Gem-R cell lines (P &amp;lt; 0.05). GSK3β was independently associated with poor overall and disease-free survival in PC patients. Combined Teriflunomide and Gemcitabine treatment exhibited superior synergistic anti-tumor potential, as evidenced by reducing PC cell proliferation, clonogenicity, invasion, and migration. The combined treatment with Teriflunomide and Gemcitabine primarily inhibited GSK3β phosphorylation, resulting in the silencing of the downstream AKT/mTOR pathway. Lentiviral-based silencing of GSK3β inhibited the AKT/mTOR pathway and reduced the IC50s of Gemcitabine in PC cells. Furthermore, co-administrating both drugs to Gem-R Mia-PaCa-2 xenograft mice significantly reduced tumor growth rates and volumes. These findings were recapitulated in patient-derived 3D-organoids, where the combined treatment resulted in fewer and smaller organoids vs. each drug individually (P &amp;lt; 0.05). Conclusions: We provide novel evidence that Teriflunomide helps overcome resistance to Gemcitabine by inhibiting the GSK3β/AKT/mTOR pathway, which could improve treatment outcomes in PC. Citation Format: Caiming Xu, Yuan Li, Silei Sui, Meiling Chen, Laleh Melstorm, Haiyong Han, Steven T. Rosen, Ajay Goel. Teriflunomide overcomes gemcitabine resistance by inhibiting the GSK3β/mTOR pathway in 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 7192.

O93: Calcium channel blockers are associated with improved survival in pancreatic cancer patients undergoing neoadjuvant chemotherapy and resection

Abstract Background Repurposing existing drugs for use in oncology is more safe, efficient and cost-effective than novel drug discovery. Calcium signalling is increasingly recognised to have a key role in chemoresistance and many of the hallmarks of cancer. This study aims to assess the impact of calcium channel blockers (CCB) in pancreatic cancer. Methods Retrospective population study including patients in the SEER-Medicare linked database who underwent resection with curative intent of pancreatic ductal adenocarcinoma diagnosed between 2007 and 2017. Adjusted cox regression models were built to assess the impact on overall survival. As laboratory studies suggest a chemosensitising effect, we assessed the impact of CCB separately in patients receiving chemotherapy. Results 6,223 patients were included, of whom 660 were prescribed CCB. 591 patients received neoadjuvant chemotherapy prior to resection; in this cohort CCB prescription was associated with a significant improvement in overall survival when adjusting for multiple prognostic factors (aHR=0.715, 0.514-0.996, P=0.047). This effect was not observed in patients who did not receive neoadjuvant chemotherapy (aHR=1.082, 0.982-1.191, P=0.112), or in the overall cohort (aHR=1.056, 0.963-1.158, P=0.248), suggesting a chemosensitising effect. Discussion CCB prescription was associated with improved overall survival in patients receiving neoadjuvant chemotherapy prior to pancreatic cancer resection. The association was specific to the group of patients receiving neoadjuvant chemotherapy. This indicates a chemosensitising effect of CCB, which mirrors previous laboratory studies. This study defines those receiving neoadjuvant chemotherapy as a target population for prospective clinical trials of CCB in pancreatic cancer.

Prognostic Value of Myosteatosis and Creatinine-to-Cystatin C Ratio in Patients with Pancreatic Cancer Who Underwent Radical Surgery.

Myosteatosis is correlated with poor prognosis in some malignancies. The creatinine-to-cystatin ratio (CCR) is revealed to predict gastric cancer prognosis. However, the prognostic abilities of CCR and the combination of CCR and myosteatosis in patients with pancreatic cancer (PC) who underwent radical surgery remains unclear. The retrospective cohort study included 215 patients with PC who underwent radical surgery (January 2016-October 2021). Clinicopathological and serological data were collected on admission. Myosteatosis and other body composition indices were assessed by using computed tomography. The cutoff value of CCR was determined by using the Youden index. Risk factors responsible for poor overall survival (OS) and disease-free survival (DFS) were determined by the Cox proportional hazards model. The myosteatosis group included 104 patients (average age, 61.3 ± 9.1 years). The best cutoff value for CCR was 1.09. CCR ≤ 1.09 was an independent predictive biomarker inversely corelated with OS (P = 0.036). Myosteatosis was an independent risk factor associated with OS and DFS (P = 0.032 and P = 0.004, respectively). Patients with concomitant myosteatosis and CCR ≤ 1.09 had the worst OS (P = 0.016). Myosteatosis and CCR are prognostic biomarkers for survival in PC patients who underwent radical surgery. Patients with the coexistence of myosteatosis and CCR ≤ 1.09 deserve more attention.

Predictive machine learning models for survival outcomes in patients with pancreatic cancer.

625 Background: Identifying prognostic markers is essential for accurately assessing risk levels in pancreatic cancer patients, leading to more personalized treatment approaches. In light of this, our study endeavors to build a survival prediction model for pancreatic cancer patients using various machine learning (ML) techniques, taking into account both clinical and inflammatory factors. Methods: The research included 311 pancreatic cancer patients on a prospective basis. Their data was sourced from the Clinical Data Warehouse of National Cheng Kung University Hospital. For the purpose of predicting 6 and 12-month survival, patients were randomly allocated into training, validation, and test groups in an 8:1:1 ratio. We utilized machine learning techniques and assessed them on the QOCA Aim (Quanta Omni Cloud Care for AI Medical Platform, version 2.0) platform. The model's effectiveness was gauged using the area under the receiver operating characteristic curve (AUC). Results: The cohort exhibited a mean age of 63.5 years with a standard deviation of 11. The median overall survival was documented at 16.8 months (95% confidence interval [CI] = 15.6–18). Analytical evaluation indicated that the optimal model for prognostication of 6-month survival was the balanced bagging classifier, yielding an AUC of 93.7%. Conversely, for the 12-month survival prediction, the k-nearest neighbors (kNN) classifier was superior, demonstrating an AUC of 86.1%. Subsequent variable importance analysis elucidated that salient predictors encompassed C-Reactive protein (CRP), surgical intervention, carbohydrate antigen (CA)19-9, age at diagnosis, and the neutrophil–lymphocyte ratio (NLR). Conclusions: The findings indicated that machine learning can be employed to develop high-efficacy predictive models for survival in pancreatic cancer patients. Such models offer promise for enhanced risk categorization and personalized prognostic assessment in this patient cohort.

Abstract C034: Genome-wide CRISPR screen identifies novel immunotherapeutic targets in pancreatic cancer

Abstract Background: Cancer-cell-intrinsic properties dictate the immune contexture of tumors, impacting the outcome of immunotherapy. Despite the increasing value of CRISPR/Cas9-based loss-of-function (LOF) genetic screens for systematically assessing gene knockout phenotype in tumor cells, it still present challenges, particularly when it comes to genomic editing in the context of large scale experiments and the identification of immunomodulatory genes in in vivo application. To address this, we have established an AsCpf1 (Cas12a)-based screen platform to enable comprehensive whole genome in vivo LOF screening and uncover novel immunotherapeutic targets for pancreatic cancer, which is notoriously resistant to current immunotherapies. Methods: We designed and constructed the optimized minimal CRISPR/AsCpf1 library that targets the entire mouse genome and is only one-fourth the size of the existing genome-wide Cas9-based library. To identify novel immune-related gene vulnerabilities in pancreatic cancer, we infected cell cultures derived from the classic p48-Cre KrasLSL-G12D/+ p53+/- genetically engineered pancreatic cancer mouse model with our AsCpf1 library for in vivo LOF screen in immune-competent and -incompetent mice. Next generation sequencing analysis was performed with the resulting tumors. The potential immunomodulatory hits were called out through BAGEL analysis, using a false discovery rate (FDR) &amp;lt; 0.05, and by comparing between the two mouse groups. Results: Our AsCpf1-based screen identified highly confident hits with potential immunomodulation properties. Notably, we observed depletions of various components of the MHC complex, including H13, specifically in the immune-competent background, implicating their requirement for the regulation of anti-tumor immunity. Depletion of H13 with CRISPR/Cas9 system significantly suppressed pancreatic tumor growth in T-cell dependent manner. Further immune profiling revealed that the loss of H13 triggered potent immune response which was featured by a substantial increase in effective CD8+ T cells and reduction in immunosuppressive macrophages in both subcutaneous and orthotopic models of pancreatic cancer. These findings are in accordance with our clinically relevant analysis showing that low expression of H13 is correlated with improved patient survival in pancreatic cancer and augmented responsiveness to immune checkpoint therapies in several cancer types. Conclusions: Our AsCpf1-based LOF screening platform enables unbiased exploration of in vivo functional players at whole-genome level, which can be applied to diverse disease context and models. In our lead screen, we have identified H13 as a promising immunomodulatory target for patients with pancreatic cancer. Citation Format: Xiaofei Wang, Jintan Liu, Giulio Draetta, Haoqiang Ying, Wantong Yao. Genome-wide CRISPR screen identifies novel immunotherapeutic targets in pancreatic cancer [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 C034.

Abstract C018: Spatial profiling of tumor associated cells expressing endoplasmic reticulum stress proteins predicts poor outcomes in pancreatic cancer patients

Abstract The crosstalk between pancreatic cancer (PC) cells and cells of the tumor microenvironment (TME), such as immune cells and cancer associated fibroblasts (CAFs), has important implications for tumor progression. It is evident that the expression of endoplasmic reticulum (ER) stress proteins (e.g., BiP or CHOP) in tumor cells has survival implications for patients. For example, high BiP expression in tumor cells is correlated with poor survival in PC patients. However, the effect of these proteins in TME cells is currently unknown. We have employed quantitative multiplex immunofluorescence on a tumor microarray cohort of 259 treatment naive pancreatic cancer patient samples and 41 normal pancreas samples. We investigated the impact of expression of ER stress proteins BiP or CHOP in CAFS (α-SMA+), immune cells (CD45+), endothelial cells (CD31+) and tumor cells (PanCK+). HALO AI (Indica Labs) was used to conduct cell/tissue classifications and spatial proximity analysis. Notably, the proportion of CAFs and endothelial cells expressing BiP or CHOP was significantly (p&amp;lt;0.01-0.0001) increased in tumor sections compared to non-tumor sections. When considering the tumor sections, increased BiP expression in CAFs and endothelial cells was found to be correlated with vascular invasion (p=0.0388 and p=0.0318 respectively). Interestingly, there was also a positive correlation between the percent of total CAFs and the percent of BiP positive cells (p=0.0037, r=0.293) or CHOP positive cells (p=0.0001, r=0.235), suggesting that ER stress could be associated with activation of CAFs. Spatial analysis was next utilized to explore the distribution of cells expressing BiP or CHOP within the TME. Remarkably, when examining the average distance in a 500 μm radius, our findings showed that immune cells expressing BiP or CHOP were located significantly (p&amp;lt;0.0001) closer to tumor cells compared to non-expressing immune cells. Interestingly, increased distance of CHOP expressing immune cells to tumor cells was negatively correlated (p=0.037, r=-0.137) with tumor size. We next examined these cells within a 20 μm radius of tumor cells, as it represents a physiologically feasible distance for direct cell-cell contact. Increased numbers of CHOP CD45 cells within the 20 μm radius was correlated with poorer overall survival (p=0.0062) and event free survival (p=0.046). Similarly, in CAFS, BiP expressing cells were found on average closer to tumor cells (p&amp;lt;0.0001), although this was not associated with patient survival. The observed correlation between elevated ER stress in TME cells with adverse patient outcomes indicates the importance of BiP or CHOP as potential therapeutic targets. Furthermore, the spatial analysis results provide insights into the organization of TME cells, shedding light on the significance of ER stress in the TME. These findings contribute to our understanding of the complex interplay between ER stress, tumor biology, and patient outcomes in PC. Citation Format: Georgia M. Porter, Murray Norris, Minoti Apte, Angelica Merlot. Spatial profiling of tumor associated cells expressing endoplasmic reticulum stress proteins predicts poor outcomes in pancreatic cancer patients [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 C018.

Advancing Precision Medicine: VAE Enhanced Predictions of Pancreatic Cancer Patient Survival in Local Hospital

Advancing Precision Medicine: VAE Enhanced Predictions of Pancreatic Cancer Patient Survival in Local Hospital

Elevated tissue expression of RANKL and RANK is associated with poorer survival rates in pancreatic cancer patients.

Pancreatic cancer is a highly lethal malignancy with a growing incidence reported worldwide. Pancreatic ductal adenocarcinoma (PDAC) is the most common type of pancreatic cancer, which is often diagnosed at advanced stages, making its prognosis and medical management difficult. The identification of histopathological biomarkers has allowed a more precise stratification of pancreatic cancer patients, providing additional information about their prognosis and offering possible therapeutic targets to be explored. The prognostic value of the receptor activator of nuclear factor-kappa B (RANK) and its ligand (RANKL) has been evaluated in breast and prostate tumors, however, their usefulness has not been assessed in pancreatic cancer. In the present work, we analyzed the relationship between the protein expression of RANK and RANKL with the survival of 41 patients with pancreatic cancer followed for 60 months, by performing immunohistochemistry and Kaplan-Meier curves. Our results demonstrate a direct association of high expression levels of RANK and RANKL with poorer survival of pancreatic cancer patients in comparison to those with low/medium and null expression levels of both markers. Further studies should be conducted to explore the carcinogenic role of both components in this type of tumor, as well as additional promising translational uses.

Survival of pancreatic cancer patients treated with nab-paclitaxel (nab-P) in clinical practice: analysis of National Health Fund data

Introduction. Despite advances in the last few decades, pancreatic cancer is still characterized by systematically increasing morbidity and high mortality with a low survival rate. The introduction of nab-paclitaxel (nab-P) to the first-line treatment of patients with metastatic pancreatic adenocarcinoma in combination with gemcitabine resulted in improvements in overall survival (OS), progression-free survival (PFS) and objective response rate (ORR). Material and methods. This study analyzes OS and PFS in pancreatic cancer patients treated with nab-P in the real world setting in Poland, based on data from the National Health Fund (NFZ) database. Results. Data from 873 patients were found (2014–2019). PFS in the entire population was 169 days (95% CI 147–189) without difference between men and women, but significantly better in younger patients (29–50 years). OS in the entire population was 379 days (95% CI 337–non-assessable), with no difference between men and women. A statistically significant longer PFS and OS was demonstrated in the group of patients diagnosed in 2014–2016. Conclusion. Nab-paclitaxel, when used in clinical practice, provides treatment results similar to those in clinical trials. Collecting and periodically analyzing demographic and clinical data could help to assess the place of nab-P in the treatment of patients with pancreatic cancer more accurately.

Calcium channel blockers are associated with improved survival in pancreatic cancer patients undergoing neoadjuvant chemotherapy and resection

BackgroundRepurposing existing drugs for use in oncology is more efficient, cost-effective and safe than novel drug discovery. Calcium signalling is increasingly recognised to have a key role in chemoresistance. This study assessed the impact of calcium channel blockers (CCB) in pancreatic cancer. MethodsRetrospective population study of patients undergoing resection (curative intent) of pancreatic ductal adenocarcinoma (SEER-Medicare, 2007–2017). Cox models were built to assess the impact on overall survival. As laboratory studies suggest a chemosensitising effect, the impact of CCB was assessed separately in patients receiving neoadjuvant chemotherapy. Results6,223 patients were included, of whom 660 were prescribed CCB. In total, 591 received neoadjuvant chemotherapy; in this cohort CCB prescription was associated with improved overall survival when adjusting for multiple prognostic factors (aHR = 0.715, 0.514–0.996, P = 0.047). This effect was not observed in patients not receiving neoadjuvant chemotherapy (aHR = 1.082, 0.982–1.191, P = 0.112). ConclusionCCB prescription was associated with improved overall survival in patients receiving neoadjuvant chemotherapy prior to pancreatic cancer resection. The association was specific to the group of patients receiving neoadjuvant chemotherapy, mirroring the chemosensitising effect in laboratory studies. This defines patients receiving neoadjuvant chemotherapy as a target population for prospective clinical trials of CCB in pancreatic cancer.

Secreted frizzled related-protein 2 is prognostic for human pancreatic cancer patient survival and is associated with fibrosis.

Pancreatic adenocarcinoma (PDAC) is one of the deadliest cancers, with five-year survival rates of 9%. We hypothesized that secreted frizzled-related protein 2 (SFRP2) may influence stromal growth in pancreatic cancer, since it increases fibrosis and collagen production in non-neoplastic pathologies. We assessed SFRP2 value as a biomarker and assessed its function in PDAC. SFRP2 gene expression in patients with PDAC was analyzed using TCGA data. Disease free survival (DFS) was analyzed using Kaplan Meier test. The effect of KRAS inhibition on SFRP2 expression in PDAC cells was assessed. The associations of stromal content with SFPR2 mRNA and protein with fibrosis were analyzed. The role of SFRP2 in mesenchymal transformation was assessed by western blot in fibroblasts. Of all cancers in TCGA, SFRP2 levels were highest in PDAC, and higher in PDAC than normal tissues (n= 234, p= 0.0003). High SFRP2 levels correlated with decreased DFS (p= 0.0097). KRAS inhibition reduced SFRP2 levels. Spearman correlation was 0.81 between stromal RNA and SFRP2 in human PDAC, and 0.75 between fibrosis and SFRP2 levels in PDAC tumors. SFRP2-treated fibroblasts displayed mesenchymal characteristics. SFRP2 is prognostic for PDAC survival, regulated by KRAS, and associated with PDAC fibrosis.

Beta-blocker use and survival after pancreatic cancer surgery: A nationwide population-based cohort study.

We examined the association between use of beta-blockers and survival in pancreatic cancer patients after curative-intent surgery. Using Danish healthcare registries, we conducted a population-based cohort study of all patients undergoing curative-intent surgeryfor pancreatic cancer in Denmark 1997-2021. We defined beta-blocker use according to exposure before surgery as current (≤90 days), recent (91-365 days), or former (366-730 days) use, requiring at least one filled prescription. Patients were followed from the date of surgery for up to 5 years. We used Cox regression to compute hazard ratios (HRs) of deaths with 95% confidence intervals (CIs), adjusting for age, sex, year of diagnosis, cardiovascular disease, diabetes, liver disease, alcohol, and smoking. We also conducted an active comparator analysis, where we used angiotensin-converting enzyme inhibitors/angiotensin-receptor blockers as comparators instead of nonusers. We included 2592 patients, of which 16.7% were beta-blocker users. Median survival for the entire population was 24.4 months. Beta-blocker use was associated with increased mortality (adjusted HR: 1.18; 95% CI: 1.04-1.34). This was evident in current (adjusted HR: 1.19; 95% CI: 1.02-1.38) and recent (adjusted HR: 1.29; 95% CI: 1.04-1.59) but not former (adjusted HR: 0.91; 95% CI: 0.64-1.43) users. In the active comparator analysis, the association between beta-blocker exposure and mortality attenuated slightly (adjusted HR: 1.12; 95% CI: 0.93-1.35). We observed an association between beta-blocker use and increased mortality in patients operated for pancreatic cancer. Findings are likely explained by confounding by indication.

Circulating autoantibodies to alpha-enolase (ENO1) and far upstream element-binding protein 1 (FUBP1) are negative prognostic factors for pancreatic cancer patient survival

Pancreatic ductal adenocarcinoma (PDA) has a dismal prognosis due to a lack of early diagnostic markers and effective therapy. In PDA patients, the glycolytic enzyme and plasminogen receptor alpha-enolase (ENO1) and the transcription factor far upstream element-binding protein 1 (FUBP1) are upregulated and elicit the production of autoantibodies (aAb) that discriminate healthy subjects from PDA patients, with the latter mostly directed to post-translational phosphorylated isoforms. Here, the correlation of prognosis with circulating ENO1 and FUBP1aAb, and their protein tissue expression was analyzed in PDA patients. Circulating ENO1 and FUBP1 aAb was analyzed in two cohorts of PDA patients by ELISA (n = 470), while tissues expression was observed by immunohistochemistry (n = 45). Overall survival (OS) was estimated using the Kaplan–Meier method, while the Cox model was used to estimate the hazard ratios (HR) adjusted for the main prognostic factors. Logistic models were applied to assess associations between death and its risk indicators. All statistical analyses were performed with Stata version 15. Unlike ENO1 aAb, there was a significant correlation between FUBP1 aAb and FUBP1 expression in tumors (p = 0.0268). In addition, we found that high ENO1 (p = 0.016) and intermediate FUBP1 aAb levels (p = 0.013) were unfavorable prognostic factors. Notably, it was found that high anti-FUBP1 aAb level is a good prognostic marker for tail-body PDA (p = 0.016). Our results suggest that different levels of circulating aAb to ENO1 and FUBP1 predict a poor outcome in PDA patients and can be used to improve therapeutic strategies.

A retrospective, multicentre, nationwide analysis of the impact of splenectomy on survival of pancreatic cancer patients

A retrospective, multicentre, nationwide analysis of the impact of splenectomy on survival of pancreatic cancer patients

An AI-driven Predictive Model for Pancreatic Cancer Patients Using Extreme Gradient Boosting

Pancreatic cancer is one of the deadliest carcinogenic diseases affecting people all over the world. The majority of patients are usually detected at Stage III or Stage IV, and the chances of survival are very low once detected at the late stages. This study focuses on building an efficient data-driven analytical predictive model based on the associated risk factors and identifying the most contributing factors influencing the survival times of patients diagnosed with pancreatic cancer using the XGBoost (eXtreme Gradient Boosting) algorithm. The grid-search mechanism was implemented to compute the optimum values of the hyper-parameters of the analytical model by minimizing the root mean square error (RMSE). The optimum hyperparameters of the final analytical model were selected by comparing the values with 243 competing models. To check the validity of the model, we compared the model’s performance with ten deep neural network models, grown sequentially with different activation functions and optimizers. We also constructed an ensemble model using Gradient Boosting Machine (GBM). The proposed XGBoost model outperformed all competing models we considered with regard to root mean square error (RMSE). After developing the model, the individual risk factors were ranked according to their individual contribution to the response predictions, which is extremely important for pancreatic research organizations to spend their resources on the risk factors causing/influencing the particular type of cancer. The three most influencing risk factors affecting the survival of pancreatic cancer patients were found to be the age of the patient, current BMI, and cigarette smoking years with contributing percentages of 35.5%, 24.3%, and 14.93%, respectively. The predictive model is approximately 96.42% accurate in predicting the survival times of the patients diagnosed with pancreatic cancer and performs excellently on test data. The analytical methodology of developing the model can be utilized for prediction purposes. It can be utilized to predict the time to death related to a specific type of cancer, given a set of numeric, and non-numeric features.

DUSP1 promotes pancreatic cancer cell proliferation and invasion by upregulating nephronectin expression

Abstract Objectives To explore the role of dual-specific phosphatase 1 (DUSP1) in the proliferation, migration and invasion of pancreatic cancer (PC). Methods TCGA and GTEx databases were used to investigate the relationship between DUSP1 expression and prognosis of PC patients. Expression efficiency of DUSP1 was validated by qPCR and western blotting. The proliferation of SW1990 and PANC-1 cells with DUSP1 overexpression or knockout was detected by EdU assays. The migratory and invasive abilities of cells were detected by wound healing and transwell assays. Results DUSP1 was highly expressed in PC and associated with poor prognosis of patients. Overexpression of DUSP1 promoted the proliferation, migration and invasion of PC cells by regulating nephronectin (NPNT), whereas knockout of DUSP1 exhibited the opposite effects. NPNT expression was positively correlated with DUSP1, and the overall survival of PC patients with high levels of NPNT was shorter. Conclusions DUSP1 promoted the proliferation, migration and invasion of PC cells by upregulating NPNT, suggesting DUSP1 may be a potential target for PC treatment.