Survival In Pancreatic Adenocarcinoma Research Articles

Signal enhancement ratio of multi-phase contrast-enhanced MRI: an imaging biomarker for survival in pancreatic adenocarcinoma.

To evaluate signal enhancement ratio (SER) for tissue characterization and prognosis stratification in pancreatic adenocarcinoma (PDAC), with quantitative histopathological analysis (QHA) as the reference standard. This retrospective study included 277 PDAC patients who underwent multi-phase contrast-enhanced (CE) MRI and whole-slide imaging (WSI) from three centers (2015-2021). SER is defined as (SIlt - SIpre)/(SIea - SIpre), where SIpre, SIea, and SIlt represent the signal intensity of the tumor in pre-contrast, early-, and late post-contrast images, respectively. Deep-learning algorithms were implemented to quantify the stroma, epithelium, and lumen of PDAC on WSIs. Correlation, regression, and Bland-Altman analyses were utilized to investigate the associations between SER and QHA. The prognostic significance of SER on overall survival (OS) was evaluated using Cox regression analysis and Kaplan-Meier curves. The internal dataset comprised 159 patients, which was further divided into training, validation, and internal test datasets (n = 60, 41, and 58, respectively). Sixty-five and 53 patients were included in two external test datasets. Excluding lumen, SER demonstrated significant correlations with stroma (r = 0.29-0.74, all p < 0.001) and epithelium (r = -0.23 to -0.71, all p < 0.001) across a wide post-injection time window (range, 25-300 s). Bland-Altman analysis revealed a small bias between SER and QHA for quantifying stroma/epithelium in individual training, validation (all within ± 2%), and three test datasets (all within ± 4%). Moreover, SER-predicted low stromal proportion was independently associated with worse OS (HR = 1.84 (1.17-2.91), p = 0.009) in training and validation datasets, which remained significant across three combined test datasets (HR = 1.73 (1.25-2.41), p = 0.001). SER of multi-phase CE-MRI allows for tissue characterization and prognosis stratification in PDAC. The signal enhancement ratio of multi-phase CE-MRI can serve as a novel imaging biomarker for characterizing tissue composition and holds the potential for improving patient stratification and therapy in PDAC. Imaging biomarkers are needed to better characterize tumor tissue in pancreatic adenocarcinoma. Signal enhancement ratio (SER)-predicted stromal/epithelial proportion showed good agreement with histopathology measurements across three distinct centers. Signal enhancement ratio (SER)-predicted stromal proportion was demonstrated to be an independent prognostic factor for OS in PDAC.

Tumor Size Combined With CA-19 Level Improves Prediction of Survival of Patients With Pancreatic Adenocarcinoma Undergoing Perioperative Chemotherapy and Resection.

Five-year survival in pancreatic adenocarcinoma is less than 20%. While previous studies have postulated that a carbohydrate antigen 19-9 (CA19-9) threshold could predict outcome of resection, the role for CA19-9 in decision-making remains unclear. This study aims to assess whether CA19-9 levels combined with tumor size improve prediction of post-resection survival. A retrospective analysis was conducted on 109 patients with pancreatic adenocarcinoma who underwent perioperative chemotherapy followed by resection. The primary outcome of mortality was, divided into short (<1year) or prolonged (>2years). Univariate and multivariable analyses compared the tumor size-adjusted CA19-9 between the outcome groups. Twenty-seven (24.78%) and eighty-two (75.23%) patients were in the short survival and prolonged-survival groups, respectively. The mean CA19-9 was significantly greater in the short vs prolonged group (P < .001). Analyzing CA19-9 level by tumor size, the association of high CA19-9 and short survival was significant for small (≤2cm) and large tumor (>4cm), but not for intermediate-size tumors (2-4cm). Adjusting for preoperative variable did not change this association. CA 19-9 in combination with tumor size better identifies patients with prolonged post-resection survival. This prediction is most accurate in patients with either small (≤2cms) or large (>4cms) tumors compared to intermediate-size tumors.

Important Radiologic and Clinical Factors for Predicting Overall Survival in Pancreatic Adenocarcinoma Patients Who Underwent FOLFIRINOX.

To predict poor overall survival (OS) in pancreatic adenocarcinoma (PAC) who underwent FOLFIRINOX (5-fluorouracil/leucovorin/irinotecan/oxaliplatin) using clinical and computed tomography (CT) findings. A total of 189 patients with PAC who received FOLFIRINOX were retrospectively included. Two reviewers assessed CT findings and resectability based on National Comprehensive Cancer Network guidelines. They determined tumor size changes according to Response Evaluation Criteria in Solid Tumors (RECIST 1.1). Delta measurements were performed. Clinical results, such as whether to perform surgery, were also investigated. A Cox proportional hazard model was used to identify significant predictors for OS. A CT-based nomogram was constructed to predict OS. Seventy-four patients (39.2%) underwent surgery. For OS, rim enhancement of PAC on baseline CT (hazard ratio [HR], 1.75; 95% confidence interval [CI], 1.10-2.77; P = 0.018), high delta tumor on baseline CT (HR, 2.46; 95% CI, 1.55-3.91; P < 0.001), progressive disease at follow-up CT (HR, 8.89; 95% CI, 2.94-26.87; P < 0.001), and without surgery (HR, 2.81; 95% CI, 1.49-5.30; P = 0.001) were important features related to poor prognosis. The nomogram showed good predictive ability for the survival. Both clinical and CT findings were useful for predicting OS after FOLFIRINOX in PAC.

CUL4A Ubiquitin Ligase Is an Independent Predictor of Overall Survival in Pancreatic Adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy with dismal prognosis. Genomic instability due to defects in cell-cycle regulation/mitosis or deficient DNA-damage repair is a major driver of PDAC progression with clinical relevance. Deregulation of licensing of DNA replication leads to DNA damage and genomic instability, predisposing cells to malignant transformation. While overexpression of DNA replication-licensing factors has been reported in several human cancer types, their role in PDAC remains largely unknown. We aimed here to examine the expression and prognostic significance of the DNA replication-licensing factors chromatin licensing and DNA replication factor 1 (CDT1), cell-division cycle 6 (CDC6), minichromosome maintenance complex component 7 (MCM7) and also of the ubiquitin ligase regulator of CDT1, cullin 4A (CUL4A), in PDAC. Expression levels of CUL4, CDT1, CDC6 and MCM7 were evaluated by immunohistochemistry in 76 formalin-fixed paraffin-embedded specimens of PDAC patients in relation to DNA-damage response marker H2AX, clinicopathological parameters and survival. We also conducted bioinformatics analysis of data from online available databases to corroborate our findings. CUL4A and DNA replication-licensing factors were overexpressed in patients with PDAC and expression of CDT1 positively correlated with H2AX. Expression of CUL4A and CDT1 positively correlated with lymph node metastasis. Importantly, elevated CUL4A expression was associated with reduced overall survival and was an independent indicator of poor prognosis on multivariate analysis. Our findings implicate CUL4A, CDT1, CDC6 and MCM7 in PDAC progression and identify CUL4A as an independent prognostic factor for this disease.

Association between TP53 gain of function and loss of function mutational subgroups and survival in pancreatic adenocarcinoma.

694 Background: TP53 is a commonly mutated tumor suppressor in pancreatic adenocarcinoma (PDAC) but the clinical implications for different classes of TP53 variants remain unclear. In contrast to loss of function (LOF) mutations, TP53 gain of function (GOF) mutations alter DNA conformational binding (e.g. R175H, G245S, R249S, R282H) or modify DNA contact hotspots (e.g. R248Q, R248W, R273H) and are associated with aggressive phenotypes. Here, we analyze progression-free survival (PFS) on standard therapies and overall survival (OS) of PDAC patients (pts) within TP53 mutational subgroups: GOF, LOF, and wild type (WT). Methods: We analyzed longitudinal outcomes across 775 pts with next generation DNA sequencing (NGS) results from Perthera’s Real-World Evidence database who received at least 1 line of therapy in the advanced setting for PDAC. PFS was evaluated from initiation of 1st line for advanced disease until discontinuation. Hazard ratios and p-values were computed via Cox regression when comparing OS relative to date of advanced diagnosis and PFS on subsets who received 1st line FOLFIRINOX (FFX) or 1st line gemcitabine/nab-paclitaxel (GA). Differences in frequencies of genomic alterations between TP53 mutational subgroups were analyzed by Fisher’s exact test. Results: In the TP53 LOF subgroup, median PFS on 1st line GA was significantly worse than 1st line FFX (Table) but this difference was not observed in TP53 GOF or WT subgroups. Irrespective of 1st line therapy choice, median OS in the WT subgroup (2.1y [1.8-2.4]) was significantly longer (p&lt;0.05) than pts with TP53 GOF (1.5y [1.3-2.1]) or TP53 LOF (1.4y [1.3-1.5]). KRAS mutations were enriched (unadjusted p&lt;0.05) for co-occurrence with TP53 in GOF (93.7%) and LOF (93.3%) subgroups relative to WT (74.5%). Mutations in BRCA1/2 were less common in the TP53 GOF subgroup (2.5%) relative to LOF (5.1%) and WT (11.6%). ATM mutations as well as an expanded set of genomic alterations within the DDR pathway were also enriched with similar trends (GOF&lt;LOF&lt;WT). Other potentially confounding factors will be discussed in the context of multivariate OS/PFS analyses. Conclusions: TP53 mutations correlated with worse prognosis in advanced PDAC. Potential predictive associations favoring FFX over GA in the TP53 LOF subgroup (but not in GOF or WT subgroups) warrant further exploration. [Table: see text]

Treatment of pancreatic adenocarcinoma in relation to survival in the U.S. Military Health System

BackgroundPancreatic cancer has a high case fatality and relatively short survival after diagnosis. Treatment is paramount to improving survival, but studies on the effects of standard treatment by surgery or chemotherapy on survival in U.S. healthcare settings is limited. Further, variability in access to care may impact treatment and outcomes for patients. We aimed to assess the relationship between standard treatment(s) and survival of pancreatic adenocarcinoma in a population with access to comprehensive healthcare. MethodsWe used the Military Cancer Epidemiology (MilCanEpi) database, which includes data from the Department of Defense cancer registry and medical encounter data from the Military Health System (MHS), to study a cohort of 1408 men and women who were diagnosed with pancreatic adenocarcinoma between 1998 and 2014. Treatment with surgery or chemotherapy in relation to overall survival was examined in multivariable time-dependent Cox regression models. ResultsOverall, 75 % of 441 patients with early-stage and 51 % of 967 patients with late-stage pancreatic adenocarcinoma received treatment. In early-stage disease, surgery alone or surgery with chemotherapy were both associated with statistically significant 52 % reduced risks of death, but chemotherapy alone was not. In late-stage disease, surgery alone, chemotherapy alone, or both surgery and chemotherapy significantly reduced the risk of death by 42 %, 25 %, and 52 %, respectively. ConclusionsOur findings from the MHS demonstrate improved survival after treatment with surgery or surgery with chemotherapy for early- or late-stage pancreatic cancer and after chemotherapy for late-stage pancreatic cancer. In the era of immunotherapy and personalized medicine, further research on treatment and survival of pancreatic cancer in observational settings is needed.

Impact on Survival of Early Versus Late Initiation of Adjuvant Chemotherapy After Pancreatic Adenocarcinoma Surgery: A Target Trial Emulation.

We examined the impact of early (0-4weeks after discharge) versus late (> 4-8weeks after discharge) initiation of adjuvant chemotherapy on pancreatic adenocarcinoma survival. We used Danish population-based healthcare registries to emulate a hypothetical target trial using the clone-censor-weight approach. All eligible patients were cloned with one clone assigned to 'early initiation' and one clone assigned to 'late initiation'. Clones were censored when the assigned treatment was no longer compatible with the actual treatment. Informative censoring was addressed using inverse probability of censoring weighting. We included 1491 patients in a hypothetical target trial, of whom 32.3% initiated chemotherapy within 0-4weeks and 38.3% between > 4 and 8weeks after discharge for pancreatic adenocarcinoma surgery; 206 (13.8%) initiated chemotherapy after > 8weeks, and 232 (15.6%) did not initiate chemotherapy. Median overall survival was 30.4 and 29.9months in late and early initiators, respectively. The absolute differences in OS, comparing late with early initiators, were 3.2% (95% confidence interval [CI] - 1.5%, 7.9%), - 0.7% (95% CI - 7.2%, 5.8%), and 3.2% (95% CI - 2.8%, 9.3%) at 1, 3, and 5years, respectively. Late initiators had a higher increase in albumin levels as well as higher pretreatment albumin values. Postponement of adjuvant chemotherapy up to 8weeks after discharge from pancreatic adenocarcinoma surgery is safe and may allow more patients to receive adjuvant therapy due to better recovery.

Improved Overall Survival of Patients with Pancreatic Cancer through Multiagent Chemotherapy and Increased Rates of Surgical Resection.

Seminal trials have demonstrated improved survival in pancreatic adenocarcinoma with novel multiagent chemotherapy regimens. To understand the clinical ramifications of this paradigm shift, we reviewed our institutional experience. This retrospective cohort study utilized a prospective database at a single institution to study all patients diagnosed with and treated for pancreatic adenocarcinoma between 2000 and 2020. 1,572 patients were included of which 36% were diagnosed before (Era 1) and 64% after (Era 2) 2011. Survival improved in Era 2 (Median survival 10 vs 8months, HR .79; P < .001). The survival advantage for Era 2 was primarily seen in patients with high-risk disease (12 vs10months, HR .71; P < .001). A similar trend was noted for patients undergoing surgical resection (26 vs 21months, HR .80; P = .081) and with imminently resectable tumors (19 vs 15months, HR .88; P = .4); however, this was not statistically significant. There was no survival advantage for patients with stage IV disease (4 vs 4months). Patients in Era 2 were more likely to undergo surgery (OR 2.78; CI 2.00-3.92, P < .001). This increase was driven primarily by increased surgical resection for those with high-risk disease (42 vs 20%, OR 3.74; P < .001). This single institutional study showed improved survival after the shift to novel chemotherapy regimens. This was driven by improved survival for patients with high-risk disease and may be due to more effective eradication of microscopic metastatic disease with adjuvant chemotherapy and increased resection rates.

Real World Data for Pancreatic Adenocarcinoma from a Population-Based Study in France.

Pancreatic cancer is associated with high mortality rates, and most cases are diagnosed at advanced stages. This study aimed to evaluate the prognostic factors for survival in pancreatic adenocarcinoma. Data from the Finistere registry of digestive database were used in this analysis. This retrospective population-based study included 2117 patients with pancreatic adenocarcinoma diagnosed between 2005 and 2019. Cox regression was used to assess the impact of different prognostic factors. The overall median age was 74 (IQR 65.0-81.0). The majority of pancreatic adenocarcinoma 1120 (52.90%) occurred in the head of the pancreas. The type of surgical resection correlated with age (pancreaticoduodenectomy performed in 13.39% of patients aged under 65 years and only 1.49% of patients aged ≥ 80 years). For the entire cohort, 1-year mortality rate after diagnosis was 77.81%. Chemotherapy was associated with better survival for both operated (HR 0.17 95% CI 0.22; 0.64 p &lt; 0.001) and unoperated patients (HR 0.41 95% CI 0.27; 0.61 p &lt; 0.001). Palliative radiotherapy was associated with improved survival (HR 0.69 95% CI 0.56; 0.85 p &lt; 0.001). Among operated patients, the presence of lung metastases (median 34.06; CI 20.06; 34.66) was associated with better survival compared with liver metastases (median 21.10; CI 18.10; 28.96), peritoneal carcinomatosis (median 11.00; CI 8.53; 14.63), or distant metastases (median 15.16; CI 12.66; 18.13) (p = 0.0001). Age, curative surgery, positive lymph nodes, chemotherapy, and palliative radiotherapy were corelated with overall survival. Surgical resection is the only potentially curative treatment, but less than a quarter of patients were eligible.

Disparities in pancreatic adenocarcinoma survival by medicaid status: A national risk analysis

Background: Pancreatic adenocarcinoma (ACC) has one of the highest mortality rates among all malignancies. While previous studies have analyzed socioeconomic factors’ effect on ACC survival, survival outcomes of Medicaid patients, totaling around 81 million in 2022, are poorly characterized.

Identification of a Four Cancer Stem Cell-Related Gene Signature and Establishment of a Prognostic Nomogram Predicting Overall Survival of Pancreatic Adenocarcinoma.

Cancer stem cells (CSCs) are now being considered as the initial component in the development of pancreatic adenocarcinoma (PAAD). Our aim was to develop a CSCrelated signature to assess the prognosis of PAAD patients for the optimization of treatment. Differentially expressed genes (DEGs) between pancreatic tumor and normal tissue in the Cancer Genome Atlas (TCGA) were screened out, and the weighted gene correlation network analysis (WGCNA) was employed to identify the CSC-related gene sets. Then, univariate, Lasso Cox regression analyses and multivariate Cox regression were applied to construct a prognostic signature using the CSC-related genes. Its prognostic performance was validated in TCGA and ICGC cohorts. Furthermore, Univariate and multivariate Cox regression analyses were used to identify independent prognostic factors in PAAD, and a prognostic nomogram was established. The Kaplan-Meier analysis, ROC curve and C-index indicated the good performance of the CSC-related signature at predicting overall survival (OS). Univariate Cox regression and multivariate Cox regression revealed that the CSC-related signature was an independent prognostic factor in PAAD. The nomogram was superior to the risk model and AJCC stage in predicting OS. In terms of mutation and tumor immunity, patients in the high-risk group had higher tumor mutation burden (TMB) scores than patients in the low-risk group, and the immune score and the ESTIMATE score were significantly lower in the high-risk group. Moreover, according to the results of principal component analysis (PCA) and Gene Set Enrichment Analysis (GSEA), the low-risk and high-risk groups displayed different stemness statuses based on the risk model. Our study identified four CSC-related gene signatures and established a prognostic nomogram that reliably predicts OS in PAAD. The findings may support new ideas for screening therapeutic targets to inhibit stem characteristics and the development of PAAD.

Combined Evaluation of mRNA and Protein Expression, Promoter Methylation, and Immune Infiltration of UBE2I in Pan-Digestive System Tumors.

Background Digestive system tumors (DSTs) have high morbidity and mortality worldwide. This study explored the potential value of ubiquitin-conjugating enzyme E2 I (UBE2I) in pan-digestive system tumors (pan-DSTs). Methods Differential expression, tumor stages, and survival outcomes of UBE2I in pan-DSTs were determined using the GEPIA database. The TIMER database was used to confirm the correlation of UBE2I expression with pan-DSTs and immune infiltrates. Differential analyses of UBE2I promoter methylation and protein levels were performed using the UALCAN database. The underlying mechanisms of UBE2I involvement in pan-DSTs were visualized using interaction networks. The diagnostic value of UBE2I in pan-DSTs was identified using the Oncomine database. Results UBE2I was differentially and highly expressed in cholangiocarcinoma (CHOL), pancreatic adenocarcinoma (PAAD), colon adenocarcinoma (COAD), rectal adenocarcinoma (READ), liver hepatocellular carcinoma (LIHC), and stomach adenocarcinoma (STAD). According to survival analysis, upregulated UBE2I was associated with adverse overall and disease-free survival in PAAD and favorable overall survival in READ. UBE2I expression was partially linked to the purity of immune infiltration in COAD, LIHC, PAAD, READ, and STAD, as indicated by the immune infiltration analysis. Promoter methylation analysis showed differential and high methylation of UBE2I in PAAD as well as stratified analysis by gender, nodal metastasis, and race. Protein expression analysis in colon cancer revealed that UBE2I had differential and high expression in tumors as well as stratified analysis by gender, tumor histology, race, and tumor stage. Mechanism explorations demonstrated that in COAD and PAAD, UBE2I was involved in spliceosomal snRNP complex, Notch signaling pathway, etc. Diagnostic analysis indicated that UBE2I had consistent diagnostic value for COAD and PAAD. Conclusions Upregulated UBE2I may be a diagnostic and surveillance predictive signature for PAAD and COAD. The potential significance of immune infiltrates and promoter methylation in PAAD and COAD needs further exploration.

Abstract 5060: A deep learning based pancreatic adenocarcinoma survival prediction model applicable to adenocarcinoma of other organs

Abstract Introduction: To analyze how the histomorphological features of adenocarcinoma lesions are related to the survival of patients, we developed a deep learning based pancreatic adenocarcinoma survival model that predicts death risk through the general adenocarcinoma feature extractor (GAFE). Our pancreatic adenocarcinoma survival model and GAFE was trained with hematoxylin and eosin (H&amp;E) stained whole slide images (WSIs). Also, to measure the generalization performance, we predict the death risk of rectum adenocarcinoma and breast adenocarcinoma using the pancreatic adenocarcinoma survival model. Design: The whole data analyzed in this study was from The Cancer Genome Atlas (TCGA). We used a self-supervised contrastive learning method to train GAFE with randomly chosen 328 adenocarcinoma H&amp;E stained WSIs. These WSIs are consisted of 92 lung (TCGA-LUAD), 100 colon (TCGA-COAD), 97 prostate (TCGA-PRAD) and 39 stomach (TCGA-STAD) adenocarcinoma WSIs. For the pancreatic adenocarcinoma survival model, we used 179 WSIs of TCGA pancreatic adenocarcinoma (TCGA-PAAD) dataset labeled with survival events and periods. There existed 66 uncensored data, and we used 5-fold cross validation. Each WSI was divided into 256*256 pixel-wise patches. Feature vectors were extracted from the patches using the GAFE. Then the attention-based multi-instance learning was applied to train the survival model. The trained model returned a death risk for each patient. We used 122 adenocarcinoma H&amp;E stained WSIs of rectum (TCGA-READ) and 999 of breast (TCGA-BRCA) from TCGA to test the generalization performance for different organs. Result: We used 5-fold cross validation for testing the pancreatic adenocarcinoma survival model. The mean value of C-index from the TCGA-PAAD test datasets was 0.7258 where the highest and the lowest C-index was 0.7784 and 0.6598. Using the model with median performance (C-index: 0.7216), we measured death risk and divided patients into 50% of high-risk and 50% of low-risk groups. From this, the p-value was 0.01986 for the log-rank test.To analyze the performance of the generalization, we ensembled 5 models from the above. We tested our ensembled model on TCGA-READ and TCGA-BRCA. The C-index for TCGA-Read was 0.6941 where the C-index for TCGA-BRCA was 0.5711. Conclusion: We found that adenocarcinoma’s histomorphological features had some correlation with pancreatic adenocarcinoma survival prediction. Moreover, we could see the possibility of transferability of adenocarcinoma histomorphological knowledge and survival analysis to other organs such as rectum adenocarcinoma and breast adenocarcinoma. Citation Format: Joonho Lee, Geongyu Lee, Tae-Yeong Kwak, Sun Woo Kim, Hyeyoon Chang. A deep learning based pancreatic adenocarcinoma survival prediction model applicable to adenocarcinoma of other organs [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5060.

Secreted HSP90α-LRP1 Signaling Promotes Tumor Metastasis and Chemoresistance in Pancreatic Cancer.

The extracellular heat shock protein 90α (eHSP90α) has been reported to promote cancer cell motility. However, whether pancreatic cancer (PC) cells expressed membrane-bound or secreted HSP90α, as well as its underlying mechanism for PC progression, were still unclear. Our study demonstrated that the amounts of secreted HSP90α proteins were discrepant in multiple PC cells. In addition, highly invasive Capan-2 cells have a higher level of secreted HSP90α compared with those of less invasive PL45 cells. The conditioned medium of Capan-2 cells or recombinant HSP90α treatment stimulated the migration and invasion of PC cells, which could be prevented with a neutralizing anti-HSP90α antibody. Furthermore, secreted HSP90α promoted elements of epithelial–mesenchymal transition in PL45 cells, including increases in vimentin and Snail expressions, decreases in E-cadherin expression, and changes in cell shape towards a mesenchymal phenotype, but these phenomena were reversed by the anti-HSP90α antibody in Capan-2 cells. In addition, high levels of low-density lipoprotein receptor-related protein 1 (LRP1) were associated with worsened patient survival in pancreatic adenocarcinoma. We demonstrated LRP1 as a receptor of eHSP90α for its stimulatory role in metastasis, by activating the AKT pathway. In addition, silencing LRP1 enhanced the chemosensitivity to gemcitabine and doxorubicin in Capan-2 cells. Therefore, our study indicated that blocking secreted HSP90α underlies an aspect of metastasis and chemoresistance in PC.

CDC25C is a prognostic biomarker and correlated with mitochondrial homeostasis in pancreatic adenocarcinoma

ABSTRACT Pancreatic adenocarcinoma (PAAD) is a common digestive tract malignant tumor with an extremely poor prognosis. The survival and prognosis may significantly improve if it is diagnosed early. Therefore, identifying biomarkers for early diagnosis is still considered a great clinical challenge in PAAD. Cell Division Cycle 25C (CDC25C), a cardinal cell cycle regulatory protein, directly mediates the G2/M phase and is intimately implicated in tumor development. In the current study, we aim to explore the possible functions of CDC25C and determine the potential role of CDC25C in the early diagnosis and prognosis of PAAD. Expression analysis indicated that CDC25C was overexpressed in PAAD . In addition, survival analysis revealed a strong correlation between the enhanced expression of CDC25C and poor survival in PAAD. Furthermore, pathway analysis showed that CDC25C is related to TP53 signaling pathways, glutathione metabolism, and glycolysis. Mechanically, our in vitro experiments verified that CDC25C was capable of promoting cell viability and proliferation. CDC25C inhibition increases the accumulation of ROS, inhibits mitochondrial respiration, suppresses glycolysis metabolism and reduces GSH levels. To summarize, CDC25C may be involved in energy metabolism by maintaining mitochondrial homeostasis. Our results suggested that CDC25C is a potential biological marker and promising therapeutic target of PAAD.

Identification of KRAS G12V associated clonal neoantigens and immune microenvironment in long-term survival of pancreatic adenocarcinoma

ObjectiveTo investigate the molecular characteristics in tumor immune microenvironment that affect long-term survival of patients with pancreatic adenocarcinoma (PAAD).MethodsThe tumor related genetic features of a female PAAD patient (over 13-year survival) who suffered from multiple recurrences and metastases, and six operations over one decade were investigated deeply. Genomic features and immune microenvironment signatures of her primary lesion as well as six metastatic tumors at different time-points were characterized.ResultsHigh-frequency clonal neoantigenic mutations identified in these specimens revealed the significant associations between clonal neoantigens with her prognosis after each surgery. Meanwhile, the TCGA and ICGC databases were employed to analyse the function of KRAS G12V in pancreatic cancer.ConclusionsThe genomic analysis of clonal neoantigens combined with tumor immune microenvironment could promote the understandings of personalized prognostic evaluation and the stratification of resected PAAD individuals with better outcome.

Immune-related genes LAMA2 and IL1R1 correlate with tumor sites and predict poor survival in pancreatic adenocarcinoma.

Aims: The aim of this study was to identify the immune- and locus-associated genes in pancreatic ductal adenocarcinoma and evaluate their value in prognosis. Methods: The pancreatic ductal adenocarcinoma stromal and immune scores were calculated with the estimation of stromal and immune cells in malignant tumor tissues using expression data algorithm. The authors screened the differentially expressed genes to generate immune- and stromal-related differentially expressed genes. Next, the authors conducted weighted correlation network analysis to find the gene sets related to tumor sites. Results: IL1R1 and LAMA2 were identified as the site- and immune-related genes in pancreatic ductal adenocarcinoma, and their high expression in pancreatic head cancer exhibited high immune scores and predicted unfavorable prognosis. Conclusion: The authors identified IL1R1 and LAMA2 as immune- and locus-associated genes, and their high expression predicted a poor prognosis.

Development and validation of a novel glycolysis-related risk signature for predicting survival in pancreatic adenocarcinoma

BackgroundPancreatic adenocarcinoma (PAAD) is one of the leading causes of cancer-related deaths worldwide. Through data mining, an increasing number of biomarkers have been identified to predict the survival of patients with PAAD. However, the ability of single gene biomarkers to predict patient survival is still insufficient. This study aimed to develop a novel risk signature for predicting the survival of patients with PAAD. MethodsmRNA expression profiling was performed for a large PAAD cohort (n = 177) identified using The Cancer Genome Atlas database (TCGA). Gene set enrichment analysis (GSEA) was performed to detect whether the gene sets showed significant differences between PAAD and adjacent normal tissues. Univariate Cox regression was used to analyze and identify genes related to overall survival (OS). Multivariate Cox regression was subsequently used to confirm the prognostic genes and obtain the coefficients. By analyzing the expression level of selected genes weighted by their coefficients through linearly combining, we constructed a risk score formula for prognostic prediction. The three-mRNA signature for survival prediction was validated using the Kaplan–Meier method. ResultsWe demonstrated that a set of three genes (KIF20A, CHST2, and MET) were significantly associated with OS. Based on this three-gene signature, 177 PAAD patients were classified into high-risk and low-risk groups using the median risk score as the cut-off value. We also validated the reliability of this three-gene signature in the GSE28735 dataset from the Gene Expression Omnibus (GEO) database. Additionally, multivariate Cox regression analysis revealed that the three-gene signature had an independent prognostic value. ConclusionTo the best of our knowledge, this is the first study to develop a glycolysis-related risk signature for predicting the survival of patients with pancreatic adenocarcinoma. Our findings provide insight into the identification of PAAD patients with poor prognosis. We also identified novel therapeutic targets for this disease.

A 3-Decade Analysis of Pancreatic Adenocarcinoma After Solid Organ Transplant.

Solid organ transplant (SOT) recipients have moderately increased risk of pancreatic adenocarcinoma (PAC). We evaluated the incidence and survival of PAC in 2 cohorts and aimed to identify potential risk factors. This study performed a retrospective cohort analysis. Cohort A was extracted from the United Network of Organ Sharing data set and cohort B from SOT recipients evaluated at 3 Mayo Clinic transplant centers. The primary outcome was age-adjusted annual incidence of PAC. Descriptive statistics, hazard ratios, and survival rates were compared. Cohort A and cohort B included 617,042 and 29,472 SOT recipients, respectively. In cohort A, the annual incidence rate was 12.78 per 100,000 in kidney-pancreas, 13.34 in liver, and 21.87 in heart-lung transplant recipients. Receiving heart-lung transplant, 50 years or older, and history of cancer (in either recipient or donor) were independent factors associated with PAC. Fifty-two patients developed PAC in cohort B. Despite earlier diagnosis (21.15% with stage I-II), survival rates were similar to those reported for sporadic (non-SOT) patients. We report demographic and clinical risk factors for PAC after SOT, many of which were present before transplant and are common to sporadic pancreatic cancer. Despite the diagnosis at earlier stages, PAC in SOT portends a very poor survival.

CD137 agonist-based combination immunotherapy enhances activated, effector memory T cells and prolongs survival in pancreatic adenocarcinoma.

Pancreatic ductal adenocarcinoma(PDAC) is resistant to the PD-1/PD-L1 blockade therapy. Previously, the combination of PD-1 blockade and vaccine therapy was shown to have a modest antitumor activity in murine models of PDAC. We used a murine syngeneic model of metastatic PDAC to identify, among multiple T cell modulators tested, which therapeutic agents in combination with the GVAX cancer vaccine and an anti-PD-1 antagonist antibody(αPD-1) are able to improve the survival. We found that an anti-CD137 agonist antibody(αCD137) most significantly improved survival in the mouse PDAC model. Moreover, αPD-1 and αCD137 together in combination with vaccine therapy more significantly increased the expression of costimulatory molecules CD137 and OX40 on CD4+PD-1+ and CD8+PD-1+ T cells comparing to αPD-1 or αCD137, respectively, suggesting that T cell activation within PDACs were enhanced by a synergy of αCD137 and αPD-1. On another hand, αCD137 treatment led to an increase in effector memory T cells independent of αPD-1. Although αCD137 does not increase the cytotoxic effector T cell function, the addition of αCD137 to GVAX+αPD-1 increased expression of IFNγ in EOMES+exhausted tumor-infiltrating T cells. Taken together, this preclinical study established the mechanism of targeting CD137 to enhance effector memory and activated T cells in PDAC. Immunohistochemistry analysis of resected human PDACs following the neo-adjuvant GVAX treatment showed increased levels of CD8+ T cells in those with high levels of CD137 expression, supporting an ongoing clinical trial of testing CD137 as a potential target in treating PDACs that are inflamed with T cells by vaccine therapy.