Prognostic Factor In Pancreatic Cancer Research Articles

ASO Author Reflections: A New Prognostic Factor for Pancreatic Cancer.

ASO Author Reflections: A New Prognostic Factor for Pancreatic Cancer.

High levels of human epididymis protein 4 mRNA and protein expression are associated with chemoresistance and a poor prognosis in pancreatic cancer.

Pancreatic cancer is associated with an exceedingly poor prognosis, warranting the development of novel therapeutic strategies and discovery of prognostic predictors. Given that chemoresistance-related molecules are reportedly associated with the poor prognosis of pancreatic cancer, the present study aimed to identify molecules that could be efficacious therapeutic targets for pancreatic cancer. First, 10 patient-derived xenografts (PDXs) were established from patients with pancreatic cancer. Subsequently, after treating tumor tissue generated from the PDXs with standard drugs, next-generation sequencing (NGS) was performed using these tissues. The results of NGS analysis and immunohistochemical analysis on 80 pancreatic cancer tissues revealed that human epididymis protein 4 (HE4) expression in the anticancer drug-treated PDX group was higher than that in the untreated PDXs. In addition, chemoresistance ability was observed in tumor cell lines overexpressing HE4. Furthermore, Kaplan-Meier analysis of tumor tissues from 80 patients with pancreatic cancer was performed and it was found that patients with a high HE4 expression level had a poor survival rate compared with those who had a low HE4 expression level. Multivariate analysis also indicated the high expression level of HE4 was an independent poor prognostic biomarker. Thus, it was concluded that high gene and protein expression levels of HE4 mediate chemoresistance and are independent prognostic factors for pancreatic cancer.

Preoperative carbohydrate antigen 19-9 and standard uptake value of positron emission tomography-computed tomography as prognostic markers in patients with pancreatic ductal adenocarcinoma.

Among various prognostic factors of pancreatic cancer, preoperative clinical information is obtained by imaging modality. This study aimed to evaluate clinical usefulness of preoperative carbohydrate antigen and preoperative standard uptake value in 18F-fluorodeoxyglucose positron emission tomography as predictive biological markers for resectable pancreatic ductal adenocarcinoma. A total of 189 patients with PDAC who underwent preoperative PET-computed tomography were evaluated. Patients underwent neoadjuvant chemotherapy, and R2 resection was excluded. The correlation between SUVmax and clinicopathologic parameters was analyzed. The C-tree statistical method was used to estimate cutoff values of logCA19-9 and SUVmax for survival rate. A multivariate analysis was conducted to identify prognostic factors for overall survival. The median duration of OS was 26 months, and the 5-year survival rate was 22.4%. The optimal cutoff values for CA19-9 level was 150 U/mL and SUVmax was 5.5. When subjects were divided into three groups according to the combination of CA19-9 level and SUVmax from C-tree (high-risk group, CA19-9 > 150 U/mL and SUVmax > 5.5; intermediate-risk group, CA19-9 ≤ 150 U/mL and SUVmax > 5.5 or CA19-9 > 150 U/mL and SUVmax ≤ 5.5; and low-risk group, CA19-9 ≤ 150 U/mL and SUVmax ≤ 5.5), there was a significant 5YSR difference (5.6%, 24.3%, and 36.5%, P < .001). The multivariate analysis revealed high SUVmax, high preoperative CA19-9 level, venous invasion, and adjuvant chemotherapy were prognostic factors of OS. CA19-9 and SUVmax are strong prognostic biological factors in resectable PDAC. Moreover, patients with high CA19-9 level and SUVmax are not indicated for upfront surgery.

Identification of genomic alterations and associated transcriptomic profiling reveal the prognostic significance of MMP14 and PKM2 in patients with pancreatic cancer.

Pancreatic cancer is characterized by multiple genomic alterations, including KRAS mutations, TP53 mutations and CDKN2A deletion. However, the prognostic relevance of those genomic alterations and associated transcriptomic profiling in pancreatic cancer are unclear. Integrated analysis of The Cancer Genome Atlas (TCGA) datasets revealed that KRAS mutation, TP53 mutation and CDKN2A deletion were all bad prognostic factors in pancreatic cancer. And KRAS mutation, TP53 mutation and CDKN2A deletion were coordinated and co-occurred in pancreatic cancer. Transcriptomic analysis showed that MMP14 and PKM2 were both up-regulated by KRAS mutation, TP53 mutation or CDKN2A deletion. Also, MMP14 and PKM2 were both associated with unfavorable outcomes in pancreatic cancer. Compared with normal tissues, MMP14 and PKM2 were up-regulated in pancreatic cancer tissues. Moreover, MMP14 and PKM2 were highly expressed in high grade of pancreatic cancer. Furthermore, MMP14 and PKM2 were correlated with each other, and the combination of MMP14 and PKM2 could be used as better prognostic markers than MMP14 or PKM2 alone. At last, the high expression and bad prognostic effects of MMP14 and PKM2 in pancreatic cancer were validated using tissue microarray. Overall, the genomic alterations and associated transcriptomic profiling analysis suggested new prognostic makers of MMP14 and PKM2 in pancreatic cancer.

Bioinformatics analysis combined with experiments to explore potential prognostic factors for pancreatic cancer

BackgroundPancreatic cancer is a common malignant tumor of the digestive tract. It has a high degree of malignancy and poor prognosis. Finding effective molecular markers has great significance for pancreatic cancer diagnosis and treatment. This study aimed to investigate DLGAP5 expression in pancreatic cancer and explore the possible mechanisms and clinical value of DLGAP5 in tumorigenesis and tumor development.MethodsDifferentially expressed genes were screened using the Gene Expression Omnibus (GEO) data set GSE16515. Gene Ontology (GO)-based functional analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways enrichment analysis were performed on the corresponding proteins of the above genes using the Database for Annotation, Visualization, and Integrated Discovery (DAVID). The Kaplan–Meier Plotter database was used to analyze the relationship between differentially expressed genes and pancreatic cancer prognosis. The most prognostic gene, DLGAP5, was screened out, and the Oncomine and gene expression profiling interactive analysis (GEPIA) databases were used to analyze its expression in pancreatic cancer and other cancer tissues. The Cancer Genome Atlas (TCGA) database was used to analyze the overall survival of DLGAP5. Gene set enrichment analysis (GSEA) was performed to explore its possible molecular mechanisms in pancreatic cancer. Furthermore, the biological behavior of DLGAP5 in pancreatic cancer was verified by cell function experiments.ResultsA total of 201 significant upregulated differentially expressed genes and 79 downregulated genes were selected. The biological processes with significant enrichment of differential genes included cell adhesion, apoptosis, wound healing, leukocyte migration, angiogenesis. Pathways were mainly enriched in tumor-related signaling pathways such as cancer pathways, the extracellular matrix-receptor interaction pathway, and the p53 signaling pathway. DLGAP5 was significantly expressed in pancreatic cancer, and its expression level had a significant effect on patients’ survival time and progression-free survival. GSEA results indicated that DLGAP5 had significantly enriched into signaling pathways such as the cell cycle, the p53 signaling pathway, and oocyte meiosis. The experimental results showed that when we knocked down the expression of DLGAP5 in pancreatic cancer cells, their proliferation ability was significantly inhibited, and their invasion and migration ability significantly decreased.ConclusionsDLGAP5 can be used as a prognostic indicator for pancreatic cancer and affect the occurrence and development of pancreatic cancer.

The Role of Location of Tumor in the Prognosis of the Pancreatic Cancer

Identification of prognostic factors is important to improve treatment outcomes in pancreatic cancer. This study aimed to investigate the effect of the location of pancreatic cancer on survival and to determine whether it was a significant prognostic factor. Altogether, 2483 patients diagnosed with pancreatic cancer were examined. Comparative analysis of clinicopathologic characteristics, survival analysis, and multivariate analysis were performed. Cancers of the pancreatic head or the uncinate process were present in 49.5% of patients. The head/uncinate cancers had more clinical T1/T2 tumors (59.4% vs. 35.5%, p < 0.001) and a significantly higher 5-year survival rate (8.9% vs. 7.3%, p < 0.001) than the body/tail cancers. The 5-year survival rate in patients with head/uncinate cancers was significantly lower in the resectable (p = 0.014) and the locally advanced groups (p = 0.007). In patients who underwent resection with curative intent, the 5-year survival rate was lower in the head/uncinate group (p = 0.046). The overall outcome of the head/uncinate cancers was better than the body/tail cancers, due to the high proportion of resectable cases. In patients who underwent curative resection, the head/uncinate cancers had a higher number of T1/T2 tumors, but worse outcomes. In the multivariate analysis, tumor location was not an independent prognostic factor for pancreatic cancer.

Prognostic Significance of the Modified Glasgow Prognostic Score in Patients With Pancreatic Cancer: A Meta-Analysis.

Background:The prognostic value of the modified Glasgow prognostic score (mGPS) in patients with pancreatic cancer is controversial, based on previous studies. Therefore, this meta-analysis aimed to explore the relationship between mGPS and prognosis in pancreatic cancer.Methods:The databases PubMed, Web of Science, Embase, and the Cochrane Library were searched to identify eligible studies. Hazard ratios (HRs) and 95% confidence intervals (CIs) were used to estimate the associations between mGPS score and survival outcomes.Results:A total of 26 studies with 5198 patients were included in this meta-analysis. In a pooled analysis, elevated mGPS predicted poorer overall survival (OS; HR = 1.98, 95% CI, 1.65-2.37, P < .001). In addition, elevated mGPS was also significantly associated with worse progression-free survival (PFS), disease-free survival (DFS), and cancer-specific survival (CSS; HR = 1.95, 95% CI, 1.36-2.80, P < .001). Subgroup analyses confirmed a significant association between mGPS and survival outcomes.Conclusions:Our meta-analysis demonstrated that high mGPS was correlated to worse OS, PFS, DFS, and CSS in patients with pancreatic cancer. Therefore, mGPS could be employed as an effective prognostic factor for pancreatic cancer in clinical practice.

The systemic inflammation response index (SIRI) predicts oncological outcome and correlates with tumor burden in metastatic pancreatic cancer.

e15537 Background: The SIRI, defined by neutrophil x monocyte/lymphocyte 109/L, has recently emerged as a prognostic factor for pancreatic cancer. However, the association between SIRI values after chemotherapy and tumor response has not been evaluated. Methods: 161 metastatic pancreatic cancer patients were retrospectively analyzed. Associations between overall survival (OS), chemotherapy and SIRI were analyzed. A larger number of patients with pre-treatment SIRI (pre-SIRI) were collected so, post-treatment SIRI (post-SIRI) evaluated after three cycles of chemotherapy, was adjusted for analysis. Results: Median age 66 years. 59 (36%) received gemcitabine + nab-paclitaxel, 40 (24%) gemcitabine, 22 (17%) mFOLFIRINOX, 13 (7%) other regimens. 27 (16%) had not received treatment. Pre-SIRI≥2.3×109/L was an independent, negative predictor of OS compared to pre-SIRI &lt; 2.3×109/L [5 versus 16 months, Hazard Ratio (HR) 2.87, Confidence Interval (CI) 95% 2.02-4.07, P&lt; 0.0001]. In the whole cohort, we observed SIRI values increased after treatment (median pre-SIRI: 1.6×109/L; post-SIRI: 2.3×109/L; P= 0.007). Thus, we analyzed the association between tumor response measured by RECIST and pre-SIRI and post- SIRI values. Patients with progressive disease (PD) showed a higher pre-SIRI than those who had a response to chemotherapy (2.7×109/L versus 1.2×109/L, respectively; P&lt; 0.001). We also observed a statistically significant increase in post-SIRI values for PD compared to tumor response (3.2×109/L versus 1.7×109/L, respectively; P= 0.012). As observed for pre-SIRI, post-SIRI ≥2.3×109/L showed a shorter OS compared to post-SIRI &lt; 2.3×109/L (8 versus 17 months, respectively; P= 0.016). Furthermore, patients with pre-SIRI ≥2.3×109/L were more likely to benefit from mFOLFIRINOX showing a median OS of 17 months compared to 6 and 4 months for gemcitabine + nab-paclitaxel and gemcitabine, respectively ( P&lt; 0.001). Conversely, there was no difference for pre-SIRI &lt; 2.3×109/L: 15.9 months versus 16.5 and 16, respectively. Conclusions: SIRI≥2.3×109/L was a prognostic factor for metastatic pancreatic cancer. An elevated post-SIRI showed an association with disease progression and a negative impact on survival. Therefore, an increase in SIRI could be related to high tumor burden and be useful to appropriately select patients who would benefit of a more intensive first-line chemotherapy regimen.

High expression of olfactomedin-4 is correlated with chemoresistance and poor prognosis in pancreatic cancer.

Pancreatic cancer has an extremely poor prognosis, and identification of novel predictors of therapeutic efficacy and prognosis is urgently needed. Chemoresistance-related molecules are correlated with poor prognosis and may be effective targets for cancer treatment. Here, we aimed to identify novel molecules correlated with chemoresistance and poor prognosis in pancreatic cancer. We established 10 patient-derived xenograft (PDX) lines from patients with pancreatic cancer and performed next-generation sequencing (NGS) of tumor tissues from PDXs after treatment with standard drugs. We established a gene-transferred tumor cell line to express chemoresistance-related molecules and analyzed the chemoresistance of the established cell line against standard drugs. Finally, we performed immunohistochemical (IHC) analysis of chemoresistance-related molecules using 80 pancreatic cancer tissues. From NGS analysis, we identified olfactomedin-4 (OLFM4) as having high expression in the PDX group treated with anticancer drugs. In IHC analysis, OLFM4 expression was also high in PDXs administered anticancer drugs compared with that in untreated PDXs. Chemoresistance was observed by in vitro analysis of tumor cell lines with forced expression of OLFM4. In an assessment of tissue specimens from 80 patients with pancreatic cancer, Kaplan-Meier analysis showed that patients in the low OLFM4 expression group had a better survival rate than patients in the high OLFM4 expression group. Additionally, multivariate analysis showed that high expression of OLFM4 was an independent prognostic factor predicting poor outcomes. Overall, our study revealed that high expression of OLFM4 was involved in chemoresistance and was an independent prognostic factor in pancreatic cancer. OLFM4 may be a candidate therapeutic target in pancreatic cancer.

Prognostic value of COL6A3 in pancreatic adenocarcinoma.

Backgrounds/AimsPancreatic cancer is one of the most fatal human malignancies with poor prognosis, despite advances in therapy. Here, we evaluated the potential role of collagen type VI α3 chain (COL6A3) as a non-invasive biomarker for pancreatic adenocarcinoma.MethodsIn this study, we investigated immunohistochemically the expression of COL6A3 in 30 patients with resectable pancreatic adenocarcinoma by immunohistochemistry in a tissue sample of the cancer and a tissue sample of normal pancreas for each patient. Also, we looked for associations between COL6A3 and other prognostic factors of pancreatic cancer.ResultsAll of the pancreatic cancer tissue samples revealed in different ranges of intensity from weak (+) in 16.67%, moderate (+2) in 50%, to strongly positive (+3) in 33.33% staining for COL6A3. We found no moderate or strongly positive staining in normal pancreatic tissue. There was only weak positive staining in 23 samples (76.67%) and 7 (23.30%) were negative. Also, there was significant correlation between COL6A3 moderate and strongly expression and negative prognostic factors for pancreatic cancer.ConclusionsThe greatest density of COL6A3 was observed in pancreatic cancer tissues and was correlated with negative prognostic factors for pancreatic cancer. Therefore, we suggest that COL6A3 could be used as prognostic factor in pancreatic cancer, but more studies need to prove its value.

Ubiquitin specific peptidase 5 enhances STAT3 signaling and promotes migration and invasion in Pancreatic Cancer.

Purpose: Ubiquitin specific peptidase 5 (USP5) has been reported to promote the progression of several malignant tumors. It may affect cancer development via modulating cell cycle and colony formation. In pancreatic cancer, the biological function of USP5, especially in migration and invasion remains unclear.Methods: USP5 protein expression levels in primary pancreatic cancer and lymph node metastasis tissues were detected using immunohistochemistry (IHC). χ2 test, Kaplan-Meier analysis, univariate and multivariate analyses were used to evaluate the relationship between USP5 expression and clinicopathological feature. RT-qPCR were carried out to quantitate the mRNA expression levels of USP5 in pancreatic cancer cell lines. CCK8 and Colony formation assay were performed to prove how USP5 works in proliferation. Evaluation of tumor metastasis was made by Transwell and wound healing assay. EMT and STAT3 signaling related markers were detected by western blot.Results: (1) USP5 protein expression levels were related to tumor differentiation, CEA and CA19-9 level. (2) Univariate and multivariate analyses showed that high USP5 expression is an unfavorable prognostic factor for pancreatic cancer. Kaplan-Meier analysis directly indicated that patients with high USP5 expression had shorter overall survival. (3) Increased USP5 expression is related to pancreatic cancer in both proliferation and metastasis. (4) USP5 was proved to mediate STAT3 signaling in pancreatic cancer cells.Conclusions: The results suggest that USP5 is highly expressed and might have clinical significance for pancreatic cancer patients. High USP5 expression promotes both progression and metastasis by activating STAT3 signaling. Thus, USP5 might be a potential target in pancreatic cancer treatment.

Prognostic Factors in Pancreatic Cancer

Svoronos, Christos MD; Tsoulfas, Georgios MD, PhD, FACS, FICS; Chatzitheoklitos, Efthimios MD, PhD Author Information

Identification of a Nine-Gene Signature and Establishment of a Prognostic Nomogram Predicting Overall Survival of Pancreatic Cancer.

Background: Pancreatic cancer is highly lethal and aggressive with increasing trend of mortality in both genders. An effective prediction model is needed to assess prognosis of patients for optimization of treatment.Materials and Methods: Seven datasets of mRNA expression and clinical data were obtained from gene expression omnibus (GEO) database. Level 3 mRNA expression and clinicopathological data were obtained from The Cancer Genome Atlas pancreatic ductal adenocarcinoma (TCGA-PAAD) dataset. Differentially expressed genes (DEGs) between pancreatic tumor and normal tissue were identified by integrated analysis of multiple GEO datasets. Univariate and Lasso Cox regression analyses were applied to identify overall survival-related DEGs and establish a prognostic gene signature whose performance was evaluated by Kaplan-Meier curve, receiver operating characteristic (ROC), Harrell's concordance index (C-index) and calibration curve. GSE62452 and GSE57495 were used for external validation. Gene set enrichment analysis (GSEA) and tumor immunity analysis were applied to elucidate the molecular mechanisms and immune relevance. Multivariate Cox regression analysis was used to identify independent prognostic factors in pancreatic cancer. Finally, a prognostic nomogram was established based on the TCGA PAAD dataset.Results: A nine-gene signature comprising MET, KLK10, COL17A1, CEP55, ANKRD22, ITGB6, ARNTL2, MCOLN3, and SLC25A45 was established to predict overall survival of pancreatic cancer. The ROC curve and C-index indicated good performance of the nine-gene signature at predicting overall survival in the TCGA dataset and external validation datasets relative to classic AJCC staging. The nine-gene signature could classify patients into high- and low-risk groups with distinct overall survival and differentiate tumor from normal tissue. Univariate Cox regression revealed that the nine-gene signature was an independent prognostic factor in pancreatic cancer. The nomogram incorporating the gene signature and clinical prognostic factors was superior to AJCC staging in predicting overall survival. The high-risk group was enriched with multiple oncological signatures and aggressiveness-related pathways and associated with significantly lower levels of CD4+ T cell infiltration.Conclusion: Our study identified a nine-gene signature and established a prognostic nomogram that reliably predict overall survival in pancreatic cancer. The findings may be beneficial to therapeutic customization and medical decision-making.

Abstract 4833: Antibody-drug conjugate targeting glypican-1 shows tumor growth inhibition in cholangiocarcinoma

Abstract Cholangiocarcinoma is one of the most highly malignant cancers. Many patients need systemic chemotherapy for tumor development and recurrence, but their prognosis is poor. Therefore new treatment options are urgently required. We confirmed that the expression of glypican-1 (GPC1) was enhanced in cholangiocarcinoma. GPC1 is a cell surface membrane protein and has been reported as a poor prognostic factor in pancreatic cancer. In this study, we aimed to develop a new therapy for cholangiocarcinoma by the antibody-drug conjugate (ADC) targeting GPC1. By immunohistochemical analysis, enhanced expression of GPC1 was observed in clinical specimens of cholangiocarcinoma. KKU-055 and KKU-100 cells, which are cell lines of cholangiocarcinoma, had high expression of GPC1. In the KKU-055 xenograft model when we administered fluorescently-labeled GPC1 antibody to mice, it accumulated in tumor tissue. We developed a new anti-GPC1 monoclonal antibody (mAb) with highly internalizing activity. The anti-GPC1 mAb was conjugated with the cytotoxic agent monomethyl auristatin F (MMAF). GPC1-ADC showed potent antitumor effect toward KKU-055 and KKU-100 cells compared with the control ADC. In the KKU-055 xenograft model, GPC1-ADC had significant and potent tumor growth inhibition in a dose-dependent manner. In summary, our newly-developed GPC1-ADC showed significant tumor growth inhibition against GPC1-positive cholangiocarcinoma cell lines. Our preclinical data demonstrated that targeting GPC1 by ADC is a promising therapy for GPC1-positive cholangiocarcinoma. Citation Format: Keiichiro Yokota, Satoshi Serada, Shigehiro Tsujii, Kosuke Hiramatsu, Tsutomu Namikawa, Ichiro Murakami, Kazuhiro Hanazaki, Tetsuji Naka. Antibody-drug conjugate targeting glypican-1 shows tumor growth inhibition in cholangiocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4833.

Abstract 2146: High expression of Olfactomedin-4 correlates with chemoresistance and poor prognosis for pancreatic cancer

Abstract Background: Pancreatic cancer has an extremely poor prognosis and novel therapeutic strategies are desperately needed. It is considered that suitable molecules as therapeutic targets are resistant to chemotherapy and correlate with poor prognosis. In this experiment, we aimed to identify the optimal therapeutic targets in pancreatic cancer. Materials and Methods: We established 10 lines of patient derived xenografts (PDXs) for pancreatic cancer. Next generation sequencer (NGS) analysis was performed for PDXs which were administered chemotherapy and untreated PDXs as a control. Furthermore, we performed immunohistochemistry (IHC) analysis for the protein expression of identified molecules from PDXs and post-operative pathologic specimens from 80 patients with pancreatic cancer. When chemotherapy was added on tumor cell lines forcibly expressing the molecule, antitumor effect was compared with the control. Results: As a result of NGS analysis, we identified Olfactomedin-4 (OLFM4) molecule which was commonly shown high expression in chemotherapy administered PDXs. In IHC analysis, OLFM4 molecule expression was shown high expression with chemotherapy administered PDXs compared to untreated PDXs. For the analysis to use tumor cell lines forcedly expressing OLFM4 in vitro, the reduction rate of the tumor cell numbers was significantly lower than control vector, even if the concentration of the chemotherapy agent was increased. In a study using tissue specimens of 80 pancreatic cancer patients, Kaplan-Meier analysis showed that low expression of OLFM4 had a better survival rate than patients with high expression (p=0.0926, log-rank test). In multivariate analysis, it was shown that the high expression of OLFM4 was an independent poor prognostic factor with a statistically significant difference (p=0.044, Cox proportional hazards). Conclusions: It was demonstrated that high expression of OLFM4 was involved in chemoresistance and was an independent prognostic factor for pancreatic cancer. This molecule might be a candidate of therapeutic target in pancreatic cancer. Citation Format: Ryotaro Ohkuma, Erica Yada, Yutaro Kubota, Kazuyuki Hamada, Hiroo Ishida, Yuya Hirasawa, Hirotsugu Ariizumi, Etsuko Satoh, Junji Tsurutani, Kiyoshi Yoshimura, Tetsuro Sasada, Takeshi Aoki, Masahiko Murakami, Tomoko Norose, Nobuyuki Ohike, Masafumi Takimoto, Takuya Tsunoda, Satoshi Wada. High expression of Olfactomedin-4 correlates with chemoresistance and poor prognosis for pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2146.

S100P regulates the collective invasion of pancreatic cancer cells into the lymphatic endothelial monolayer.

Lymph node metastasis is an independent prognostic factor in pancreatic cancer. However, the mechanisms of lymph node colonization are unknown. As a mechanism of lymphatic metastasis, it has been reported for other types of cancer that spheroids from tumor cells cause circular chemorepellent‑induced defects(CCIDs) in lymphatic endothelial monolayers. In pancreatic cancer, such mechanisms of metastasis have not been elucidated. The present study evaluated the involvement of this new mechanism of metastasis in pancreatic cancer and investigated the associated factors. In human pancreatic cancer tissue, it was observed that clusters of cancer cells penetrated the wall of lymphatic ducts around the primary tumor. An invitro co‑culture system was then used to analyze the mechanisms of tumor cell‑mediated disruption of lymphatic vessels. Time‑lapse microscopic imaging revealed that spheroids from pancreatic cancer cells caused circular defects in lymphatic endothelial monolayers. CCID formation ability differed depending on the cell line. Neither aggregation of spheroids nor adhesion to lymphatic endothelial cells(LECs) exhibited a significant correlation with this phenomenon. The addition of supernatant from cultured cancer cells enhanced CCID formation. Microarray analysis revealed that the expression of S100 calcium binding proteinP(S100P) was significantly increased when LECs were treated with supernatant from cultured cancer cells. Addition of a S100P antagonist significantly suppressed the migration of LECs and CCID formation. The present findings demonstrated that spheroids from pancreatic cancer cells caused circular defects in lymphatic endothelial monolayers. These CCIDs in pancreatic cancer were partly regulated by S100P, suggesting that S100P may be a promising target to inhibit lymph node metastasis.

Impact of KRAS mutations in clinical features and survival in pancreatic cancer patients: A single institution experience.

e15779 Background: Pancreatic cancer (PC) is currently one of the most lethal tumors. In recent years, although improvements have been developed in the detection and treatment of this disease, the 5-year survival is less than 10%. KRAS plays a key role in ras/mitogen-activated protein kinase signaling. Somatic mutation in KRAS mutations have been shown to be early events in the carcinogenesis of PC. KRAS mutations as a prognostic factor for PC remains inconclusive. Methods: We performed a retrospective study of our patients (pts) to demonstrate the impact of KRAS mutations in clinical features and survival in real-life clinical practice. This was an observational study of all patients with histological confirmed PC referred to Medical Oncology between April 2017 to December 2018 and followed until February 2019. KRAS mutations were analyzed by sequencing codons 12, 13, and 61 in diagnostic tumor tissues from formalin fixed paraffin embedded tissue using PCR and liquid biopsy test (BEAMing technology). Categorical variables were statistically analyzed with Fisher’s exact test and continuous variables with T-student for differences between both groups. Survival was analyzed by Kaplan–Meier estimation and log-rank testing while Cox regression was used to estimed hazard ratios. Results: Our study cohort was 64 pts. 43% of pts died, the most die at home (25%). Median follow-up was 552 days (18 months). Metastatic pts had an expected overall survival (OS) of 376 days, locally advanced 525 days and localized stage 592 days but not statistically significant difference (p = 0.11). Wild-type pts had an expected OS of 559 days and KRAS mutated 389 days with statistically significant difference. (p = 0.032). Conclusions: KRAS mutations are associated with a poorer survival in patients with pancreatic cancer in all stages. These results suggest that KRAS mutations may be an important biomarker in determining response and prognosis in patients with high risk and in developing specific treatments for these patients in clinical applications.[Table: see text]

ITGA3 serves as a diagnostic and prognostic biomarker for pancreatic cancer.

Background and objective: ITGA3 is a cell surface adhesion protein that interacts with extracellular matrix proteins which function in cancer metastasis. We examined the relationship of pancreatic ITGA3 expression with the clinical and pathological characteristics of patients with pancreatic cancer.Methods: Data mining was used to analyze pancreatic cancer data from The Cancer Genome Atlas database. A Chi squared test was used to evaluate correlations of ITGA3 expression with clinical and pathological parameters. Receiver operating characteristic (ROC) analysis was used to evaluate the diagnostic performance of ITGA3 expression. Survival analysis and Cox regression analysis were used to examine the prognostic value of ITGA3 expression. Gene Set Enrichment Analysis (GSEA) was used to identify signaling pathways related to ITGA3 expression.Results: Pancreatic expression of ITGA3 was greater in patients with pancreatic cancer than those without cancer, and was also associated with histological type, histological grade, stage, T classification, vital status, and relapse. ROC analysis indicated that ITGA3 had significant diagnostic value, in that high expression correlated with poor overall survival and relapse-free survival, especially in patients with early-stage cancer. Cox analysis indicated that high ITGA3 expression was an independent prognostic factor for pancreatic cancer. GSEA analysis identified 9 signaling pathways that were enriched in the presence of high ITGA3 expression.Conclusion: Expression of ITGA3 can be used as a diagnostic and prognostic biomarker in pancreatic cancer.

Evaluation of the prognostic significances of γ-secretase genes in pancreatic cancer.

With the growing requirement for novel prognostic biomarkers for pancreatic cancer, many studies have focused on clinical and/or genomic variables. Although many studies have been performed, carbohydrate antigen 19-9 is the only biomarker in clinical use. Therefore, the present study examined whether γ-secretase genes, including presenilin (PSEN), nicastrin (NCSTN), presenilin enhancer protein 2 (PSENEN), and anterior pharynx-defective 1 (APH1-), could serve as prognostic factors for pancreatic cancer. The cohorts selected included >100 pancreatic cancer patients. Patient data were downloaded from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GSE21501). The prognostic roles of the γ-secretase genes were analyzed by several survival analysis methods. Among the γ-secretase genes, the prognosis tended to be worse in the 2 cohorts with increasing expression of PSEN1, APH1A, and PSENEN, while the remaining genes were the opposite in the 2 cohorts. Notably, although the patient characteristics were quite different, APH1A was statistically significantly associated with prognosis in the 2 cohorts. The hazard ratio of APH1A for overall survival was 1.598 (TCGA) and 2.724 (GSE21501). These results contribute to the study of γ-secretase in pancreatic cancer. We believe that γ-secretase, particularly APH1A, will be a new prognostic biomarker for pancreatic cancer.

Pathomorphological features of metastatic lymph nodes as predictors of postoperative prognosis in pancreatic cancer.

To investigate the pathological features of metastatic lymph nodes (LN) in pancreatic ductal adenocarcinoma (PDAC) and to determine factors with prognostic implications.Metastatic LN status is a proven significant factor for predicting postoperative prognosis in pancreatic cancer patients. However, the effective prognostic criteria regarding metastatic LNs for such disease remain unknown.We retrospectively reviewed 98 patients with R0/1 resection for PDAC. All metastatic LNs were evaluated for the pathomorphological features of metastasis and analyzed in terms of postoperative outcomes. Various morphological patterns of metastasis were assessed in 440 positive LNs and then classified into 4 groups: common type, direct type (continuously invaded by the main tumor), scatter type (multiple tumor clusters among the normal LN tissues), and isolated tumor cell (ITC).The pathological stage was defined as stage IIA in 10% and IIB in 90% patients. Common-type metastasis was noted in 55% positive LNs of 75% node-positive patients; direct type in 36% LNs of 69% patients; scatter type in 5% LNs of 14% patients; and ITCs in 5% LNs of 18% patients. Significant difference was noted only in recurrence-free survival (RFS) but not in overall survival (OS) in the common-type; only in OS but not in RFS for the scatter type; and neither in RFS nor OS for both direct type and ITC. Multivariate analysis revealed that only LN ratio and curability were independent predictive factors of poor.The tumor distribution patterns in metastatic LNs are the postoperative prognostic factors in pancreatic cancer.