Comparison of adjuvant nab-paclitaxel plus gemcitabine, S-1 and gemcitabine chemotherapy for resectable pancreatic cancer: a real-world study.

Background: A survival benefit has been seen for both adjuvant nab-paclitaxel plus gemcitabine (AG) and S-1 chemotherapy compared to gemcitabine (GEM) for resectable pancreatic cancer in the APACT (2019) and JASPAC01 trials (2016), respectively. However, supporting evidence regarding the effectiveness of AG or S-1 compared to gemcitabine in real-world clinical practice remains lacking. Methods: Our study included all 246 pancreatic cancer patients who underwent surgical treatment and received postoperative adjuvant chemotherapy with AG, S-1, or GEM except for those meeting exclusion criteria (R2 resection, neoadjuvant therapy, or synchronous malignancy) at Tianjin Medical University Cancer Institute and Hospital from June 2015 to July 2021. The primary outcome was overall survival (OS) and recurrence-free survival (RFS). Results: In total, 246 patients were included, of whom 54(22%) received adjuvant AG, 103(41%) received adjuvant S-1, and 89(37%) received adjuvant GEM. Adjuvant S-1 was associated with a prolonged OS compared to GEM (median OS S-1 vs GEM: 27.0 vs 20.0 months; HR: 0.65, P = .016) and a significantly prolonged RFS compared to GEM (median RFS S-1 vs GEM: 20.0 vs 8.2 months; HR: 0.58, P = .002). After adjusting for known prognostic factors in multivariate Cox regression analysis, this survival benefit persists and is consistent in most subgroups in our subgroup analysis. However, no statistically significant differences in OS or RFS were seen between patients treated with AG and patients treated with GEM. Conclusions: In this retrospective real-world study, adjuvant S-1 chemotherapy was associated with improved survival compared to GEM while no differences in OS or RFS were observed for AG compared to GEM.

Nuclear PLD1 combined with NPM1 induces gemcitabine resistance through tumorigenic IL7R in pancreatic adenocarcinoma.

OBJECTIVE: Pancreatic ductal adenocarcinoma (PDAC) is a highly malignant gastrointestinal cancer with a 5-year survival rate of only 9%. Of PDAC patients, 15%-20% are eligible for radical surgery. Gemcitabine is an important chemotherapeutic agent for patients with PDAC; however, the efficacy of gemcitabine is limited due to resistance. Therefore, reducing gemcitabine resistance is essential for improving survival of patients with PDAC. Identifying the key target that determines gemcitabine resistance in PDAC and reversing gemcitabine resistance using target inhibitors in combination with gemcitabine are crucial steps in the quest to improve survival prognosis in patients with PDAC. METHODS: We constructed a human genome-wide CRISPRa/dCas 9 overexpression library in PDAC cell lines to screen key targets of drug resistance based on sgRNA abundance and enrichment. Then, co-IP, ChIP, ChIP-seq, transcriptome sequencing, and qPCR were used to determine the specific mechanism by which phospholipase D1 (PLD1) confers resistance to gemcitabine. RESULTS: PLD1 combines with nucleophosmin 1 (NPM1) and triggers NPM1 nuclear translocation, where NPM1 acts as a transcription factor to upregulate interleukin 7 receptor (IL7R) expression. Upon interleukin 7 (IL-7) binding, IL7R activates the JAK1/STAT5 signaling pathway to increase the expression of the anti-apoptotic protein, BCL-2, and induce gemcitabine resistance. The PLD1 inhibitor, Vu0155069, targets PLD1 to induce apoptosis in gemcitabine-resistant PDAC cells. CONCLUSIONS: PLD1 is an enzyme that has a critical role in PDAC-associated gemcitabine resistance through a non-enzymatic interaction with NPM1, further promoting the downstream JAK1/STAT5/Bcl-2 pathway. Inhibiting any of the participants of this pathway can increase gemcitabine sensitivity.

Survival outcomes of neoadjuvant therapy followed by radical resection versus upfront surgery for stage I-III pancreatic ductal adenocarcinoma: a retrospective cohort study.

BACKGROUND: Neoadjuvant therapy remains controversial in treating resectable pancreatic ductal adenocarcinoma (PDAC) patients. This study aims to assess the impact of neoadjuvant therapy on survival in patients with PDAC according to their clinical stage. METHODS: Patients with resected clinical Stage I-III PDAC from 2010 to 2019 were identified in the surveillance, epidemiology, and end results database. A propensity score matching method was utilized within each stage to reduce potential selection bias between patients who underwent neoadjuvant chemotherapy followed by surgery and patients who underwent upfront surgery. An overall survival (OS) analysis was performed using the Kaplan-Meier method and a multivariate Cox proportional hazards model. RESULTS: A total of 13 674 patients were included in the study. The majority of the patients ( N =10 715, 78.4%) underwent upfront surgery. Patients receiving neoadjuvant therapy followed by surgery had significantly longer OS than those with upfront surgery. Subgroup analysis revealed that the neoadjuvant chemoradiotherapy group's OS is comparable to neoadjuvant chemotherapy. In clinical Stage IA PDAC, there was no difference in survival between the neoadjuvant treatment and upfront surgery groups before or after matching. In stage IB-III patients, neoadjuvant therapy followed by surgery improved OS before and after matching compared to upfront surgery. The results revealed the same OS benefits using the multivariate Cox proportional hazards model. CONCLUSION: Neoadjuvant therapy followed by surgery could improve OS over upfront surgery in Stage IB-III PDAC but did not provide a significant survival advantage in Stage IA PDAC.

Preoperative ultrasound combined with routine blood tests in predicting the malignant risk of pancreatic cystic neoplasms.

OBJECTIVE: Accurate preoperative identification of benign or malignant pancreatic cystic neoplasms (PCN) may help clinicians make better intervention choices and will be essential for individualized treatment. METHODS: Preoperative ultrasound and laboratory examination findings, and demographic characteristics were collected from patients. Multiple logistic regression was used to identify independent risk factors associated with malignant PCN, which were then included in the nomogram and validated with an external cohort. The Net Reclassification Index (NRI) and Integrated Discrimination Improvement (IDI) were calculated to evaluate the improvement in the predictive power of the new model with respect to that of a combined imaging and tumor marker prediction model. RESULTS: Malignant PCN were found in 83 (40.7%) and 33 (38.7%) of the model and validation cohorts, respectively. Multivariate analysis identified age, tumor location, imaging of tumor boundary, blood type, mean hemoglobin concentration, neutrophil-to-lymphocyte ratio, carbohydrate antigen 19-9, and carcinoembryonic antigen as independent risk factors for malignant PCN. The calibration curve indicated that the predictions based on the nomogram were in excellent agreement with the actual observations. A nomogram score cutoff of 192.5 classified patients as having low vs. high risk of malignant PCN. The model achieved good C-statistics of 0.929 (95% CI 0.890-0.968, P < 0.05) and 0.951 (95% CI 0.903-0.998, P < 0.05) in predicting malignancy in the development and validation cohorts, respectively. NRI = 0.268; IDI = 0.271 (P < 0.001 for improvement). The DCA curve indicated that our model yielded greater clinical benefits than the comparator model. CONCLUSIONS: The nomogram showed excellent performance in predicting malignant PCN and may help surgeons select patients for detailed examination and surgery. The nomogram is freely available at https://wangjunjinnomogram.shinyapps.io/DynNomapp/.

ESE3-positive PSCs drive pancreatic cancer fibrosis, chemoresistance and poor prognosis via tumour-stromal IL-1ß/NF-κB/ESE3 signalling axis.

BACKGROUND: Desmoplastic stroma, a feature of pancreatic ductal adenocarcinoma (PDAC), contains abundant activated pancreatic stellate cells (PSCs). How PSCs promote PDAC progression remains incompletely understood. METHODS: Effect of epithelium-specific E-twenty six factor 3 (ESE3)-positive PSCs on PDAC fibrosis and chemoresistance was examined by western blot, RT-PCR, immunofluorescence, flow cytometry assay, chromatin immunoprecipitation, luciferase assay, immunohistochemistry and subcutaneous pancreatic cancer mouse model. RESULTS: ESE3 expression increased in PSCs in PDAC tissues compared with those in normal PSCs. Clinical data showed that ESE3 upregulation in PSCs was positively correlated with tumour size, pTNM stage, CA19-9, carcinoembryonic antigen and serum CA242 level. ESE3 overexpression in PSCs was an independent negative prognostic factor for disease-free survival and overall survival amongst patients with PDAC. Mechanistically, the conditional medium from the loss and gain of ESE3-expressing PSCs influenced PDAC chemoresistance and tumour growth. ESE3 directly induced the transcription of α-SMA, collagen-I and IL-1ß by binding to ESE3-binding sites on their promoters to activate PSCs. IL-1ß upregulated ESE3 in PSCs through NF-κB activation, and ESE3 was required for PSC activation by tumour cell-derived IL-1ß. CONCLUSION: Inhibiting the IL-1ß/ESE3 (PSCs)/IL-1ß-positive feedback loop is a promising therapeutic strategy to reduce tumour fibrosis and increase chemotherapeutic efficacy in PDAC.

Perioperative Serum Scoring Systems Predict Early Recurrence and Poor Prognosis of Resectable Pancreatic Cancer.

Objective: Some patients with pancreatic ductal adenocarcinoma (PDAC) are prone to rapid recurrence or metastasis after radical resection. However, evaluation methods for effectively identifying these patients are lacking. In this study, we established perioperative serum scoring systems to screen patients with early recurrence and poor prognosis. Methods: We systematically analysed 44 perioperative serum parameters, including systemic inflammatory parameters, coagulation system parameters, tumor markers, and 18 clinicopathological characteristics of 218 patients with radical resection in our centre. Univariate Cox regression and LASSO regression models were used to screen variables. Kaplan-Meier survival analysis was used to compare relapse-free survival and overall survival. Multivariate Cox regression was used to evaluate the independent risk variables. AUC and C-index were used to reveal the effectiveness of the models. In addition, the effectiveness was also verified in an independent cohort of 109 patients. Results: Preoperative systemic immune coagulation cascade (SICC) (including increased neutrophil to lymphocyte ratio, decreased lymphocyte to monocyte ratio, increased platelet and fibrinogen) and increased postoperative tumor markers (TMs) (CA199, CEA and CA242) were independent risk factors for early recurrence of resectable pancreatic cancer. On this basis, we established the preoperative SICC score and postoperative TMs score models. The patients with higher preoperative SICC or postoperative TMs score were more likely to have early relapse and worse prognosis. The nomogram based on preoperative SICC, postoperative TMs, CACI, smoking index, vascular cancer embolus and adjuvant chemotherapy can effectively evaluate the recurrence rate (AUC1 year: 0.763, AUC2 year: 0.679, AUC3 year: 0.657) and overall survival rate (AUC1 year: 0.770, AUC3 year: 0.804, AUC5 year: 0.763). Conclusion: Preoperative SICC and postoperative TMs can help identify resectable PDAC patients with early recurrence and poor prognosis.

OXCT1 Enhances Gemcitabine Resistance Through NF-κB Pathway in Pancreatic Ductal Adenocarcinoma.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is a type of malignant tumor with a five-year survival rate of less than 10%. Gemcitabine (GEM) is the most commonly used drug for PDAC chemotherapy. However, a vast majority of patients with PDAC develop resistance after GEM treatment. METHODS: We screened for GEM resistance genes through bioinformatics analysis. We used immunohistochemistry to analyze 3-oxoacid CoA-transferase 1 (OXCT1) expression in PDAC tissues. The survival data were analyzed using the Kaplan-Meier curve. The expression levels of the genes related to OXCT1 and the NF-κB signaling pathway were quantified using real-time quantitative PCR and western blot analyses. We performed flow cytometry to detect the apoptosis rate. Colony formation assay was performed to measure the cell proliferation levels. The cytotoxicity assays of cells were conducted using RTCA. The downstream pathway of OXCT1 was identified via the Gene Set Enrichment Analysis. Tumor growth response to GEM in vivo was also determined in mouse models. RESULTS: Bioinformatics analysis revealed that OXCT1 is the key gene leading to GEM resistance. Patients with high OXCT1 expression exhibited short relapse-free survival under GEM treatment. OXCT1 overexpression in PDAC cell lines exerted inhibitory effect on apoptosis after GEM treatment. However, the down-regulation of OXCT1 showed the opposite effect. Blocking the NF-κB signaling pathway also reduced GEM resistance of PDAC cells. Tumor growth inhibition induced by GEM in vivo reduced after OXCT1 overexpression. Moreover, the effect of OXCT1 on GEM refractoriness in PDAC cell lines was reversed through using an NF-κB inhibitor. CONCLUSION: OXCT1 promoted GEM resistance in PDAC via the NF-κB signaling pathway both in vivo and in vitro. Our results suggest that OXCT1 could be used as a potential therapeutic target for patients with PDAC.

The imaging features of extrapancreatic perineural invasion (EPNI) in pancreatic Cancer：A comparative retrospective study.

BACKGROUND: Extrapancreatic perineural invasion (EPNI) is a risk factor for the prognosis of patients with pancreatic cancer. Few reliable clinical indicators can be used to evaluate EPNI. METHODS: We reviewed clinicopathological information of pancreatic cancer patients received radical surgery in our center from 2014 to 2019. The minimum distance between the tumor boundary and celiac artery (CA), superior mesenteric arteria (SMA) was respectively measured on enhanced-contrast CT images. Receiver Operating Characteristic (ROC) analysis was used to evaluate the diagnostic efficacy, and the optimal cut-off value was determined by Youden index. The latter was used as a diagnostic indicator for imaging perineural invasion (iPNI). K-M method and Cox risk regression model were applied to analyze the prognostic value of iPNI. RESULTS: A total of 384 patients were enrolled in this study. ROC analysis showed the minimum distance is an efficient indicator, and the best cut-off value 6.5 mm provided 71.63% sensitivity and specificity 84.31%. Cox regression model showed that iPNI was an independent risk factor for disease-free survival (DFS) and overall survival (OS). Subgroup analysis indicated that patients with larger tumor size and iPNI positive suggested a worse prognosis. CONCLUSIONS: The minimum distance between tumor boundary and arteries is an efficient imaging indicator for diagnosing EPNI. iPNI is an independent risk factor for DFS and OS. The novel typing method based on plexus pancreaticus capitalis (PLX) potentially invaded may have guiding significance for extent of dissection.

PERK-eIF2α-ERK1/2 axis drives mesenchymal-endothelial transition of cancer-associated fibroblasts in pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC) is characterized by remarkable desmoplasia, usually driven by cancer-associated fibroblasts (CAFs), influencing patient prognosis. CAFs are a group of plastic cells responsible for tumor growth and metastasis. Fibroblasts have been reported to directly contribute to angiogenesis by undergoing mesenchymal-endothelial transition (MEndoT) after ischemic injury in the heart, brain, and hindlimbs. However, whether CAFs can undergo similar transdifferentiation in the hostile tumor microenvironment and directly contribute to tumor angiogenesis remains unclear. Herein, we provide evidence that CAFs can adopt an endothelial cell-like phenotype and directly contribute to tumor angiogenesis in vitro and in vivo. Furthermore, this program is regulated by the PERK-eIF2α-ERK1/2 axis. Pharmacological inhibition of PERK with GSK2606414 limited the phenotypic transition of CAFs. In conclusion, our results suggest that CAFs contribute to tumor angiogenesis by undergoing the MEndoT, thus representing therapeutic targets for improving PDAC prognosis.

Serum insulin-like growth factor binding protein 2 levels as biomarker for pancreatic ductal adenocarcinoma-associated malnutrition and muscle wasting.

BACKGROUND: Malnutrition and muscle wasting are common features frequently observed in pancreatic ductal adenocarcinoma (PDAC) patients with cancer cachexia. They are associated with reduced survival and quality of life. Nutrition therapy is an important part of multimodal cancer care in PDAC. However, due to the complexity of nutrition assessment, only 30-60% of patients with nutritional risks receive nutritional treatment at present. It is important to identify biomarkers that may be used to improve management of PDAC-associated malnutrition. Serum insulin-like growth factor binding protein 2 (IGFBP2) has emerged as a potential serum biomarker in a variety of tumours. However, its association with malnutrition and muscle wasting in PDAC is unclear. METHODS: We evaluated the tumour IGFBP2 expression and serum IGFBP2 level in 98 PDAC patients using immunohistochemistry and enzyme-linked immunosorbent assay and analysed the correlation between them. Furthermore, we explored the relationship between IGFBP2 of both tumour and serum and nutritional status (Patient-Generated Subjective Global Assessment and skeletal muscle index). Pan02 IGFBP2 stable transfection cell lines, Pan02 PLV-IGFBP2 cells, and PLKO-IGFBP2 cells were injected subcutaneously into the flank of C57BL/6 mouse. Serum IGFBP2 levels, food intake, and body weight of these mice were measured. The degree of muscle atrophy is characterized by haematoxylin and eosin, Oil Red O, and Masson's trichrome staining. The mRNA and protein expression of several essential muscle-related signal proteins such as atrogin-1 and muscle RING finger 1 was measured. RESULTS: Among 98 patients, we found that tumour IGFBP2 expression is related to plasma IGFBP2 levels (rs  = 0.562, P < 0.001), and they significantly increased among patients with Patient-Generated Subjective Global Assessment ≥9 and correlated with overall survival. Moreover, serum IGFBP2 level is negatively correlated with skeletal muscle index (rs  = -0.600, P < 0.001) and Hounsfield units (rs  = -0.532, P < 0.001). In mice injected with Pan02 PLV-IGFBP2 cell, circulating IGFBP2 was elevated while body weight and food intake were decreased when compared with Pan02 PLV-Control group. These mice also exhibited significantly aggravated muscle fibre atrophy, lipid deposition, and increased collagen tissue, and the expression of mRNA and protein of atrogin-1 and muscle RING finger 1 in the gastrocnemius muscle is increased. Conversely, these symptoms were alleviated in the PLKO-IGFBP2 group. CONCLUSIONS: In the current study, there is a significant correlation between serum IGFBP2 levels, malnutrition, and muscle atrophy in PDAC. Our results suggested that serum IGFBP2 level might be a promising biomarker and intervention targets for PDAC-associated severe malnutrition and muscle wasting.

KIF23 enhances cell proliferation in pancreatic ductal adenocarcinoma and is a potent therapeutic target.

BACKGROUND: In recent research, high expression of kinesin family member 23 (KIF23), one of the kinesin motor proteins involved in the regulation of cytokinesis, has been shown to be related to poor prognosis in glioma and paclitaxel-resistant gastric cancer, as a results of the enhancement of proliferation, migration, and invasion. In this study, we analyzed the role of KIF23 in the progression of pancreatic ductal adenocarcinoma. METHODS: A bioinformatic method was used to analyze the KIF23 mRNA level in pancreatic tumor tissues compared with normal pancreatic tissues and to analyze the connection between high KIF23 expression and prognosis. We examined the expression of KIF23 using immunohistochemistry and analyzed the connection between the expression of KIF23 and clinicopathological features in pancreatic ductal adenocarcinoma patients. In addition, a colony formation assay, MTT assay, and western blot assay were performed in vitro, along with a mouse xenograft model in vivo, to analyze the effect of KIF23 on proliferation. Further, the correlation between KIF23 and CDCA8 was analyzed by TCGA and immunohistochemical data. RESULTS: Bioinformatic results showed that KIF23 mRNA expression was higher in pancreatic tumor tissues than in normal pancreatic tissues and a poor prognosis has been linked to the high expression of KIF23. Immunohistochemistry revealed that KIF23 was highly expressed at the protein level and high expression of KIF23 correlated with adverse clinicopathological features. Our experimental results demonstrated that knockdown of KIF23 could inhibit the proliferation of pancreatic cells. Further, a positive correlation between KIF23 and CDCA8 expression existed, and KIF23 might promote pancreatic cancer proliferation by affecting CDCA8 expression. CONCLUSIONS: Our data showed that high expression of KIF23 is associated with a poor prognosis, and KIF23 might be a potential therapeutic target for pancreatic ductal adenocarcinoma.

Effect of Perioperative CEA and CA24-2 on Prognosis of Early Resectable Pancreatic Ductal Adenocarcinoma.

Patients with resectable pancreatic ductal adenocarcinoma (PDAC) show differential prognosis after radical resection. Currently, cancer grading and surgical criteria depend heavily on imaging and anatomical diagnosis. It's essential to set up a model with reliable prognostic factors during the perioperative period to assess prognosis in PDAC patients. In this study, 103 patients diagnosed with PDAC who underwent radical resection were recruited. The predictive value of preoperative carcinoembryonic antigen (CEA), postoperative CA24-2 and the combination of two for overall survival (OS) were evaluated. Both pre-CEA and post-CA24-2 were found to be independent prognostic factors for OS according to multivariate analyses. Kaplan-Meier analysis revealed that CEA and CA24-2 as well as the combination of two were correlated with poor OS. In addition, patients with both markers elevated have worse prognosis than patients with either pre-CEA or post-CA24-2 elevated. Thus, we concluded that the combination of CEA and CA24-2 can be used as a prognostic factor for stage I and II resectable PDAC patients.

Integrated analysis of gene expression and copy number variations in MET proto­oncogene­transformed human primary osteoblasts.

The aim of the present study was to screen the potential osteosarcoma (OS)­associated genes and to obtain additional insight into the pathogenesis of OS. Transcriptional profile (ID: GSE28256) and copy number variations (CNV) profile were downloaded from Gene Expression Omnibus database. Differentially expressed genes (DEGs) between MET proto­oncogene­transformed human primary osteoblast (MET­HOB) samples and the control samples were identified using the Linear Models for Microarray Data package. Subsequently, CNV areas and CNVs were identified using cut­off criterion of >30%­overlap within the cases using detect_cnv.pl in PennCNV. Genes shared in DEGs and CNVs were obtained and discussed. Additionally, the Database for Annotation, Visualization and Integrated Discovery was used to identify significant Gene Ontology (GO) functions and pathways in DEGs with P<0.05. A total of 1,601 DEGs were screened out in MET­HOBs and compared with control samples, including 784 upregulated genes, such as E2F transcription factor 1 (E2F1) and 2 (E2F2) and 817 downregulated genes, such as retinoblastoma 1 (RB1) and cyclin D1 (CCND1). DEGs were enriched in 344 GO terms, such as extracellular region part and extracellular matrix and 14 pathways, including pathways in cancer and extracellular matrix­receptor interaction. Additionally, 239 duplications and 439 deletions in 678 genes from 1,313 chromosome regions were detected. A total of 12 genes were identified to be CNV­driven genes, including cadherin 18, laminin subunit α 1, spectrin ß, erythrocytic, ciliary rootlet coiled­coil, rootletin pseudogene 2, ß­1,4-N-acetyl-galactosaminyltransferase 1, G protein regulated inducer of neurite outgrowth 1, EH domain binding protein 1­like 1, growth factor independent 1, cathepsin Z, WNK lysine deficient protein kinase 1, glutathione S­transferase mu 2 and microsomal glutathione S­transferase 1. Therefore, cell cycle­associated genes including E2F1, E2F2, RB1 and CCND1, and cell adhesion­associated genes, such as CDH18 and LAMA1 may be used as diagnosis and/or therapeutic markers for patients with OS.

Detection of Circulating Tumor Cells Using Negative Enrichment Immunofluorescence and an In Situ Hybridization System in Pancreatic Cancer.

Pancreatic cancer (PC) is the most lethal type of gastrointestinal cancer, and early detection and monitoring is an urgent problem. Circulating tumor cells (CTCs) are emerging as a non-invasive biomarker for tumor detection. However, the low sensitivity is a main problem in the traditional CellSearch System for detecting CTCs, especially in patients with PC. In this study, we used negative enrichment (NE), immunofluorescence and in situ hybridization (FISH) of chromosome 8 (NE-iFISH) to capture and identify CTCs in PC patients. We showed that the NE-iFISH system exhibited a dramatically high detection rate of CTCs in PC patients (90%). The diagnostic rate of PC reached 97.5% when combining CTCs ≥ 2 and carbohydrate antigen 19-9 (CA19-9) > 37 µmol/L. The 1-year survival in the group of CTCs < 3 was significantly higher than that of CTCs ≥ 3 (p = 0.043). In addition, we analyzed the role of chromosomal instability in CTCs detection. The group of triploid (three hybridization signals of chromosome 8) CTCs ≥ 3 showed a shorter 1-year survival (p = 0.0279) and overall survival (p = 0.0188) than the group with triploid CTCs < 3. Importantly, the triploid CTC number but not the overall CTC counts could be a predictor of chemo-sensitivity. Moreover, circulating tumor microembolus (CTMs) were found in stage IV patients, and were positively related to the poor response to chemotherapy. In conclusion, the NE-iFISH system significantly improved the positive detection rate of CTCs and triploid CTC could be used to predict prognosis or the response to the chemotherapy of PC patients. CTM is a potential indicator of the chemotherapeutic effect in advanced PC patients.

SCF, regulated by HIF-1α, promotes pancreatic ductal adenocarcinoma cell progression.

Stem cell factor (SCF) and hypoxia-inducible factor-1α (HIF-1α) both have important functions in pancreatic ductal adenocarcinoma (PDAC). This study aims to analyze the expression and clinicopathological significance of SCF and HIF-1α in PDAC specimens and explore the molecular mechanism at PDAC cells in vitro and in vivo. We showed that the expression of SCF was significantly correlated with HIF-1α expression via Western blot, PCR, chromatin immunoprecipitation (ChIP) assay, and luciferase assay analysis. The SCF level was also correlated with lymph node metastasis and the pathological tumor node metastasis (pTNM) stage in PDAC samples. The SCF higher-expression group had significantly lower survival rates than the SCF lower-expression group (p<0.05). Hypoxia up-regulated the expression of SCF through the hypoxia-inducible factor (HIF)-1α in PDAC cells at the protein and RNA levels. When HIF-1α was knocked down by RNA interference, the SCF level decreased significantly. Additionally, ChIP and luciferase results demonstrated that HIF-1α can directly bind to the hypoxia response element (HRE) region of the SCF promoter and activate the SCF transcription under hypoxia. The results of colony formation, cell scratch, and transwell migration assay showed that SCF promoted the proliferation and invasion of PANC-1 cells under hypoxia. Furthermore, the down-regulated ability of cell proliferation and invasion following HIF-1α knockdown was rescued by adding exogenous SCF under hypoxia in vitro. Finally, when the HIF-1α expression was inhibited by digoxin, the tumor volume and the SCF level decreased, thereby proving the relationship between HIF-1α and SCF in vivo. In conclusion, SCF is an important factor for the growth of PDAC. In our experiments, we proved that SCF, a downstream gene of HIF-1α, can promote the development of PDAC under hypoxia. Thus, SCF might be a potential therapeutic target for PDAC.

Clinical and Prognostic Significance of Coagulation Assays in Pancreatic Cancer Patients With Absence of Venous Thromboembolism.

OBJECTIVES: Activation of coagulation and fibrinolysis is frequently observed in patients with cancer, even with absence of thrombosis. Furthermore, plasma coagulation parameters were associated with tumor progression, metastasis, and prognosis. Few studies have investigated these associations in pancreatic cancer (PA). This study aimed to investigate the clinical and prognostic significance of various plasma coagulation tests in PA patients with absence of venous thromboembolism (VTE). MATERIALS AND METHODS: A total of 139 PA patients with the absence of VTE were included in the analysis. Patients were followed up for at least 12 months until death. Pretreatment coagulation parameters including prothrombin time (PT), international normalized ratio (INR), activated partial thromboplastin time (APTT), fibrinogen (F), antithrombin-III (AT-III), protein C (PC), factor-VIII (F-VIII), and D-dimer (DD) were evaluated. A total of 40 age-matched and sex-matched healthy individuals without coagulation disorder were enrolled as the control group. RESULTS: Patients were inclined to have higher levels of PT, INR, APTT, F, F-VIII, and DD and lower levels of AT-III and PC than the control group (P<0.01 for all, except P=0.022 for INR and P=0.015 for AT-III). Patients with advanced tumor stages were likely to have higher median DD levels and lower AT-III levels than the control group (P=0.005 and P<0.001, respectively). DD levels were higher in patients with advanced pathology grade (P<0.001). Plasma DD levels (hazards ratio=1.71; 95% confidence interval, 1.07-2.73; P=0.025) were identified as the significantly independent prognostic predictors. CONCLUSIONS: PA patients are susceptible to activation of hemostasis system. Pretreatment plasma DD level was a potential predictor of prognosis in PA patients without VTE.

Stem cell factor is a novel independent prognostic biomarker for hepatocellular carcinoma after curative resection.

Stem cell factor (SCF), a ligand of c-kit, is a hematopoietic growth factor. Uncontrolled activity of SCF/c-kit signaling pathway contributes to the formation of a variety of human malignancies. In this study, we determined whether SCF expression could risk-stratify patients with hepatocellular carcinoma (HCC) after curative resection. HCC tissues from 160 patients were collected during curative resection and stained with SCF and CD34, a marker for microvessel density (MVD), using immunohistochemistry. Two statistical analyses were performed: an independent continuous and a multivariate categorical analysis, with test/validation set-defined cut points, and Kaplan-Meier estimated outcome measures of overall survival (OS) and relapse-free survival (RFS). We found that higher levels of SCF confer worse OS (continuous P = 0.014; and categorical P = 0.009), and RFS (continuous P = 0.002; categorical P = 0.003) of patients with HCC. SCF varies independently from MVD-CD34, tumor node metastasis, histologic grade, age and gender, and retains prognostic significance when analysed as a categorical variable in a multivariate analysis . We confirmed that MVD-CD34 is also an independent prognostic marker for patients with HCC. The levels of SCF and CD34 showed a positive and significant correlation (P < 0.0001) and double low expression confers superior OS (median = 48 months) and RFS (median = 24 months), whereas double high expression confers shortest RFS (median = 10.5 months) compared with single measurements. The prognostic values of SCF and CD34 were independently determined in this study and we propose that both of them are independent prognostic markers for HCC.

CypA, a gene downstream of HIF-1α, promotes the development of PDAC.

Hypoxia-inducible factor-1α (HIF-1α) is a highly important transcription factor involved in cell metabolism. HIF-1α promotes glycolysis and inhibits of mitochondrial respiration in pancreatic ductal adenocarcinoma (PDAC). In response to tumor hypoxia, cyclophilin A (CypA) is over-expressed in various cancer types, and is associated with cell apoptosis, tumor invasion, metastasis, and chemoresistance in PDAC. In this study, we showed that both HIF-1α and CypA expression were significantly associated with lymph node metastasis and tumor stage. The expression of CypA was correlated with HIF-1α. Moreover, the mRNA and protein expression of CypA markedly decreased or increased following the suppression or over-expression of HIF-1α in vitro. Chromatin immunoprecipitation analysis showed that HIF-1α could directly bind to the hypoxia response element (HRE) in the CypA promoter regions and regulated CypA expression. Consistent with other studies, HIF-1α and CypA promoted PDAC cell proliferation and invasion, and suppressed apoptosis in vitro. Furthermore, we proved the combination effect of 2-methoxyestradiol and cyclosporin A both in vitro and in vivo. These results suggested that,CypA, a gene downstream of HIF-1α, could promote the development of PDAC. Thus, CypA might serve as a potential therapeutic target for PDAC.

Improvement in treatment and outcome of pancreatic ductal adenocarcinoma in north China.

BACKGROUND: The incidence of pancreatic cancer has increased in China in the last decade, though efforts have been made in early detection and multimodality treatment. The aim of this study is to describe the decade-based development in early diagnosis and treatment modalities, as well as outcome for patients with pancreatic ductal adenocarcinoma (PDAC) in a high-volume facility. METHODS: All the PDAC patients underwent surgery between 1991 and 2009 and were selected from the database of TianJin Cancer Institute and Hospital. Decade-based changes in early diagnosis, treatment modalities, and outcome of the patients were retrospectively analyzed. RESULTS: Of the 565 patients with PDAC, patients in this decade (n = 460) had better overall survival than those in the last decade (n = 105), median survival was 10 months and 3 months, respectively. Patients in this decade had significantly improved in (P < 0.001) 2-year (14.7%) and 5-year survival rates (3.5%) as compared to those in the last decade (6.7% and 3.4%, respectively). Patients with metastasis at diagnosis in the last decade and this decade were 54% and 26% (P < 0.001), respectively. More patients in this decade had underwent R0/R1 resection (33% vs 20%, P = 0.010), chemotherapy (37% vs 12%, P < 0.001), and radical resection (34% vs 21%, P = 0.014) than those in the last decade. CONCLUSION: Patients operated on for PDAC in this decade had a better outcome than those in the last decade. Early detection, improved resection margin, and development in multimodality treatment contribute to this improvement.

Surgical treatment of pancreatic neuroendocrine tumors: report of 112 cases.

OBJECTIVES: To review the clinical data of a group of patients with pancreatic neuroendocrine tumors (pNETs) and to investigate the role of surgery in the treatment for pNETs by analyzing clinical manifestations and postoperative course of this rare disease. METHODS: A total of 112 patients (aged 21-76 years; 45 males) who underwent treatment between 1980 and 2003 were recruited in this study. Patients' data related to demographics and characteristics, diagnostic studies, surgical and tumor characteristics and survival were retrospectively reviewed. RESULTS: Forty-six patients (41.1%) had a well-differentiated neuroendocrine tumor (WDT), 44 (48.2%) a well-differentiated neuroendocrine carcinoma (WD-Ca) and 12 (10.7%) a poorly differentiated neuroendocrine carcinoma (PD-Ca). Nonfunctional tumors were seen in 65 (58.0%) patients, whereas functional tumors were found in 47 (42.0%) patients, including 26 insulinomas, 17 gastrinomas, 2 VIPomas, 1 glucagonoma, and 1 ACTHoma. The sensitivity of computed tomography was 87.1%. Surgical resection was performed in 99 (88.4%) patients. Thirty-eight (33.9%) patients underwent partial pancreaticoduodenectomy, 32 (28.6%) had distal pancreatectomy and 29 (25.9%) underwent enucleation. No surgery-related death occurred. The common postoperative complications were pancreatic fistula (15.2%), wound infection (13.4%) and delayed gastric emptying (6.3%). Three (5%) patients had reoperation due to intra-abdominal abscess and postoperative hemorrhage. Twenty-six (55.3%) of the 47 functional tumors were malignant, whereas 40 (61.5%) of the 65 nonfunctional tumors were malignant. Survival was significantly related to the type of neuroendocrine tumor (p = 0.001). The overall 5-year actual survival rate of patients with WD-Ca (n = 54) was 56%, significantly less than that of patients with WDT (n = 46, 91%, p = 0.001). All the patients of PD-Ca (n = 12) group died in 5 years. The 5-year survival rate differed significantly between patients with tumor node metastasis (TNM) stage I and II disease and those with stage III and IV tumors (p = 0.011). Patients with stage III had better prognosis than those with stage IV tumors (p = 0.007). Patients' long-term survival was closely correlated with vascular invasion (p = 0.008) and resection margin (p = 0.004). CONCLUSIONS: PNETs can be safely resected. Microscopic vascular invasion and positive resection margin are helpful for predicting patient survival. Malignant cases should be treated with aggressive radical surgery to achieve complete tumor resection and potential for long-term survival.