Development of a MicroRNA Signature Predictive of Recurrence and Survival in Pancreatic Ductal Adenocarcinoma
Nikhil SebastianAmy WebbKenneth W. MerrellEugene J. KoayAdam R. WolfeLizhi ZhangT.J. WilhiteDalia ElganainyRyan RobbWei ChenJordan M. CloydMary DillhoffAllan TsungLaith AbushahinAnne M. NoonanTerence M. Williams
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Optimal patient selection for radiotherapy in pancreatic ductal adenocarcinoma (PDAC) is unestablished. Molecular profiling may select patients at high risk for locoregional recurrence (LRR) who would benefit from radiation.We included resectable pancreatic cancer (R-PDAC) patients, divided into training and validation cohorts, treated among three institutions with surgery and adjuvant chemotherapy, and borderline resectable or locally advanced pancreatic cancer (BR/LA-PDAC) patients treated with chemotherapy with or without radiation at the primary study institution. We isolated RNA from R-PDAC surgical specimens. Using NanoString, we identified miRNAs differentially expressed between normal and malignant pancreatic tissue. ElasticNet regression identified two miRNAs most predictive of LRR in the training cohort, miR-181b/d and miR-575, which were used to generate a risk score (RS). We evaluated the association of the median-dichotomized RS with recurrence and overall survival (OS).We identified 183 R-PDAC and 77 BR/LA-PDAC patients with median follow up of 37 months treated between 2001 and 2014. On multivariable analysis of the R-PDAC training cohort (n = 90), RS was associated with worse LRR (HR = 1.34; 95%CI 1.27-11.38; p = 0.017) and OS (HR = 2.89; 95%CI 1.10-4.76; p = 0.027). In the R-PDAC validation cohort, RS was associated with worse LRR (HR = 2.39; 95%CI 1.03-5.54; p = 0.042), but not OS (p = 0.087). For BR/LA-PDAC, RS was associated with worse LRR (HR = 2.71; 95%CI 1.14-6.48; p = 0.025), DR (HR = 1.93; 95%CI 1.10-3.38; p = 0.022), and OS (HR = 1.97; 95%CI 1.17-3.34; p = 0.011). Additionally, after stratifying by RS and receipt of radiation in BR/LA-PDAC patients, high RS patients who did not receive radiation had worse LRR (p = 0.018), DR (p = 0.006), and OS (p < 0.001) compared to patients with either low RS or patients who received radiation, irrespective of RS.RS predicted worse LRR and OS in R-PDAC and worse LRR, DR, and OS in BR/LA-PDAC. This may select patients who would benefit from radiation and should be validated prospectively.Keywords:
Adjuvant Chemotherapy
Aberrant secreted protein acidic and rich in cysteine (SPARC) expression has been reported to play an important role in the tumor development. However, the pattern and the role of SPARC in pancreatic cancer remain largely unknown. Therefore, we further deciphered the role of SPARC played in pancreatic cancer. We first evaluated the SPARC expression in human pancreatic cancer tissues and pancreatic cancer cells. Then we forced expression and silenced SPARC expression in pancreatic cancer cell lines MIA PaCa2 and PANC-1, respectively, using lentivirus vectors. We characterized the stable cells in vitro. In this study, we found that SPARC expression was weak in cancer cells in specimens which negatively correlated with the expression level of phosphorylated pRB and poorer outcome. Moreover, our results demonstrated that SPARC negatively regulated pancreatic cell growth in vitro. Furthermore, we disclosed that the activation of p53 and p27Kip1 may involve in the effect of SPARC on pancreatic cancer cells. SPARC is downregulated in pancreatic cancer cells and retards the growth of pancreatic cancer cell. Taken together, these results indicate SPARC may be a potential target for pancreatic cancer therapy.
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Pancreatic cancer is one of the most aggressive, drug-resistant and lethal types of cancer with poor prognosis. Various factors including reactive oxygen species, cytokines, growth factors, and extracellular matrix proteins are reported to be involved in the development of pancreatic cancer. However, the pathogenesis of pancreatic cancer has not been completely elucidated. Oxidative stress has been shown to contribute to the development of pancreatic cancer. Evidences supporting the role of reactive oxygen species and cytokines as a risk for pancreatic cancer and the concept of antioxidant supplementation as a preventive approach for pancreatic cancer have been proposed. Here, we review the literature on oxidative stress, cytokine expression, inflammatory signaling, and natural antioxidant supplementation in relation to pancreatic cancer.
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Early detection of pancreatic cancer is notoriously difficult. A novel cancer diagnostic method using the ability of nematodes to detect odor of urine samples has been developed (N-NOSE). This method has a high sensitivity and specificity for various cancers; however, it has not yet been verified in pancreatic cancer. We examined the usefulness of this method to aid early diagnosis of pancreatic cancer in a cancer center.We collected urine samples and clinical data from patients hospitalized in our division, between July 2017 and February 2019. We excluded patients with a known current or past history of other cancers. We investigated the relationship between the results of N-NOSE and the presence of pancreatic cancer.There were 95 noncancer cases and 104 pancreatic cancer cases. The sensitivity and specificity of N-NOSE for pancreatic cancer were 84.6% (88/104) and 60% (57/95), respectively. N-NOSE was able to detect stages 0 to I pancreatic cancer and had a higher correlation with early-stage pancreatic cancer than advanced stage.N-NOSE has sufficient sensitivity and specificity for use in clinical practice, and it holds great potential as a diagnostic aid for pancreatic cancer, especially for early-stage pancreatic cancer.
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Objective:To study on whether radiotherapy affects on T cell subgroups,and to research on the effects of immunoenhancing agents on the immune side effects of radiotherapy.Methods:Sixty-six malignant tumour patients were divided into two groups,radiotherapy alone and radiotherpay plus immunoinhancing agents therapy groups.All patients were subjected to high energy X-rays and electronic rays outer local reginal therapy.T cell subgroups levels were measured before and after the radiotherapy.Results:CD 3,CD 4 and CD 8 decreased significantly after radiotherapy (P0.05) in radiotherapy alone group.There were no differences in CD 3,CD 4 and CD 8 before and after radiotherapy in the group of radiotherapy plus immunoinhancing agents therapy.Conclusions:Radiotherapy may cause the decrease in T cells of all subgroups and immunoinhancing agents may antagonize the side effects of radiotherapy. [
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Objective: To explore the effect of adjuvant chemotherapy with surgery on the prognosis for the patients with Ⅰ lung adenocarcinoma.Methods: 160 patients with(Ⅰa + Ⅰb) lung adenocarcinoma were selected in our hospital.The patients were divided into operation group and operation plus postoperative chemotherapy group.The therapeutic effect between these two groups was compared.Results: Among these patients,survival rates of 1,3,5-year in operation group were 96.25%,87.50% and 78.75% respectively,and those in adjuvant chemotherapy group were 98.75%,93.75% and 86.25% respectively in Ⅰ a lung adenocarcinoma;survival rates of 1,3,5-year in operation group were 85.00%,66.25% and 58.75%respectively,but those in adjuvant chemotherapy group were 95.00%,77.50% and 68.75% respectively in Ⅰb lung adenocarcinoma.Compared with operation,postoperative chemotherapy achieved significant results in Ⅰa and Ⅰb and had a significant difference in survival rates(P0.05 or P0.01).Conclusion: Adjuvant chemotherapy with operation is better than operation alone in the prognosis of Ⅰlung adenocarcinoma.The chemotherapy treatment for lung adenocarcinoma can achieve significant effect,and may be worthy of wide use in clinical.
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