Purpose To determine the long-term prognosis in each phenotypic subset of breast cancer related to residual cancer burden (RCB) after neoadjuvant chemotherapy alone, or with concurrent human epidermal growth factor receptor 2 (HER2)-targeted treatment. Methods We conducted a pathologic review to measure the continuous RCB index (wherein pathologic complete response has RCB = 0; residual disease is categorized into three predefined classes of RCB index [RCB-I, RCB-II, and RCB-III]), and yp-stage of residual disease. Patients were prospectively observed for survival. Three patient cohorts received paclitaxel (T) followed by fluorouracil, doxorubicin, and cyclophosphamide (T/FAC): original development cohort (T/FAC-1), validation cohort (T/FAC-2), and independent validation cohort (T/FAC-3). Another validation cohort received FAC chemotherapy only, and a fifth cohort received concurrent trastuzumab (H) with sequential paclitaxel and fluorouracil, epirubicin, and cyclophosphamide (FEC; H+T/FEC). Phenotypic subsets were defined by hormone receptor (HR) and HER2 status at diagnosis, classified as HR-positive/HER2-negative, HER2-positive (HR-negative/HER2-positive or HR-positive/HER2-positive), or triple receptor-negative. Relapse-free survival estimates were determined from Kaplan-Meier analysis and compared using the log-rank test. Results Five cohorts (T/FAC-1 [n = 219], T/FAC-2 [n = 262], T/FAC-3 [n = 342], FAC [n = 132], and H+T/FEC [n = 203]) had median event-free follow-up of 13.5, 9.1, 6.8, 16.4, and 7.1 years, respectively. Continuous RCB index was prognostic within each phenotypic subset, independent of other clinical-pathologic variables. RCB classes stratified prognostic risk overall, within each phenotypic subset, and within yp-stage categories. Estimates of 10-year relapse-free survival rates in the four RCB classes (pathologic complete response, RCB-I, RCB-II, and RCB-III) were 86%, 81%, 55%, and 23% for triple receptor-negative; 83%, 97%, 74%, and 52% for HR-positive/HER2-negative in the combined T/FAC cohorts; and 95%, 77%, 47%, and 21% in the H+T/FEC cohort. Conclusion RCB was prognostic for long-term survival after neoadjuvant chemotherapy in all three phenotypic subsets of breast cancer. Our institutional findings should be externally validated.
Carcinoembryonic antigen (CEA) is one of the most widely used tumor markers and is increased in 30%-60% of patients with pancreatic cancer. Although carbohydrate antigen 19-9 (CA19-9) is the most important serum biomarker in pancreatic cancer, the diagnostic and prognostic value of CEA is gradually being recognized.The MEDLINE, EMBASE, and Web of Science databases were searched for related literature published until January 2017. Diagnostic accuracy variables were pooled using the Meta-Disc software. The pooled hazard ratios (HRs) for prognostic data were calculated and analyzed using Stata software.A total of 3,650 participants enrolled in 19 studies met our inclusion criteria. The pooled sensitivity, specificity, positive likelihood ratio, and negative likelihood ratio of a CEA-based panel were 0.45 (95% confidence interval [CI], 0.41-0.50), 0.89 (95% CI, 0.86-0.91), 5.39 (95% CI, 3.16-9.18), and 0.55 (95% CI, 0.41-0.72), respectively. The area under the curve (AUC, 0.90) and Q-value (0.84) of the CEA-based panel indicated a significantly higher diagnostic accuracy compared with CEA or CA19-9 alone. Moreover, there was also a significant association between high levels of CEA and worse overall survival (HR, 1.43; 95% CI, 1.31-1.56).Our meta-analysis indicated that elevated serum CEA level, as a vital supplementary to CA19-9, can play an important role in the clinical diagnosis of pancreatic cancer patients and predict poor prognosis.
Abstract Background: Immune-related long noncoding RNAs (irlncRNAs) have been demonstrated to be actively involved in the regulation of immune status. With this study, we aimed to establish a risk model of irlncRNAs and further investigate the roles of irlncRNAs in prognosis prediction and the immune landscape in pancreatic cancer. Methods: The transcriptome profiles and clinical information of pancreatic cancer patients were retrieved from The Cancer Genome Atlas (TCGA). Immune-related genes (irgenes) downloaded from ImmPort were used to screen the lncRNAs by correlation analysis (R>0.5, p<0.001). Random survival forest (RSF) and survival tree analysis showed that 9 irlncRNAs were highly correlated with overall survival (OS) according to the variable importance (VIMP) and the minimal depth. Then, Cox regression was used to establish a risk model with 3 irlncRNAs, which was evaluated by Kaplan-Meier analysis. In addition, we performed Cox regression analysis to establish the clinical prognostic model, which showed that the risk score was the only independent prognostic factor (p<0.001). A nomogram was drawn to visualize the clinical features. Wilcoxon signed-rank test and analysis of the correlations between the risk score and immune cells was applied to explore the potential irlncRNAs related to immune status. Results: A total of 176 samples were randomly divided into a training set (n=123) and a test set (n=53). A total of 1903 irlncRNAs were identified after Pearson correlation analysis between irgenes and lncRNAs. A total of 9 irlncRNAs were identified in the survival tree analysis, and 3 irlncRNAs (LINC00462, LINC01887, RP11-706C16.8) were used to establish a risk model. The areas under curve (AUC) of the receiver operating characteristic (ROC) for 36 months, 30 months, 24 months, 18 months, 12 months and 6 months were 0.778, 0.774, 0.751, 0.753, 0.780 and 0.756, respectively, with a concordance index (C-index) of 0.696. In the clinical prognostic model, the C-index increased from 0.599 to 0.682 after combining the risk scores. Furthermore, a high risk was associated with increased infiltration of CD4+ T cells, M0 macrophages and M1 macrophages. Conclusions: We established a novel three-irlncRNA risk model. The clinical evaluation showed its robustness in predicting the prognosis and immune landscape of pancreatic cancer.
Pancreatic cancer has the poorest prognosis among all human malignant solid tumors, mainly due to its high invasive and metastatic biological features. microRNAs (miRNAs) are a group of endogenous and small non-coding RNA molecules 18-25 nucleotides in length, functioning as either tumor-suppressor genes or oncogenes. Evidence has shown that regulation of miRNAs in pancreatic cancer is associated with tumor growth, invasion, metastasis and resistance to therapy. Over the last decade, many studies have also found that there is a close relationship between miRNAs and biological characteristics of pancreatic cancer invasion and metastasis, such as the presence of cancer stem cells, epithelial-mesenchymal transition (EMT) phenotype, DNA methylation or epigenetic alteration, and the activation of some specific signaling pathways. Therefore, better understanding of the complex role of miRNAs in the development and progression of pancreatic cancer metastasis may provide new insights that could be of therapeutic consequence. In this brief review, we discuss the literature concerning the correlation between miRNAs and pancreatic cancer, focusing on miRNAs that contribute to pancreatic cancer invasion and metastasis, particularly on cancer stem cell characteristics, the EMT process, epigenetic modifications and tumor-associated signaling pathways.
<div>Abstract<p>Methylthioadenosine phosphorylase (MTAP) is a key enzyme associated with the salvage of methionine and adenine that is deficient in 20% to 30% of pancreatic cancer. Our previous study revealed that MTAP deficiency indicates a poor prognosis for patients with pancreatic ductal adenocarcinoma (PDAC). In this study, bioinformatics analysis of The Cancer Genome Atlas (TCGA) data indicated that PDACs with MTAP deficiency display a signature of elevated glycolysis. Metabolomics studies showed that that MTAP deletion–mediated metabolic reprogramming enhanced glycolysis and <i>de novo</i> purine synthesis in pancreatic cancer cells. Western blot analysis revealed that MTAP knockout stabilized hypoxia-inducible factor 1α (HIF1α) protein via posttranslational phosphorylation. RIO kinase 1 (RIOK1), a downstream kinase upregulated in MTAP-deficient cells, interacted with and phosphorylated HIF1α to regulate its stability. <i>In vitro</i> experiments demonstrated that the glycolysis inhibitor 2-deoxy-d-glucose (2-DG) and the <i>de novo</i> purine synthesis inhibitor l-alanosine synergized to kill MTAP-deficient pancreatic cancer cells. Collectively, these results reveal that MTAP deficiency drives pancreatic cancer progression by inducing metabolic reprogramming, providing a novel target and therapeutic strategy for treating MTAP-deficient disease.</p>Significance:<p>This study demonstrates that MTAP status impacts glucose and purine metabolism, thus identifying multiple novel treatment options against MTAP-deficient pancreatic cancer.</p></div>
To determine the contents of thymidine phosphorylase (TP) and dihydropyrimidine dehydrogenase (DPD) in pancreatic cancer to provide a basis for the clinical use of capecitabine in pancreatic cancer patients.The contents of TP and DPD in pancreatic cancer and adjacent normal tissues from 20 patients were determined by ELISA and the TP to DPD ratios in the cancer and adjacent normal tissue were compared.TP content was 5- to 283-fold higher in tumor tissue (mean 74-fold) than in the adjacent normal tissue (P < 0.01). DPD in the cancer tissue increased significantly. So did the TP to DPD ratio, when compared to that in normal pancreatic tissue (P < 0.01).The increased TP to DPD ratio in pancreatic cancer suggests that capecitabine could be activated by the cancer, these capable of selectively kill the tumor cells.
Lipid rafts are cholesterol- and sphingolipid-enriched specialized membrane domains within the plasma membrane. Lipid rafts regulate the density and activity of signal receptors by compartmentalizing them, promoting signalling cascades that play important roles in the survival, death and metastasis of cancer cells. In this review, we emphasize the current concept initially postulated by F. Mollinedo and C. Gajate on the importance of lipid rafts in cancer survival, death and metastasis by describing representative signalling pathways, including the IGF system and the PI3K/AKT, Fas/CD95, VEGF/VEGFR2 and CD44 signalling pathways, and we also discuss the concept of CASMER (cluster of apoptotic signalling molecule-enriched rafts), coined, originally introduced and further advanced by F. Mollinedo and C. Gajate in the period 2005-2010. Then, we summarize relevant research progress and suggest that lipid rafts play important roles in the survival, death and metastasis of cancer cells, making them promising targets for cancer therapy.
The prognosis for pancreatic cancer (PC) is poor; however, the timely and accurate treatment of this disease will significantly improve prognosis. Serum biomarkers involve non-invasive tests that facilitate the early detection of tumors, predict outcomes and assess responses to therapy, so that the patient can be continuously monitored and receive the most appropriate therapy. Studies have reported that cancer antigen (CA)125 [also known as mucin 16 (MUC16)] has functional significance in the tumorigenic, metastatic and drug resistant properties of PC. Our aim was to use this biomarker in the diagnosis, detection of metastasis, prognosis and in the monitoring of the treatment effects of PC. Members of the Chinese Study Group for Pancreatic Cancer (CSPAC) reviewed the literature on CA125/MUC16 and developed an objective consensus on the clinical utility of CA125/MUC16 for PC. They confirmed the role of CA125/MUC16 in tumorigenesis and the progression of PC, and recommended monitoring CA125/MUC16 levels in all aspects of the diagnosis and treatment of PC, particularly those that involve the monitoring of treatments. In addition, they suggested that the combination of other biomarkers and imaging techniques, together with CA125/MUC16, would improve the accuracy of the clinical decision-making process, thereby facilitating the optimization of treatment strategies. Periodic clinical updates of the use of CA125/MUC16 have been established, which are important for further analyses and comparisons of clinical results from affiliates and countries, particularly as regards the in-depth biological function and clinical translational research of this biomarker.
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