The significance of relative dose intensity in adjuvant chemotherapy of pancreatic ductal adenocarcinoma-including the analysis of clinicopathological factors influencing relative dose intensity.
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ABSTRACT:
SUBMITTER: Yabusaki N
PROVIDER: S-EPMC5265784 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BackgroundPancreatic ductal adenocarcinoma is one of the most aggressive malignancies, and often involves invasion and distant metastasis from the early tumor stages. Myosin II reportedly plays a key role in regulating tumor progression and metastasis.AimsWe examined whether myosin regulatory light polypeptide 9 (MYL9) regulates cancer cell proliferation.Methods and resultsTo investigate the expression pattern and clinical significance of MYL9 in pancreatic ductal adenocarcinoma, we performed immunohistochemical analysis of samples collected from 101 patients with pancreatic ductal adenocarcinoma. The expression of MYL9 was investigated to evaluate its functional role and contribution to proliferation and apoptosis in pancreatic ductal adenocarcinoma cells in vitro. The results showed that MYL9 was predominantly expressed in the cytoplasm and membrane of pancreatic ductal adenocarcinoma cells. Multivariate analysis indicated that MYL9 acted as an independent prognostic factor for overall survival and distant metastasis-free survival. MYL9 expression was strongly associated with malignancy in in vitro analyses, including proliferation and anti-apoptotic activities.ConclusionsOur findings suggest that MYL9 is an independent prognostic factor of pancreatic ductal adenocarcinoma. MYL9 is a crucial biomarker and potential therapeutic target for pancreatic ductal adenocarcinoma.
| S-EPMC9575502 | biostudies-literature
Project description:BackgroundMost patients with advanced pancreatic adenocarcinoma (PA) treated with FOLFIRINOX experience adverse events requiring dose reduction. We aimed to assess the association between relative dose intensity (RDI) and disease control in a European setting.MethodsWe retrospectively included patients with advanced PA treated with three or more cycles of FOLFIRINOX between 2011 and 2018 in six French centers. We computed the cumulative single-agent RDI (csRDI) before the first reassessment for each FOLFIRINOX agent (oxaliplatin, irinotecan, 5FU bolus, and 5FU intravenous infusion) and the cumulative multi-drug RDI (cmRDI) of their combination. The association between RDI and disease control or objective response at first reassessment was evaluated using multivariable logistic regression models controlling for performance status, liver metastases, and center.ResultsWe included 243 patients. Median csRDIs were 81%, 79%, 75%, and 85% for oxaliplatin, irinotecan, 5FU bolus, and 5FU intravenous infusion, respectively. Median cmRDI was 80%. None of the RDIs was significantly associated with disease control or objective response. Including RDI in a clinical model did not improve its ability to predict disease control; the area under the curve was 0.79 (95% CI: 0.73-0.85) with RDI versus 0.78 (95% CI: 0.72-0.85) without. Similar results were observed for the objective response.ConclusionPragmatic dose adjustments of FOLFIRINOX should be made by oncologists without considering a loss of effect.
| S-EPMC8287268 | biostudies-literature
Project description:Mucin-type O-glycans are involved in cancer initiation and progression, although details of their biological and clinicopathological roles remain unclear. The aim of this study was to investigate the clinicopathological significance of β1,3-N-acetylglucosaminyltransferase 6 (β3Gn-T6), an essential enzyme for the synthesis of core 3 O-glycan and several other O-glycans in pancreatic ductal adenocarcinoma (PDAC). We performed immunohistochemical and lectin-histochemical analyses to detect the expression of β3Gn-T6 and several O-glycans in 156 cases of PDAC with pancreatic intraepithelial neoplasias (PanINs) and corresponding normal tissue samples. The T antigen, Tn antigen, sialyl Lewis X (sLeX) antigen, and sLeX on core 2 O-glycan were more highly expressed in PDAC cells than in normal pancreatic duct epithelial cells (NPDEs). Conversely, the expression of 6-sulfo N-acetyllactosamine on extended core 1 O-glycan was found in NPDEs and was low in PDAC cells. These glycan expression levels were not associated with patient outcomes. β3Gn-T6 was expressed in ~20% of PDAC cases and 30-40% of PanINs but not in NPDEs. Higher expression of β3Gn-T6 was found in PDAC cells in more differentiated adenocarcinoma cases showing significantly longer disease-free survival in both univariate and multivariate analyses. In addition, the expression of β3Gn-T6 in PDAC cells and PanINs significantly correlated with the expression of MUC5AC in these cells, suggesting that β3Gn-T6 expression is related to cellular differentiation status of the gastric foveolar phenotype. Thus, it is likely that β3Gn-T6 expression in PDAC cells is a favorable prognostic factor in PDAC patients, and that the expression of β3Gn-T6 correlates with the gastric foveolar phenotype in pancreatic carcinogenesis.
| S-EPMC7703919 | biostudies-literature
Project description:BACKGROUND:Poor prognosis of pancreatic cancer (PanCa) is associated with lack of an effective early diagnostic biomarker. This study elucidates significance of MUC13, as a diagnostic/prognostic marker of PanCa. METHODS:MUC13 was assessed in tissues using our in-house generated anti-MUC13 mouse monoclonal antibody and analyzed for clinical correlation by immunohistochemistry, immunoblotting, RT-PCR, computational and submicron scale mass-density fluctuation analyses, ROC and Kaplan Meir curve analyses. RESULTS:MUC13 expression was detected in 100% pancreatic intraepithelial neoplasia (PanIN) lesions (Mean composite score: MCS = 5.8; AUC >0.8, P < 0.0001), 94.6% of pancreatic ductal adenocarcinoma (PDAC) samples (MCS = 9.7, P < 0.0001) as compared to low expression in tumor adjacent tissues (MCS = 4, P < 0.001) along with faint or no expression in normal pancreatic tissues (MCS = 0.8; AUC >0.8; P < 0.0001). Nuclear MUC13 expression positively correlated with nodal metastasis (P < 0.05), invasion of cancer to peripheral tissues (P < 0.5) and poor patient survival (P < 0.05; prognostic AUC = 0.9). Submicron scale mass density and artificial intelligence based algorithm analyses also elucidated association of MUC13 with greater morphological disorder (P < 0.001) and nuclear MUC13 as strong predictor for cancer aggressiveness and poor patient survival. CONCLUSION:This study provides significant information regarding MUC13 expression/subcellular localization in PanCa samples and supporting the use anti-MUC13 MAb for the development of PanCa diagnostic/prognostic test.
| S-EPMC5995635 | biostudies-literature
Project description:BackgroundAdvances in genomics have greatly improved the survival rate in cancer patients. However, due to genetic heterogeneity, pancreatic ductal adenocarcinoma (PDAC) is still difficult to diagnose early, and its survival rate is extremely low. Therefore, we identified biomarkers that predict the prognosis of PDAC patients using independent cohort data.Materials and methodsTo develop a novel prognostic biomarker, we used the gene expression and clinical data from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO). Kaplan-Meier survival curve using median values of genes as cutoff showed that EIF4G1 was the only statistically significant gene in the 3 cohorts. We analyzed the prognostic significance of EIF4G1 using the time-dependent area under the curve (AUC) of Uno's C-index, the AUC value of the receiver operating characteristics (ROC) at 3 years, and multivariate Cox analysis. We also compared EIF4G1 levels between tumors and matched non-tumor tissues.ResultsEIF4G1 is the only prognostic gene in patients with PDAC, which was selected by Kaplan-Meier survival analysis. The survival curve showed that high expression of EIF4G1 was associated with poor prognosis of PDAC with a good discriminative ability in 3 independent cohorts. The risk stratifying ability of EIF4G1 was demonstrated by analyzing C-indices and AUC values. Multivariate Cox regression confirmed its prognostic significance. EIF4G1 expression was significantly higher in PDAC tissues than in the matched normal tissues.ConclusionEIF4G1 could be used as a novel prognostic marker for PDAC and to determine suitable treatment options.
| S-EPMC6472433 | biostudies-literature
Project description:Adenocarcinomas of the pancreatic duct (PDAC) are characteristically aggressive tumors that are extremely challenging to treat as curative surgical resection, the definitive treatment, is seldom possible. Regretably, most patients are diagnosed with metastatic disease at the time of initial presentation. In addition, current chemotherapeutic concepts that are used for advanced disease stages show frustrating results. Thus, there is an urgent need to identify novel therapeutic molecular targets that are associated with PDAC disease. Recently, the chemokine receptor CXCR4 has been demonstrated to be highly expressed in metastatic PDAC. However, the results of the published data on CXCR4 and its association with clinicopathological variables and prognosis in PDAC seem to be heterogeneous. Consequently, to clarify the relevance of CXCR4 as a biomarker in PDAC we performed a comprehensive literature search by using PubMed and Web of Science databases to identify articles that focused on the expression of CXCR4 in PDAC by using immunohistochemistry. Subsequently, data from nine relevant studies, encompassing 1183 patients were extracted, qualitatively assessed, and entered into a meta-analysis. By using a random effects model, the pooled hazard ratio of the seven studies that reported on patients overall survival revealed a correlation between expression of CXCR4 and poor prognosis (HR 1.49; 95% CI: 1.04-2.14; P = 0.03; I2 = 74%). Although heterogeneity became evident, subgroup analyses confirmed the prognostic value of CXCR4 in PDAC, especially in high-quality studies that performed multivariate analysis. In addition, meta-analysis revealed a strong association of CXCR4 expression with the UICC stage (OR: 3.40; 95% CI: 1.67-6.92; P = 0.0007; I2 = 0%) and metastatic disease (N-status: OR: 2.55; 95% CI: 1.56-4.15; P = 0.0002; I2 = 26%; recurrence to the liver: OR: 2.80; 95% CI: 1.48-5.29; P = 0.001; I2 = 0%). Taken together, our meta-analysis suggests that CXCR4 represents a useful prognostic biomarker in PDAC and might therefore be evaluated as a potential therapeutic target in the treatment of metastatic cancer disease of the pancreas.
| S-EPMC4474597 | biostudies-literature
Project description:BackgroundSurvival after surgery for pancreatic ductal adenocarcinoma (PDAC) remains poor. Thus, novel therapeutic concepts focus on the development of targeted therapies. In this context, inhibitor of apoptosis protein (IAP) survivin is regarded as a promising oncotherapeutic target. However, its expression and prognostic value in different tumour compartments of PDAC have not been studied.MethodsImmunohistochemical analysis of survivin in different PDAC tumour compartments from 236 consecutive patients was correlated with clinicopathological variables and survival.ResultsIn comparison to healthy pancreatic tissue high nuclear (p < 0.001) and high cytoplasmic (p < 0.01) survivin expression became evident in the tumour centre, along the invasion front and in lymph node metastases. Cytoplasmic overexpression of survivin in tumour centres was related to the presence of distant metastasis (p = 0.016) and UICC III/IV stages (p = 0.009), while high cytoplasmic expression at the invasion front grouped with venous infiltration (p = 0.022). Increased nuclear survivin along the invasion front correlated with perineural invasion (p = 0.035). High nuclear survivin in tumour centres represented an independent prognostic factor for overall survival of pancreatic tail carcinomas (HR 13.5 95%CI (1.4-129.7)) and correlated with a limited disease-free survival in PDAC (HR 1.80 95%CI (1.04-3.12)).ConclusionSurvivin is associated with advanced disease stages and poor prognosis. Therefore, survivin will help to identify patients with aggressive tumour phenotypes that could benefit from the inclusion in clinical trials incorporating survivin inhibitors in PDAC.
| S-EPMC9322386 | biostudies-literature
Project description:LIM-domain only protein 7 (LMO7) has been suggested to act as a tumor suppressor for murine lung adenocarcinoma, while its splice variant p100 LMO7/#16 is associated with invasion and metastasis of rat AH130W1 cells. However, the importance of LMO7 in human lung cancer is unknown. We investigated LMO7 protein expression by immunohistochemistry in tumor tissues obtained from 57 patients with adenocarcinoma of the lung using a rabbit anti-LMO7 antibody. Signals for LMO7 were localized to the apical surface of the bronchial epithelium and to the cell membranes of pneumocytes in non-cancerous pulmonary tissues, but were noted circumferentially around the plasma membrane of cancer cells in all 57 patients with adenocarcinoma. The LMO7-positive group (24 patients, 42%) showed equivocal to strong expression of LMO7 in more than 50% cancer cells, while the remaining 33 patients (58%) showed LMO7 expression in less than 50% of their cancer cells. The latter group had significantly more advanced disease than the LMO7-positive group with regard to T factor (p=0.011), nodal involvement (p=0.026) and p-stage (p=0.010; χ(2) test). Multivariate analysis using a logistic regression model showed that LMO7 expression was independently associated with the T factor (p=0.041). Kaplan-Meier analysis showed that a poor prognosis was associated with low expression of LMO7 (p=0.036; log-rank test). Our findings are consistent with earlier observations and demonstrate that LMO7 is inversely correlated with the development and prognosis of human lung adenocarcinoma.
| S-EPMC3440790 | biostudies-literature
Project description:Pancreatic ductal adenocarcinoma (PDAC) is one of the leading causes of cancer mortality. Although advances have been made in understanding the pathogenesis of PDAC, the outcome still remains poor. The aim of this study is to conduct a meta-analysis to evaluate the precise association between SMAD4 loss and clinicopathological significance in PDAC. A literature search was made in PubMed, Web of Science, Google scholar, and EMBASE for related publications. The data were extracted and assessed by two reviewers independently. Analysis of pooled data was performed, Odds Ratio or Hazard Ratio with corresponding confidence intervals was calculated and summarized. 12 relevant articles were included for full review in detail and meta-analysis. The frequency of SMAD4 protein loss was significantly increased in PDAC than in nonmalignant pancreatic tissue, Odd Ratio was 0.05 with 95% confidence interval 0.01-0.23, p<0.0001. SMAD4 loss was significantly associated with poor overall survival in patients with PDAC, Hazard Ratio was 0.61 with 95% confidence interval 0.38-0.99, p=0.05. SMAD4 loss was not correlated with the size, grades, and lymph node metastasis of PDAC. In conclusion, SMAD4 is a biomarker for the diagnosis of PDAC. SMAD4 loss is significantly related to poor prognosis in patients with PDAC.
| S-EPMC5369995 | biostudies-literature
Project description:Resection is the only curative treatment for pancreatic ductal adenocarcinoma (PDAC). Although the outcome of technically resectable PDAC has improved with advances in surgery and adjuvant therapy, the 5-year survival rate remains low at 20% to 40%. More effective therapy is needed. Almost 15 years ago, the National Comprehensive Cancer Network guidelines proposed a resectability classification of PDAC based on preoperative imaging. Since then, treatment strategies for PDAC have been devised based on resectability. The standard of care for resectable PDAC is adjuvant chemotherapy after R0 resection, as shown by the results of pivotal clinical trials. With regard to neoadjuvant treatment, several recent clinical trials comparing neoadjuvant treatment with upfront resection have been conducted on resectable PDAC and borderline resectable PDAC, and the benefits and efficacy of neoadjuvant treatment for pancreatic cancer has become clearer. The significance of neoadjuvant treatment for resectable PDAC remains controversial, but in borderline resectable PDAC the efficacy of neoadjuvant treatment has been further recognised, although the standard of care has not yet been established. Several promising clinical trials for PDAC are ongoing. This review presents previous and ongoing trials of perioperative treatment for resectable and borderline resectable PDAC, focusing on the difference between Asian and Western countries.
| S-EPMC10502496 | biostudies-literature