Tumor‐associated N1 and N2 neutrophils predict prognosis in patients with resected pancreatic ductal adenocarcinoma: A preliminary study
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ABSTRACT:
SUBMITTER: Yin H
PROVIDER: S-EPMC9632487 | biostudies-literature | 2022 Nov
REPOSITORIES: biostudies-literature
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Project description:BackgroundThe prognostic effect of tumour budding was retrospectively analysed in a cohort of 173 patients with resected pancreatic ductal adenocarcinomas (PDACs) of the prospective clinical multicentre CONKO-001 trial.MethodsHaematoxylin and eosin (H&E)-stained whole tissue slides were evaluated. In two independent approaches, the mean number of tumour buds was analysed according to the consensus criteria in colorectal cancer, in one 0.785 mm2 field of view and additionally in 10 high-power fields (HPF) (HPF = 0.238 mm2).ResultsTumour budding was significantly associated with a higher tumour grade (p < 0.001) but not with distant or lymph node metastasis. Regardless of the quantification approach, an increased number of tumour buds was significantly associated with reduced disease-free survival (DFS) and overall survival (OS) (10 HPF approach DFS: HR = 1.056 (95% CI 1.022-1.092), p = 0.001; OS: HR = 1.052 (95% CI 1.018-1.087), p = 0.002; consensus method DFS: HR = 1.037 (95% CI 1.017-1.058), p < 0.001; OS: HR = 1.040 (95% CI 1.019-1.061), p < 0.001). Recently published cut-offs for tumour budding in colorectal cancer were prognostic in PDAC as well.ConclusionsTumour budding is prognostic in the CONKO-001 clinical cohort of patients. Further standardisation and validation in additional clinical cohorts are necessary.
| S-EPMC5988658 | biostudies-literature
Project description:BackgroundEpidermal growth factor receptor (EGFR) is highly expressed in pancreatic ductal adenocarcinoma (PDAC) and is involved in tumorigenesis and development. However, EGFR expression alone has limited clinical and prognostic significance. Recently, the cross-talk between EGFR and G-protein-coupled chemokine receptor CXCR4 has become increasingly recognized.MethodsIn the present study, immunohistochemical staining of EGFR and CXCR4 was performed on paraffin-embedded specimens from 131 patients with surgically resected PDAC. Subsequently, the associations between EGFR expression, CXCR4 expression, EGFR/CXCR4 coexpression and clinicopathologic factors were assessed, and survival analyses were performed.ResultsIn total, 64 (48.9%) patients expressed EGFR, 68 (51.9%) expressed CXCR4, and 33 (25.2%) coexpressed EGFR and CXCR4. No significant association between EGFR and CXCR4 expression was observed (P = 0.938). EGFR expression significantly correlated with tumor differentiation (P = 0.031), whereas CXCR4 expression significantly correlated with lymph node metastasis (P = 0.001). EGFR/CXCR4 coexpression was significantly associated with lymph node metastasis (P = 0.026), TNM stage (P = 0.048), and poor tumor differentiation (P = 0.004). By univariate survival analysis, both CXCR4 expression and EGFR/CXCR4 coexpression were significant prognostic factors for poor disease-free survival (DFS) and overall survival (OS). Moreover, EGFR/CXCR4 coexpression significantly increased the hazard ratio for both recurrence and death compared with EGFR or CXCR4 protein expression alone. Multivariate survival analysis demonstrated that EGFR/CXCR4 coexpression was an independent prognostic factor for DFS (HR = 2.33, P<0.001) and OS (HR = 2.48, P = 0.001).ConclusionsIn conclusion, our data indicate that although EGFR expression alone has limited clinical and prognostic significance, EGFR/CXCR4 coexpression identified a subset of PDAC patients with more aggressive tumor characteristics and a significantly worse prognosis. Our results suggest a potentially important "cross-talk" between CXCR4 and EGFR intracellular pathways and indicate that the simultaneous inhibition of these pathways might be an attractive therapeutic strategy for PDAC.
| S-EPMC4332630 | biostudies-literature
Project description:BACKGROUND AND AIMS: Pancreaticoduodenectomy (PD) is a major operative intervention performed most commonly for malignancy in the head of pancreas. The aim of this study was to evaluate the utilization of blood transfusion for PD and to determine whether this had prognostic significance in a subset of patients with pancreatic ductal adenocarcinoma (PDAC). MATERIAL AND METHODS: Data on blood transfusion requirement were retrospectively collected for patients undergoing PD from 1998 to 2005. Standard prognostic factors and survival data were also collected in patients with PDAC. RESULTS: One-hundred-and-seventy patients underwent PD. Seventy-six patients (45%) received transfusion. The median (interquartile range) number of units of red cell concentrate (RCC) transfused perioperatively (intraoperatively and within 24 h of surgery) was 1.5 (0.5-2.5). The median preoperative haemoglobin (Hb) was 126 g/dl. The median number of units of RCC transfused perioperatively in patients with Hb <126 g/dl was 2 (1-3); for those with Hb > or = 126 g/dl the median was 0 (0-1); p=0.003. Forty-nine patients who were resected for PDAC were subjected to survival analysis. Univariate and multivariate analyses showed that only posterior resection margin invasion was associated with an adverse outcome (margin positive 198 [143-470] days vs margin negative 398 [303-859] days; p=0.02). Perioperative RCC transfusion requirement was not a significant predictor of survival (transfusion 408 [214-769] days vs no transfusion 331 [217-391] days; p=0.18). Furthermore, RCC transfusion within 30 days of operation was not a significant predictor of poor survival (transfusion 331 [201-459] days vs no transfusion 317 [196-769] days; p=0.43). CONCLUSIONS: PD can be performed with a moderately low requirement for RCC transfusion; however, low preoperative haemoglobin is a predictor for the requirement of RCC transfusion. Administration of RCC transfusion does not appear to be a significant adverse prognostic factor in patients with resected PDAC.
| S-EPMC2215364 | biostudies-other
Project description:Claudin-18.2 (CLDN18.2) is specifically expressed in pancreatic precancerous lesions and pancreatic ductal adenocarcinoma (PDAC). We assessed the clinical characteristics of patients with CLDN18.2-overexpressing pancreatic cancer to identify patients who might benefit from CLDN18-targeted treatment. A total of 130 patients with surgically resected PDAC were investigated for the immunohistochemical expression of claudin-18 (CLDN18). The CLDN18 staining intensities (0–3+) and relative proportion of positive tumor cells were analyzed by two independent raters. Tumors positive for CLDN18 expression were defined as ≥80% of tumor cells with 2+ or 3+ staining intensity in a CLDN18 immunohistochemical assay. Positive CLDN18 expression was present in 41/130 (31.5%) surgically resected PDACs and the relative proportion of positive tumor cells and the staining intensity were directly correlated (p < 0.001). Positive CLDN18 expression was significantly associated with well-differentiated tumors (p < 0.001) and less regional node involvement (p = 0.045). The positive CLDN18-expressing group showed no statistical difference in median overall survival (17.4 months vs. 20.6 months, p = 0.770) compared to the negative CLDN18-expressing group. Distant nodal metastasis was more frequent in the positive CLDN18-expressing group (p = 0.011). CLDN18 is frequently expressed in PDAC, and high CLDN18-expressing PDACs showed some different clinicopathologic characteristics. High CLDN18 expression was not associated with prognosis in patients with surgically resected PDAC.
| S-EPMC10455540 | biostudies-literature
Project description:BackgroundFrequent disease relapse and a lack of effective therapies result in a very poor outcome in pancreatic ductal adenocarcinoma (PDAC) patients. Thus, identification of prognostic biomarkers and possible therapeutic targets is essential. Besides their function in cell-cell adhesion, desmogleins may play a role in tumour progression and invasion that has not been investigated in PDAC to date. This study evaluated desmoglein expression as a biomarker in PDAC.MethodsUsing immunohistochemistry, we examined desmoglein 1 (DSG1), desmoglein 2 (DSG2) and desmoglein 3 (DSG3) expression in the tumour tissue of 165 resected PDAC cases. Expression levels were correlated to the patients' clinicopathological parameters and postoperative survival times. We confirmed these results in two independent gene expression data sets.ResultsA total of 36% of the tumours showed high DSG3 expression that correlated significantly with shorter patient survival (P=0.011) and poor tumour differentiation (P<0.001), whereas no such association was detected for DSG1 or DSG2. In RNA-Seq data and in microarray expression data, high DSG3 expression correlated significantly with poor survival (P=0.000356 and P=0.00499).ConclusionsWe identify DSG3 as a negative prognostic biomarker in resected PDAC, as high DSG3 expression is associated with poor overall survival and poor tumour-specific survival. These findings suggest DSG3 and its downstream signalling pathways as possible therapeutic targets in DSG3-expressing PDAC.
| S-EPMC4815888 | biostudies-literature
Project description:BackgroundProgrammed cell death protein 1 (PD-1) is a key immune checkpoint that regulates peripheral tolerance and protects against autoimmunity. Programmed death ligand-2 (PD-L2) is a less studied ligand to PD-1 and has yet to be fully explored, especially in pancreatic ductal adenocarcinoma (PDAC).MethodsIn this study, we performed immunohistochemistry to detect the PD-L2, CD3, CD8, transforming growth factor-β2 (TGF-β2) and FOXP3 levels in paraffin sections from 305 patients with resected PDAC as a training set. Expression levels of intratumoral and stromal immune markers were compared in relation to survival using Kaplan-Meier curves, random survival forest model and survival tree analysis. A multivariable Cox proportional-hazards model of associated markers was used to calculate the risk scores.ResultsPD-L2 was expressed in 71.5% of PDAC samples and showed strong correlations with CD3+, CD8+ T cells and FOXP3+ regulatory T cell densities. High levels of intratumoral PD-L2 and FOXP3 were related to poor survival; only stromal FOXP3 overexpression was associated with worse prognosis. Four patterns generated from survival tree analysis demonstrated that PD-L2lowstromalFOXP3low patients had the longest survival, while PD-L2highintratumoralCD3low patients had the shortest survival (P < 0.001). The area under the curve was 0.631(95% confidence interval (CI): 0.447-0.826) for the immune marker-based signature and 0.549 (95% CI: 0.323-0.829; P < 0.001) for the clinical parameter-based signature, which was consistent with the results in the validation set including 150 patients (P < 0.001). A higher risk score indicated shorter survival and could serve as an independent prognostic factor. PD-L2 was also showed associated with TGF-β2 and other immune molecules based on bioinformatics analysis.ConclusionsOur work highlighted PD-L2 as a promising immunotherapeutic target with prognostic value combined with complex tumor infiltrating cells in PDAC.
| S-EPMC6716876 | biostudies-literature
Project description:BackgroundRNA-sequencing-based classifiers can stratify pancreatic ductal adenocarcinoma (PDAC) into prognostically significant subgroups but are not practical for use in clinical workflows. Here, we assess whether histomorphological features may be used as surrogate markers for predicting molecular subgroup and overall survival in PDAC.MethodsNinety-six tissue samples from 50 patients with non-resectable PDAC were scored for gland formation, stromal maturity, mucin, necrosis, and neutrophil infiltration. Prognostic PDAC gene expression classifiers were run on all tumors using whole transcriptome sequencing data from the POG trial (NCT02155621). Findings were validated using digital TCGA slides (n = 50). Survival analysis used multivariate Cox proportional-hazards tests and log-rank tests.ResultsThe combination of low gland formation and low neutrophil infiltration was significantly associated with the poor prognosis PDAC molecular subgroup (basal-like or squamous) and was an independent predictor of shorter overall survival, in both frozen section (n = 47) and formalin-fixed paraffin-embedded (n = 49) tissue samples from POG patients, and in the TCGA samples. This finding held true in the subgroup analysis of primary (n = 17) and metastatic samples (n = 79). The combination of high gland formation and high neutrophils had low sensitivity but high specificity for favorable prognosis subgroups.ConclusionsThe assessment of gland formation and neutrophil infiltration on routine histological sections can aid in prognostication and allow inferences to be made about molecular subtype, which may help guide patient management decisions and contribute to our understanding of heterogeneity in treatment response.
| S-EPMC7897949 | biostudies-literature
Project description:BackgroundPancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignancies and is not a clinically homogeneous disease, but subsets of patients with distinct prognosis and response to therapy can be identified by genome-wide analyses. Mutations in major PDAC driver genes were associated with poor survival. By bioinformatics analysis, we identified protocadherins among the most frequently mutated genes in PDAC suggesting an important role of these genes in the biology of this tumor. Promoter methylation of protocadherins has been suggested as a prognostic marker in different tumors, but in PDAC this epigenetic modification has not been extensively studied. Thus, we evaluated whether promoter methylation of three frequently mutated protocadherins, PCDHAC2, PCDHGC5 and PCDH10 could be used as survival predictors in PDAC patients.MethodsDNA extracted from 23 PDACs and adjacent non-neoplastic pancreatic tissues were bisulfite treated. Combined Bisulfite Restriction Analysis (COBRA) coupled to denaturing high-performance liquid chromatography (dHPLC) detection and bisulfite genomic sequencing (BGS) were used to determine the presence of methylated CpG dinucleotides in the promoter amplicons analyzed.ResultsIn an exploratory analysis, two protocadherins showed the same pattern of CpG methylation in PDAC and adjacent non-neoplastic pancreatic tissues: lack of methylation for PCDHAC2, complete methylation for PCDHGC5. Conversely, the third protocadherin analyzed, PCDH10, showed a variable degree of CpG methylation in PDAC and absence of methylation in adjacent non-neoplastic pancreatic tissues. At Kaplan-Meier analysis, high levels of PCDH10 methylation defined according to the receiver operating characteristic (ROC) curve analysis were significantly associated with worse progression-free survival (PFS) rates (P = 0.008), but not with overall survival (OS). High levels of PCDH10 methylation were a prognostic factor influencing PFS (HR = 4.0: 95% CI, 1.3-12.3; P = 0.016), but not the OS.ConclusionsIn this study, we show for the first time that the methylation status of PCDH10 can predict prognosis in PDAC patients with a significant impact on the outcome in terms of progression-free survival. High levels of PCDH10 promoter methylation could be useful to identify patients at high risk of disease progression, contributing to a more accurate stratification of PDAC patients for personalized clinical management.
| S-EPMC6518703 | biostudies-literature
Project description:The aim of this study was to investigate the role of tumor-associated neutrophils (TANs) in the metastasis of pancreatic ductal adenocarcinoma (PDAC), to explore the regulation of TANs, and to determine the mechanisms governing the metastasis of PDAC. The correlation between neutrophils and the patient's clinical pathological data was first evaluated. Then, the effects of neutrophils on the invasion of PDAC were analyzed using a combination of conditioned media, direct and indirect coculture of human peripheral blood neutrophils, and PDAC cell lines (Panc-1, MiaPaCa-2 and AsPC-1). The cytokines secreted by neutrophils were detected through ELISA. TAN density was significantly correlated with poor metastasis-free survival (P < .05). Through coculture, it was found that the effect of neutrophils on pancreatic cancer cells was dependent on concentration, and a high concentration of neutrophils showed a lethal effect, while a low concentration of neutrophils primarily promoted the migration ability of cancer cells. The results of the wound-healing assay, the Transwell invasion assay, and laser confocal microscopy confirmed the promoting effect and indicated that the effect of neutrophils toward cancer cells may function indirectly by releasing a series of cytokines. The results of ELISA show that this effect may be achieved through the secretion of a large amount of TNF-α and TGF-β1 by neutrophils. Our study indicated that neutrophils may increase the metastasis of PDAC by releasing a series of cell cytokines, such as TNF-α and TGF-β1.
| S-EPMC7583704 | biostudies-literature
Project description:ObjectiveTo improve prediction, the AJCC staging system was revised to be consistent with upfront surgery (UFS) and neoadjuvant therapy (NAT) for PDAC.BackgroundThe AJCC staging system was designed for patients who have had UFS for PDAC, and it has limited predictive power for patients receiving NAT.MethodsWe examined 146 PDAC patients who had resection after NAT and 1771 who had UFS at Changhai Hospital between 2012 and 2021. The clinicopathological factors were identified using Cox proportional regression analysis, and the Neoadjuvant Therapy Compatible Prognostic (NATCP) staging was developed based on these variables. Validation was carried out in the prospective NAT cohort and the SEER database. The staging approach was compared to the AJCC staging system regarding predictive accuracy.ResultsThe NAT cohort's multivariate analysis showed that tumor differentiation and the number of positive lymph nodes independently predicted OS. The NATCP staging simplified the AJCC stages, added tumor differentiation, and restaged the disease based on the Kaplan-Meier curve survival differences. The median OS for NATCP stages IA, IB, II, and III was 31.7 months, 25.0 months, and 15.8 months in the NAT cohort and 30.1 months, 22.8 months, 18.3 months, and 14.1 months in the UFS cohort. Compared to the AJCC staging method, the NATCP staging system performed better and was verified in the validation cohort.ConclusionsRegardless of the use of NAT, NATCP staging demonstrated greater predictive abilities than the existing AJCC staging approach for resected PDAC and may facilitate clinical decision-making based on accurate prediction of patients' OS.
| S-EPMC10463422 | biostudies-literature