Telomere-related prognostic biomarkers for survival assessments in pancreatic cancer.

Human telomeres are linked to genetic instability and a higher risk of developing cancer. Therefore, to improve the dismal prognosis of pancreatic cancer patients, a thorough investigation of the association between telomere-related genes and pancreatic cancer is required. Combat from the R package "SVA" was performed to correct the batch effects between the TCGA-PAAD and GTEx datasets. After differentially expressed genes (DEGs) were assessed, we constructed a prognostic risk model through univariate Cox regression, LASSO-Cox regression, and multivariate Cox regression analysis. Data from the ICGC, GSE62452, GSE71729, and GSE78229 cohorts were used as test cohorts for validating the prognostic signature. The major impact of the signature on the tumor microenvironment and its response to immune checkpoint drugs was also evaluated. Finally, PAAD tissue microarrays were fabricated and immunohistochemistry was performed to explore the expression of this signature in clinical samples. After calculating 502 telomere-associated DEGs, we constructed a three-gene prognostic signature (DSG2, LDHA, and RACGAP1) that can be effectively applied to the prognostic classification of pancreatic cancer patients in multiple datasets, including TCGA, ICGC, GSE62452, GSE71729, and GSE78229 cohorts. In addition, we have screened a variety of tumor-sensitive drugs targeting this signature. Finally, we also found that protein levels of DSG2, LDHA, and RACGAP1 were upregulated in pancreatic cancer tissues compared to normal tissues by immunohistochemistry analysis. We established and validated a telomere gene-related prognostic signature for pancreatic cancer and confirmed the upregulation of DSG2, LDHA, and RACGAP1 expression in clinical samples, which may provide new ideas for individualized immunotherapy.

Clinical neutrophil-associated genes as reliable predictors of hepatocellular carcinoma.

Background: Growing evidence suggests that infiltrating neutrophils are key players in hepatocellular carcinoma (HCC) tumor progression. However, a comprehensive analysis of the biological roles of neutrophil infiltration and related genes in clinical outcomes and immunotherapy is lacking. Methods: HCC samples were obtained from the TCGA and GEO databases. The CIBERSORT algorithm was used to reveal the TIME landscape. Gene modules significantly associated with neutrophils were found using weighted gene co-expression network analysis (WGCNA), a "dynamic tree-cut" algorithm, and Pearson correlation analysis. Genes were screened using Cox regression analysis and LASSO and prognostic value validation was performed using Kaplan-Meier curves and receiver operating characteristic (ROC) curves. Risk scores (RS) were calculated and nomograms were constructed incorporating clinical variables. Gene set variation analysis (GSVA) was used to calculate signaling pathway activity. Immunophenoscore (IPS) was used to analyze differences in immunotherapy among samples with different risk scores. Finally, the relationship between RS and drug sensitivity was explored using the pRRophetic algorithm. Results: 10530 genes in 424 samples (50 normal samples, 374 tumor samples) were obtained from the TCGA database. Using WGCNA, the "MEbrown" gene module was most associated with neutrophils. Nine genes with prognostic value in HCC (PDLIM3, KLF2, ROR2, PGF, EFNB1, PDZD4, PLN, PCDH17, DOK5) were finally screened. Prognostic nomograms based on RS, gender, tumor grade, clinical stage, T, N, and M stages were constructed. The nomogram performed well after calibration curve validation. There is an intrinsic link between risk score and TMB and TIME. Samples with different risk scores differed in different signaling pathway activity, immunopharmaceutical treatment and chemotherapy sensitivity. Conclusion: In conclusion, a comprehensive analysis of neutrophil-related prognostic features will help in prognostic prediction and advance individualized treatment.

Development and validation of a competing risk model for second primary pancreatic ductal adenocarcinoma: A population-based study.

Background: With advances in early diagnosis and treatment, the number of cancer survivors continues to grow, and more and more cancer survivors face the threat of second primary cancer (SPM). Second primary pancreatic ductal adenocarcinoma (spPDAC) is an important subclass of SPM, but its prognostic characteristics are poorly understood. Methods: A total of 5,439 spPDAC samples and 67,262 primary pancreatic ductal adenocarcinoma (pPDAC) samples were extracted from the SEER database for this study. Survival differences between spPDAC and pPDAC samples were compared using Kaplan-Meier curves and log-rank tests. The Fine and Gray proportional subdistributed hazard method was used to analyze potential associations between clinical variables and pancreatic ductal adenocarcinoma-specific death (PDACSD) and death from other causes. After that, the clinical variables significantly related to PDACSD were screened out to construct a competing risk nomogram, which was used to evaluate the probability of the occurrence of PDACSD. The C-index was used to evaluate the discriminative ability of the model. The area under the curve (AUC) was used to verify the discrimination of the model. The calibration curve was used to verify the calibration of the model. Decision curve analysis (DCA) was used to validate the clinical utility of the model. Results: Compared with patients with spPDAC, the pPDAC sample had a better prognosis (p = 0.0017). Across all spPDAC samples, the three most common sites of first-present cancer were the prostate, breast, and digestive system. Age (p < 0.001), race (p = 0.006), interval (p = 0.016), location (p < 0.001), T stage (p = 0.003), M stage (p < 0.001), chemotherapy (p < 0.001), and radiotherapy (p = 0.006) were the clinical variables associated with PDACSD screened by multivariate competing risks analysis. The concordance index values for the training and validation sets were 0.665 (95% CI, 0.655, 0.675) and 0.666 (95% CI, 0.650, 0.682), respectively. AUC, calibration curve, and DCA indicated that the model we constructed had good discrimination, calibration, and clinical utility. Conclusions: In conclusion, we first analyzed the impact of previous cancer history on prognosis. We then constructed a competing risk model that can predict the probability of developing PDACSD in spPDAC. This model has good discriminative ability, calibration, and clinical practicability and has certain guiding value for clinical decision-making.

Irreversible Electroporation Treatment With Intraoperative Biliary Stenting for Unresectable Perihilar Cholangiocarcinoma: A Pilot Study.

BACKGROUND: Treating perihilar cholangiocarcinoma (PHCC) is particularly difficult due to the fact that it is usually in an advanced stage at the time of diagnosis. Irreversible electroporation treatment (IRE) involves the local administration of a high-voltage electric current to target lesions without causing damage to surrounding structures. This study investigated the safety and efficacy of using IRE in conjunction with intraoperative biliary stent placement in cases of unresectable PHCC. METHODS: This study enrolled 17 patients with unresectable Bismuth type III/IV PHCC who underwent IRE in conjunction with intraoperative biliary stent placement (laparotomic) in two medical centers in Asia between June 2015 and July 2018. Analysis focused on the perioperative clinical course, the efficacy of biliary decompression, and outcomes (survival). RESULTS: Mean total serum bilirubin levels (mg/dL) on postoperative day (POD) 7, POD30, and POD90 were significantly lower than before IRE (respectively 3.46 vs 4.54, p=0.007; 1.21 vs 4.54, p<0.001; 1.99 vs 4.54, p<0.001). Mean serum carbohydrate antigen 19-9 (CA19-9, U/ml) levels were significantly higher on POD3 than before the operation (518.8 vs 372.4, p=0.001) and significantly lower on POD30 and POD90 (respectively 113.7 vs 372.4, p<0.001; 63.9 vs 372.4, p<0.001). No cases of Clavien-Dindo grade III/IV adverse events or mortality occurred within 90 days post-op. The median progression-free survival was 21.5 months, and the median overall survival was 27.9 months. All individuals who survived for at least one year did so without the need to carry percutaneous biliary drainage (PTBD) tubes. CONCLUSIONS: It appears that IRE treatment in conjunction with intraoperative biliary stent placement is a safe and effective approach to treating unresectable PHCC. The decompression of biliary obstruction without the need for PTBD tubes is also expected to improve the quality of life of patients.