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Background: Concurrent chemoradiotherapy (CCRT) is suggested before resection surgery in the control of rectal cancer. Unfortunately, treatment outcomes are widely variable and highly patient-specific. Notably, rectal cancer patients with distant metastasis generally have a much lower survival rate. Accordingly, a better understanding of the genetic background of patient cohorts can aid in predicting CCRT efficacy and clinical outcomes for rectal cancer before distant metastasis., Methods: A published transcriptome dataset (GSE35452) (n=46) was utilized to distinguish prospective genes concerning the response to CCRT. We recruited 172 rectal cancer patients, and the samples were collected during surgical resection after CCRT. Immunohistochemical (IHC) staining was performed to evaluate the expression level of regenerating family member 3 alpha (REG3A). Pearson's chi-squared test appraised the relevance of REG3A protein expression to clinicopathological parameters. The Kaplan-Meier method was utilized to generate survival curves, and the log-rank test was performed to compare the survival distributions between two given groups., Results: Employing a transcriptome dataset (GSE35452) and focusing on the inflammatory response (GO: 0006954), we recognized that REG3A is the most significantly upregulated gene among CCRT nonresponders (log2 ratio=1.2472, p=0.0079). Following IHC validation, high immunoexpression of REG3A was considerably linked to advanced post-CCRT tumor status (p<0.001), post-CCRT lymph node metastasis (p=0.042), vascular invasion (p=0.028), and low-grade tumor regression (p=0.009). In the multivariate analysis, high immunoexpression of REG3A was independently correlated with poor disease-specific survival (DSS) (p=0.004) and metastasis-free survival (MeFS) (p=0.045). The results of the bioinformatic analysis also supported the idea that REG3A overexpression is implicated in rectal carcinogenesis., Conclusion: In the current study, we demonstrated that REG3A overexpression is correlated with poor CCRT effectiveness and inferior patient survival in rectal cancer. The predictive and prognostic utility of REG3A expression may direct patient stratification and decision-making more accurately for those patients., (©The Author(s) 2024. Open Access. This article is licensed under a Creative Commons CC-BY International License.)

Objective: To reduce the risk of locoregional recurrence, the addition of neoadjuvant concurrent chemoradiotherapy (CCRT) is recommended before surgical management for rectal cancer patients. However, despite identical tumor histology, individual patient response to neoadjuvant CCRT varies greatly. Accordingly, a comprehensive molecular characterization that is used to predict CCRT efficacy is instantly needed. Methods: Pearson's chi-squared test was utilized to correlate dehydrogenase/reductase 9 (DHRS9) expression with clinicopathological features. Survival curves were created applying the Kaplan-Meier method, and the log-rank test was conducted to compare prognostic utility between high and low DHRS9 expression groups. Multivariate Cox proportional hazards regression analysis was applied to identify independent prognostic biomarkers based on variables with prognostic utility at the univariate level. Results: Utilizing a public transcriptome dataset, we identified that the DHRS9 gene is the most considerably upregulated gene related to epithelial cell differentiation (GO: 0030855) among rectal cancer patients with CCRT resistance. Employing immunohistochemical staining, we also demonstrated that high DHRS9 immunoexpression is considerably associated with an aggressive clinical course and CCRT resistance in our rectal cancer cohort. Among all variables with prognostic utility at the univariate level, only high DHRS9 immunoexpression was independently unfavorably prognostic of all three endpoints (all p ≤ 0.048) in the multivariate analysis. In addition, applying bioinformatic analysis, we also linked DHRS9 with unrevealed functions, such as keratan sulfate and mucin synthesis which may be implicated in CCRT resistance. Conclusion: Altogether, DHRS9 expression may serve as a helpful predictive and prognostic biomarker and assist decision-making for rectal cancer patients who underwent neoadjuvant CCRT., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Chen, Hsu, Lee, Yang, Tian, Kuo, Li, Tsai, Wu, Yeh, Chou and Lai.)

Objective: Neoadjuvant concurrent chemoradiotherapy (CCRT) followed by surgery is now the standard care for patients with advanced rectal cancer. Because a certain proportion of these patients have poor response to CCRT, the risk stratification of survival outcomes needs to be investigated. DNA repair responses in tumor cells can regulate malignant potential and therapy resistance. In this study, we analyzed the clinical significance of principal DNA repair effectors in patients with rectal cancer., Methods: We applied data mining for DNA repair pathways in a published transcriptome for rectal cancer cases, and identified that tumors with BRCA2 downregulation correlated with poor response to CCRT. We next examined BRCA2 expression by using immunohistochemistry staining in tumor tissues of 172 patients with rectal cancer. The correlation between BRCA2 expression levels and clinical variables was further analyzed in this rectal cancer cohort., Results: Among clinical and pathological factors, low BRCA2-expression was significantly correlated with higher pre-treatment (Tx) tumor status (P = .013), post-Tx tumor (P < .001) and nodal status (P = .044), vascular invasion (P = .008), and poor tumor regression grades (P < .001). In analyses of survival outcomes, patients with low BRCA2-expression were associated with shorter local recurrence-free survival (LRFS; P = .0005) and disease-specific survival (P = .0269). Multivariate analyses confirmed the independent prognostic value of low BRCA2-expression for shorter LRFS (P = .045, hazard ratio = 4.695)., Conclusion: Low BRCA2-expression is a significant predictor for tumors in advanced stages, poor response to CCRT, and shorter survivals in patients with rectal cancer. Poly (adenosine diphosphate-ribose) polymerase inhibitors targeting DNA repair response in cells have demonstrated clinical efficacy in BRCA2-mutated patients with cancer. Further studies evaluating the efficacy of CCRT combined with these inhibitors in low BRCA2-expressing rectal cancers are encouraged., Competing Interests: Declaration of Competing Interest The authors indicate that they have no potential conflicts of interest., (Copyright © 2020. Published by Elsevier GmbH.)

Background/aim: Pyrimethamine (PYR), an anti-malarial drug is known to inhibit various types of human cancer cells. The aim of this study was to investigate the anti-tumour effects of pyrimethamine (PYR) and its underlying molecular mechanisms using the human NSCLC cell line A549., Materials and Methods: PYR was dissolved in dimethyl sulfoxide to determine its apoptotic activity on A549 cells. Cell viability was determined by the MTT assay. Cell cycle, mitochondrial membrane potential, and Annexin V-FITC early apoptosis detection were evaluated by flow cytometry. Cyclin-dependent kinase (CDK) and Bcl-2 family protein expression was determined by western blotting., Results: PYR reduced cell viability percentage and induced G 0 /G 1 arrest, which was associated with down-regulation of cyclins D1 and E, CDK4, and CDK2, and up-regulation of p21. PYR induced sub-G 1 accumulation, Annexin-V binding, caspase-9 and -3 activation, poly (ADPribose) polymerase cleavage, and mitochondrial dysfunction in A549 cells. Moreover, PYR effectively inhibited NSCLC tumour growth in an A549 xenograft model., Conclusion: PYR demonstrated anti-tumour effects on NSCLC in vitro and in vivo, indicating its therapeutic potential against human NSCLC., (Copyright© 2018, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Importance: Concurrent chemoradiotherapy delivers a high level of tumor control and survival benefits for patients with nasopharyngeal carcinoma (NPC). However, many uncertainties still exist regarding the outcomes of chemoradiotherapy, making a more precise survival prognostic system necessary., Objective: To introduce a new staging system that combines tumor and clinical characteristics to improve the accuracy of prognosis for patients with NPC., Design, Setting, and Participants: This cohort study enrolled 207 patients with newly diagnosed NPC who underwent concurrent chemoradiotherapy between January 1, 2007, and December 31, 2014, at Chi-Mei Medical Center in Tainan, Taiwan. Data on these patients were collected from the cancer registry database of the Chi-Mei Medical Center. Patients who had a history of cancer or were unable to complete a full course of radiotherapy were excluded. Follow-up was completed on September 30, 2016, and the data analysis was performed from January 1, 2017, to February 28, 2017., Main Outcomes and Measures: The risk factors associated with 5-year disease-specific survival were incorporated into the American Joint Committee on Cancer (AJCC) and the International Union Against Cancer TNM staging system to construct a new prognostic staging system. The χ2 test for linear trend, the Akaike information criterion, and the C statistic were used to evaluate the monotonicity and discriminatory ability of the new prognostic staging system and the AJCC TNM staging system., Results: Of the 207 patients enrolled in the study, 157 (75.8%) were men, and the mean (SD) age was 48 (11) years. Multivariate analysis identified advanced clinical T stage (adjusted hazard ratio [aHR], 3.20; 95% CI, 1.58-6.48), poor performance status (aHR, 2.62; 95% CI, 1.30-5.28), and cumulative cisplatin dose lower than 100 mg/m2 (aHR, 2.28; 95% CI, 1.10-4.74) as independent prognostic factors. The β coefficients from the Cox proportional hazards regression model were used to develop an integer-based, weighted point system; advanced clinical T stage, poor performance, and cumulative cisplatin dose lower than 100 mg/m2 were each assigned a score of 1. The sum of these risk scores was stratified into new stage I (score of 0), new stage II (score of 1), new stage III (score of 2), and new stage IV (score of 3). Compared with the AJCC TNM staging system, the new prognostic staging category had better monotonicity with a higher χ2 value (17.8 vs 25.6) for linear trend, better discriminatory ability with a smaller Akaike information criterion (367 vs 360), and a greater C statistic (0.702 vs 0.740) for 5-year disease-specific survival., Conclusions and Relevance: The new prognostic staging system has a better accuracy of prognosis of survival than the routinely used AJCC TNM staging system and thus is more useful in identifying high-risk patients for more intense treatment and care.

Importance: Inflammatory status is associated with outcome in oral squamous cell carcinoma (OSCC). Combining the preoperative neutrophil to lymphocyte ratio (NLR) and histopathologic features may provide clinicians with more exact information regarding the prognosis of OSCC., Objective: To compare the prognostic performance of the routinely used pathologic TNM staging with a new staging category that incorporates the NLR and histopathologic features., Design, Setting, and Participants: This retrospective cohort study included 396 patients with newly diagnosed OSCC who underwent major surgery at a medical center from January 1, 2006, through December 31, 2013. Follow-up was completed on October 31, 2015, and data analysis was performed from January 1, 2016, through April 30, 2016., Main Outcomes and Measures: The multivariate Cox proportional hazards regression model was used to determine the clinical or pathologic factors associated with 5-year disease-specific survival (DSS), and these factors were assigned integer points to create a new staging category. The monotonicity and discriminatory ability of the pathologic TNM staging and new staging category were evaluated with the linear trend χ2 test, Akaike information criterion, and Harrell C statistic., Results: In total, 396 patients who underwent major surgery with curative intent for OSCC with or without adjuvant therapy were included in this study (mean [SD] age, 53 [11] years; 367 men [92.7%] and 29 women [7.3%]). Perineural invasion (adjusted hazard ratio [aHR], 1.74; 95% CI, 1.23-2.46), high NLR (aHR, 1.60; 95% CI, 1.11-2.30), advanced pT (T3 + T4) classification (aHR, 1.59; 95% CI, 1.13-2.25), and advanced pN (N2) classification (aHR, 3.96; 95% CI, 2.78-5.63) were independent prognostic survival factors. The β coefficients from the Cox proportional hazards regression model were used to develop an integer-based weighted point system (perineural invasion, score of 1; NLR, score of 1; advanced pT, score of 1; and advanced pN, score of 3). The summations of these risk scores were stratified for the new staging category as follows: new stage I, score of 0; new stage II, score of 1; new stage III, score of 2 or 3; and new stage IV, score of 4 to 6. Compared with the American Joint Committee on Cancer staging category, this new staging category provided better monotonicity with a higher linear trend χ2 value (106 vs 49), better discriminatory ability with smaller Akaike information criterion (1497 vs 1533), and greater Harrell C statistic (0.73 vs 0.69) for 5-year DSS. The results remained robust after adjusting other risk factors., Conclusions and Relevance: In this study, new staging category had better DSS discriminatory ability and could help to identify high-risk patients for intense adjuvant therapy.