Epigenetic modification in radiotherapy and immunotherapy for cancers.

Radiotherapy (RT) is one of the primary treatment modalities in managing cancer patients. Recently, combined RT and immunotherapy (IT) (i.e., radio-IT [RIT]) have been aggressively investigated in managing cancer patients. However, several issues in conducting RIT are challenging, such as incorporating advanced irradiation techniques, predictive/prognostic biomarkers, and other treatment modalities. Several clinical efforts and novel biomarkers have been introduced and developed to solve these challenges. For example, stereotactic radiosurgery/stereotactic radiotherapy, stereotactic body radiotherapy/stereotactic ablative body radiotherapy, and FLASH-RT have been applied for delivering precise irradiation to lung and liver tumors in conjunction with IT. Besides, several novel IT agents and incorporations of other therapies, such as targeted and thermal therapies, have been further investigated. The present study reviewed the emerging challenges of RIT in modern oncology. We also evaluated clinical practice, bench research, and multimodality treatments. In addition to several clinically applicable biomarkers, we emphasize the roles of advanced irradiation techniques and epigenetic modification as predictive/prognostic biomarkers and potential therapeutic targets. For example, 6(m) A-based epigenetic agents demonstrate the potential to enhance the treatment effects of RIT. However, further prospective randomized trials should be conducted to confirm their roles.

Association of spironolactone use with risk of urinary tract cancer in the general population: A matched population-based cohort study.

PURPOSE: The correlation between spironolactone usage and cancer risk has sparked interest. The objective of this study is to examine the association between spironolactone use and the incidence of urinary tract cancer in the general population. METHODS: We conducted a matched population-based cohort study. The study population was obtained from the Taiwan National Health Insurance Research Database (TNHIRD) during the period from 2000 to 2016. The multivariate Cox proportional hazard model was performed to examine the impact of spironolactone use on the risk of urinary tract cancer. A total of 8,608 individuals exposed to spironolactone were exact matched by 1:1 ratio with unexposed controls on factors including age, gender, comorbidities, CCI scores and socioeconomic status. The incidences of urinary tract cancer, including prostate, renal and bladder cancer, were estimated in both spironolactone exposed and non-exposed cohorts. RESULTS: After adjusting for confounding variables, the multivariate Cox regression analysis showed no significant association between spironolactone exposure and urinary tract cancer incidence, including bladder (adjusted hazard ratio [aHR] = 1.19, 95% confidence interval [CI] = 0.72-1.96, p = 0.50), renal (aHR = 1.75, 95% CI = 0.99-3.07, p = 0.053), and prostate cancer (aHR = 0.67, 95% CI = 0.43-1.04, p = 0.07). When the population was stratified into low (cumulative dose < = 29,300 mg) and high (cumulative dose >29,300 mg) dose of spironolactone, only high dose of spironolactone use was significantly associated with a reduced risk of prostate cancer (aHR = 0.45, 95% CI = 0.23-0.89, p = 0.02), while being associated with an elevated risk of renal cancer (aHR = 2.09, 95% CI = 1.07-4.08, p = 0.03). However, no clear cumulative dose-response relationship was observed in theses associations. CONCLUSIONS: High cumulative dose of spironolactone may be potentially associated with a decreased incidence of prostate cancer and an increased incidence of renal cancer, while no significant association was observed with bladder cancer incidence. However, given the lack of support from the dose-response pattern, the available evidence is inconclusive to establish a definitive association between spironolactone use and urinary tract cancer.

Molecular subtypes of breast cancer predicting clinical benefits of radiotherapy after breast-conserving surgery: a propensity-score-matched cohort study.

BACKGROUND: Based on the molecular expression of cancer cells, molecular subtypes of breast cancer have been applied to classify patients for predicting clinical outcomes and prognosis. However, further evidence is needed regarding the influence of molecular subtypes on the efficacy of radiotherapy (RT) after breast-conserving surgery (BCS), particularly in a population-based context. Hence, the present study employed a propensity-score-matched cohort design to investigate the potential role of molecular subtypes in stratifying patient outcomes for post-BCS RT and to identify the specific clinical benefits that may emerge. METHODS: From 2006 to 2019, the present study included 59,502 breast cancer patients who underwent BCS from the Taiwan National Health Insurance Research Database. Propensity scores were utilized to match confounding variables between patients with and without RT within each subtype of breast cancer, namely luminal A, luminal B/HER2-negative, luminal B/HER2-positive, basal-like, and HER2-enriched ones. Several clinical outcomes were assessed, in terms of local recurrence (LR), regional recurrence (RR), distant metastasis (DM), disease-free survival (DFS), and overall survival (OS). RESULTS: After post-BCS RT, patients with luminal A and luminal B/HER2-positive breast cancers exhibited a decrease in LR (adjusted hazard ratio [aHR] = 0.18, p < 0.0001; and, 0.24, p = 0.0049, respectively). Furthermore, reduced RR and improved DFS were observed in patients with luminal A (aHR = 0.15, p = 0.0004; and 0.29, p < 0.0001), luminal B/HER2-negative (aHR = 0.06, p = 0.0093; and, 0.46, p = 0.028), and luminal B/HER2-positive (aHR = 0.14, p = 0.01; and, 0.38, p < 0.0001) breast cancers. Notably, OS benefits were found in patients with luminal A (aHR = 0.62, p = 0.002), luminal B/HER2-negative (aHR = 0.30, p < 0.0001), basal-like (aHR = 0.40, p < 0.0001), and HER2-enriched (aHR = 0.50, p = 0.03), but not luminal B/HER2-positive diseases. Remarkably, when considering DM, luminal A patients who received RT demonstrated a lower cumulative incidence of DM than those without RT (p = 0.02). CONCLUSION: In patients with luminal A breast cancer who undergo BCS, RT could decrease the likelihood of tumor metastasis. After RT, the tumor's hormone receptor status may predict tumor control regarding LR, RR, and DFS. Besides, the HER2 status of luminal breast cancer patients may serve as an additional predictor of OS after post-BCS RT. However, further prospective studies are required to validate these findings.

Hazard-based risk grouping effectively stratifying breast cancer patients in post-irradiation long-term heart diseases: a population-based cohort study.

Background: Even though advanced radiotherapy techniques provide a better protective effect on surrounding normal tissues, the late sequelae from radiation exposure to the heart are still considerable in breast cancer patients. The present population-based study explored the role of cox-regression-based hazard risk grouping and intended to stratify patients with post-irradiation long-term heart diseases. Materials and methods: The present study investigated the Taiwan National Health Insurance (TNHI) database. From 2000 to 2017, we identified 158,798 breast cancer patients. Using a propensity score match of 1:1, we included 21,123 patients in each left and right breast irradiation cohort. Heart diseases, including heart failure (HF), ischemic heart disease (IHD), and other heart diseases (OHD), and anticancer agents, including epirubicin, doxorubicin, and trastuzumab, were included for analysis. Results: Patients received left breast irradiation demonstrated increased risks on IHD (aHR, 1.16; 95% CI, 1.06-1.26; p < 0.01) and OHD (aHR, 1.08; 95% CI, 1.01-1.15; p < 0.05), but not HF (aHR, 1.11; 95% CI, 0.96-1.28; p = 0.14), when compared with patients received right breast irradiation. In patients who received left breast irradiation dose of >6,040 cGy, subsequent epirubicin might have a trend to increase the risk of heart failure (aHR, 1.53; 95% CI, 0.98-2.39; p = 0.058), while doxorubicin (aHR, 0.59; 95% CI, 0.26-1.32; p = 0.19) and trastuzumab (aHR, 0.93; 95% CI, 0.33-2.62; p = 0.89) did not. Older age was the highest independent risk factor for post-irradiation long-term heart diseases. Conclusion: Generally, systemic anticancer agents are safe in conjunction with radiotherapy for managing post-operative breast cancer patients. Hazard-based risk grouping may help stratify breast cancer patients associated with post-irradiation long-term heart diseases. Notably, radiotherapy should be performed cautiously for elderly left breast cancer patients who received epirubicin. Limited irradiation dose to the heart should be critically considered. Regular monitoring of potential signs of heart failure may be conducted.

IRAK2, an Immune and Radiation-Response Gene, Correlates with Advanced Disease Features but Predicts Higher Post-Irradiation Local Control in Non-Metastatic and Resected Oral Cancer Patients.

Gene Ontology (GO) analysis can provide a comprehensive function analysis for investigating genes, allowing us to identify the potential biological roles of genes. The present study conducted GO analysis to explore the biological function of IRAK2 and performed a case analysis to define its clinical role in disease progression and mediating tumor response to RT. Methods: We performed a GO enrichment analysis on the RNA-seq data to validate radiation-induced gene expression. A total of 172 I-IVB specimens from oral squamous cell carcinoma patients were collected for clinical analysis, from which IRAK2 expression was analyzed by immunohistochemistry. This was a retrospective study conducted between IRAK2 expression and the outcomes of oral squamous cell carcinoma patients after radiotherapy treatment. We conducted Gene Ontology (GO) analysis to explore the biological function of IRAK2 and performed a case analysis to define its clinical role in mediating tumor response to radiotherapy. GO enrichment analysis to validate radiation-induced gene expression was performed. Clinically, 172 stage I-IVB resected oral cancer patients were used to validate IRAK2 expression in predicting clinical outcomes. GO enrichment analysis showed that IRAK2 is involved in 10 of the 14 most enriched GO categories for post-irradiation biological processes, focusing on stress response and immune modulation. Clinically, high IRAK2 expression was correlated with adverse disease features, including pT3-4 status (p = 0.01), advanced overall stage (p = 0.02), and positive bone invasion (p = 0.01). In patients who underwent radiotherapy, the IRAK2-high group was associated with reduced post-irradiation local recurrence (p = 0.025) compared to the IRAK2-low group. IRAK2 plays a crucial role in the radiation-induced response. Patients with high IRAK2 expression demonstrated more advanced disease features but predicted higher post-irradiation local control in a clinical setting. These findings support IRAK2 as a potential predictive biomarker for radiotherapy response in non-metastatic and resected oral cancer patients.

Impact of preeclampsia/eclampsia on hemorrhagic and ischemic stroke risk: A 17 years follow-up nationwide cohort study.

BACKGROUND AND PURPOSES: The long-term risk of stroke in women with preeclampsia/eclampsia is a concerning issue. In this study we further investigated different stroke subtypes and differentiated follow-up time intervals. METHODS: Between 2000 and 2017, 1,384,427 pregnant women were registered in the National Health Insurance Research Database in Taiwan. After excluding women with previous stroke history and exact matching with all confounders, 6,053 women with preeclampsia/eclampsia and 24,212 controls were included in the analysis sample. RESULTS: Over the 17-year follow-up, the adjusted hazard ratio (aHR) for stroke in women with preeclampsia/eclampsia was 2.05 (95% confidence interval, CI = 1.67-2.52, p<0.001). The 17 years overall aHR of both ischemic and hemorrhagic stroke were 1.98 and 3.45, respectively (p<0.001). The stroke subtypes, hemorrhagic and ischemic, had different time trend risks, and hemorrhagic stroke risks kept higher than that of ischemic stroke. The aHR of ischemic stroke reached a peak during 1-3 years after childbirth (aHR = 3.09). The aHR of hemorrhagic stroke reached a peak during 3-5 years (aHR = 7.49). CONCLUSIONS: Stroke risk persisted even after decades, for both ischemic and hemorrhagic subtypes. Women with preeclampsia/eclampsia history should be aware of the long-term risk of stroke.

Impact of Hypertensive Disorders of Pregnancy on the Risk of Stroke Stratified by Subtypes and Follow-Up Time.

BACKGROUND AND PURPOSE: Hypertensive disorders of pregnancy (HDP) comprise 4 subtypes. Previous studies have not investigated the relationship between stroke risk, different HDP subtypes, and follow-up time, which was the purpose of this study. METHODS: Data of 17 588 women aged 18 to 45 years who had a history of HDP in Taiwan from 2000 to 2017 was retrospectively reviewed. After matching with confounders, 13 617 HDP women and 54 468 non-HDP women were recruited. RESULTS: HDP women had an adjusted hazard ratio (aHR) of 1.71 (95% CI, 1.46-2.00) for stroke, and 1.60 (1.35-1.89) and 2.98 (2.13-4.18) for ischemic and hemorrhagic stroke, respectively (P<0.001 for all). The overall stroke risk in the HDP group was still 2.04 times 10 to 15 years after childbirth (1.47-2.83, P<0.001). Although the risks of both ischemic and hemorrhagic stroke persisted, their risk time trends were different. The risk of ischemic stroke reached peak during 1 to 3 years after childbirth with an aHR of 2.14 (1.36-3.38), while hemorrhagic stroke risk gradually increased and had an aHR of 4.64 (2.47-8.73) after 10 to 15 years of childbirth (both P<0.001). Among the 4 HDP subtypes, chronic hypertension with superimposed preeclampsia had the highest stroke risk (aHR=3.86, 1.91-7.82, P<0.001), followed by preeclampsia-eclampsia (aHR=2.00, 1.63-2.45, P<0.001), and gestational hypertension (aHR=1.68, 1.13-2.52, P<0.05); chronic preexisting hypertension had the lowest stroke risk (aHR=1.27, 0.97-1.68, P>0.05). Furthermore, multiple HDP combined with preeclampsia had aHR of 5.48 (1.14-26.42, P<0.05). CONCLUSIONS: The effect of HDP on the risk of future stroke persisted for up to 17 years, both for ischemic and hemorrhagic strokes. The presence of multiple HDP and preeclampsia further increase the stroke risk.

IRAK2, an IL1R/TLR Immune Mediator, Enhances Radiosensitivity via Modulating Caspase 8/3-Mediated Apoptosis in Oral Squamous Cell Carcinoma.

Predicting and overcoming radioresistance are crucial in radiation oncology, including in managing oral squamous cell carcinoma (OSCC). First, we used RNA-sequence to compare expression profiles of parent OML1 and radioresistant OML1-R OSCC cells in order to select candidate genes responsible for radiation sensitivity. We identified IRAK2, a key immune mediator of the IL-1R/TLR signaling, as a potential target in investigating radiosensitivity. In four OSCC cell lines, we observed that intrinsically low IRAK2 expression demonstrated a radioresistant phenotype (i.e., OML1-R and SCC4), and vice versa (i.e., OML1 and SCC25). Next, we overexpressed IRAK2 in low IRAK2-expression OSCC cells and knocked it down in high IRAK2-expression cells to examine changes of irradiation response. After ionizing radiation (IR) exposure, IRAK2 overexpression enhanced the radiosensitivity of radioresistant cells and synergistically suppressed OSCC cell growth both in vitro and in vivo, and vice versa. We found that IRAK2 overexpression restored and enhanced radiosensitivity by enhancing IR-induced cell killing via caspase-8/3-dependent apoptosis. OSCC patients with high IRAK2 expression had better post-irradiation local control than those with low expression (i.e., 87.4% vs. 60.0% at five years, P = 0.055), showing that IRAK2 expression was associated with post-radiation recurrence. Multivariate analysis confirmed high IRAK2 expression as an independent predictor for local control (HR, 0.11; 95% CI, 0.016 - 0.760; P = 0.025). In conclusion, IRAK2 enhances radiosensitivity, via modulating caspase 8/3-medicated apoptosis, potentially playing double roles as a predictive biomarker and a novel therapeutic target in OSCC.

Interleukin-17F expression is elevated in hepatitis C patients with fibrosis and hepatocellular carcinoma.

BACKGROUND: The role of interleukin (IL) 17A in chronic liver diseases had been extensively studied, but the function of IL-17F, which shares a high degree of homology with IL-17A, in the progression of chronic hepatic diseases is poorly understood. The aim of the study was to evaluate the association between IL-17F and liver diseases including, fibrosis and hepatocellular carcinoma (HCC). METHODS: Hepatic tumor samples from both hepatitis C virus (HCV) positive and negative patients (without HBV and HCV, NBNC) were examined with quantitative PCR and immunohistochemistry staining for inflammatory cytokine genes expression. In addition, 250 HCV patients naïve for interferon treatment were also subjected to enzyme-linked immunosorbent Assay (ELISA) for their serum cytokine concentrations. RESULTS: Serum IL-17F concentrations were significantly elevated in HCV patients with severe fibrosis stages. In accordance with serum data, IL-17F expression was also found higher in HCV-associated HCC tissues compared with NBNC HCC tissues at both the mRNA and protein levels. CONCLUSIONS: Our data suggest that IL-17F might be used as a valuable biological marker than IL-17A during chronic fibrosis progression and HCC development in HCV patients.