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Oral squamous cell carcinoma (OSCC) is a prevalent and aggressive malignancy, with metastasis being the leading cause of death in patients. Unfortunately, therapeutic options for metastatic OSCC remain limited. Peptidylarginine deiminases (PADI) are implicated in various tumorigenesis and metastasis processes across multiple cancers. However, the role of PADI2, a type of PADI, in OSCC is not well understood. This study aimed to explore the impact of PADI2 on epithelial-mesenchymal transition (EMT), angiogenesis, and OSCC metastasis. The effect of PADI2 on EMT was evaluated using cell lines by Western blot analysis with shRNA targeting PADI2. In addition, the selective PADI2 inhibitor AFM32a was used to assess the effect of PADI2 on cancer metastasis and angiogenesis in animal models. Our findings indicated that PADI2 expression correlated with EMT changes, and PADI2 knockdown reversed these changes, reducing cell proliferation, cell migration, and invasion. PADI2 inhibition also diminished tube formation in HUVECs and decreased secretion of angiogenesis-related chemokines CCL3, CCL5 and CCL20. In a mouse model, AFM32a markedly reduced lung metastasis and production of CCL3 and CCL5. Our in vitro and in vivo studies suggested inhibiting PADI2 could prevent OSCC metastasis by impeding EMT and angiogenesis via AKT/mTOR signaling pathway. These results highlight PADI2 as a potential therapeutic target for combating OSCC metastasis., (© 2024. The Author(s), under exclusive licence to Springer Nature B.V.)

Colorectal cancer (CRC) long-term survivor is a rapid enlarging group. However, the effectiveness of 23-valent pneumococcal polysaccharide vaccine (PPSV23) on this group is unknown. This nationwide population-based study in Taiwan was designed to examine the effect of PPSV23 on incidence rate ratio (IRR) of pneumonia hospitalization, cumulative incidence, and overall survival rate for these long-term CRC survivors. This cohort study was based on the Taiwan Cancer Registry and Taiwan National Health Insurance Research Database from 2000-2017. After individual exact matching to covariates with 1:1 ratio, there were a total of 1,355 vaccinated and 1,355 unvaccinated survivors. After adjusted by multivariate Poisson regression model, vaccinated group had a non-significantly lower pneumonia hospitalization risk than unvaccinated, with an adjusted IRR of 0.879 ( p  = .391). Besides, vaccinated group had both lower cumulative incidence rate and higher overall survival time than unvaccinated.

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., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Chen et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Craniospinal irradiation (CSI) poses a challenge to treatment planning due to the large target, field junction, and multiple organs at risk (OARs) involved. The aim of this study was to evaluate the performance of knowledge-based planning (KBP) in CSI by comparing original manual plans (MP), KBP RapidPlan initial plans (RP I ), and KBP RapidPlan final plans (RP F ), which received further re-optimization to meet the dose constraints., Patients and Methods: Dose distributions in the target were evaluated in terms of coverage, mean dose, conformity index (CI), and homogeneity index (HI). The dosimetric results of OARs, planning time, and monitor unit (MU) were evaluated., Results: All MP and RP F plans met the plan goals, and 89.36% of RP I plans met the plan goals. The Wilcoxon tests showed comparable target coverage, CI, and HI for the MP and RP F groups; however, worst plan quality was demonstrated in the RP I plans than in MP and RP F . For the OARs, RP F and RP I groups had better dosimetric results than the MP group ( P < 0.05 for optic nerves, eyes, parotid glands, and heart). The planning time was significantly reduced by the KBP from an average of 677.80 min in MP to 227.66 min ( P < 0.05) and 307.76 min ( P < 0.05) in RP I , and RP F , respectively. MU was not significantly different between these three groups., Conclusions: The KBP can significantly reduce planning time in CSI. Manual re-optimization after the initial KBP is recommended to enhance the plan quality., (© 2024 Wei-Ta Tsai et al., published by Sciendo.)

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., (© 2023. The Author(s).)

The dose-response effect of proton pump inhibitors on colorectal cancer prognosis is still under exploration. This population-based study in Taiwan was designed to examine the effect of proton pump inhibitors on overall death, colorectal cancer-specific death, and recurrence in colorectal cancer patients with different cumulative proton pump inhibitor dose levels. This cohort study was based on the Taiwan Cancer Registry and Taiwan National Health Insurance Research Database from 2005 to 2020. After frequency matching with a 1:1 ratio, a total of 20,889 users with proton pump inhibitors and 20,889 without proton pump inhibitors were analyzed. The cumulative defined daily dose level of proton pump inhibitor was stratified to explore the dose-response relationship. A proton pump inhibitor exposure cumulative defined daily dose > 60 after colorectal cancer diagnosis had higher risk of all-cause death than non-proton pump inhibitor users with adjusted hazard ratios of 1.10 (95% CIs: 1.04-1.18). For recurrence, a proton pump inhibitor exposure cumulative defined daily dose > 60 had reduced recurrence risk with an adjusted hazard ratio of 0.84 (95% CIs: 0.76-0.93). This study demonstrated that the long-term use of proton pump inhibitors in patients with colorectal cancer was associated with an increased risk of death that related to the proton pump inhibitor exposure cumulative defined daily dose > 60 and had different dose-response effect in various dose level.

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., 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., (© 2023 Lee, Tsai, Yang, Hung, Chiou, Liu, Chen, Chew, Yu, Hsu Wu and Lin.)

The use of ultraviolet fluorescence markers in medical simulations has become popular in recent years, especially during the COVID-19 pandemic. Healthcare workers use ultraviolet fluorescence markers to replace pathogens or secretions, and then calculate the regions of contamination. Health providers can use bioimage processing software to calculate the area and quantity of fluorescent dyes. However, traditional image processing software has its limitations and lacks real-time capabilities, making it more suitable for laboratory use than for clinical settings. In this study, mobile phones were used to measure areas contaminated during medical treatment. During the research process, a mobile phone camera was used to photograph the contaminated regions at an orthogonal angle. The fluorescence marker-contaminated area and photographed image area were proportionally related. The areas of contaminated regions can be calculated using this relationship. We used Android Studio software to write a mobile application to convert photos and recreate the true contaminated area. In this application, color photographs are converted into grayscale, and then into black and white binary photographs using binarization. After this process, the fluorescence-contaminated area is calculated easily. The results of our study showed that within a limited distance (50-100 cm) and with controlled ambient light, the error in the calculated contamination area was 6%. This study provides a low-cost, easy, and ready-to-use tool for healthcare workers to estimate the area of fluorescent dye regions during medical simulations. This tool can promote medical education and training on infectious disease preparation.

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.

We thank Li and colleagues for their insightful comments [...].

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&lt;0.001). The 17 years overall aHR of both ischemic and hemorrhagic stroke were 1.98 and 3.45, respectively (p&lt;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., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2022 Chuang et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Clarithromycin is widely used to treat various bacterial infections and has been reported to have potential cardiovascular risk. However, it is uncertain whether this association was dose dependent and confounded by indication bias in patients with stable coronary heart disease (CHD)., Methods: This cohort study retrospectively analyzed a national health insurance claims data from Taiwan's 2005 Longitudinal Generation Tracking Database. We used a new-user design and 1:1 propensity score matching. A total of 9,631 eligible clarithromycin users and 9,631 non-users in 2004-2015 were subject to final analysis. All patients were followed-up after receiving clarithromycin or on the matched corresponding date until occurrence of cardiovascular morbidity in the presence of competing mortality, all-cause and cause-specific mortality, or through the end of 2015. The effect of cumulative dose, exposure duration, and indications of clarithromycin on cardiovascular outcomes were also addressed., Results: Clarithromycin use, compared with non-use, was associated with higher risk for all-cause [adjusted hazard ratios (aHR), 1.43; 95% confidence interval, 1.29-1.58], cardiovascular (1.35; 1.09-1.67), and non-cardiovascular (1.45; 1.29-1.63) mortality, but not for overall cardiovascular morbidity. Further analysis of individual cardiovascular morbidity demonstrated major risk for heart events (1.25; 1.04-1.51) in clarithromycin users than non-users. However, there was no relationship of cumulative dose, exposure duration, and indications of clarithromycin on cardiovascular outcomes. Analyses of the effects over time showed that clarithromycin increased cardiovascular morbidity (1.21; 1.01-1.45), especially heart events (1.39; 1.10-1.45), all-cause (1.57; 1.38-1.80), cardiovascular (1.58; 1.20-2.08), and non-cardiovascular (1.57; 1.35-1.83) mortality during the first 3 years. Thereafter, clarithromycin effect on all outcomes almost dissipated., Conclusion: Clarithromycin use was associated with increased risk for short-term cardiovascular morbidity (especially, heart events) and mortality without a dose-response relationship in patients with stable CHD, which was not dose dependent and confounded by indications. Hence, patients with stable CHD while receiving clarithromycin should watch for these short-term potential risks., 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 Yu, Chen, Li, Chiou and Chen.)

Histamine-2-receptor antagonist (H2RA) has shown beneficial effects on the kidney, heart, and sepsis in animal models and on the heart and COVID-19 infection in clinical studies. However, H2RAshave been used as a reference in most epidemiological studies examining the association of proton pump inhibitors (PPI) with outcomes. Therefore, we aimed to evaluate the effect of H2RA on renal and survival outcomes in chronic kidney disease (CKD) patients. We used a Taiwanese nationalhealth insurance database from 2001 to 2016 to screen 45,767 CKD patients for eligibility. We identified new users of PPI ( n = 7121), H2RA ( n = 48,609), and users of neither PPI nor H2RA (as controls) ( n = 47,072) during follow-up, and finally created 1:1:1 propensityscore-matchedcohorts; each cohort contained 4361 patients. Participants were followed up after receivingacid-suppression agents or on the corresponding date until the occurrence of end-stage renal disease (ESRD) in the presence of competing mortality, death, or through the end of 2016. Compared toneither users, H2RAand PPI users demonstrated adjusted hazard ratios of 0.40 (95% confidence interval, 0.30-0.53) for ESRDand 0.64 (0.57-0.72) for death and 1.15 (0.91-1.45) for ESRD and 1.83 (1.65-2.03) for death, respectively. A dose-response relationship betweenH2RA use with ESRD and overall, cardiovascular, and non-cardiovascular mortality was detected. H2RA consistently provided renal and survival benefits on multivariable stratified analyses and multiple sensitivity analyses. In conclusion, dose-dependent H2RA use was associated with a reduced risk of ESRD and overall mortality in CKD patients, whereas PPI use was associated with an increased risk of overall mortality, not in a dose-dependent manner.

Objectives: Accelerator-based stereotactic radiosurgery (SRS) is a noninvasive and effective treatment modality widely used for benign brain tumors. This study aims to report 20-year treatment outcomes in our institute., Materials and Methods: From May 2001 to December 2020, 127 patients treated with LINAC-based single-fraction SRS for their benign brain lesions were included. A neurosurgeon and two radiation oncologists retrospectively reviewed all data. Computed tomography (CT) simulation was performed after head-frame fixation under local anesthesia. All planning CT images were co-registered and fused with gadolinium-enhanced magnetic resonance imaging taken within 3 months for lesions targeting and critical organs delineation. The marginal dose was prescribed at 60%-90% isodose lines, respectively, to cover ≥95% planning target volume. Outcome evaluations included clinical tumor control rate (TCR), defined as the need for salvage therapy, and radiological response, defined as no enlargement of >2 cm in the maximal diameter. Overall survival (OS) and adverse reaction (defined according to CTCAE 5.0) were also analyzed., Results: The present study included 76 female and 51 male patients for analysis. The median age was 59 years (range, 20-88 years). Their diagnoses were vestibular schwannoma (VS, n = 54), nonvestibular cranial nerve schwannoma ( n = 6), meningioma ( n = 50), and pituitary adenoma ( n = 17). Totally 136 lesions were treated in a single fraction, predominantly skull base tumors, accounting for 69.1%. Median and mean follow-up duration was 49 and 61 months (range, 1-214 months), Overall TCR was 92.9%. The 5-year disease-specific TCR for VS, nonvestibular schwannoma, meningioma, and pituitary adenoma were 97.4%, 91.7%, 93.8%, and 83.3%. Salvage therapy was indicated for eight patients at 4-110 months after SRS. Among symptomatic patients, post-SRS symptom(s) was improved, stable, and worse in 68.2%, 24.3%, and 3.6%, respectively. Radiological response rate for 111 evaluable patients was 94.6% (shrinkage, 28.8%; stable, 65.8%). OS was 96.1% without treatment-related mortality. One patient with post-SRS cranial nerve injury (0.8%, involving the trigeminal nerve, grade 2 toxicities). No grade 3-4 acute or late toxicity was found., Conclusion: Our results suggested that LINAC-based SRS effectively controls tumor growth and tumor-related neurological symptoms for patients with benign brain tumors. SRS is less aggressive, associated with low neurological morbidity and no mortality. Continuous follow-up is indicated to conclude longer outcomes., Competing Interests: There are no conflicts of interest., (Copyright: © 2022 Tzu Chi Medical Journal.)

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.

In addition to causing the nondisjunction of maize B and normal A chromosomes at the second megaspore division during embryo sac development, the r-X1 deletion results in terminal deficiencies (TDs) in various A chromosomal arms, but whether the r-X1 deletion also induces TDs of the maize B chromosome remains unknown. To answer this question, the chromosomal composition in the r-X1-containing progeny of r-X1/R-r female parents carrying two standard B chromosomes was determined. Nine of 104 (8.7%) examined kernels contained a smaller telocentric B chromosome, and one of these (designated Bdef-1) was further identified as a TD with a breakpoint in the third distal heterochromatic region of the B chromosome. Thus, the results indicated that the r-X1 deletion could also induce TDs of the maize B chromosome during megaspore divisions. The Bdef-1 chromosome lacked nondisjunctional behavior, and this behavior was restored by the presence of the B chromosome in the cell. A transmission analysis of the Bdef-1 chromosome revealed that loss of the distal portion of the B chromosome reduced female but not male transmission of the B chromosome. Furthermore, the Bdef-1 chromosome was used to more finely map B-derived miRNA genes on the B chromosome. Our results indicate that the r-X1 deletion results in TDs of the B chromosome in maize, and the r-X1 deletion system can thus be used to generate a series of terminally truncated B chromosomes that may be used to map features of the B chromosome, including genes and properties related to B chromosome functions., (© 2021. The Author(s), under exclusive licence to Springer Nature B.V.)

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., 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 © 2021 Yu, Chan, Lin, Chiou, Lin, Chen, Lee, Chi, Chen, Huang, Chew, Hsu, Yang and Hung.)

Salmonella causes salmonellosis, is a facultative anaerobe and is one of the common Gram-negative bacteria. Salmonella has anti-tumor potential and tumor-targeting activity. The heparin sulfate on cell surfaces can be cleaved by heparanase that is an endo-β-D-glucuronidase. Heparanase can destroy the extracellular matrix and is involved in tumor metastasis and angiogenic activity. Previously, Salmonella was demonstrated to inhibit tumor metastasis. It remains unclear whether Salmonella inhibits metastasis by regulating heparanase. The expression of heparanase in Salmonella -treated tumor cells was found to be decreased. Transwell and wound-healing assays demonstrated the inhibition of cell migration after Salmonella treatment. Salmonella was found to influence the levels of phosphate-protein kinase B (P-AKT) and phosphate-extracellular regulated protein kinases (P-ERK), which are involved in heparanase expression. Salmonella reduced the heparanase expression induced upregulating PERK and PAKT signaling pathways. The mice bearing an experimental metastasis tumor model was used to evaluate the anti-tumor metastatic effects of Salmonella . Compared with the control group, Salmonella significantly reduced the number of metastatic nodules and enhanced survival. The results of our study indicate that Salmonella plays a vital role in the inhibition of tumor metastasis through the downregulation of heparanase., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer. Several treatment options are available for managing HCC patients, classified roughly as local, local-regional, and systemic therapies. The high post-monotherapy recurrence rate of HCC urges the need for the use of combined modalities to increase tumor control and patient survival. Different international guidelines offer treatment recommendations based on different points of view and classification systems. Radiotherapy (RT) is a well-known local-regional treatment modality for managing many types of cancers, including HCC. However, only some of these treatment guidelines include RT, and the role of combined modalities is rarely mentioned. Hence, the present study reviewed clinical evidence for the use of different combined modalities in managing HCC, focusing on modern RT's role. Modern RT has an increased utility in managing HCC patients, mainly due to two driving forces. First, technological advancement ( e.g. , stereotactic body radiotherapy and advanced proton-beam therapy) enables precise delivery of radiation to increase tumor control and reduce side effects in the surrounding normal tissue. Second, the boom in developing target therapies and checkpoint-blockade immunotherapy prolongs overall survival in HCC patients, re-emphasizing the importance of local tumor control. Remarkably, RT combines with systemic therapies to generate the systemic therapy augmented by radiotherapy effect, a benefit now being actively investigated., Competing Interests: Conflict-of-interest statement: The authors declare no conflict of interest., (©The Author(s) 2021. Published by Baishideng Publishing Group Inc. All rights reserved.)

Objectives: Recently, Stereotactic Body Radiotherapy (SBRT) has been suggested for managing hepatocellular carcinoma (HCC) curatively. Thus, we conducted this clinical study to evaluate retrospectively the effect of individualized audio-visual (AV) coaching, respiratory modulated SBRT., Materials and Methods: Between 2014 and 2018, 29 patients with inoperable Barcelona Clinic Liver Cancer (BCLC) stage 0-B HCC received AV coaching, respiratory-modulated SBRT. We constructed a task-oriented multidisciplinary team to establish a standard operation process of respiratory modulation procedures and developed our AV coaching devices. In the training period, a goodness-of-fit test was applied individually. SBRT was delivered with a total dose of 40-54 Gy in 5-6 fractions individually. Freedom from local progression (FFLP) and overall survival (OS) were estimated using SPSS (version 17, SPSS Inc., Chicago, IL, USA) life tables., Results: The patient characteristics were as follows: 32.7 ± 16 mm in maximum tumor diameter (range 11-94); BCLC stage 0: 3.4%, BCLC A: 48.3%, BCLC B: 48.3%; Child-Pugh classification A: 86.2%, Child-Pugh classification B: 13.8%, and a median of 2 prior liver-directed treatments (range 0-7). One-, 2-, and 3-year rates of FFLP of SBRT were 96.6%, 96.6%, and 96.6%, respectively. One-, 2-, and 3-year rates of OS were 81.5%, 72.4%, and 67.2%, respectively. No adverse event (AE) occurred in 41.4% of patients, 48.3% developed grade (G) 1-2 AE, 10.3% had G3 AE and none had G4-5 AE., Conclusion: Respiration-modulated SBRT is a promising noninvasive treatment option for patients with inoperable and localized HCC. Our data show that SBRT provides comparable tumor control to historical curative options like surgery and radiofrequency ablation of localized tumors. Thus, we are conducting a further prospective clinical trial with the intent to demarcate the clinical effectiveness of SBRT in a larger population of patients with HCC., Competing Interests: There is no conflict of interest., (Copyright: © 2021 Tzu Chi Medical Journal.)

Background: Subjects with head and neck cancer (HNC) often experience post-treatment side effects, particularly radiation-induced oral mucositis (RIOM). This study aimed to explore the association of Chinese herbal medicine use with the sequent risk of RIOM among them., Methods: This cohort study used a nationwide health insurance database to identify subjects newly diagnosed with HNC, aged 20 to 60 years, who received treatment between 2000 and 2007. Among them, a total of 561 cases received CHM after HNC onset (CHM users); the remaining 2395 cases were non-CHM users. All patients were followed to the end of 2012 to identify any treatment for RIOM as the end point. Cox proportional hazards regression was used to compute the adjusted hazard ratio (aHR) of RIOM by CHM use., Results: During the follow-up period, 183 CHM users and 989 non-CHM users developed RIOM at incidence rates of 40.98 and 57.91 per 1000 person-years, respectively. CHM users had a lower RIOM risk than the non-CHM users (aHR: 0.68; 95% Confidence Interval: 0.58-0.80). The most potent effect was observed in those taking CHM for more than 1 year. Use of Baizhi, Danshen, Shao-Yao-Gan-Cao-Tang, Gan-Lu-Yin, Huangqin, Shu-Jing-Huo-Xue-Tang, and Xin-Yi-Qing-Fei-Tang, was significantly related to a lower risk of RIOM., Conclusion: Findings of this study indicated that adding CHM to conventional clinical care could be helpful in protecting those with HNC against the onset of RIOM. Further clinical and mechanistic studies are warranted.

Background: The 23-valent pneumococcal polysaccharide vaccine (PPSV23) is indicated for adults who have a high risk of pneumonia; however, its effectiveness in patients with prostate cancer who are at a risk of pneumonia because of age and cancer treatments, including androgen-deprivation therapy, is unknown., Methods: Between 2000 and 2010, 38,735 patients with prostate cancer were diagnosed in Taiwan. After exclusions and exact matching for age, previous pneumonia, and influenza vaccination, 2188 vaccinated patients and 2188 unvaccinated patients were recruited. The incidence density of all-cause bacterial pneumonia hospitalizations was analyzed., Results: Over 7 years of follow-up, patients who received the PPSV23 had a significantly lower incidence density, with 142.8 per 1000 person-years versus 162.0 per 1000 person-years for unvaccinated patients. More patients in the vaccinated cohort were never hospitalized for pneumonia compared with those in the unvaccinated cohort (64.2% vs 62.2%, respectively). After adjusting for the Charlson comorbidity index, cancer treatment modalities, and socioeconomic levels, the risk of pneumonia-related hospitalization in the PPSV23 vaccination cohort was 0.48 times lower than that in the unvaccinated cohort (adjusted incidence rate ratio, 0.48; P = .046). For patients who received the influenza vaccination, subgroup analysis demonstrated that PPSV23 vaccination significantly decreased the risk (adjusted incidence rate ratio, 0.45; P < .001). Compared with unvaccinated controls, PPSV23-vaccinated patients had a lower cumulative incidence for the first occurrence of pneumonia-related hospitalization (34.49% vs 36.36%; P = .178) and higher overall survival (47.5% and 42.3%, respectively; P < .001)., Conclusions: Vaccination of elderly patients who have prostate cancer with the relatively common and inexpensive PPSV23 can decrease the risk of pneumonia and prolong survival., (© 2020 American Cancer Society.)

Rice domestication/adaptation is a good model for studies of the development and spread of this important crop. Mutations that caused morphological and physiological change, followed by human selection/expansion, finally led to the improvement of phenotypes suitable for different kinds of environments. We used the sequence information for Heading date 1 (Hd1) gene to reveal the association between sequence changes and flowering phenotypes of rice in different regions. Seven loss-of-function hd1 haplotypes had been reported. By data-mining the genome sequencing information in the public domain, we discovered 3 other types. These loss-of-function allele haplotypes are present in subtropical and tropical regions, which indicates human selection. Some of these haplotypes are present locally. However, types 7 and 13 are present in more than one-third of the world's rice accessions, including landraces and modern varieties. In the present study, phylogenetic, allele network and selection pressure analyses revealed that these two haplotypes might have occurred early in Southeastern Asia and then were introgressed in many local landraces in nearby regions. We also demonstrate that these haplotypes are present in weedy rice populations, which again indicates that these alleles were present in rice cultivation for long time. In comparing the wild rice sequence information, these loss-of-function haplotypes occurred in agro but were not from wild rice., Competing Interests: The authors have declared that no competing interests exist.

Radiotherapy (RT) is a crucial treatment modality in managing cancer patients. However, irradiation dose sprinkling to tumor-adjacent normal tissues is unavoidable, generating treatment toxicities, such as radiation-associated cardiovascular dysfunction (RACVD), particularly for those patients with combined therapies or pre-existing adverse features/comorbidities. Radiation oncologists implement several efforts to decrease heart dose for reducing the risk of RACVD. Even applying the deep-inspiration breath-hold (DIBH) technique, the risk of RACVD is though reduced but still substantial. Besides, available clinical methods are limited for early detecting and managing RACVD. The present study reviewed emerging challenges of RACVD in modern radiation oncology, in terms of clinical practice, bench investigation, and multidisciplinary care. Several molecules are potential for serving as biomarkers and therapeutic targets. Of these, miRNAs, endogenous small non-coding RNAs that function in regulating gene expression, are of particular interest because low-dose irradiation, i.e., 200 mGy (one-tenth of conventional RT daily dose) induces early changes of pro-RACVD miRNA expression. Moreover, several miRNAs, e.g., miR-15b and miR21, involve in the development of RACVD, further demonstrating the potential bio-application in RACVD. Remarkably, many RACVDs are late RT sequelae, characterizing highly irreversible and progressively worse. Thus, multidisciplinary care from oncologists and cardiologists is crucial. Combined managements with commodities control (such as hypertension, hypercholesterolemia, and diabetes), smoking cessation, and close monitoring are recommended. Some agents show abilities for preventing and managing RACVD, such as statins and angiotensin-converting enzyme inhibitors (ACEIs); however, their real roles should be confirmed by further prospective trials., (Copyright © 2020 Lee, Liu, Hung, Yu, Chi, Chiou, Chen, Lin, Huang, Chew, Hsu, Chan and Lin.)

The commonly used vaccine for adults with a high risk of pneumonia is 23-valent pneumococcal polysaccharide vaccine (PPSV23). However, its effectiveness in patients with colorectal cancer has not been investigated. This study aimed to investigate the effectiveness of PPSV23 in reducing the risk of pneumonia among elderly patients with colorectal cancer.A total of 120,605 newly diagnosed patients with colorectal cancer were identified from the Taiwan National Health Insurance Research Database between 1996 and 2010. Of these patients, 18,468 were 75 years or older in 2007 to 2010, and 3515 received PPSV23. People aged 75 years or older have been considered eligible for receiving PPSV23 vaccination in Taiwan since 2007. The specific "vaccination period" of October 2008 to December 2008 was used to minimize the potential immortal time bias. Therefore, 893 patients who received PPSV23 outside this vaccination period or died before 2009 and 2960 unvaccinated patients who died before 2009 were excluded. After the propensity score was matched with a 1:3 ratio, 2622 vaccinated patients and 7866 unvaccinated patients were recruited. A multivariate log-linear Poisson regression model was performed and adjusted for potential confounders, including influenza vaccination, vaccination period, cancer treatment modalities, comorbidities, and sociodemographic variables.After 2 years of follow-up, the incidence rate of the pneumonia hospitalization of the vaccinated patients was significantly lower than that of the unvaccinated patients at 85.53 per 1000 person-years (PYs) of the former and 92.38 per 1000 PYs of the latter. The proportions of patients who had 2, 3, and >3 pneumonia hospitalizations per year were consistently lower in the vaccinated group than in the unvaccinated group (1.9% vs 2.0%, 0.5% vs 0.9%, and 0.7% vs 1.1%, respectively). After adjustment for covariates was made, PPSV23 vaccine was significantly associated with a reduced risk of pneumonia hospitalization, with an adjusted incidence rate ratio of 0.88 (P = .040). The overall pneumonia-free survival rate was also significantly higher in the vaccinated patients than in the unvaccinated patients (P = .001).PPSV23 vaccination was associated with a significantly reduced rate of pneumonia hospitalization in elderly patients with colorectal cancer.

Background: Hepatocellular carcinoma (HCC) accounts for 75-85% of primary liver cancers and is prevalent in the Asia-Pacific region. Till now, trans-arterial chemoembolization (TACE) is still one of common modalities in managing unresectable intermediate-stage HCC. However, post-TACE residual viable HCC is not uncommon, resulting in unsatisfied overall survival after TACE alone. Recently, stereotactic ablative radiotherapy (SABR) has been suggested to manage HCC curatively. However, evidence from phase-III trials is largely lacking. Hence, the present phase III randomized trial is designed to compare clinical outcomes between SABR and re-TACE for unresectable HCC patients who had incomplete response after initial TACE., Methods: The present study is an open-label, parallel, randomized controlled trial. A total of 120 patients will be included into two study groups, i.e., SABR and re-TACE, with a 1:1 allocation rate. A 3-year allocating period is planned. Patients with incomplete response after initial TACE will be enrolled and randomized. The primary endpoint is 1-year freedom-form-local-progression rate. Secondary endpoints are disease-progression-free survival, overall survival, local control, response rate, toxicity, and duration of response of the treated tumor., Discussion: SABR has been reported as an effective modality in managing intermediate-stage HCC patients, but evidence from phase-III randomized trials is largely lacking. As a result, conducting randomized trials to demarcate the role of SABR in these patients is warranted, especially in the Asia-Pacific region, where HBV- and HCV-related HCCs are prevalent., Trial Registration: Before enrolling participants, the present study was registered prospectively on ClinicalTrials.gov (trial identifier, NCT02921139 ) on Sep. 29, 2016. This study is ongoing.

Grain size is a key determiner of grain weight, one of the yield components in rice (Oryza sativa). Therefore, to increase grain yield, it is important to elucidate the detailed mechanisms regulating grain size. The Large grain (Lgg) mutant, found in the nonautonomous DNA-based active rice transposon1 (nDart1)-tagged lines of Koshihikari, is caused by a truncated nDart1-3 and 355 bp deletion in the 5' untranslated region of LGG, which encodes a putative RNA-binding protein, through transposon display and cosegregation analysis between grain length and LGG genotype in F2 and F3. Clustered regularly interspaced short palindromic repeats/CRISPR-associated 9-mediated knockout and overexpression of LGG led to longer and shorter grains than wild type, respectively, showing that LGG regulates spikelet hull length. Expression of LGG was highest in the 0.6-mm-long young panicle and gradually decreased as the panicle elongated. LGG was also expressed in roots and leaves. These results show that LGG functions at the very early stage of panicle development. Longitudinal cell numbers of spikelet hulls of Lgg, knockout and overexpressed plants were significantly different from those of the wild type, suggesting that LGG might regulate longitudinal cell proliferation in the spikelet hull. RNA-Seq analysis of 1-mm-long young panicles from LGG knockout and overexpressing plants revealed that the expressions of many cell cycle-related genes were reduced in knockout plants relative to LGG-overexpressing plants and wild type, whereas some genes for cell proliferation were highly expressed in knockout plants. Taken together, these results suggest that LGG might be a regulator of cell cycle and cell division in the rice spikelet hull., (� The Author(s) 2019. Published by Oxford University Press on behalf of Japanese Society of Plant Physiologists. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Objective: The prognosis of intrahepatic vascular invasion, including unilateral or main portal vein tumor thrombosis (PVTT) and hepatic vein thrombosis, is still poor. Many patients with intrahepatic vascular invasions never receive radiotherapy (RT). In recent years, more conformal RT techniques such as intensity-modulated RT (IMRT) have been developed and applied to treat other cancers and have significantly improved treatment results and decreased side effects. The purpose of this study is to evaluate the treatment results in patients with intrahepatic vascular invasion and explore the role of IMRT in these treatments., Materials and Methods: There were a total of 73 patients with newly diagnosed AJCC stage IIIB hepatocellular carcinoma (HCC), with either PVTT or hepatic vein tumor thrombosis between 2007 and 2015 in our hospital. IMRT was used for all patients who received RT. Prognostic factors, including treatment modalities, liver function, and comorbidities, were analyzed using univariate and multivariate analysis with the Cox model. Survival time was analyzed using the Kaplan-Meier method., Results: The longest follow-up time was 45.3 months. The median age was 67 years. Univariate analyses indicated that IMRT, transarterial chemoembolization (TACE), target therapy (sorafenib), tumor size, Child-Pugh class, and ascites were significantly associated with overall survival (OS). In multivariate analysis, IMRT (hazard ratio [HR], 0.495; P = 0.019), sorafenib (HR, 0.340; P = 0.013), tumor size (HR, 2.085; P = 0.020), and Child-Pugh class ( P = 0.004), were independent prognostic predictors for patients with intrahepatic vessel invasion, but TACE and ascites were not. The outcomes of patients who had different treatment modalities were significantly different ( P < 0.001). Patients who received IMRT with TACE had the best outcomes. Patients who received an RT dose above 5400 cGy had better outcomes than those who with a dose below 5400 cGy, although the results were not significantly different ( P = 0.248)., Conclusion: IMRT is an important treatment component for patients with intrahepatic vascular invasion. Combined treatment modalities, such as IMRT with TACE, could improve the outcomes of HCC patients with intrahepatic vessel invasion., Competing Interests: There is no conflict of interest.

Background: Activation of Ras oncogene in human tumors is associated with radiation-associated metastatic potential. Although ionizing radiation is one important method of cancer treatments, it has been shown to enhance matrix metalloproteinases (MMPs) activity and facilitates a more aggressive cancer phenotype. Our previous studies showed that andrographolide with lower dose rates of radiation could inhibit RAS-transformed cancer metastasis in vivo; however, the molecular mechanisms are not yet clear. In this study, we aimed to explore the anti-metastatic effect of andrographolide combined with radiation on Ras-transformed cells., Methods: RAS-transformed cells were treated with andrographolide in the presence or absence of irradiation (2-4 Gy) or angiotensin II to examine cell invasion. In vivo tumorigenesis assays were also performed. The MMP-2 activity was detected by using Gelatin zymography. Signal transduction of NF-κB subunit, p65 and phosphor-ERK 1/2, were examined by using Western blotting analysis., Results: Treatment with andrographolide inhibited migration of Ras-transformed cells. Andrographolide treatment with radiation significantly inhibited cancer metastasis in vivo. We found that andrographolide exhibited anti-migration and anti-invasive ability against cancer metastasis via inhibition of MMP2 activity rather than affected MMP-9 and EMT. In addition, combined andrographolide with radiation appeared to be more effective in reducing MMP-2 expression, and this effect was accompanied by suppression of ERK activation that inhibits cancer cell migration and invasion., Conclusions: These findings suggest that andrographolide enhances the anti-metastatic effect of radiation in Ras-transformed cells via suppression of ERK-mediated MMP-2 activity., Competing Interests: The authors have declared that no competing interests exist.

To obtain a clear intact section of a ripened rice grain, which is suitable for biochemical and histological analysis, the Kawamoto method using a specific adhesive film was applied using a cryomicrotome. The longitudinal and sagittal sections were easily obtained together with the cross-section, and cell characteristics were clearly discerned in the ripened grain. It was demonstrated that the Kawamoto method is readily applicable for intact sectioning of hard tissue, including ripened grain. Intact section sampling may be useful for enzymatic analysis and transcriptomic analysis of plant tissue.

Objective: The Advisory Committee on Immunization Practices in 2012 recommended the 23-valent pneumococcal polysaccharide vaccine (PPSV23) for adults with high risk of pneumonia. However, its effectiveness in cancer survivors has not been investigated. Our aim was to investigate the effectiveness of PPSV23 in these patients., Design: Population-based matched cohort study., Setting: Claim data were obtained from 1 million people registered with the National Health Insurance Research Database in 1996, and followed to 2010. People aged ≥75 years are eligible for receiving PPSV23 vaccination in Taiwan since 2007., Participants: Among the 30 249 patients with cancer, 6784 patients were 75 years or older eligible for PPSV23 vaccination. Among them, 1887 survived 5 or more years (ie, cancer survivors) after cancer diagnosis. We identified 377 cancer survivors who received PPSV23. A total of 754 propensity score matched unvaccinated patients were randomly selected., Intervention: PPSV23 vaccination., Primary Outcome Measures: The primary outcome was pneumonia hospitalisation. Potential confounders include influenza vaccination, vaccination period, cancer treatment modalities, comorbidities and sociodemographic variables., Results: After 2 years of follow-up, vaccinated patients had a significantly lower incidence rate of pneumonia hospitalisation at 73.66 per 1000 person-years (PYs), compared with 117.82 per 1000 PYs for unvaccinated patients. Additionally, the prevalence for pneumonia hospitalisation frequency of >0-1,>1-2,>2-3 and >3 times per PY was all consistently lower in the vaccinated group (6.63% vs 9.28%, 1.86% vs 2.52%, 0.80% vs 1.59% and 0.27% vs 0.53%, respectively). After adjustment for covariates, PPSV23 vaccine was significantly associated with reduced pneumonia hospitalisation risk, with an adjusted incidence rate ratio of 0.695 (p=0.030). While the cumulative pneumonia incidence was also significantly lower in the vaccinated patients (p=0.027), the overall survival time was similar (p=0.136)., Conclusions: PPSV23 vaccination was associated with a significantly reduced rate of pneumonia hospitalisation in long-term cancer survivors., Competing Interests: Competing interests: None declared., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Objective: Pulmonary radiotherapy has been reported to increase a risk of pneumonopathy, including pneumonitis and secondary pneumonia, however evidence from population-based studies is lacking. The present study intended to explore whether postoperative irradiation increases occurrence of severe pneumonopathy in lung cancer patients., Design, Setting and Participants: The nationwide population-based study analysed the Taiwan National Health Insurance Research Database (covered >99% of Taiwanese) in a real-world setting. From 2000 to 2010, 4335 newly diagnosed lung cancer patients were allocated into two groups: surgery-RT (n=867) and surgery-alone (n=3468). With a ratio of 1:4, propensity score was used to match 11 baseline factors to balance groups., Interventions/exposures: Irradiation was delivered to bronchial stump and mediastinum according to peer-audited guidelines., Outcomes/measures: Hospitalised pneumonia/pneumonitis-free survival was the primary end point. Risk factors and hazard effects were secondary measures., Results: Multivariable analysis identified five independent risk factors for hospitalised pneumonopathy: elderly (>65 years), male, irradiation, chronic obstructive pulmonary disease (COPD) and chronic kidney disease (CKD). Compared with surgery-alone, a higher risk of hospitalised pneumonopathy was found in surgery-RT patients (HR, 2.20; 95% CI, 1.93-2.51; 2-year hospitalised pneumonia/pneumonitis-free survival, 85.2% vs 69.0%; both p<0.0001), especially in elderly males with COPD and CKD (HR, 13.74; 95% CI, 6.61-28.53; p<0.0001). Unexpectedly, we observed a higher risk of hospitalised pneumonopathy in younger irradiated-CKD patients (HR, 13.07; 95% CI, 5.71-29.94; p<0.0001) than that of elderly irradiated-CKD patients (HR, 4.82; 95% CI, 2.88-8.08; p<0.0001)., Conclusions: A high risk of hospitalised pneumonopathy is observed in irradiated patients, especially in elderly males with COPD and CKD. For these patients, close clinical surveillance and aggressive pneumonia/pneumonitis prevention should be considered. Further investigations are required to define underlying biological mechanisms, especially for younger CKD patients., Competing Interests: Competing interests: None declared., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Radiation therapy (RT) is the current standard adjuvant approach for oral squamous cell carcinoma (OSCC) patients. Radioresistance is a major contributor to radiotherapy failure. In this study, we used patient-derived cells and a radiation-resistant cell line in vitro and in vivo for two purposes: evaluate the anti-tumor effects and understand the mechanisms in the dual PI3K/mTOR signaling pathway regulation of radiosensitization. Our findings indicate that in OML1-R cells, the radioresistance phenotype is associated with activation of the PI3K/AKT/mTOR signaling pathway. Compared to a combination of PI3K or mTOR inhibitors and radiation, dual blockade of the PI3K and mTOR kinases significantly improved radiation efficacy in oral cancer and patient-derived OSCC cells. Dual PI3K/mTOR inhibition enhanced the effect of radiation by inhibiting AKT/mTOR signaling pathways and caused G1 phase arrest, which is associated with downregulation of cyclin D1/CDK4 activity, leading to growth inhibition. In nude mice xenografted with radioresistant OML1-R cells, the combined treatment was also more effective than RT alone in reducing tumor growth. This treatment was also demonstrated to be dependent on the inhibition of protein kinase-dependent S6 kinase pathway and eIF4E-mediated cap-dependent translation. These findings indicate that activation of the PI3K/AKT/mTOR signaling pathway has a role in radioresistance of OSCC. We determined that a PI3K/mTOR inhibitor combined with radiation exhibits synergistic inhibition of the AKT/mTOR axis and induces cell cycle arrest. Our results show the therapeutic potential of drugs targeting the PI3K/AKT/mTOR signaling pathway should be new candidate drugs for radiosensitization in radiotherapy., Competing Interests: CONFLICTS OF INTEREST Nothing to declare.

Radiotherapy (RT) is useful in managing cancer diseases. In clinical practice, early initiation of RT is crucial for enhancing tumor control. But, delivering precise RT requires a series of pre-RT working processes in a tight staff-cooperation manner. In this regard, using information system to conduct e-control and e-alerts has been suggested to improve practice effectiveness; however, this effect is not well defined in a real-world RT setting.We designed an information system to perform e-control and e-alerts for the whole process of pre-RT workflow to shorten processing time, to improve overall staff satisfaction, and to enhance working confidence.A quality-improving study conducted in a large RT center.Externally validated data were retrospectively analyzed for comparison before (from Sep. 2012 to Dec. 2012, n = 223) and after (from Sep. 2013 to Dec. 2013, n = 240) implementation of pre-RT e-control and e-alerts.Applying the e-control with delay-working e-alerts in pre-RT workflow was the main intervention.Nine workstations were identified in pre-RT workflow. The primary outcome measure was the processing time in each pre-RT workstations before and after implementing the e-control and e-alerts. Secondary measures were staff-working confidence and near-missing cases during the process of pre-RT workflow.After implementing e-control, overall processing time of pre-RT workflow was shortened from 12.2 days to 8.9 days (P < .001). Follow-up data (till Jul. 2016) showed a durable effect of 9.2 days, being still below the predefined threshold of <10 days.Using a multidisciplinary-cooperating information system is useful to conduct e-control and e-alerts in the whole process of pre-RT workflow. Clinical effectiveness, staff satisfaction, and working confidence are able to be enhanced obviously.

Molecular imaging of reporter gene expression in cancer cells can provide rapid, sensitive and non-invasive monitoring of tumor behavior. The aim of the present study was to establish a non-invasive method to measure tumor size and distribution in vivo . Briefly, H-Ras-transformed cells were stably transfected with a plasmid containing the luciferase gene (Luc), designated as Ras/Luc. Ras/Luc cells were injected into the back or tail vein of nude BALB/cAnN-Foxn1nu/CrlNarl mice (age, 6-8 weeks). Mice were subsequently administered D-luciferin via intra-peritoneal injection, prior to image acquisition. Photons emitted from the mice were detected via an imaging system. Tumor size and distribution in vivo were quantified as photons/second. Andrographolide has demonstrated radiosensitization in previous in vitro and in vivo studies. In the present study, the potential effects of andrographolide cancer metastasis were investigated further, using an imaging system. Preliminary results of andrographolide combined with radiation indicated the inhibition of cancer metastasis. The present mechanistic study of andrographolide-mediated effects demonstrated that activated extracellular signal regulated kinase protein and H 2 O 2 production levels were significantly increased by andrographolide. In summary, the present study established a non-invasive method to measure tumor size and distribution in vivo and indicated that andrographolide may be a potential therapeutic strategy in cancer therapy.

Background: Frequent multidisciplinary communication is essential in conducting daily radiotherapy (RT) practice. However, traditional oral or paper-based communication has limitations. E-communication has been suggested, but its effects are still not well demarcated in the field of radiation oncology., Objects: In our web-based integrated information platform, we constructed a ping-pong-type e-communication function to transfer specific notations among multidisciplinary RT staffs. The purpose was to test whether applying this e-communication can increase effectiveness of multidisciplinary cooperation when compared with oral or paper-based practice. Staff satisfaction and clinical benefits were also demonstrated., Design and Setting: A real-world quality-improving study was conducted in a large center of radiation oncology., Participants and Dataset Used: Before and after applying multidisciplinary e-communication (from 2014 to 2015), clinical RT staffs were surveyed for their user experience and satisfaction (n = 23). For measuring clinical effectiveness, a secondary database of irradiated head and neck cancer patients was re-analyzed for comparing RT toxicities (n = 402)., Interventions: Applying ping-pong-type multidisciplinary reflective e-communication was the main intervention., Outcome Measures: For measuring staff satisfaction, eight domains were surveyed, such as timeliness, convenience, and completeness. For measuring clinical effectiveness of multidisciplinary cooperation, event rates of severe (i.e., grade 3-4) RT mucositis and dermatitis were recorded., Results: Overall, when compared with oral communication only, e-communication demonstrated multiple benefits, particularly on notation-review convenience (2.00 ± 1.76 vs 9.19 ± 0.81; P < 0.0001).When compared with paper-based practice, e-communication showed statistically significant benefits on all eight domains, especially on notation-review convenience (5.05 ± 2.11 vs 9.19 ± 0.81; P < 0.0001) and convenience of feedback notation (4.81 ± 1.72 vs 8.76 ± 1.09; P < 0.0001).Moreover, staff satisfaction was gradually increased from oral (3.57 ± 1.94), paper-based (5.57 ± 2.06), to e-communication (8.76 ± 0.70; P < 0.0001). Secondary measurement confirmed these observations.Before and after facilitating multidisciplinary cooperation by using e-communication, severe (i.e., grade 3-4) mucositis and dermatitis were decreased from 21.7% to 10% then to 5.1%., Conclusions: Replacing oral or paper-based practice with e-communication is useful in facilitating RT multidisciplinary teamwork. Staff satisfaction and clinical effectiveness can be increased.

As the number of long-term cervical cancer survivors continues to increase because of improvements in treatment, concerns about second primary malignancy have grown. The high-risk area of second primary cancers in cervical cancer survivors is the pelvis. Pelvic inflammatory disease (PID) could be a useful marker for gynecological cancers. Thus, we designed a large-scale, nationwide, controlled cohort study to investigate whether PID or other risk factors increased the risk of second primary cancers in patients with cervical cancer treated by surgery alone.Between 2000 and 2010, a total of 24,444 cervical cancer patients were identified using the Registry Data for Catastrophic Illness and the National Health Insurance Research Database (NHIRD) of Taiwan. Patients who received definite surgery were selected. To exclude the effect on second primary malignancy by treatment modalities, all cervical patients who ever having received adjuvant or definite radiotherapy or chemotherapy for primary cervical cancer were excluded. Finally, 3860 cervical cancer patients treated by surgery alone without adjuvant treatments were analyzed.Cox proportional hazards model was used for multivariate analysis and the Kaplan-Meier method was used to assess the cumulative risks. Regarding the incidence of second primary cancers, the standardized incidence ratio (SIR) was used.The median follow-up time was 56.6 months. The 6-year cumulative risk of second primary cancers is 0.16% and 0.12% for PID and without PID, respectively. After adjustment for confounders, age of less than 50 years, the presence of diabetes mellitus, and PID were significantly positivity associated with the risk of second primary cancers. The hazard ratios (HRs) of age less than 50 years, diabetes mellitus, and PID were 1.38 (95% CI = 1.11-2.04), 1.40 (95% CI = 1.06-1.85), and 1.35 (95% CI = 1.00-1.81), respectively. A higher incidence of second primary cancers was observed in the genitals, bladder, and colon.In conclusion, the incidence of second primary cancers was higher in the genitals, bladder, and colon in patients with cervical cancer treated with surgery alone. The patients with PID had a higher risk of second primary cancers., Competing Interests: The authors have no conflicts of interest to disclose.

With increasing use of cardiac fluoroscopic intervention, the incidence of fluoroscopy-induced radiation ulcer is increasing. Radiation ulcer is difficult to manage and currently there are no treatment guidelines. To identify the optimal treatment approaches for managing cardiac fluoroscopy-induced radiation ulcers, we retrospectively reviewed medical records of 13 patients with fluoroscopy-induced radiation ulcers receiving surgical interventions and following up in our hospital from 2012 to 2015. Conventional wound care and hyperbaric oxygen therapy were of little therapeutic benefit. Twelve patients received reconstruction with advancement flap or split thick skin graft. One-stage radical excision of radiation damaged area in eight cases with immediate reconstruction led to better outcomes than conservative excisions in four cases. Radical surgical excision to remove all the radiation damaged tissues in combination with immediate reconstruction appears to offer the optimal treatment results for cardiac fluoroscopy-induced radiation ulcers. Adequate excision of the damaged areas in both vertical (to the muscular fascia) and horizontal (beyond the sclerotic areas) dimension is pivotal to achieve good treatment outcomes.

Background: Clinically, elderly patients with unresectable bulky hepatocellular carcinoma (HCC) are difficult to manage, especially in those with co-infections of hepatitis B and C virus. Herein, we reported such a case treated with radiotherapy (RT) by using combined simultaneously integrated inner-escalated boost and volumetric-modulated arc radiotherapy (SIEB-VMAT). After RT, significant symptoms alleviation and durable tumor control were observed., Case Summary: At presentation, an 85-year-old male patient complained abdominal distention/pain, poor appetite, and swelling over bilateral lower limbs for 1 month. On physical examination, a jaundice pattern was noted. Laboratory studies showed impaired liver and renal function. Abdominal computed tomography (CT) revealed a 12.5-cm bulky tumor over the caudate lobe of the liver. Biopsy was done, and hepatocellular carcinoma (HCC) was reported histopathologically. As a result, AJCC stage IIIA (cT3aN0M0) and BCLC stage C were classified. Surgery, radiofrequency ablation (RFA), trans-catheter arterial chemoembolization (TACE), and sorafenib were not recommended because of his old age, central bulky tumor, and a bleeding tendency. Thus, RT with SIEB-VMAT technique was given alternatively. RT was delivered in 26 fractions, with dose gradience as follows: 39 Gy on the outer Plan Target Volume (PTV), 52 Gy in the middle PTV, and 57.2 Gy in the inner PTV. Unexpectedly, cyproheptadine (a newly recognized potential anti-HCC agent) was retrospectively found to be prescribed for alleviating skin itching and allergic rhinitis since the last 2 weeks of the RT course (2 mg by mouth Q12h for 24 months).After RT, significant symptoms alleviation and tumor volume reduction were observed for 32 months till multiple bone metastases. Before and after RT, a large tumor volume reduction rate of 88.7% was observed (from 608.4 c.c. to 68.7 c.c.). No severe treatment toxicity was noted during and after RT. The patient died due to aspiration pneumonia with septic shock at 4 months after bone metastases identified., Conclusions: SIEB-VMAT physically demonstrated double benefits of intratumor dose escalation and extra-tumor dose attenuation. Significant tumor regression and symptoms alleviation were observed in this elderly patient with unresectable bulky HCC. Further prospective randomized trials are encouraged to demarcate effective size of SIEB-VMAT with or without cyproheptadine.

A number of cardiac fluoroscopic interventions have increased rapidly worldwide over the past decade. Percutaneous transluminal coronary angioplasty (PTCA) and stent implantation have become increasingly popular, and these advancements have allowed patients to receive repetitive treatments for restenosis. However, these advancements also significantly increase radiation exposure that may lead to higher cumulative doses of radiation. In the present study, a nationwide population-based case-controlled study was used to explore the risk of leukemia after cardiac angiographic fluoroscopic intervention.A total of 5026 patients with leukemia and 100,520 control patients matched for age and sex (1:20) by a propensity score method without any cancer history were enrolled using the Registry Data for Catastrophic Illness and the National Health Insurance Research Database (NHIRD) of Taiwan between 2008 and 2010. All subjects were retrospectively surveyed (from year 2000) to determine receipt of cardiac fluoroscopic interventions. Data were analyzed using conditional logistic regression models, and estimated crude and adjusted odds ratios (95% confidence interval).After adjusting for age, gender, and comorbidities, PTCA was found to be associated with an increased risk of leukemia with an adjusted OR of 1.566 (95% CI, 1.282-1.912), whereas coronary angiography alone without PTCA and cardiac electrophysiologic study were not. Our results also showed that an increased frequency of PTCA and coronary angiography was associated with a higher risk of leukemia (adjusted OR: 1.326 to 1.530 [all P < 0.05]). Gender subgroup analyses demonstrated that men were associated with a higher risk of leukemia compared with women.These results provide additional data in the quantification of the long-term health effects of radiation exposure derived from the cardiac fluoroscopic diagnostic and therapeutic intervention. PTCA alone or PTCA with coronary angiography was associated with an elevated risk of leukemia. Continued follow-up of existing cohorts will be valuable to help assess lifetime risks of cancer., Competing Interests: The authors have no funding and conflicts of interest to disclose.

Rice (Oryza sativa) is one of the world's most important crops. Rice researchers make extensive use of insertional mutants for the study of gene function. Approximately half a million flanking sequence tags from rice insertional mutant libraries are publicly available. However, the relationship between genotype and phenotype is very weak. Transgenic plant assays have been used frequently for complementation, overexpression or antisense analysis, but sequence changes caused by callus growth, Agrobacterium incubation medium, virulence genes, transformation and selection conditions are unknown. We used high-throughput sequencing of DNA from rice lines derived from Tainung 67 to analyze non-transformed and transgenic rice plants for mutations caused by these parameters. For comparison, we also analyzed sequence changes for two additional rice varieties and four T-DNA tagged transformants from the Taiwan Rice Insertional Mutant resource. We identified single-nucleotide polymorphisms, small indels, large deletions, chromosome doubling and chromosome translocations in these lines. Using standard rice regeneration/transformation procedures, the mutation rates of regenerants and transformants were relatively low, with no significant differences among eight tested treatments in the Tainung 67 background and in the cultivars Taikeng 9 and IR64. Thus, we could not conclusively detect sequence changes resulting from Agrobacterium-mediated transformation in addition to those caused by tissue culture-induced somaclonal variation. However, the mutation frequencies within the two publically available tagged mutant populations, including TRIM transformants or Tos17 lines, were about 10-fold higher than the frequency of standard transformants, probably because mass production of embryogenic calli and longer callus growth periods were required to generate these large libraries., (© 2016 The Authors The Plant Journal © 2016 John Wiley & Sons Ltd.)

DNA repair genes play critical roles in response to carcinogen-induced and anticancer therapy-induced DNA damage. Benzo[a]pyrene (BaP), the most carcinogenic polycyclic aromatic hydrocarbon (PAH), is classified as a group 1 carcinogen by International Agency for Research on Cancer. The aims of this study were to (1) evaluate the effects of BaP on DNA repair activity and expression of DNA repair genes in vitro and (2) examine the role of xeroderma pigmentosum, complementation group D (XPD) mRNA expression in human head and neck cancers. Host cell reactivation assay showed that BaP inhibited nucleotide excision repair in H1299 lung cancer cells. DNA repair through the non-homologous end-joining pathway was not affected by BaP. Real-time quantitative reverse-transcription polymerase chain reaction (RT-PCR) and Western blot demonstrated that XPD was downregulated by BaP treatment. BaP exposure did not apparently affect expression of another 11 DNA repair genes. BaP treatment increased the DNA damage marker γ-H2AX and ultraviolet (UV) sensitivity, supporting an impairment of DNA repair in BaP-treated cells. XPD expression was also examined by quantitative RT-PCR in 68 head and neck cancers, and a lower XPD mRNA level was found in smokers' cancer specimens. Importantly, reduced XPD expression was correlated with patient 5-year overall survival rate (35 vs. 56%) and was an independent prognostic factor (hazard ratio: 2.27). Data demonstrated that XPD downregulation was correlated with BaP exposure and human head and neck cancer survival.

To evaluate effectiveness of 23-valent pneumococcal polysaccharide vaccine (PPSV23) inoculated during defined "vaccination period," first 6 months post cancer diagnosis (ie, an anti-cancer treatment period), in elderly lung cancer patients on community-acquired pneumonia (CAP) hospitalization incidence.This was a nationwide population-based cohort study of 157 newly diagnosed elderly lung cancer patients receiving PPSV23 during "vaccination period", and 628 age and sex one-to-one matched controls enrolled in the National Health Insurance Research Database (NHIRD) of Taiwan between 2007 and 2010. All patients were ≥75 years old and still survival post "vaccination period." Incidence density (ID) of all-cause inpatient CAP and cumulative survival risk were analyzed by multivariate Poisson regression and Kaplan-Meier method, respectively.After a 4-year follow-up, IDs of all-cause inpatient CAP for vaccination and control cohorts were 297 and 444 per 1000 PYs, respectively. Less vaccinated patients had CAP incidence density >1 time per PY (12.7% vs 21.2%) than non-vaccinated patients. After adjusting for potential confounding variables, like influenza vaccination, comorbidities, cancer treatment modalities, and socioeconomic status, adjusted inpatient CAP incidence rate in PPSV23 vaccination cohort was 0.74 times lower than control cohort (incidence rate ratio [IRR] = 0.740, P = 0.0339). Two-year cumulative CAP hospitalization rates and overall survival rates were 37.1% vs. 55.4%, and 46.6% vs. 26.2%, respectively, for lung cancer patients with and without PPSV23 (both P < 0.001). Subgroup analysis showed that for elderly lung cancer patients not ever receiving influenza vaccine, PPSV23 still had trend to reduce all-cause inpatient CAP.For elderly lung cancer patients aged ≥75 years, PPSV23 inoculated during anti-cancer treatment period could reduce CAP hospitalizations and improve survival.

Purpose: This study aimed to evaluate the salivary gland function changes by sialoscintigraphy in locally advanced nasopharyngeal cancer (NPC) after intensity modulated radiotherapy (IMRT)., Materials and Methods: Salivary function was assessed by sialoscintigraphy. Quantitative sialoscintigraphy was performed in 24 NPC patients prior to and after IMRT. Results were categorized in four groups according to the duration of treatment. The sialoscintigraphy parameters were examined., Results: Sialoscintigraphy showed a significant difference in the secretion of each interval groups. The parameters of scintigraphy, except maximum accumulation (MA) of submandibular glands, decreased first after radiotherapy, and then recovered. However, the MA of submandibular glands was continuously downhill after radiation., Conclusions: The sialoscintigraphy parameters of each gland changed with the different radiation dose and follow-up intervals. The salivary function was influenced after radiotherapy in locally advanced NPC, especially, in the submandibular gland. Strategies to improve the salivary function should be assessed.

Objective: The aim of this study is to evaluate the liver metastasis risk among colorectal cancer patients with liver cirrhosis., Methods: This was a nationwide population-based cohort study of 2973 newly diagnosed colorectal cancer patients with liver cirrhosis and 11 892 age-sex matched controls enrolled in Taiwan between 2000 and 2010. The cumulative risk by Kaplan-Meier method, hazard ratio by the multivariate Cox proportional model and the incidence density were evaluated., Results: The median time interval from the colorectal cancer diagnosis to the liver metastasis event was 7.42 months for liver cirrhosis group and 7.67 months for non-liver cirrhosis group. The incidence density of liver metastasis was higher in the liver cirrhosis group (61.92/1000 person-years) than in the non-liver cirrhosis group (47.48/1000 person-years), with a significantly adjusted hazard ratio of 1.15 (95% CI = 1.04-1.28, P = 0.007). The 10-year cumulative risk of liver metastasis for the liver cirrhosis and the non-liver cirrhosis group was 27.1 and 23.6%, respectively (P = 0.006). For early cancer stage with locoregional disease patients receiving surgery alone without adjuvant anti-cancer treatments, patients with liver cirrhosis (10-year cumulative risk 23.9 vs. 15.7%, P < 0.001) or cirrhotic symptoms (10-year cumulative risk 25.6 vs. 16.6%, P = 0.009) both still had higher liver metastasis risk compared with their counterparts. For etiologies of liver cirrhosis, the 10-year cumulative risk for hepatitis B virus and hepatitis C virus, hepatitis B virus, hepatitis C virus, other causes and non-liver cirrhosis were 29.5, 28.9, 27.5, 26.7 and 23.4%, respectively, (P = 0.03)., Conclusions: Our study found that liver metastasis risk was underestimated and even higher in colorectal cancer patients with liver cirrhosis., (© The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Radioresistance is still an emerging problem for radiotherapy of oral cancer. Aberrant epigenetic alterations play an important role in cancer development, yet the role of such alterations in radioresistance of oral cancer is not fully explored. Using a methylation microarray, we identified promoter hypermethylation of FHIT (fragile histidine triad) in radioresistant OML1-R cells, established from hypo-fractionated irradiation of parental OML1 radiosensitive oral cancer cells. Further analysis confirmed that transcriptional repression of FHIT was due to promoter hypermethylation, H3K27me3 and overexpression of methyltransferase EZH2 in OML1-R cells. Epigenetic interventions or depletion of EZH2 restored FHIT expression. Ectopic expression of FHIT inhibited tumor growth in both in vitro and in vivo models, while also resensitizing radioresistant cancer cells to irradiation, by restoring Chk2 phosphorylation and G2/M arrest. Clinically, promoter hypermethylation of FHIT inversely correlated with its expression and independently predicted both locoregional control and overall survival in 40 match-paired oral cancer patient samples. Further in vivo therapeutic experiments confirmed that inhibition of DNA methylation significantly resensitized radioresistant oral cancer cell xenograft tumors. These results show that epigenetic silencing of FHIT contributes partially to radioresistance and predicts clinical outcomes in irradiated oral cancer. The radiosensitizing effect of epigenetic interventions warrants further clinical investigation.

Hepatocellular carcinoma (HCC) is an aggressive malignant tumor with a high mortality rate. The optimal therapeutic choice for early HCC is surgical resection. However, the rate of intrahepatic recurrence is high. The objective of this study was to evaluate the effect of various factors on the survival of patients with early HCC. Between January 1st, 2006 and December 31st, 2013, a total of 89 patients who underwent surgery for HCC were retrospectively enrolled. The analysis was conducted using the Student's t-test, Chi-square test, Kaplan-Meier method and Cox proportional hazard regression model to assess potential confounding and predictive variables. The 3-year overall survival (OS) rate was 71%. The 3-year OS rates in patients with and those without vascular invasion were 62.1 and 92.8%, respectively (P<0.003). Based on the multivariate analysis, postoperative pathological vascular invasion (hazard ratio = 4.96; 95% confidence interval: 1.55-15.9) remained an independent predictor of adverse long-term outcome. Furthermore, vascular invasion was significantly associated with intrahepatic metastasis. These data emphasize the need for effective adjuvant therapy in selected high-risk patients with early HCC. Further studies are required to determine the optimal approach to further improving the prognosis of early HCC.