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Supplemental Digital Content is available in the text., 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 (P0.05). Furthermore, multiple HDP combined with preeclampsia had aHR of 5.48 (1.14−26.42, P

Radiotherapy (RT) is an effective treatment modality for managing resected oral squamous cell carcinoma (OSCC) patients. The present study conducted gene ontology to explore the functional biological analysis of IRAK2 and performed case analysis to define its clinical role in disease progression and mediating tumor response to RT. Transcriptome sequencing data from the OML1 oral cancer cell line was analyzed to explore IR-responding genes. For identified significant IR-responsive genes, gene ontology (GO) analysis was conducted for exploring their involved bio-logical processes. From Jan. 2007 to Dec. 2014, 172 OSCC patients who received radical surgery with (n = 93) and without (n = 79) postoperative RT were identified for clinical validation. Their OSCC formalin-fixed paraffin-embedded histological samples were examined retrospectively to define IRAK2 expression. After irradiation treatments, IRAK2 upregulation was identified obviously suggesting its role as a potential radiation biomarker. Moreover, GO enrichment analysis showed IRAK2 involved ten of 14 top enriched post-irradiation biological processes, focusing on stress response and immune modulation in vitro. Clinically, high IRAK2 expression was correlated with several 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 RT, the IRAK2-high group was associated with fewer post-irradiation local recurrence (multivariate HR, 0.243; 95% CI, 0.071–0.838; P = 0.025) than the IRAK2-low group. However, the local control benefit did not translate into patient survival. On the other hand, for patients with no RT, IRAK2 did not predict local control. IRAK2 plays a crucial role in the radiation-induced response. In summary, patients with high IRAK2 expression demonstrated more advanced disease features but predicted higher post-irradiation local control than those with low expression. These findings support IRAK2 as a potential predictive biomarker for RT response in OSCC patients. Further prospective clinical studies are encouraged.

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.

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.

Urothelial carcinoma (UC) is the second most common malignancy of the urinary system with high rate of recurrence, UC patients therefore needed to be treated with surgery followed by chemotherapy. Development of novel therapeutics with minimal side-effect is an urgent issue. Our previous study showed that cyproheptadine (CPH), an anti-histamine, exhibited antitumor activity in UC in vitro and in an xenograft model. In this study, we performed RNA-Seq to examine genes that are differentially expressed after treatment with CPH in UC cells. Our result showed that several genes, including IRF6, were upregulated after treatment with CPH in BFTC905 UC cells. Further experiments found that treatment of CPH could restore the expression of IRF6 in several other UC cell lines, which is due to promoter hypomethylation and enrichment of H3K27 acetylation, as well as H3K4 mono-methylation. Importantly, treatment of CPH can inhibit tumor growth in a syngeneic mouse tumor model. The tumor growth can be further inhibited by combination treatment of CPH and immune checkpoint blockade. Flow cytometric analysis of the tumor found that NK cells are significantly enriched in the CPH treatment group, as compared to DMSO control. Co-culture experiments confirmed that UC cells pretreated with CPH showed an increased NK-92-mediated cytotoxicity. In conclusion, these results suggested that treatment of CPH can inhibit tumor growth, by epigenetic priming of IRF6 in UC. The role of CPH in eliciting anti-tumor innate immune response deserves further investigation. Citation Format: Pie-Che Chen, Guan-Ling Lin, Hon-Yi Lin, Wan-Hong Huang, Yu-Ming Chuang, Ru-Inn Lin, Shu-Fen Wu, Cheng-Huang Shen, Michael W.Y. Chan. Cyproheptadine exhibits anti-tumor activity by reversing the epigenetic silencing of IRF6 in urothelial carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2243.

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.

Objective No study ever investigated the long-term risk of stroke in women with pre-eclampsia/eclampsia. The purpose of this study is to explore long-term stroke risks, differentiating subtypes and their time trends. Design Nationwide population-based cohort study 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 pre-eclampsia/eclampsia and 24,212 controls were recruited. Main Outcome Measures Hemorrhagic and ischemic strokes after child-birth Results Over the 17-year follow-up, the adjusted hazard ratio (aHR) for stroke in women with a history of pre-eclampsia/eclampsia was 2.05 (95% confidence interval, CI = 1.67-2.52, p

Ovarian cancer is the most lethal cancer of the female reproductive system. In that regard, several epidemiological studies suggest that long‐term exposure to estrogen could increase ovarian cancer risk, although its precise role remains controversial. To decipher a mechanism for this, we previously generated a mathematical model of how estrogen‐mediated upregulation of the transcription factor, E2F6, upregulates the ovarian cancer stem/initiating cell marker, c‐Kit, by epigenetic silencing the tumor suppressor miR‐193a, and a competing endogenous (ceRNA) mechanism. In this study, we tested that previous mathematical model, showing that estrogen treatment of immortalized ovarian surface epithelial cells upregulated both E2F6 and c‐KIT, but downregulated miR‐193a. Luciferase assays further confirmed that microRNA‐193a targets both E2F6 and c‐Kit. Interestingly, ChIP‐PCR and bisulphite pyrosequencing showed that E2F6 also epigenetically suppresses miR‐193a, through recruitment of EZH2, and by a complex ceRNA mechanism in ovarian cancer cell lines. Importantly, cell line and animal experiments both confirmed that E2F6 promotes ovarian cancer stemness, whereas E2F6 or EZH2 depletion derepressed miR‐193a, which opposes cancer stemness, by alleviating DNA methylation and repressive chromatin. Finally, 118 ovarian cancer patients with miR‐193a promoter hypermethylation had poorer survival than those without hypermethylation. These results suggest that an estrogen‐mediated E2F6 ceRNA network epigenetically and competitively inhibits microRNA‐193a activity, promoting ovarian cancer stemness and tumorigenesis.

Background Urothelial carcinoma (UC) is the second most common malignancy of the urinary system with high rate of recurrence, UC patients therefore needed to be treated with surgery followed by chemotherapy. Development of novel therapeutics with minimal side-effect is an urgent issue. Our previous study showed that cyproheptadine (CPH), an anti-histamine, exhibited antitumor activity in UC in vitro and in an xenograft model. However, the molecular mechanism of how CPH inhibits tumor progression is not fully understood. Methods Genes that were upregulated after treatment with CPH in UC cells, were examined by RNA-Seq. Real-time quantitative PCR (RT-qPCR) was employed to detect IRF6 expression while COBRA assay and bisulphite pyrosequencing were used to examine promoter methylation of IRF6. Enrichment of total H3K27 acetylation and H3K4 mono-methylation were detected by western blotting. Colony formation and flow cytometry were used to examine proliferation and apoptosis in UC cells overexpressed or depleted with IRF6. Nude mice xenograft model was used to examine the effect of IRF6 in UC. Results Our result showed that several genes, including IRF6 were upregulated after treatment with CPH in BFTC905 UC cells. Further experiments found that treatment of CPH could restore the expression of IRF6 in several other UC cell lines, probably due to promoter hypomethylation and enrichment of H3K27 acetylation and H3K4 mono-methylation. These results may be due to the fact that CPH could alter the activity, but not the expression of epigenetic modifiers. Finally, re-expression of IRF6 in UC inhibited tumor growth in vitro and in an xenograft mouse model, by inducing apoptosis. Conclusion In conclusion, our results suggested that CPH may be an epigenetic modifier, modulating the expression of the potential tumor suppressor IRF6, in inhibiting tumor growth in UC.

Additional file 1: Table S1. Primer information.

Additional file 3: Figure S1. Original gel images.

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.

During the treatment planning stage of the radiotherapy, the medical physicists or doctors have to delineate the contour of the tumor and the organs at risk in order to accurately deliver enough radiation energy to the tumor and reduce such exposure to the surrounding normal tissues. Organ contouring is a time-consuming and laborious task. An automatic contouring tool is definitely required to fulfill the needs of the increasing cancer population. In this work, we proposed a fusion model that combines the network characteristics of a sequential model (sensor3D) and Attention U-Net. In which the convolutional LSTM layer is applied to study the spatial correlation between different layers in a CT image data set. The attention mechanism suppresses the irrelevant features from the complex image content and focuses on the useful messages of target organs. The clinical data contained CT image series of 108 patients and was acquired from a local hospital with IRB approval. The proposed model segmented five types of organs, lung, liver, stomach, esophagus, and heart. The segmentation accuracy rates of Dice Similarity Coefficient (DSC) were 99.27%, 95.48%, 88.19%, 80.81%, and 93.8%, respectively. We further developed a user interface that converts the AI-generated results into DICOM-RT format. Therefore the radiologists can fine-tune the results under the software used to do the routine manual-delineation tasks.

Purpose/objective(s) Definitive chemoradiation is essential in non-operative thoracic esophageal cancer. Concerns have posed onto the possible radiation-induced lymphopenia and correlation with different survival outcomes. Neutrophil to lymphocyte ratio (NLR) is a simple way to surrogate the inflammation-immunity status and predict survival. We aim to evaluate the clinical variables and radiation dosimetric parameters associated with hematologic variables changes. Materials/methods Between 2010 and 2015, we identified 93 newly diagnosed thoracic esophageal squamous-cell cancer patients who had completed definitive concurrent chemoradiotherapy (CCRT). Patients' clinical, dosimetric, and hematological data, including absolute neutrophil count, absolute lymphocyte count, and NLR were analyzed at baseline and during CCRT. Cox regression model and Kaplan-Meier analyses were used to validate different survival outcomes. The possible relationships between clinical, hematologic, and dosimetric variables were tested using Spearman's rank or Pearson correlation coefficients, and a further multivariable logistic regression model was created to verify these significant variables. Results The participant group (mean age = 58.6 y) predominantly comprised males (94%) with 27% stage II (n = 25) and 73% stage III (n = 68). Median overall survival (OS) was 13 months (95% confidence interval: 10.304-15.696). We confirmed that baseline NLR (NLR-b) and highest NLR during CCRT (NLR-h) significantly predicted OS, progression-free survival, disease-specific survival, and freedom from distant metastasis. Dichotomized NLR-b with > 3.68 or ≤3.68 also predicted the survival outcomes. Primary esophageal tumor length (Spearman's correlation coefficient r = 0.324, P = 0.011) and baseline body weight (Spearman's r = -0.251, P = 0.019) were significantly correlated with baseline NLR > 3.68. In multivariable logistic regression, primary esophageal tumor length (OR = 1.345, P = 0.021) remained associated with a higher NLR-b. For NLR-h, lung V5 (Pearson r = 0.254, P = 0.014) and V10 (Pearson r = 0.317, P = 0.002) were significantly correlated. In the percentage of ALC nadir decreased during CCRT, lung V5 (Pearson r = 0.299, P = 0.005) and heart V10 (Pearson r = 0.273, P = 0.011) were significantly correlated. Conclusion Inflammation predicts survival outcomes and is correlated with tumor size. Low-dose thoracic irradiation affects inflammation-immunity dynamics because lung V5 and V10 are related to NLR-h; lung V5 and heart V10 with extent of lymphocyte decrease. A novel approach to decrease these unnecessary exposures may further improve survival outcomes in esophageal cancer treated with CCRT.

// Chih-Chia Yu 1, 2, * , Shih-Kai Hung 2, 3, * , Hon-Yi Lin 2, 3 , Wen-Yen Chiou 2, 3 , Moon-Sing Lee 2, 3 , Hui-Fen Liao 4 , Hsien-Bin Huang 1 , Hsu-Chueh Ho 5 and Yu-Chieh Su 6, 7 1 Department of Life Science and Institute of Molecular Biology, National Chung Cheng University, Chia-Yi, Taiwan, R.O.C 2 Department of Radiation Oncology, Dalin Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Taiwan, R.O.C 3 School of Medicine, Tzu Chi University, Hualian, Taiwan, R.O.C 4 Department of Biochemical Science and Technology, National Chiayi University, Chia-Yi, Taiwan, R.O.C 5 Department of Otolaryngology, Dalin Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Taiwan, R.O.C 6 Division of Hematology and Oncology, E-Da Hospital, Kaohsiung, Taiwan 7 School of Medicine, I-Shou University, Kaohsiung, Taiwan, R.O.C * These authors (Chih-Chia Yu and Shih-Kai Hung) contributed equally to this work Correspondence to: Yu-Chieh Su, email: hepatoma@gmail.com Keywords: PI3K/mTOR pathway, radiation, radiosensitization, radioresistant, oral cancer Received: September 23, 2016 Accepted: June 20, 2017 Published: August 02, 2017 ABSTRACT 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.

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.

MicroRNAs (miRNAs) have been shown to play a crucial role in the progression of human cancers, including urothelial carcinoma (UC), the sixth-most common cancer in the world. Among them, miR-34a has been implicated in the regulation of cancer stem cells (CSCs), however, its role in UC has yet to be fully elucidated. In this study, bioinformatics and experimental analysis confirmed that miR-34a targets CD44 (a CSC surface marker) and c-Myc (a well-known cell cycle regulator) in UC. We found that, surprisingly, most UC cell lines and patient samples did express miR-34a, although epigenetic silencing by promoter hypermethylation of miR-34a expression was observed only in UMUC3 cells, and a subset of patient samples. Importantly, overexpression of c-Myc, a frequently amplified oncogene in UC, was shown to upregulate CD44 expression through a competing endogenous RNA (ceRNA) mechanism, such that overexpression of the c-Myc 3&prime, UTR upregulated CD44, and vice versa. Importantly, we observed a positive correlation between the expression of c-Myc and CD44 in clinical samples obtained from UC patients. Moreover, overexpression of a dominant-negative p53 mutant downregulated miR-34a, but upregulated c-Myc and CD44, in UC cell lines. Functionally, the ectopic expression of miR-34a was shown to significantly suppress CD44 expression, and subsequently, suppression of cell growth and invasion capability, while also reducing chemoresistance. In conclusion, it appears that aberrant promoter methylation, and c-Myc-mediated ceRNA mechanisms, may attenuate the function of miR-34a, in UC. The tumor suppressive role of miR-34a in controlling CSC phenotypes in UC deserves further investigation.

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. 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. 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. Before enrolling participants, the present study was registered prospectively on ClinicalTrials.gov (trial identifier, NCT02921139 ) on Sep. 29, 2016. This study is ongoing.

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 H2O2 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.

Objective: Cardiovascular events induced in breast cancer patients receiving radiotherapy (RT), chemotherapy (CT), or a combination of both (CRT) can increase the risk of death. This nationwide population-based study aims to estimate the risk of cardiovascular complications with a follow-up period of 5 years. Materials and Methods: The study cohorts consisted of all patients hospitalized with a principal diagnosis of breast cancer who underwent treatment in 2002. The Cox proportional hazard model and Kaplan–Meier plot were analyzed to compare the cardiovascular event-free survival rate among breast cancer patients treated with different modalities. Results: Of the 5514 breast cancer patients identified, 289 patients had cardiovascular disease (CVD): 110 (5.7%) from the surgery-alone group, 24 (4.1%) from the RT group, 79 (4.6) from the CT group, and 76 (5.8%) from the CRT group. Breast cancer patients who undergo CT and CRT at an age less than 55 years had a higher risk of CVD when compared with the surgery-alone group (for both groups, p

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.

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.

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

ObjectiveHepatocellular carcinoma (HCC) is a common cause of cancer mortality. Resection is the best choice for HCC. Our objective was to evaluate the impact of various factors that affected survival in patients with resectable HCC.Materials and methodsBetween January 1, 2007 and December 31, 2013, 107 patients with a diagnosis of HCC who underwent surgery were enrolled retrospectively. The analysis was carried using t tests, the Kaplan–Meier method, and Cox proportional hazard regression model to identify potential confounding and predicting variables.ResultsThe 3-year overall survival rates in patients with surgical margins >1 mm and ≤1 mm were 79% and 59% (p = 0.02), respectively, and those in patients with and without vascular invasion were 57% and 93% (p