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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.

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.

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.

A temporal focusing multiphoton illumination (TFMI) method is proposed for achieving selective volume illumination (SVI) (i.e., illuminating only the volume of interest) in light-field microscopy (LFM). The proposed method minimizes the background noise of the LFM images and enhances the contrast, and thus improves the imaging quality. Three-dimensional (3D) volumetric imaging is achieved by reconstructing the LFM images using a phase-space deconvolution algorithm. The experimental results obtained using 100-nm fluorescent beads show that the proposed TFMI-LFM system achieves lateral and axial resolutions of 1.2 µm and 1.1 µm, respectively, at the focal plane. Furthermore, the TFMI-LFM system enables 3D images of the single lobe of the drosophila mushroom body with GFP biomarker (OK-107) to be reconstructed in a one-snapshot record.

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

Significance: Line scanning-based temporal focusing multiphoton microscopy (TFMPM) has superior axial excitation confinement (AEC) compared to conventional widefield TFMPM, but the frame rate is limited due to the limitation of the single line-to-line scanning mechanism. The development of the multiline scanning-based TFMPM requires only eight multiline patterns for full-field uniform multiphoton excitation and it still maintains superior AEC. Aim: The optimized parallel multiline scanning TFMPM is developed, and the performance is verified with theoretical simulation. The system provides a sharp AEC equivalent to the line scanning-based TFMPM, but fewer scans are required. Approach: A digital micromirror device is integrated in the TFMPM system and generates the multiline pattern for excitation. Based on the result of single-line pattern with sharp AEC, we can further model the multiline pattern to find the best structure that has the highest duty cycle together with the best AEC performance. Results: The AEC is experimentally improved to 1.7 μm from the 3.5 μm of conventional TFMPM. The adopted multiline pattern is akin to a pulse-width-modulation pattern with a spatial period of four times the diffraction-limited line width. In other words, ideally only four π/2 spatial phase-shift scans are required to form a full two-dimensional image with superior AEC instead of image-size-dependent line-to-line scanning. Conclusions: We have demonstrated the developed parallel multiline scanning-based TFMPM has the multiline pattern for sharp AEC and the least scans required for full-field uniform excitation. In the experimental results, the temporal focusing-based multiphoton images of disordered biotissue of mouse skin with improved axial resolution due to the near-theoretical limit AEC are shown to clearly reduce background scattering.

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.

In this study, a smart rapid laser scanning system with 3D small object detection for disabling caterpillars has integrated. A monocular camera vision system was developed which works in tandem with rapid laser scanning system. Two caterpillar species Orgyia Postica and Porthesia Taiwana were considered and their original images were used to train YOLO for identification. Color transform from RGB to HSV was applied to Orgyia Postica, and for Porthesia Taiwana, RGB color space was maintained, to successfully detect the caterpillar’s head. The centre of the caterpillar’s head was positively approximated by using k-means clustering algorithm. These identified coordinates were then exposed to automatically controlled laser beam. Compact CW lasers of wavelength 450 nm with 1.738 W power with beam diameter 2.5 mm was used and their respective effects were studied. The entire setup was controlled using the NVIDIA Jetson TX2 embedded system. It was observed that even a precise exposure of second long laser beams on the head incapacitated the caterpillar from further ingestion of food. Therefore, this synergistic utilization of deep learning and lasers seems to be a beneficial and promising approach to effectively control the pest population, thereby preventing crop damage and improving the yield.

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.

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.

Light field technique at a single shot can get the whole volume image of observed sample. Therefore, the original frame rate of the optical system can be taken as the volumetric image rate. For dynamically imaging whole micron-scale biosample, a light field microscope with temporal focusing illumination has been developed. In the light field microscope, the f-number of the microlens array (MLA) is adopted to match that of the objective; hence, the subimages via adjacent lenslets do not overlay each other. A three-dimensional (3D) deconvolution algorithm is utilized to deblur the out-of-focusing part. Conventional light field microscopy (LFM) illuminates whole volume sample even noninteresting parts; nevertheless, whole volume excitation causes even more damage on bio-sample and also increase the background noise from the out of range. Therefore, temporal focusing is integrated into the light field microscope for selecting the illumination volume. Herein, a slit on the back focal plane of the objective is utilized to control the axial excitation confinement for selecting the illumination volume. As a result, the developed light field microscope with the temporal focusing multiphoton illumination (TFMPI) can reconstruct 3D images within the selected volume, and the lateral resolution approaches to the theoretical value. Furthermore, the 3D Brownian motion of two-micron fluorescent beads is observed as the criterion of dynamic sample. With superior signal-to-noise ratio and less damage to tissue, the microscope is potential to provide volumetric imaging for vivo sample.

Summary Objectives In resected buccal cancer patients, an unexpected close surgical margin has been observed to correlate with poor clinical outcomes. However, close surgical margin alone does not independently guide post-operative therapies, revealing a clinical debate. Hence, the present study intended to explore epigenetic-based bio-predictors for further stratifying this debating patient population. Materials and methods Between 2000 and 2008, we retrospectively recruited 44 resected buccal cancer patients with a close surgical margin of ⩽5 mm. All patients had post-operative radiotherapy. Genomic DNA was extracted from tumor-enrich areas that contained cancer cells of >70%. Methylation-specific PCR was performed to detect promoter methylation of four tumor suppressor genes, including RASSF1A, DAPK, IRF8, and SFRP1. Post-irradiation locoregional control was defined as the primary end point. Results There were 40 males and 4 females, with a median age of 53.5 years (range, 32–82 years). Multivariate analysis identified two independent predictors for locoregional recurrence: very close margin of ⩽1 mm (HR: 4.96; 95% CI, 1.63–15.09; P = 0.018) and promoter hypermethylation of DAPK (HR: 2.83; 95% CI, 1.05–7.63; P = 0.042). The highest risk of locoregional recurrence was observed in patients with both of the two factors (HR, 8.05; 95% CI, 2.56–25.82; P = 0.002) when compared with patients with none. Shorter disease-free survival, but not overall survival, was also observed. Conclusion More aggressive managements should be considered in resected buccal cancer patients with both very close margin and DAPK promoter hypermethylation rather than post-operative observation or radiotherapy alone.

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.

Objectives A close margin of ≤3 mm results in a high risk for locoregional recurrence, but still is not an independent factor that helps to guide the use of aggressive postoperative therapies in patients with resected buccal mucosa carcinoma. This suggests there is a diversity of clinical outcomes in this group of patients. The present study explores the predictors among this clinically debated group of patients. Materials and Methods From 2000 to 2008, 30 resected buccal mucosa carcinoma patients with a close margin of ≤3 mm were retrospectively included in this study. All patients were treated with radical surgery together with postoperative radiotherapy (RT) or chemoradiotherapy (CCRT). Locoregional/local/regional control, disease-free status, disease-specific survival and overall survival were the study end points. Results Two factors were observed that were able to predict 5-year locoregional control. These were a pathological N classification (pN0 vs. pN1-2, 71.5% vs. 30.0%, p = 0.044) and a very close margin (> 1 mm vs. ≤1 mm, 81.8% vs. 50.7%, p = 0.040). Remarkably, the predicting effect of a very close margin was well translated into disease-free status (81.8% vs. 47.1%, p = 0.024) and disease-specific survival (100% vs. 70.6%, p = 0.037). After multivariate analysis, a very close margin of ≤1 mm was found to independently predict a high risk of locoregional recurrence (HR, 9.528; 95% CI, 1.326–18.481; p = 0.025) and disease failure at any site (HR, 12.778; 95% CI, 1.934–25.217; p = 0.013). Conclusion More aggressive postoperative treatments should be considered for resected buccal mucosa carcinoma patients with a very close margin of ≤1 mm.

ObjectivePulmonary 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 participantsThe 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/exposure(s)Irradiation was delivered to bronchial stump and mediastinum according to peer-audited guidelines.Outcome(s)/measure(s)Hospitalised pneumonia/pneumonitis-free survival was the primary end point. Risk factors and hazard effects were secondary measures.ResultsMultivariable 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 pConclusionsA 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.

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

// Hon-Yi Lin 1,6,8 , Shih-Kai Hung 1,6 , Moon-Sing Lee 1,6 , Wen-Yen Chiou 1,6 , Tze-Ta Huang 2,6,7 , Chih-En Tseng 3,6 , Liang-Yu Shih 3,6 , Ru-Inn Lin 1,6,8 , Jora M.J. Lin 8,9 , Yi-Hui Lai 8,9 , Chia-Bin Chang 8,9 , Feng-Chun Hsu 1 , Liang-Cheng Chen 1 , Shiang-Jiun Tsai 1 , Yu-Chieh Su 4,6 , Szu-Chi Li 4,6 , Hung-Chih Lai 4,6 , Wen-Lin Hsu 5,6 , Dai-Wei Liu 5,6 , Chien-Kuo Tai 8,9 , Shu-Fen Wu 8,9 and Michael W.Y. Chan 8,9,10 1 Department of Radiation Oncology, Buddhist Dalin Tzu Chi General Hospital, Taiwan, ROC 2 Department of Oral and Maxillofacial Surgery, Buddhist Dalin Tzu Chi General Hospital, Taiwan, ROC 3 Department of Anatomic Pathology, Buddhist Dalin Tzu Chi General Hospital, Taiwan, ROC 4 Department of Hematology-Oncology, Buddhist Dalin Tzu Chi General Hospital, Taiwan, ROC 5 Department of Radiation Oncology, Buddhist Tzu Chi General Hospital, Hualien, Taiwan, ROC 6 School of Medicine, Tzu Chi University, Hualien, Taiwan, ROC 7 Institute of Oral Medicine, National Cheng Kung University, Tainan, Taiwan, ROC 8 Institute of Molecular Biology, National Chung Cheng University, Min-Hsiung, Chia-Yi, Taiwan, ROC 9 Department of Life Science, National Chung Cheng University, Min-Hsiung, Chia-Yi, Taiwan, ROC 10 Human Epigenomics Center, National Chung Cheng University, Min-Hsiung, Chia-Yi, Taiwan, ROC Correspondence: Michael W.Y. Chan, email: // Keywords : Epigenetics, FHIT, oral cancer, radiotherapy, resistance Received : September 03, 2014 Accepted : November 24, 2014 Published : November 25, 2014 Abstract 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.

Background Increased risk of ischemic stroke has been validated for several cancers, but limited study evaluated this risk in cervical cancer patients. Our study aimed to evaluate the risk of ischemic stroke in cervical cancer patients. Methods The study analyzed data from the 2003 to 2008 National Health Insurance Research Database (NHIRD) provided by the National Health Research Institutes in Taiwan. Totally, 893 cervical cancer patients after radiotherapy and 1786 appendectomy patients were eligible. The Kaplan-Meier method and the Cox proportional hazards model were used to assess the risk of ischemic stroke. Results The 5-year cumulative risk of ischemic stroke was significantly higher for the cervical cancer group than for the control group (7.8% vs 5.1%; p p = 0.04; HR = 1.37, p = 0.07) and in patients with more than two comorbid risk factors (5 years cumulative stroke rate of two comorbidities: 15% compared to no comorbidities: 4%). Conclusions These study demonstrated cervical cancer patients had a higher risk of ischemic stroke than the general population, especially in younger patients. Strategies to reduce this risk should be assessed.

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

Background Venous thromboembolism (VTE) is a life-threatening condition that occurs as a complication of cervical cancer. The aim of this study was to evaluate the incidence of VTE in cervical cancer patients during a 5-year follow-up. Methods The study analyzed data deposited between 2003 and 2008 in the National Health Insurance Research Database (NHIRD), provided by the National Health Research Institutes in Taiwan. Totally, 1013 cervical cancer patients after treatment and 2026 appendectomy patients were eligible. The Kaplan-Meier method and the Cox proportional hazards model were used to assess the VTE risk. Results The 5-year cumulative risk for VTE was significantly higher in the cervical cancer group than in the control group (3.3% vs 0.3%, p vs 30.3%, p Conclusions The cumulative risk of VTE was significantly higher in cervical cancer patients, and these patients also had lower survival rates. Strategies to reduce these risks need to be examined.

Background Current staging systems have limited ability to adjust optimal therapy in advanced nasopharyngeal carcinoma (NPC). This study aimed to delineate the correlation between tumor volume, treatment outcome and chemotherapy cycles in advanced NPC. Methods A retrospective review of 110 patients with stage III-IV NPC was performed. All patients were treated first with neoadjuvant chemotherapy, then concurrent chemoradiation, and followed by adjuvant chemotherapy as being the definitive therapy. Gross tumor volume of primary tumor plus retropharyngeal nodes (GTVprn) was calculated to be an index of treatment outcome. Results GTVprn had a close relationship with survival and recurrence in advanced NPC. Large GTVprn (≧13 ml) was associated with a significantly poorer local control, lower distant metastasis-free rate, and poorer survival. In patients with GTVprn ≧ 13 ml, overall survival was better after ≧4 cycles of chemotherapy than after less than 4 cycles. Conclusions The incorporation of GTVprn can provide more information to adjust treatment strategy.

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 Illumina 27K methylation BeadChip microarray, we identified promoter hypermethylation of FHIT (fragile histidine triad) in radioresistant OML1-R cells, established from hypo-fractionated irradiation (5-Gy by 10 fractions) of parental OML1 radiosensitive oral cancer cells. Further analysis confirmed that transcriptional repression of FHIT was due to promoter hypermethylation and H3K27me3 as demonstrated by MBDcap-PCR, bisulfite pyrosequencing and ChIP-PCR. These phenomenon were partially attributed to overexpression of EZH2 and DNMT3a, 3b in OML1-R cells. In consistent with these observations, treatment of 5-azaDC, EZH2 inhibitor (GSK343) or depletion of EZH2 by lentiviral knockdown restored FHIT expression in OML1-R cells. Interestingly, knockdown of EZH2 also reversed histone modifications (increased of H3K4me3 and decreased of H3K27me3) and reduced promoter methylation of FHIT thus suggesting that H3K27me3 linked to DNA methylation in this loci. We also analyzed the expression of FHIT in primary human oral keratinocyte (HOK) and four other oral cancer cell lines (OCSL, SCC25, SAS, and SCC4). FHIT expression demonstrated a tight inverse relationship with its promoter methylation. Ectopic expression of FHIT restored radiosensitivity (single fraction, 10-Gy) in OML1-R cells and oral cancer cells (SAS, SCC25) showing epigenetic silencing of FHIT. These phenomenon may be due to restoration of Chk2 phosphorylation, induction of apoptosis and G2/M check point. Reciprocal experiments also showed that depletion of FHIT in OSCL cells, which highly express FHIT, slightly enhanced radioresistance. Clinically, bisulfite pyrosequencing and iummnohistochemistry revealed that promoter hypermethylation of FHIT inversely correlated with its expression. Patients with higher FHIT methylation (methylation>10%, n = 22) are associated with lower locoregional control (P Citation Format: Hon-Yi Lin, Shih-Kai Hung, Moon-Sing Lee, Wen-Yen Chiou, Tze-Ta Huang, Chih-En Tseng, Liang-Yu Shih, Ru-Inn Lin, Jora Lin, Yi-Hui Lai, Chia-Bin Chang, Feng-Chun Hsu, Liang-Cheng Chen, Shiang-Jiun Tsai, Yu-Chieh Su, Szu-Chi Li, Hung-Chih Lai, Wen-Lin Hsu, Dai-Wei Liu, Chien-Kuo Tai, Shu-Fen Wu, Michael W. Chan. DNA methylome analysis identifies epigenetic silencing of FHIT as a determining factor for radiosensitivity in oral cancer and its implication in treatment and outcome prediction. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3314. doi:10.1158/1538-7445.AM2015-3314

Background Most treatment failure of buccal mucosal cancer post surgery is locoregional recurrence. We tried to figure out how close the surgical margin being unsafe and needed further adjuvant treatment. Methods Between August 2000 and June 2008, a total of 110 patients with buccal mucosa carcinoma (25 with stage I, 31 with stage II, 11 with stage III, and 43 with Stage IV classified according to the American Joint Committee on Cancer 6th edition) were treated with surgery alone (n = 32), surgery plus postoperative radiotherapy (n = 38) or surgery plus adjuvant concurrent chemoradiotherapy (n = 40). Main outcome measures: The primary endpoint was locoregional disease control. Results The median follow-up time at analysis was 25 months (range, 4-104 months). The 3-year locoregional control rates were significantly different when a 3-mm surgical margin (≤3 versus >3 mm, 71% versus 95%, p = 0.04) but not a 5-mm margin (75% versus 92%, p = 0.22) was used as the cut-off level. We also found a quantitative correlation between surgical margin and locoregional failure (hazard ratio, 2.16; 95% confidence interval, 1.14 - 4.11; p = 0.019). Multivariate analysis identified pN classification and surgical margin as independent factors affecting disease-free survival and locoregional control. Conclusions Narrow surgical margin ≤3 mm, but not 5 mm, is associated with high risk for locoregional recurrence of buccal mucosa carcinoma. More aggressive treatment after surgery is suggested.

ObjectiveThe aim of this study was to retrospectively analyze locally advanced buccal cancer in order to determine tumor characteristics and any other prognostic factors that may influence the survival of patients with the disease.Patients and MethodsThe records of 54 patients with stage III to IV locally advanced buccal cancer (TNM system) who were seen from August 2000 to June 2008 at one institution were reviewed. The patients received radical surgery and then adjuvant treatment. The adjuvant treatment in cluded concurrent chemoradiotherapy or radiotherapy alone. The chemotherapy protocol consisted of two 4-weekly courses of concurrent cisplatin and 5-fluorouracil followed by another two 4-weekly courses after radiotherapy, with regimens of cisplatin (60–100 mg/m2/day) on day 1 and 5-fluorouracil (1000 mg/m2/day) on days 1–5.ResultsThe 3-year cumulative overall survival, disease-specific survival, disease-free survival, locoregional control, and distant metastasis-free survival rates were 66%, 69%, 58%, 65%, and 92%, respectively. Univariate analysis indicated that the pN classification, the surgical margin, and the presence of extracapsular spread were significantly associated with overall survival. On multivariate analysis, pN classification and surgical margin significantly affected disease-free survival. The pN classification (pN0 vs. pN1–3) and the surgical margin (< 1 vs.≥ 1 mm) were the two most significant factors affecting clinical outcome.ConclusionThe presence of lymph node involvement, the presence of extracapsular spread and a surgical margin < 1 mm were strong prognostic factors that were associated with tumor control. More aggressive postoperative therapy is suggested for patients with buccal mucosa carcinoma if these factors exist.