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The uncertainties of four-dimensional computed tomography (4DCT), also called as residual motion artefacts (RMA), induced from irregular respiratory patterns can degrade the quality of overall radiotherapy. This study aims to quantify and reduce those uncertainties. A comparative study on quantitative indicators for RMA was performed, and based on this, we proposed a new 4DCT sorting method that is applicable without disrupting the current clinical workflow. In addition to the default phase sorting strategy, both additional amplitude information from external surrogates and the quantitative metric for RMA, investigated in this study, were introduced. The comparison of quantitative indicators and the performance of the proposed sorting method were evaluated via 10 cases of breath-hold (BH) CT and 30 cases of 4DCT. It was confirmed that N-RMSD (normalised root-mean-square-deviation) was best matched to the visual standards of our institute's regime, manual sorting method, and could accurately represent RMA. The performance of the proposed method to reduce 4DCT uncertainties was improved by about 18.8% in the averaged value of N-RMSD compared to the default phase sorting method. To the best of our knowledge, this is the first study that evaluates RMA indicators using both BHCT and 4DCT with visual-criteria-based manual sorting and proposes an improved 4DCT sorting strategy based on them., Competing Interests: The authors have declared that no competing interests exist.

Objective: This study aimed to identify the distinct barriers and knowledge level of cervical cancer screening among female university students and establish intervention strategies to overcome these barriers., Methods: This study used a mixed-methods design with 26 female university students aged 20-29 years. We first conducted a quantitative online survey for the same study participants, divided them into three groups, and conducted focus group interviews (FGIs). Group A: participants who had sexual experience and had undergone cervical cancer screening; Group B: participants who had sexual experience and had not undergone cervical cancer screening; Group C: participants who did not have sexual experience and had not undergone cervical cancer screening., Results: The participants' ages were 21.92 ± 1.26 years. The knowledge levels for cervical cancer and screening were low to moderate. The four main themes that emerged as barriers to cervical cancer screening through the FGIs were: 1) socio-cultural barrier: conservative social perception of unmarried women's sexual life, 2) knowledge barrier: lack of knowledge and information, 3) psychological barrier: discomfort, and 4) practical barrier: time-consuming. The three themes identified for strategies were: 1) socio-cultural intervention: changing social perceptions and ensuring confidentiality, 2) educational intervention: improvement of knowledge and accessibility, and 3) alternative screening intervention: comfortable screening methods., Conclusions: While university students' sexual experience rapidly increased, the socio-cultural perceptions of sexual health remained closed, and they had a reasonably low level of knowledge about cervical cancer screening. Therefore, various strategies sensitive to female university students' culture should be implemented to increase the knowledge level, and social efforts should be made to change the socio-cultural perception of unmarried young women's sexual health., Competing Interests: The authors have declared that no competing interests exist.

Postoperative pancreatic fistula (POPF) is a common complication following pancreaticoduodenectomy (PD). However, risk factors for this complication remain controversial. We conducted a retrospective analysis of 107 patients who underwent PD. POPF was diagnosed in strict accordance with the definition of the 2016 update of pancreatic fistula from the International Study Group on Pancreatic Fistula (ISGPF). Univariate and multivariate logistic regression analyses were performed to identify independent risk factors for POPF. A total of 19 (17.8%) subjects of pancreatic fistula occurred after PD, including 15 (14.1%) with grade B POPF and 4 (3.7%) with grade C POPF. There were 33 (30.8%) patients with biochemical leak. Risk factors for POPF (grade B and C) were larger area of visceral fat (odds ratio [OR], 1.40; p = 0.040) and pathology other than pancreatic adenocarcinoma or pancreatitis (OR, 12.45; p = 0.017) in the multivariate regression analysis. This result could assist the surgeon to identify patients at a high risk of developing POPF., Competing Interests: The authors have declared that no competing interests exist.

Background: Pancreatic pseudocysts (PC) and walled-off necrosis (WON) are common complications of severe pancreatitis. Endoscopic ultrasound (EUS)-guided drainage has replaced surgery as the standard treatment for PC/WON. We developed a novel lumen-apposing metal stent (LAMS) with an anti-reflux valve to prevent infectious complications caused by food reflux into the cyst cavity. This retrospective study investigated the efficacy and safety of EUS-guided drainage using this LAMS., Methods: We investigated and compared the treatment outcomes and complications rates between EUS-guided drainage using a novel LAMS (n = 10) versus plastic stents (n = 18) from December 2013 to October 2016. Technical success was defined as successful stent placement without immediate complications. Clinical success was defined as resolution of the PC/WON and disappearance of symptoms., Results: Among 10 patients in LAMS group, 4 patients had complicated PC and 6 patients had WON. In the plastic stent group, 15 and 3 patients had PC and WON, respectively. The median fluid collection size before treatment was 82.5 (interquartile range [IQR], 60.75-118.25) mm and 92.0 (IQR, 75.75-130.25) mm in the LAMS and plastic stent groups, respectively. There were no statistically significant differences in technical success rates (90% vs. 94.4%; p = 0.999), clinical success rates (80% vs. 77.8%; p = 0.999), and complication rates (20% vs. 27.8%; p = 0.999) between the two groups., Conclusions: Treatment outcomes of EUS-guided drainage using a novel LAMS were feasible despite the significantly high proportion of WON. The LAMS allowed acceptable treatment outcomes for EUS-guided drainage., Competing Interests: The authors have declared that no competing interests exist.

Postoperative adhesion is a natural phenomenon that occurs in damaged tissue cells. Several anti-adhesion agents are currently used, but there is no leading-edge product with excellent adhesion-preventive effects. The purpose of this study was to develop ideal anti-adhesive agents using human-derived acellular dermal matrix (ADM). We developed 5 new biocompatible thermosensitive anti-adhesion barriers (AABs) using micronized human-derived ADM, hyaluronic acid, and temperature-sensitive and biocompatible synthesized polymers. The biocompatibility, anti-adhesion effect, and biodegradability of these AABs were compared with those of commercial thermosensitive anti-adhesion agents. No cytotoxic effects were observed in vitro and in vivo. Animal testing of adhesion resistance confirmed that the adhesion area, strength, and grade of AAB03 were statistically superior to those of the control group. Factors related to adhesion formation, such as lymphocytes, macrophages, microvessels, and collagen fiber density, were observed using specific staining methods; the results confirmed that AAB03 group exhibited significantly lower macrophage counts, microvessel density, and collagen fiber density than the control groups. Furthermore, AAB03 was completely absorbed by 6 weeks. Thus, AAB03 has the potential to be used as a high-performance anti-adhesion agent., Competing Interests: The authors of this manuscript have read the journal's policy and declare they have the following competing interests: YP, JIK, and HGK are paid employees of B&C BIO Co., Ltd. There are no patents, products in development, or marketed products to declare. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Purpose: This study aimed to evaluate the dosimetric accuracy of respiratory gated volumetric modulated arc therapy (VMAT) for lung stereotactic body radiation therapy (SBRT) under simulation conditions similar to the actual clinical situation using patient-specific lung phantoms and realistic target movements., Methods: Six heterogeneous lung phantoms were fabricated using a 3D-printer (3DISON, ROKIT, Seoul, Korea) to be dosimetrically equivalent to actual target regions of lung SBRT cases treated via gated VMAT. They were designed to move realistically via a motion device (QUASAR, Modus Medical Devices, Canada). Using the lung phantoms and a homogeneous phantom (model 500-3315, Modus Medical Devices), film dosimetry was performed with and without respiratory gating for VMAT delivery (TrueBeam STx; Varian Medical Systems, Palo Alto, CA, USA). The measured results were analyzed with the gamma passing rates (GPRs) of 2%/1 mm criteria, by comparing with the calculated dose via the AXB and AAA algorithms of the Eclipse Treatment Planning System (version 10.0.28; Varian Medical Systems)., Results: GPRs were greater than the acceptance criteria 80% for all film measurements with the stationary and homogeneous phantoms in conventional QAs. Regardless of the heterogeneity of phantoms, there were no significant differences (p > 0.05) in GPRs obtained with and without target motions; the statistical significance (p = 0.031) was presented between both algorithms under the utilization of heterogeneous phantoms., Conclusions: Dosimetric verification with heterogeneous patient-specific lung phantoms could be successfully implemented as the evaluation method for gated VMAT delivery. In addition, it could be dosimetrically confirmed that the AXB algorithm improved the dose calculation accuracy under patient-specific simulations using 3D printed lung phantoms., Competing Interests: The authors have declared that no competing interests exist.

Purpose: To develop a 4D dose reconstruction method and to evaluate the delivered dose in respiratory-gated volumetric modulated arc therapy (VMAT)., Materials and Methods: A total 112 treatment sessions of gated VMAT for 30 stereotactic body radiotherapy (SBRT) patients (10 lung, 10 liver, and 10 pancreas) were evaluated. For respiratory-gated SBRT, 4DCT was acquired, and the CT data at the end-exhale phase was used for a VMAT plan. The delivered dose was reconstructed using a patient's respiratory motion and machine motion acquired during the beam delivery. The machine motion was obtained from the treatment log file, while the target position was estimated from an external respiratory marker position. The target position was divided into 1-mm position bins, and sub-beams with beam isocenters corresponding to each position bin were created in a motion mimicking plan, reflecting motion data including MLC leaf positions and gantry angle and target position data during beam treatment. The reconstructed 4D dose was compared with the dose of the original plan using these dosimetric parameters; the maximum dose (Dmax) and mean dose (Dmean) of gross target volume (GTV) or organs at risk (spinal cord, esophagus, heart, duodenum, kidney, spinal cord, and stomach). The minimum dose (Dmin) to GTV was also calculated to verify cold spots in tumors., Results: There was no significant difference of dose parameters regard to the GTV in all tumors. For the liver cases, there were significant differences in the Dmax of duodenum (-4.2 ± 1.4%), stomach (-3.5 ± 4.2%), left kidney (-4.1 ± 2.8%), and right kidney (-3.2 ± 1.3%), and in the Dmean of duodenum (-3.8 ± 1.4%), stomach (-3.9 ± 2.2%), left kidney (-3.1 ± 2.8%), and right kidney (-4.1 ± 2.6%). For the pancreas cases, there were significant differences in the Dmax of stomach (2.1 ± 3.0%), and in the Dmean of liver (1.5 ± 0.6%), duodenum (-1.0 ± 1.4%), stomach (2.1 ± 1.6%), and right kidney (-1.3 ± 0.9%). The average gamma pass rates were 97.6 ± 4.8% for lung cases, 99.6 ± 0.5% for liver cases, and 99.5 ± 0.5% for pancreas cases. Most cases showed insignificant dose variation, with gamma pass rates higher than 98%, except for two lung cases with gamma pass rates of 86.9% and 90.6%. The low gamma pass rates showed larger global motion ranges resulting from the baseline shift during beam delivery., Conclusion: The actual delivered dose in thoracic and abdominal VMAT under breathing motion was verified by 4D dose reconstruction using typical treatment equipment and software. The proposed method provides a verification method for the actual delivered dose and could be a dosimetric verification QA tool for radiation treatment under various respiratory management techniques., Competing Interests: The authors have declared that no competing interests exist.

Lung cancer specialists play an important role in designing and implementing lung cancer screening. We aimed to describe their 1) attitudes toward low-dose lung computed tomography (LDCT) screening, 2) current practices and experiences of LDCT screening and 3) attitudes and opinions towards national lung cancer screening program (NLCSP). We conducted a national web-based survey of pulmonologists, thoracic surgeons, medical oncologists, and radiological oncologists who are members of Korean Association for Lung Cancer (N = 183). Almost all respondents agreed that LDCT screening increases early detection (100%), improves survival (95.1%), and gives a good smoking cessation counseling opportunity (88.6%). Most were concerned about its high false positive results (79.8%) and the subsequent negative effects. Less than half were concerned about radiation hazard (37.2%). Overall, most (89.1%) believed that the benefits outweigh the risks and harms. Most (79.2%) stated that they proactively recommend LDCT screening to those who are eligible for the current guidelines, but the screening propensity varied considerably. The majority (77.6%) agreed with the idea of NLCSP and its beneficial effect, but had concerns about the quality control of CT devices (74.9%), quality assurance of radiologic interpretation (63.3%), poor access to LDCT (56.3%), and difficulties in selecting eligible population using self-report history (66.7%). Most (79.2%) thought that program need to be funded by a specialized fund rather than by the National Health Insurance. The opinions on the level of copayment for screening varied. Our findings would be an important source for health policy decision when considering for NLCSP in Korea.

Acute pancreatitis is a common diagnosis worldwide, with gallstone disease being the most prevalent cause (50%). The American College of Gastroenterology recommends urgent endoscopic retrograde cholangiopancreatography (ERCP) (within 24 h) for patients with biliary pancreatitis accompanied by cholangitis. Most international guidelines recommend that ERCP be performed within 72 h in patients with biliary pancreatitis and a bile duct obstruction without cholangitis, but the optimal timing for endoscopy is controversial. We investigated the optimal timing for ERCP in patients with biliary pancreatitis and a bile duct obstruction without cholangitis, and whether performing endoscopy within 24 h is superior to performing it after 24 h. We analyzed the clinical data of 505 patients with newly diagnosed acute pancreatitis, from January 1, 2005 to December 31, 2014. We divided the patients into two groups according to the timing of ERCP: < 24 h (urgent) and 24-72 h (early).Among the 505 patients, 73 were diagnosed with biliary pancreatitis and a bile duct obstruction without cholangitis. The mean age of the patients was 55 years (range: 26-90 years). Bile duct stones and biliary sludge were identified on endoscopy in 45 (61.6%) and 11 (15.0%) patients, respectively. The timing of ERCP within 72 h was not associated with ERCP-related complications (P = 0.113), and the total length of hospital stay was not different between urgent and early ERCP (5.9 vs. 5.7 days, P = 0.174). No significant differences were found in total length of hospitalization or procedural-related complications, in patients with biliary pancreatitis and a bile duct obstruction without cholangitis, according to the timing of ERCP (< 24 h vs. 24-72 h).

Background: Reporting quality of randomized controlled trial (RCT) abstracts is important as readers often make their first judgments based on the abstracts. This study aims to assess the reporting quality of psychiatry RCT abstracts published before and after the release of Consolidated Standards of Reporting Trials for Abstracts (CONSORT-A) guidelines., Methods: MEDLINE/PubMed search was conducted to identify psychiatric RCTs published during 2005-2007 (pre-CONSORT) and 2012-2014 (post-CONSORT). Two independent reviewers assessed abstracts using a 18-point overall quality score (OQS) based on the CONSORT-A guidelines. Linear regression analysis was conducted to analyze factors associated with reporting quality., Results: Among 1,927 relevant articles, 285 pre-CONSORT and 214 post-CONSORT psychiatric RCT abstracts were included for analysis. The mean OQS improved from 6.9 (range: 3-13; 95% confidence interval (CI): 6.7-7.2) to 8.2 (range: 4-16; 95% CI: 7.8-8.5) after the CONSORT-A guidelines. Despite improvement, methods of randomization, allocation concealment, and funding source remained to be insufficiently reported (<5%) even after the release of CONSORT-A. High-impact general medical journals, multicenter design, positive outcome, and structured abstracts were associated with better reporting quality., Conclusions: The reporting quality in psychiatric RCT abstracts, although improved, remains suboptimal. To improve reporting quality of psychiatry RCT abstracts, greater efforts by both investigators and journal editors are required to enhance better adherence to the CONSORT-A guidelines.

Non-small-cell lung cancer (NSCLC) constitutes approximately 80% of all diagnosed lung cancers, and diagnostic markers detectable in the plasma/serum of NSCLC patients are greatly needed. In this study, we established a pipeline for the discovery of markers using 9 transcriptome datasets from publicly available databases and profiling of six lung cancer cell secretomes. Thirty-one out of 312 proteins that overlapped between two-fold differentially expressed genes and identified cell secretome proteins were detected in the pooled plasma of lung cancer patients. To quantify the candidates in the serum of NSCLC patients, multiple-reaction-monitoring mass spectrometry (MRM-MS) was performed for five candidate biomarkers. Finally, two potential biomarkers (BCHE and GPx3; AUC = 0.713 and 0.673, respectively) and one two-marker panel generated by logistic regression (BCHE/GPx3; AUC = 0.773) were identified. A validation test was performed by ELISA to evaluate the reproducibility of GPx3 and BCHE expression in an independent set of samples (BCHE and GPx3; AUC = 0.630 and 0.759, respectively, BCHE/GPx3 panel; AUC = 0.788). Collectively, these results demonstrate the feasibility of using our pipeline for marker discovery and our MRM-MS platform for verifying potential biomarkers of human diseases.

Purpose: Several studies reported the increased risk of second primary pancreatic ductal adenocarcinoma (2nd PDAC) in cancer survivors. However, data on the characteristics of 2nd PDAC are insufficient., Methods: This retrospective cohort study included 1759 patients with PDAC. They were classified as having 2nd PDAC or first primary PDAC (1st PDAC) according to a prior diagnosed cancer of different origin, at least 6 months before PDAC diagnosis., Results: There were 110 patients (6.4%) with 2nd PDAC and 1606 (93.6%) patients with 1st PDAC. Patients with 2nd PDAC presented with older age (66.5 vs. 62.2 years, p < 0.001) and higher rate of resectability (26.4% vs. 15.9%, p = 0.004) at diagnosis than those with 1st PDAC. Multivariate analysis without considering resectable status showed that 2nd PDAC (hazard ratio [HR] 0.73, 95% confidence interval [CI] 0.56-0.94, p = 0.016) was associated with better overall survival. After adjusting for resectable status, however, 2nd PDAC (HR 0.85, 95% CI 0.66-1.09, p = 0.198) was no longer associated with overall survival. When subgroups were separately analyzed according to initial treatment modality, the effectiveness of surgery and chemotherapy were similar between 2nd and 1st PDAC (33.1 vs. 28.5 months, p = 0.860 and 10.8 vs. 10.7 months, p = 0.952)., Conclusions: The proportion of resectable cases was significantly higher in 2nd PDAC. When surgery with curative aim was possible, the overall survival was increased even in patients with 2nd PDAC. These results suggest the importance of screening for second primary cancer in cancer survivors.

Objective: To investigate the impact of national implementation of age restriction on fluoroquinolone prescription in children and adolescents., Methods: Data collected from the database of Health Insurance Review and Assessment Service in South Korea, a national health insurance system to analyze fluoroquinolone prescribing practice in children and adolescents younger than 18 years, between 2007 and 2015. The age restriction was implemented in December 2009. The annual prescription rate of FQ per 100,000 person-years was calculated and an autoregressive model was used to predict the prescription pattern if an intervention had not occurred., Results: A total of 505,859 children received systemic fluoroquinolone during the study period-297,054 ciprofloxacin, and 208,805 levofloxacin. After implementation of the drug utilization review program, the annual prescription rate for ciprofloxacin declined by 97.5% (from 840 to 21 per 100,000 person-years, P < 0.001), and for levofloxacin by 96.4% (from 598 to 11 per 100,000 person-years, P < 0.001). The decline was more dramatic in the outpatient setting than in the inpatient setting for both drugs., Conclusion: The dramatic and sustained decline in prescription number and change in prescription pattern after the regulatory action suggests that the implementation under drug utilization review program was successful in controlling excessive and inappropriate use of fluoroquinolones in children, possibly guiding towards more judicious and selective prescription behavior.

Objectives: Despite a sharp increase in e-cigarette use, there is debate about whether e-cigarettes are a viable alternative for harm reduction, and the forms that regulation should take. Healthcare providers can be effective in offering guidance to patients and their families and shaping regulatory policy. We described lung cancer specialists' attitudes toward e-cigarettes and its regulation., Methods: We undertook a nationwide survey of pulmonologists, thoracic surgeons, medical and radiological oncologists who are members of Korean Association for Lung Cancer. Survey items included beliefs and attitudes toward e-cigarettes, attitudes toward e-cigarette regulation and preparedness on discussing e-cigarettes with their patients., Results: Most respondents believed that e-cigarettes are not safer than conventional tobacco cigarettes (75.7%) or smokeless tobacco (83.2%), and feared that discussing e-cigarettes with the patients would encourage use (65.4%). They did not consider it a smoking cessation treatment (78.3%), and thus would not recommend it to smokers who do not want to quit (82.2%) or who failed to quit with conventional smoking cessation treatment (74.1%). Most respondents supported all examples of e-cigarette regulations, including the safety and quality check (97.8%), warning label (97.8%), advertisement ban (95.1%), restriction of flavoring (78.4%), minimum purchasing age (99.5%), and restriction of indoor use (94.6%). Most learned about e-cigarettes from media and advertisements, or conversation with patients rather than through professional scientific resources, and reported discomfort when discussing e-cigarette with patients., Conclusion: Lung cancer specialist physicians in Korea doubt the safety of e-cigarette and use of e-cigarette as smoking cessation treatment, and supported strict regulation. However, only 20% reported that they obtained information on e-cigarettes from the scientific literature and many lacked adequate knowledge based on scientific evidence, suggesting the need for better preparedness. Nevertheless, the views of professionals revealed from our study could help to develop clinical guidelines and regulatory guidance.

Purpose: To evaluate the risk factors associated with loco-regional failure after surgical resection and to identify the subgroup that can obtain benefits from adjuvant radiotherapy (RT)., Materials and Methods: We identified patients treated with surgical resection for resectable pancreatic cancer at Severance hospital between January 1993 and December 2014. Patients who received any neoadjuvant or adjuvant RT were excluded. A total of 175 patients were included. Adjuvant chemotherapy was performed in 107 patients with either a gemcitabine-based regimen (65.4%) or 5-FU based one (34.9%)., Results: The median loco-regional failure-free survival (LRFFS) and overall survival (OS) were 23.9 and 33.6 months, respectively. A recurrence developed in 108 of 175 patients (61.7%). The predominant pattern of the first failure was distant (42.4%) and 47 patients (26.9%) developed local failure as the first site of recurrence. Multivariate analysis identified initial CA 19-9 ≥ 200 U/mL, N1 stage, perineural invasion (PNI), and resection margin as significant independent risk factors for LRFFS. Patients were divided into four groups according to the number of risk factors, including initial CA 19-9, N stage, and PNI. Patients exhibiting two risk factors had 3.2-fold higher loco-regional failure (P < 0.001) and patients with all risk factors showed a 6.5-fold increase (P < 0.001) compared with those with no risk factors. In the analysis for OS, patients with more than two risk factors also had 3.3- to 6-fold higher risk of death with statistical significance., Conclusion: The results suggest that patients who exhibit more than two risk factors have a higher risk of locoregional failure and death. This subgroup could be benefited by the effective local adjuvant treatment.

Purpose: To develop a simplified volumetric modulated arc therapy (VMAT) technique for more accurate dose delivery in thoracic stereotactic body radiation therapy (SBRT)., Methods and Materials: For each of the 22 lung SBRT cases treated with respiratory-gated VMAT, a dose rate modulated arc therapy (DrMAT) plan was retrospectively generated. A dynamic conformal arc therapy plan with 33 adjoining coplanar arcs was designed and their beam weights were optimized by an inverse planning process. All sub-arc beams were converted into a series of control points with varying MLC segment and dose rates and merged into an arc beam for a DrMAT plan. The plan quality of original VMAT and DrMAT was compared in terms of target coverage, compactness of dose distribution, and dose sparing of organs at risk. To assess the delivery accuracy, the VMAT and DrMAT plans were delivered to a motion phantom programmed with the corresponding patients' respiratory signal; results were compared using film dosimetry with gamma analysis., Results: The plan quality of DrMAT was equivalent to that of VMAT in terms of target coverage, dose compactness, and dose sparing for the normal lung. In dose sparing for other critical organs, DrMAT was less effective than VMAT for the spinal cord, heart, and esophagus while being well within the limits specified by the Radiation Therapy Oncology Group. Delivery accuracy of DrMAT to a moving target was similar to that of VMAT using a gamma criterion of 2%/2mm but was significantly better using a 2%/1mm criterion, implying the superiority of DrMAT over VMAT in SBRT for thoracic/abdominal tumors with respiratory movement., Conclusion: We developed a DrMAT technique for SBRT that produces plans of a quality similar to that achieved with VMAT but with better delivery accuracy. This technique is well-suited for small tumors with motion uncertainty.

Background and Aims: Although thicker needles theoretically allow more tissue to be collected, their decreased flexibility can cause mechanical damage to the endoscope, technical failure, and sample blood contamination. The effects of needle gauge on diagnostic outcomes of endoscopic ultrasound-guided fine-needle biopsy (EUS-FNB) of pancreatic mass lesions remain unknown. This study compared procurement rates of histologic cores obtained from EUS-FNB of pancreatic masses using 25- and 22-gauge core biopsy needles., Patients and Methods: From March 2014 to July 2014, 66 patients with solid pancreatic mass underwent EUS-FNB with both 25- and 22-gauge core biopsy needles. Among them, 10 patients were excluded and thus 56 patients were eligible for the analyses. Needle sequences were randomly assigned, and two passes were made with each needle, consisting of 10 uniform to-and-fro movements on each pass with 10 mL syringe suction. A pathologist blinded to needle sequence evaluated specimens for the presence of histologic core., Results: The mean patient age was 65.8 ± 9.5 years (range, 44-89 years); 35 patients (62.5%) were men. The mean pancreatic mass size was 35.3 ± 17.1 mm (range 14-122.3 mm). Twenty-eight patients (50%) had tumors at the pancreas head or uncinate process. There were no significant differences in procurement rates of histologic cores between 25-gauge (49/56, 87.5%) and 22-gauge (46/56, 82.1%, P = 0.581) needles or diagnostic accuracy using only histologic cores (98% and 95%). There were no technical failures or procedure-related adverse events., Conclusions: The 25-gauge core biopsy needle could offer acceptable and comparable outcomes regarding diagnostic performance including histologic core procurement rates compared to the 22-gauge core biopsy needle, although the differences were not statistically significant., Trial Registration: ClinicalTrials.gov NCT01795066.

A single tumor biopsy specimen is typically used in cancer genome studies. However, it may represent incompletely the underlying mutational and transcriptional profiles of tumor biology. Multi-regional biopsies have the advantage of increased sensitivity for genomic profiling, but they are not cost-effective. The concept of an alternative method such as the pooling of multiple biopsies is a challenge. In order to determine if the pooling of distinct regions is representative at the genomic and transcriptome level, we performed sequencing of four regional samples and pooled samples for four cancer types including colon, stomach, kidney and liver cancer. Subsequently, a comparative analysis was conducted to explore differences in mutations and gene expression profiles between multiple regional biopsies and pooled biopsy for each tumor. Our analysis revealed a marginal level of regional difference in detected variants, but in those with low allele frequency, considerable discrepancies were observed. In conclusion, sequencing pooled samples has the benefit of detecting many variants with moderate allele frequency that occur in partial regions, but it is not applicable for detecting low-frequency mutations that require deep sequencing.

Background: The importance of providing effective analgesia during sedation for complex endoscopic procedures has been widely recognized. However, repeated administration of opioids in order to achieve sufficient analgesia may carry the risk of delayed recovery after propofol based sedation. This study was done to compare recovery profiles and the satisfaction of the endoscopists and patients between conventional balanced propofol sedation and analgesia-oriented combination sedation for patients undergoing endoscopic retrograde cholangiopancreatography (ERCP)., Methods: Two hundred and two adult patients scheduled for ERCP were sedated by either the Conventional (initial bolus of meperidine with propofol infusion) or Combination (repeated bolus doses of fentanyl with propofol infusion) method. Recovery profiles, satisfaction levels of the endoscopists and patients, drug requirements and complications were compared between groups., Results: Patients of the Combination Group required significantly less propofol compared to the Conventional Group (135.0 ± 68.8 mg vs. 165.3 ± 81.7 mg, P = 0.005). Modified Aldrete scores were not different between groups throughout the recovery period, and recovery times were also comparable between groups. Satisfaction scores were not different between the two groups in both the endoscopists and patients (P = 0.868 and 0.890, respectively)., Conclusions: Considering the significant reduction in propofol dose, the non-inferiority of recovery profiles and satisfaction scores of the endoscopists and patients, analgesia oriented combination sedation may be a more safe yet effective sedative method compared to conventional balanced propofol sedation during ERCP.

Hedgehog (Hh) signaling is frequently up-regulated in fibrogenic pancreatic diseases including chronic pancreatitis and pancreatic cancer. Although recent series suggest exclusive paracrine activation of stromal cells by Hh ligands from epithelial components, debates still exist on how Hh signaling works in pathologic conditions. To explore how Hh signaling affects the pancreas, we investigated transgenic phenotypes in zebrafish that over-express either Indian Hh or Sonic Hh along with green fluorescence protein (GFP) to enable real-time observation, or GFP alone as control, at the ptf1a domain. Transgenic embryos and zebrafish were serially followed for transgenic phenotypes, and investigated using quantitative reverse transcription-polymerase chain reaction (qRT-PCR), in situ hybridization, and immunohistochemistry. Over-expression of Ihh or Shh reveals virtually identical phenotypes. Hh induces morphologic changes in a developing pancreas without derangement in acinar differentiation. In older zebrafish, Hh induces progressive pancreatic fibrosis intermingled with proliferating ductular structures, which is accompanied by the destruction of the acinar structures. Both myofibroblasts and ductular are activated and proliferated by paracrine Hh signaling, showing restricted expression of Hh downstream components including Patched1 (Ptc1), Smoothened (Smo), and Gli1/2 in those Hh-responsive cells. Hh ligands induce matrix metalloproteinases (MMPs), especially MMP9 in all Hh-responsive cells, and transform growth factor-ß1 (TGFß1) only in ductular cells. Aberrant Hh over-expression, however, does not induce pancreatic tumors. On treatment with inhibitors, embryonic phenotypes are reversed by either cyclopamine or Hedgehog Primary Inhibitor-4 (HPI-4). Pancreatic fibrosis is only prevented by HPI-4. Our study provides strong evidence of Hh signaling which induces pancreatic fibrosis through paracrine activation of Hh-responsive cells in vivo. Induction of MMPs and TGFß1 by Hh signaling expands on the current understanding of how Hh signaling affects fibrosis and tumorigenesis. These transgenic models will be a valuable platform in exploring the mechanism of fibrogenic pancreatic diseases which are induced by Hh signaling activation.

Background: SIRT1, a NAD-dependent deacetylase, has diverse roles in a variety of organs such as regulation of endocrine function and metabolism. However, it remains to be addressed how it regulates hormone release there., Methodology/principal Findings: Here, we report that SIRT1 is abundantly expressed in pituitary thyrotropes and regulates thyroid hormone secretion. Manipulation of SIRT1 level revealed that SIRT1 positively regulated the exocytosis of TSH-containing granules. Using LC/MS-based interactomics, phosphatidylinositol-4-phosphate 5-kinase (PIP5K)gamma was identified as a SIRT1 binding partner and deacetylation substrate. SIRT1 deacetylated two specific lysine residues (K265/K268) in PIP5Kgamma and enhanced PIP5Kgamma enzyme activity. SIRT1-mediated TSH secretion was abolished by PIP5Kgamma knockdown. SIRT1 knockdown decreased the levels of deacetylated PIP5Kgamma, PI(4,5)P(2), and reduced the secretion of TSH from pituitary cells. These results were also observed in SIRT1-knockout mice., Conclusions/significance: Our findings indicated that the control of TSH release by the SIRT1-PIP5Kgamma pathway is important for regulating the metabolism of the whole body.