Citations

Abstract Background Although 20 pancreatic cancer susceptibility loci have been identified through genome-wide association studies in individuals of European ancestry, much of its heritability remains unexplained and the genes responsible largely unknown. Methods To discover novel pancreatic cancer risk loci and possible causal genes, we performed a pancreatic cancer transcriptome-wide association study in Europeans using three approaches: FUSION, MetaXcan, and Summary-MulTiXcan. We integrated genome-wide association studies summary statistics from 9040 pancreatic cancer cases and 12 496 controls, with gene expression prediction models built using transcriptome data from histologically normal pancreatic tissue samples (NCI Laboratory of Translational Genomics [n = 95] and Genotype-Tissue Expression v7 [n = 174] datasets) and data from 48 different tissues (Genotype-Tissue Expression v7, n = 74–421 samples). Results We identified 25 genes whose genetically predicted expression was statistically significantly associated with pancreatic cancer risk (false discovery rate < .05), including 14 candidate genes at 11 novel loci (1p36.12: CELA3B; 9q31.1: SMC2, SMC2-AS1; 10q23.31: RP11-80H5.9; 12q13.13: SMUG1; 14q32.33: BTBD6; 15q23: HEXA; 15q26.1: RCCD1; 17q12: PNMT, CDK12, PGAP3; 17q22: SUPT4H1; 18q11.22: RP11-888D10.3; and 19p13.11: PGPEP1) and 11 at six known risk loci (5p15.33: TERT, CLPTM1L, ZDHHC11B; 7p14.1: INHBA; 9q34.2: ABO; 13q12.2: PDX1; 13q22.1: KLF5; and 16q23.1: WDR59, CFDP1, BCAR1, TMEM170A). The association for 12 of these genes (CELA3B, SMC2, and PNMT at novel risk loci and TERT, CLPTM1L, INHBA, ABO, PDX1, KLF5, WDR59, CFDP1, and BCAR1 at known loci) remained statistically significant after Bonferroni correction. Conclusions By integrating gene expression and genotype data, we identified novel pancreatic cancer risk loci and candidate functional genes that warrant further investigation.

Abstract Hypoxia‐induced extracellular matrix (ECM) deposition is an important cause of renal fibrosis that is triggered by unknown mechanisms. Human epididymis secretory protein 4 (HE4) is a newly discovered key molecule that causes ECM deposition. We used the unilateral ureteral obstruction (UUO) mouse model to investigate the expression and mechanisms of HE4 in the pathogenesis of renal fibrosis. Results were confirmed in the HK2 cell line and in human donors of kidney tissue with chronic kidney disease. Hypoxia significantly increased HE4 in renal tubular epithelial cells. HE4 overexpression activated the NF‐κB pathway through the NF‐κB transcription‐activating group P65 by phosphorylation and nuclear translocation. NF‐κB upregulated tissue inhibitor metalloproteinases 1, which may inhibit ECM degradation through inhibition of matrix metallopeptidase 2 activity. Silencing HE4 inhibited hypoxia‐induced ECM deposition and alleviated fibrosis in UUO mice in vivo and blocked NF‐κB activation in vitro. Expression of HE4 in the tubulointerstitium was positively correlated with tubulointerstitial fibrosis in tissue samples from patients with chronic kidney disease. Our results suggest that hypoxia induces renal fibrosis by upregulating HE4 and activating the HIF‐1α/HE4/NF‐κB signaling pathway. Uncovering the molecular mechanisms and function of HE4 overexpression in hypoxia‐induced renal fibrosis will provide important insights into understanding renal fibrosis and antifibrotic strategies.

Abstract Patients with acute myeloid leukemia (AML) harboring FLT3 internal tandem duplications (ITDs) have poor outcomes, in particular AML with a high (≥0.5) mutant/wild-type allelic ratio (AR). The 2017 European LeukemiaNet (ELN) recommendations defined 4 distinct FLT3-ITD genotypes based on the ITD AR and the NPM1 mutational status. In this retrospective exploratory study, we investigated the prognostic and predictive impact of the NPM1/FLT3-ITD genotypes categorized according to the 2017 ELN risk groups in patients randomized within the RATIFY trial, which evaluated the addition of midostaurin to standard chemotherapy. The 4 NPM1/FLT3-ITD genotypes differed significantly with regard to clinical and concurrent genetic features. Complete ELN risk categorization could be done in 318 of 549 trial patients with FLT3-ITD AML. Significant factors for response after 1 or 2 induction cycles were ELN risk group and white blood cell (WBC) counts; treatment with midostaurin had no influence. Overall survival (OS) differed significantly among ELN risk groups, with estimated 5-year OS probabilities of 0.63, 0.43, and 0.33 for favorable-, intermediate-, and adverse-risk groups, respectively (P < .001). A multivariate Cox model for OS using allogeneic hematopoietic cell transplantation (HCT) in first complete remission as a time-dependent variable revealed treatment with midostaurin, allogeneic HCT, ELN favorable-risk group, and lower WBC counts as significant favorable factors. In this model, there was a consistent beneficial effect of midostaurin across ELN risk groups.

AbstractDistal biliary strictures (DBS) are common and may be caused by both malignant and benign pathologies. While endoscopic procedures play a major role in their management, a comprehensive review of the subject is still lacking. Our consensus statements were formulated by a group of expert Asian pancreatico‐biliary interventional endoscopists, following a proposal from the Digestive Endoscopy Society of Taiwan, the Thai Association for Gastrointestinal Endoscopy, and the Tokyo Conference of Asian Pancreato‐biliary Interventional Endoscopy. Based on a literature review utilizing Medline, Cochrane library, and Embase databases, a total of 19 consensus statements on DBS were made on diagnosis, endoscopic drainage, benign biliary stricture, malignant biliary stricture, and management of recurrent biliary obstruction and other complications. Our consensus statements provide comprehensive guidance for the endoscopic management of DBS.

Abstract Motivation DNA methylation can be measured at the single CpG level using sodium bisulfite conversion of genomic DNA followed by sequencing or array hybridization. Many analytic tools have been developed, yet there is still a high demand for a comprehensive and multifaceted tool suite to analyze, annotate, QC and visualize the DNA methylation data. Results We developed the CpGtools package to analyze DNA methylation data generated from bisulfite sequencing or Illumina methylation arrays. The CpGtools package consists of three types of modules: (i) ‘CpG position modules’ focus on analyzing the genomic positions of CpGs, including associating other genomic and epigenomic features to a given list of CpGs and generating the DNA motif logo enriched in the genomic contexts of a given list of CpGs; (ii) ‘CpG signal modules’ are designed to analyze DNA methylation values, such as performing the PCA or t-SNE analyses, using Bayesian Gaussian mixture modeling to classify CpG sites into fully methylated, partially methylated and unmethylated groups, profiling the average DNA methylation level over user-specified genomics regions and generating the bean/violin plots and (iii) ‘differential CpG analysis modules’ focus on identifying differentially methylated CpGs between groups using different statistical methods including Fisher’s Exact Test, Student’s t-test, ANOVA, non-parametric tests, linear regression, logistic regression, beta-binomial regression and Bayesian estimation. Availability and implementation CpGtools is written in Python under the open-source GPL license. The source code and documentation are freely available at https://github.com/liguowang/cpgtools. Supplementary information Supplementary data are available at Bioinformatics online.

Objective The aim of this study was to quantitatively demonstrate radiation dose reduction for sinus and temporal bone examinations using high-resolution photon-counting detector (PCD) computed tomography (CT) with an additional tin (Sn) filter. Materials and Methods A multienergy CT phantom, an anthropomorphic head phantom, and a cadaver head were scanned on a research PCD-CT scanner using ultra-high-resolution mode at 100-kV tube potential with an additional tin filter (Sn-100 kV) and volume CT dose index of 10 mGy. They were also scanned on a commercial CT scanner with an energy-integrating detector (EID) following standard clinical protocols. Thirty patients referred to clinically indicated sinus examinations, and two patients referred to temporal bone examinations were scanned on the PCD-CT system after their clinical scans on an EID-CT. For the sinus cohort, PCD-CT scans were performed using Sn-100 kV at 4 dose levels at 10 mGy (n = 9), 8 mGy (n = 7), 7 mGy (n = 7), and 6 mGy (n = 7), and the clinical EID-CT was performed at 120 kV and 13.7 mGy (mean CT volume dose index). For the temporal bone scans, PCD-CT was performed using Sn-100 kV (10.1 mGy), and EID-CT was performed at 120 kV and routine clinical dose (52.6 and 66 mGy). For both PCD-CT and EID-CT, sinus images were reconstructed using H70 kernel at 0.75-mm slice thickness, and temporal bone images were reconstructed using a U70 kernel at 0.6-mm slice thickness. In addition, iterative reconstruction with a dedicated sharp kernel (V80) was used to obtain high-resolution PCD-CT images from a sinus patient scan to demonstrate improved anatomic delineation. Improvements in spatial resolution from the dedicated sharp kernel was quantified using modulation transfer function measured with a wire phantom. A neuroradiologist assessed the H70 sinus images for visualization of critical anatomical structures in low-dose PCD-CT images and routine-dose EID-CT images using a 5-point Likert scale (structural detection obscured and poor diagnostic confidence, score = 1; improved anatomic delineation and diagnostic confidence, score = 5). Image contrast and noise were measured in representative regions of interest and compared between PCD-CT and EID-CT, and the noise difference between the 2 acquisitions was used to estimate the dose reduction in the sinus and temporal bone patient cohorts. Results The multienergy phantom experiment showed a noise reduction of 26% in the Sn-100 kV PCD-CT image, corresponding to a total dose reduction of 56% compared with EID-CT (clinical dose) without compromising image contrast. The PCD-CT images from the head phantom and the cadaver scans demonstrated a dose reduction of 67% and 83%, for sinus and temporal bone examinations, respectively, compared with EID-CT. In the sinus cohort, PCD-CT demonstrated a mean dose reduction of 67%. The 10- and 8-mGy sinus patient images from PCD-CT were significantly superior to clinical EID-CT for visualization of critical sinus structures (median score = 5 ± 0.82 and P = 0.01 for lesser palatine foramina, median score = 4 ± 0.68 and P = 0.039 for nasomaxillary sutures, and median score = 4 ± 0.96 and P = 0.01 for anterior ethmoid artery canal). The 6- and 7-mGy sinus patient images did not show any significant difference between PCD-CT and EID-CT. In addition, V80 (sharp kernel, 10% modulation transfer function = 18.6 cm −1 ) PCD-CT images from a sinus patient scan increased the conspicuity of nasomaxillary sutures compared with the clinical EID-CT images. The temporal bone patient images demonstrated a dose reduction of up to 85% compared with clinical EID-CT images, whereas visualization of inner ear structures such as the incudomalleolar joint were similar between EID-CT and PCD-CT. Conclusions Phantom and cadaver studies demonstrated dose reduction using Sn-100 kV PCD-CT compared with current clinical EID-CT while maintaining the desired image contrast. Dose reduction was further validated in sinus and temporal bone patient studies. The ultra-high resolution capability from PCD-CT allowed improved anatomical delineation for sinus imaging compared with current clinical standard.

PurposeThe dose‐averaged linear energy transfer (LETd) for intensity‐modulated proton therapy (IMPT) calculated by one‐dimensional (1D) analytical models deviates from more accurate but time‐consuming Monte Carlo (MC) simulations. We developed a fast hybrid three‐dimensional (3D) analytical LETd calculation that is more accurate than 1D analytical model.MethodsWe used the Geant4 MC code to generate 3D LETd distributions of monoenergetic proton beams in water for all energies and used a customized error function to fit the LETd lateral profiles at various depths to the MC simulation. The 3D LETd calculation kernel was a lookup table of these fitted coefficients, and LETd was determined directly from spot energies and voxel coordinates during analytical dose calculations. We validated our new method by comparing the calculated LETd distributions to MC results using 3D Gamma index analysis with 3%/2 mm criteria in 12 patient geometries. The significance of the improvement in Gamma index analysis passing rates over the 1D analytical model was determined using the Wilcoxon rank‐sum test.ResultsThe passing rate of 3D Gamma analysis comparing LETd distributions from the hybrid 3D method and the 1D method to MC simulations was significantly improved from 94.0% ± 2.5% to 98.0% ± 1.0% (P = 0.0003). The typical time to calculate dose and LETd simultaneously using an Intel Xeon E5‐2680 2.50 GHz workstation was approximately 2.5 min.ConclusionsOur new method significantly improved the LETd calculation accuracy compared to the 1D method while maintaining significantly shorter calculation time even comparing with the GPU‐based fast MC code.

Purpose: To describe and validate the dose calculation algorithm of an independent second-dose check software for spot scanning proton delivery systems with full width at half maximum between 5 and 14 mm and with a negligible spray component. Methods: The analytical dose engine of our independent second-dose check software employs an altered pencil beam algorithm with 3 lateral Gaussian components. It was commissioned using Geant4 and validated by comparison to point dose measurements at several depths within spread-out Bragg peaks of varying ranges, modulations, and field sizes. Water equivalent distance was used to compensate for inhomogeneous geometry. Twelve patients representing different disease sites were selected for validation. Dose calculation results in water were compared to a fast Monte Carlo code and ionization chamber array measurements using dose planes and dose profiles as well as 2-dimensional–3-dimensional and 3-dimensional–3-dimensional γ-index analysis. Results in patient geometry were compared to Monte Carlo simulation using dose–volume histogram indices, 3-dimensional–3-dimensional γ-index analysis, and inpatient dose profiles. Results: Dose engine model parameters were tuned to achieve 1.5% agreement with measured point doses. The in-water γ-index passing rates for the 12 patients using 3%/2 mm criteria were 99.5% ± 0.5% compared to Monte Carlo. The average inpatient γ-index analysis passing rate compared to Monte Carlo was 95.8% ± 2.9%. The average difference in mean dose to the clinical target volume between the dose engine and Monte Carlo was −0.4% ± 1.0%. For a typical plan, dose calculation time was 2 minutes on an inexpensive workstation. Conclusions: Following our commissioning process, the analytical dose engine was validated for all treatment sites except for the lung or for calculating dose–volume histogram indices involving point doses or critical structures immediately distal to target volumes. Monte Carlo simulations are recommended for these scenarios.

Abstract Background: Phlebotomy to maintain hematocrit <45% is considered one of the cornerstones for the management of polycythemia vera (PV). However, phlebotomy procedures may be inconvenient for or poorly tolerated by some patients, and often result in iron deficiency, which may be associated with additional quality-of-life burden, such as fatigue, impaired cognitive function and restless leg syndrome. The REVEAL study (ClinicalTrials.gov, NCT02252159) is being conducted to describe contemporary demographics, burden of disease, clinical management, patient-reported outcomes, and healthcare resource utilization among patients with PV in the US. This early analysis describes the patient self-reported burden of phlebotomy at the time of enrollment. Methods: REVEAL is a multicenter, noninterventional, nonrandomized, prospective, observational study of adult patients with PV who are currently under the care of a US physician. REVEAL collects physician assessments and patient-reported outcomes during a 36-month observation period. Phlebotomy-related burden is being assessed with a new 21-item phlebotomy burden questionnaire (PBQ-21) at enrollment and every 90 days thereafter; it assesses patient-reported phlebotomy frequency, practice setting, time required for phlebotomy, inconvenience, and phlebotomy-related adverse effects. Phlebotomy-related effects and bother/inconvenience (if experienced within 24 hours after a phlebotomy procedure) are graded on a 4-point scale of 1 (not at all) to 4 (extremely). Analyses of these preliminary data were descriptive. Results: At the time of data cutoff, 865 patients were enrolled (total planned enrollment, n=2000). Median age was 67 (range, 22-95) years, 55.5% were male, and 89.5% were white. Median time from PV diagnosis to study enrollment was 53 months. Overall, 748 patients completed the PBQ-21 at enrollment and 400 (53.5%) had received a phlebotomy within 3 months prior to enrollment. Mean number of phlebotomies in the past 3 months was 2.2 (SD, 1.7). Phlebotomy was most commonly performed at a doctor's office during a regular medical visit (37.8%), at an infusion center or special cancer care center (26.8%), or at a hospital (18.3%). Patients who had phlebotomy procedures within 90 days before enrollment reported a mean total treatment time of 4.2 (SD, 4.7) hours per phlebotomy procedure; for employed patients, the mean amount of work time missed was 4.6 (SD, 15.6) hours per procedure. Fatigue, bruising, dehydration, and dizziness were among the most commonly reported adverse effects of phlebotomy (Table 1). Twenty percent of patients reported that phlebotomy procedures were moderately or extremely bothersome, inconvenient (18.3%), or painful or physically uncomfortable (16.3%). Furthermore, some patients (8.8%) reported that their family and friends were moderately or severely inconvenienced by phlebotomy procedures. Conclusion: The PBQ-21 collects important and relevant patient-reported information to systematically assess the impact of phlebotomy on patients and caregivers. From the early view of REVEAL enrollment data, a considerable proportion of patients reported fatigue, bruising, dehydration, and dizziness resulting from phlebotomy procedures. Furthermore, patients reported spending a considerable amount of time (4 hours on average) per phlebotomy procedure, which is a sizeable burden for patients who are employed. In addition, some patients reported that phlebotomy procedures may be inconvenient, painful or uncomfortable, and bothersome. REVEAL provides important information for providers to understand and address when to prescribe phlebotomy for patients with PV. Disclosures Boccia: Incyte Corporation: Honoraria. Stein:Incyte Corporation: Consultancy, Membership on an entity's Board of Directors or advisory committees. Mesa:Genentech: Research Funding; Promedior: Research Funding; NS Pharma: Research Funding; CTI Biopharma: Research Funding; Gilead: Research Funding; Incyte Corporation: Research Funding; Novartis Pharmaceuticals Corporation: Consultancy; Pfizer: Research Funding. Naim:Incyte Corporation: Employment, Equity Ownership. Cordaro:Incyte Corporation: Employment, Equity Ownership. Peng:Incyte Corporation: Employment, Equity Ownership. Sun:Incyte Corporation: Employment, Equity Ownership. Parasuraman:Incyte Corporation: Employment, Equity Ownership. Moliterno:Incyte Corporation: Membership on an entity's Board of Directors or advisory committees.