The impact of audiovisual biofeedback on 4D functional and anatomic imaging: Results of a lung cancer pilot study.

BACKGROUND AND PURPOSE: The impact of audiovisual (AV) biofeedback on four dimensional (4D) positron emission tomography (PET) and 4D computed tomography (CT) image quality was investigated in a prospective clinical trial (NCT01172041). MATERIAL AND METHODS: 4D-PET and 4D-CT images of ten lung cancer patients were acquired with AV biofeedback (AV) and free breathing (FB). The 4D-PET images were analyzed for motion artifacts by comparing 4D to 3D PET for gross tumor volumes (GTVPET) and maximum standardized uptake values (SUVmax). The 4D-CT images were analyzed for artifacts by comparing normalized cross correlation-based scores (NCCS) and quantifying a visual assessment score (VAS). A Wilcoxon signed-ranks test was used for statistical testing. RESULTS: The impact of AV biofeedback varied widely. Overall, the 3D to 4D decrease of GTVPET was 1.2±1.3cm(3) with AV and 0.6±1.8cm(3) for FB. The 4D-PET increase of SUVmax was 1.3±0.9 with AV and 1.3±0.8 for FB. The 4D-CT NCCS were 0.65±0.27 with AV and 0.60±0.32 for FB (p=0.08). The 4D-CT VAS was 0.0±2.7. CONCLUSION: This study demonstrated a high patient dependence on the use of AV biofeedback to reduce motion artifacts in 4D imaging. None of the hypotheses tested were statistically significant. Future development of AV biofeedback will focus on optimizing the human-computer interface and including patient training sessions for improved comprehension and compliance

Pulmonary ventilation imaging based on 4-dimensional computed tomography: comparison with pulmonary function tests and SPECT ventilation images.

PURPOSE: 4-dimensional computed tomography (4D-CT)-based pulmonary ventilation imaging is an emerging functional imaging modality. The purpose of this study was to investigate the physiological significance of 4D-CT ventilation imaging by comparison with pulmonary function test (PFT) measurements and single-photon emission CT (SPECT) ventilation images, which are the clinical references for global and regional lung function, respectively. METHODS AND MATERIALS: In an institutional review board-approved prospective clinical trial, 4D-CT imaging and PFT and/or SPECT ventilation imaging were performed in thoracic cancer patients. Regional ventilation (V4DCT) was calculated by deformable image registration of 4D-CT images and quantitative analysis for regional volume change. V4DCT defect parameters were compared with the PFT measurements (forced expiratory volume in 1 second (FEV1; % predicted) and FEV1/forced vital capacity (FVC; %). V4DCT was also compared with SPECT ventilation (VSPECT) to (1) test whether V4DCT in VSPECT defect regions is significantly lower than in nondefect regions by using the 2-tailed t test; (2) to quantify the spatial overlap between V4DCT and VSPECT defect regions with Dice similarity coefficient (DSC); and (3) to test ventral-to-dorsal gradients by using the 2-tailed t test. RESULTS: Of 21 patients enrolled in the study, 18 patients for whom 4D-CT and either PFT or SPECT were acquired were included in the analysis. V4DCT defect parameters were found to have significant, moderate correlations with PFT measurements. For example, V4DCT(HU) defect volume increased significantly with decreasing FEV1/FVC (R=-0.65, P<.01). V4DCT in VSPECT defect regions was significantly lower than in nondefect regions (mean V4DCT(HU) 0.049 vs 0.076, P<.01). The average DSCs for the spatial overlap with SPECT ventilation defect regions were only moderate (V4DCT(HU)0.39 ± 0.11). Furthermore, ventral-to-dorsal gradients of V4DCT were strong (V4DCT(HU) R(2) = 0.69, P=.08), which was similar to VSPECT (R(2) = 0.96, P<.01). CONCLUSIONS: An 18-patient study demonstrated significant correlations between 4D-CT ventilation and PFT measurements as well as SPECT ventilation, providing evidence toward the validation of 4D-CT ventilation imaging

Decreased Dengue Replication and an Increased Anti-viral Humoral Response with the use of Combined Toll-Like Receptor 3 and 7/8 Agonists in Macaques

Pathogenic versus protective outcomes to Dengue virus (DENV) infection are associated with innate immune function. This study aimed to determine the role of increased TLR3- and TLR7/8-mediated innate signaling after Dengue infection of rhesus macaques in vivo to evaluate its impact on disease and anti-DENV immune responses.TLR3 and TLR7/8 agonists (emulsified in Montanide) were administered subcutaneously to rhesus macaques at 48 hours and 7 days after DENV infection. The Frequency and activation of myeloid dendritic cells, plasmacytoid dendritic cells, and B cells were measured by flow cytometry while the serum levels of 14 different cytokines and chemokines were quantified. Adaptive immune responses were measured by DENV-specific antibody subtype measurements. Results showed that the combined TLR agonists reduced viral replication and induced the development of a proinflammatory reaction, otherwise absent in Dengue infection alone, without any clear signs of exacerbated disease. Specifically, the TLR-induced response was characterized by activation changes in mDC subsets concurrent with higher serum levels of CXCL-10 and IL-1Ra. TLR stimulation also induced higher titers of anti-DENV antibodies and acted to increase the IgG2/IgG1 ratio of anti-DENV to favor the subtype associated with DENV control. We also observed an effect of DENV-mediated suppression of mDC activation consistent with prior in vitro studies.These data show that concurrent TLR3/7/8 activation of the innate immune response after DENV infection in vivo acts to increase antiviral mechanisms via increased inflammatory and humoral responses in rhesus macaques, resulting in decreased viremia and melioration of the infection. These findings underscore an in vivo protective rather than a pathogenic role for combined TLR3/7/8-mediated activation in Dengue infection of rhesus macaques. Our study provides definitive proof-of-concept into the mechanism by which DENV evades immune recognition and activation in vivo

Pan-cancer analysis of whole genomes

Cancer is driven by genetic change, and the advent of massively parallel sequencing has enabled systematic documentation of this variation at the whole-genome scale(1-3). Here we report the integrative analysis of 2,658 whole-cancer genomes and their matching normal tissues across 38 tumour types from the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA). We describe the generation of the PCAWG resource, facilitated by international data sharing using compute clouds. On average, cancer genomes contained 4-5 driver mutations when combining coding and non-coding genomic elements; however, in around 5% of cases no drivers were identified, suggesting that cancer driver discovery is not yet complete. Chromothripsis, in which many clustered structural variants arise in a single catastrophic event, is frequently an early event in tumour evolution; in acral melanoma, for example, these events precede most somatic point mutations and affect several cancer-associated genes simultaneously. Cancers with abnormal telomere maintenance often originate from tissues with low replicative activity and show several mechanisms of preventing telomere attrition to critical levels. Common and rare germline variants affect patterns of somatic mutation, including point mutations, structural variants and somatic retrotransposition. A collection of papers from the PCAWG Consortium describes non-coding mutations that drive cancer beyond those in the TERT promoter(4); identifies new signatures of mutational processes that cause base substitutions, small insertions and deletions and structural variation(5,6); analyses timings and patterns of tumour evolution(7); describes the diverse transcriptional consequences of somatic mutation on splicing, expression levels, fusion genes and promoter activity(8,9); and evaluates a range of more-specialized features of cancer genomes(8,10-18).Peer reviewe

International Consensus Statement on Rhinology and Allergy: Rhinosinusitis

Background: The 5 years since the publication of the first International Consensus Statement on Allergy and Rhinology: Rhinosinusitis (ICAR‐RS) has witnessed foundational progress in our understanding and treatment of rhinologic disease. These advances are reflected within the more than 40 new topics covered within the ICAR‐RS‐2021 as well as updates to the original 140 topics. This executive summary consolidates the evidence‐based findings of the document. Methods: ICAR‐RS presents over 180 topics in the forms of evidence‐based reviews with recommendations (EBRRs), evidence‐based reviews, and literature reviews. The highest grade structured recommendations of the EBRR sections are summarized in this executive summary. Results: ICAR‐RS‐2021 covers 22 topics regarding the medical management of RS, which are grade A/B and are presented in the executive summary. Additionally, 4 topics regarding the surgical management of RS are grade A/B and are presented in the executive summary. Finally, a comprehensive evidence‐based management algorithm is provided. Conclusion: This ICAR‐RS‐2021 executive summary provides a compilation of the evidence‐based recommendations for medical and surgical treatment of the most common forms of RS

A Feasibility Study of Single-inhalation, Single-energy Xenon-enhanced CT for High-resolution Imaging of Regional Lung Ventilation in Humans.

RATIONALE AND OBJECTIVES: The objective of this study was to assess the feasibility of single-inhalation xenon-enhanced computed tomography (XeCT) to provide clinically practical, high-resolution pulmonary ventilation imaging to clinics with access to only a single-energy computed tomography scanner, and to reduce the subject's overall exposure to xenon by utilizing a higher (70%) concentration for a much shorter time than has been employed in prior studies. MATERIALS AND METHODS: We conducted an institutional review board-approved prospective feasibility study of XeCT for 15 patients undergoing thoracic radiotherapy. For XeCT, we acquired two breath-hold single-energy computed tomography images of the entire lung with a single inhalation each of 100% oxygen and a mixture of 70% xenon and 30% oxygen, respectively. A video biofeedback system for coached patient breathing was used to achieve reproducible breath holds. We assessed the technical success of XeCT acquisition and side effects. We then used deformable image registration to align the breath-hold images with each other to accurately subtract them, producing a map of lung xenon distribution. Additionally, we acquired ventilation single-photon emission computed tomography-computed tomography (V-SPECT-CT) images for 11 of the 15 patients. For a comparative analysis, we partitioned each lung into 12 sectors, calculated the xenon concentration from the Hounsfield unit enhancement in each sector, and then correlated this with the corresponding V-SPECT-CT counts. RESULTS: XeCT scans were tolerated well overall, with a mild (grade 1) dizziness as the only side effect in 5 of the 15 patients. Technical failures in five patients occurred because of inaccurate breathing synchronization with xenon gas delivery, leaving seven patients analyzable for XeCT and single-photon emission computed tomography correlation. Sector-wise correlations were strong (Spearman coefficient >0.75, Pearson coefficient >0.65, P value <.002) for two patients for whom ventilation deficits were visibly pronounced in both scans. Correlations were nonsignificant for the remaining five who had more homogeneous XeCT ventilation maps, as well as strong V-SPECT-CT imaging artifacts attributable to airway deposition of the aerosolized imaging agent. Qualitatively, XeCT demonstrated higher resolution and no central airway deposition artifacts compared to V-SPECT-CT. CONCLUSIONS: In this pilot study, single-breath XeCT ventilation imaging was generally feasible for patients undergoing thoracic radiotherapy, using an imaging protocol that is clinically practical and potentially widely available. In the future, the xenon delivery failures can be addressed by straightforward technical improvements to the patient biofeedback coaching system