Citations

SummaryPolymorphonuclear (PMN) leucocytes participate in acute inflammatory pathologies such as acute respiratory distress syndrome (ARDS) following traumatic injury and shock, which also activates the coagulation system systemically. Trauma can prime the PMN nicotinamide adenine dinucleotide phosphate (NADPH) oxidase complex for an enhanced respiratory burst, but the relative role of various priming agents in this process remains incompletely understood. We therefore set out to identify mediators of PMN priming during coagulation and trauma-shock and determine whether PMN reactive oxygen species (ROS) generated in this manner could influence organ injury and coagulation. Initial experiments demonstrated that PMN are primed for predominantly extracellular ROS production by products of coagulation, which was abrogated by CD88/C5a receptor(C5aR) inhibition. The importance of this was highlighted further by demonstrating that known PMN priming agents result in fractionally different amounts of extracellular versus intracellular ROS release depending on the agent used. Plasma from trauma patients in haemodynamic shock (n = 10) also primed PMN for extracellular ROS in a C5a-dependent manner, which correlated with both complement alternative pathway activation and thrombin generation. Furthermore, PMN primed by preincubation with products of blood coagulation directly caused loss of endothelial barrier function in vitro that was abrogated by C5aR blockade or NADPH oxidase inhibition. Finally, we show in a murine model of trauma-shock that p47phox knock-out (KO) mice with PMN incapable of generating ROS were protected from inflammatory end-organ injury and activated protein C-mediated coagulopathy. In summary, we demonstrate that trauma-shock and coagulation primes PMN for predominantly extracellular ROS production in a C5a-dependent manner that contributes to endothelial barrier loss and organ injury, and potentially enhances traumatic coagulopathy.

Abstract Glioblastoma multiforme (GBM) remains the most common and deadly primary brain tumor with minimal advances in therapeutic development for pharmacological treatment. Tumor resection followed by temozolomide (TMZ) and radiotherapy adds months to survival; however, tumor recurrence usually occurs. The fibroblast growth factor-inducible 14 (Fn14) receptor has been shown to be up-regulated in the GBM cells left behind after surgery and contributes to an invasive and pro-survival phenotype, providing a desirable molecule to target after removal of the primary tumor. Previously, L524-0366 was reported by our lab to be the first antagonist of Fn14 signaling; however, minimal efficacy/potency has limited this drug from progressing from a useful research tool to preclinical studies. Structure activity relationship (SAR) studies using the parent L524-0366 compound gave rise to K78, which was found to bind to Fn14 with enhanced affinity, while showing no binding to the structurally-related TNFα receptor. Furthermore, K78 was able to abate the downstream signaling effects initiated by the Fn14 ligand, tumor necrosis factor-like weak inducer of apoptosis (TWEAK), as well as sensitize GBM cells to the cytotoxic effects of TMZ. TWEAK-induced cellular migration was also mitigated with co-treatment of K78 in GBM cells, compared to a vehicle control. It is anticipated that further development of Fn14 antagonists will be of great importance for the advancement of GBM patient treatment and warrant further investigation as primary and combination therapy, especially for the prevention of recurrent disease. Citation Format: Bryan Harder, Chris Sereduk, Harshil Dhruv, Nghia Millard, Anthony Kim, Jeffrey Winkles, Graeme Woodworth, Holly Yin, Nhan L. Tran. Development of an antagonist to the TWEAK-Fn14 ligand-receptor interaction with enhanced efficacy/potency in glioblastoma cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4910.

PurposeThe purpose of this study was to estimate the radiation dose to the lung and breast as well as the effective dose from tube current modulated (TCM) lung cancer screening (LCS) scans across a range of patient sizes.MethodsMonte Carlo (MC) methods were used to calculate lung, breast, and effective doses from a low‐dose LCS protocol for a 64‐slice CT that used TCM. Scanning parameters were from the protocols published by AAPM's Alliance for Quality CT. To determine lung, breast, and effective doses from lung cancer screening, eight GSF/ICRP voxelized phantom models with all radiosensitive organs identified were used to estimate lung, breast, and effective doses. Additionally, to extend the limited size range provided by the GSF/ICRP phantom models, 30 voxelized patient models of thoracic anatomy were generated from LCS patient data. For these patient models, lung and breast were semi‐automatically segmented. TCM schemes for each of the GSF/ICRP phantom models were generated using a validated method wherein tissue attenuation and scanner limitations were used to determine the TCM output as a function of table position and source angle. TCM schemes for voxelized patient models were extracted from the raw projection data. The water equivalent diameter, Dw, was used as the patient size descriptor. Dw was estimated for the GSF/ICRP models. For the thoracic patient models, Dw was extracted from the DICOM header of the CT localizer radiograph. MC simulations were performed using the TCM scheme for each model. Absolute organ doses were tallied and effective doses were calculated using ICRP 103 tissue weighting factors for the GSF/ICRP models. Metrics of scanner radiation output were determined based on each model's TCM scheme, including CTDIvol, dose length product (DLP), and CTDIvol, Low Att, a previously described regional metric of scanner output covering most of the lungs and breast. All lung and breast doses values were normalized by scan‐specific CTDIvol and CTDIvol, Low Att. Effective doses were normalized by scan‐specific CTDIvol and DLP. Absolute and normalized doses were reported as a function of Dw.ResultsLung doses normalized by CTDIvol, Low Att were modeled as an exponential relationship with respect to Dw with coefficients of determination (R2) of 0.80. Breast dose normalized by CTDIvol, Low Att was modeled with an exponential relationship to Dw with an R2 of 0.23. For all eight GSF/ICRP phantom models, the effective dose using TCM protocols was below 1.6 mSv. Effective doses showed some size dependence but when normalized by DLP demonstrated a constant behavior.ConclusionLung, breast, and effective doses from LCS CT exams with TCM were estimated with respect to patient size. Normalized lung dose can be reasonably estimated with a measure of a patient size such as Dw and regional metric of CTDIvol covering the thorax such as CTDIvol, Low Att, while normalized breast dose can also be estimated with a regional metric of CTDIvol but with a larger degree of variability than observed for lung. Effective dose normalized by DLP can be estimated with a constant multiplier.

AbstractIntroductionClinical practice guidelines recommend comprehensive treatment for tobacco dependence including pharmacotherapies and behavioral interventions. Group counseling may deliver unique treatment aspects not available with other modalities. This manuscript provides a narrative review of group treatment outcomes from real-world practice settings and complements recent meta-analyses of randomized controlled trials (RCTs). Our primary goals were to determine whether group treatments delivered in these settings have yielded similar quit rates compared to individual treatment and to provide recommendations for best practices and policy.MethodsGroup treatment was defined as occurring in a clinical or workplace setting (ie, not provided as part of a research study), led by a professionally trained clinician, and offered weekly over several weeks. English language PubMed articles from January 2000 to July 2017 were searched to identify studies that included outcomes from both group and individual treatment offered in real-world settings. Additional data sources meeting our criteria were also included. Reports not using pharmacotherapy and research studies (eg, RCTs) were excluded. The primary outcome was short-term, carbon monoxide (CO)-validated point prevalence abstinence (4-week postquit date).ResultsThe review included data from 11 observational studies. In all cases, group treatment(s) had higher 4-week CO-validated quit rates (range: 35.5%–67.3%) than individual treatment(s) (range: 18.6%–53.3%).ConclusionsBest practice group treatments for tobacco dependence are generalizable from research to clinical settings and likely to be at least as effective as intensive individual treatment. The added advantages of efficiency and cost-effectiveness can be significant. Group treatment is feasible in various settings with good results.ImplicationsA major barrier to achieving high rates of tobacco abstinence is under-utilization of evidence-based treatment interventions. This review demonstrates the effectiveness and utility of group treatment for tobacco dependence. Based on the available data described in this narrative review in conjunction with existing RCT data, group treatment for tobacco dependence should be established and available in all behavioral health and medical settings. Group tobacco treatment is now one of the mandated reimbursable tobacco treatment formats within the US health care system, creating enormous opportunities for widespread clinical reach. Finally, comprehensive worksite group programs can further extend impact.

Abstract A 52-yr-old woman was referred to a tertiary medical center for evaluation of 2 yr of progressive visual symptoms and 1 yr of retro-orbital pressure. Her ophthalmologic exam was unrevealing except for mild asymmetrical impairment in color perception. A gadolinium contrast-enhanced magnetic resonance image of the head showed a left extraconal orbital apex lesion consistent with cavernous hemangioma. Computed tomography reveled bony remodeling of the medial-inferior orbital walls with superior orbital fissure expansion. The lesion was endoscopically resected and confirmed by pathological analysis. The endoscopic approach is demonstrated in detail, including correlation with cadaveric anatomic specimens ‡ . During the approach, a rescue nasoseptal flap was raised in case the orbit required further support after tumor resection, but was replaced as this was not needed. This patient had a brief period of postoperative diplopia, which resolved 1 wk after surgery. Her subjective visual deficits and pressure have also resolved. Advantages of the endoscopic approach include improved direct visualization of the lesion, lack of external skin incisions, avoidance of significant neurovascular retraction, and shorter hospital stays than alternative orbitotomy or craniotomy approaches. This 4-handed approach demands endoscopic expertise of 2 surgeons, and is often performed by rhinology-neurosurgery or rhinology-ophthalmology surgical teams. The risk of postoperative diplopia should be discussed with the patient during informed consent. ‡ Anatomic specimen photography courtesy Dr Peris-Celda.

PurposeAccuracy of dose calculation models and robustness under various uncertainties are key factors influencing the quality of intensity modulated proton therapy (IMPT) plans. To mitigate the effects of uncertainties and to improve the dose calculation accuracy, an all‐scenario robust IMPT optimization based on accurate Monte Carlo (MC) dose calculation was developed.MethodsIn the all‐scenario robust IMPT optimization, dose volume histograms (DVHs) were computed for the nominal case and for each uncertainty scenario. All scenarios were weighted by DVH values dynamically throughout optimization iterations. In contrast, probabilistic approach weighted scenarios with fixed scenario weights and worst case optimizations picked one single scenario — the worst scenario for each iteration. Uncertainties in patient setup and proton range were considered in all clinical cases studied. Graphics processing unit (GPU) computation was employed to reduce the computational time in both the MC dose calculation and optimization stages. A previously published adaptive quasi‐Newton method for proton optimization was extended to include robustness. To validate the all‐scenario algorithm extension, it was compared with the single scenario optimization target volume (OTV) based approach in clinical cases of three different disease sites. Additional comparisons with worst case optimization methods were conducted to evaluate the performance of the all‐scenario robust optimization against other robust optimizations.ResultsThe all‐scenario robust IMPT optimization spared organs at risk (OARs) better than the OTV‐based method while maintaining target coverage and improving the robustness of targets and OARs. Compared with composite and voxel‐wise worst case optimization, the all‐scenario robust optimization converged faster, and arrived at solutions of tighter DVH robustness spread, better target coverage and lower OAR dose.ConclusionAn all‐scenario robust IMPT treatment planning system was developed using an adaptive quasi‐Newton optimization method. The optimization system was GPU‐accelerated and based on MC dose calculation. Improved performance was observed in clinical cases when compared with worst case optimization methods.