IL-18 mediates sickle cell cardiomyopathy and ventricular arrhythmias.

Previous reports indicate that IL18 is a novel candidate gene for diastolic dysfunction in sickle cell disease (SCD)-related cardiomyopathy. We hypothesize that interleukin-18 (IL-18) mediates the development of cardiomyopathy and ventricular tachycardia (VT) in SCD. Compared with control mice, a humanized mouse model of SCD exhibited increased cardiac fibrosis, prolonged duration of action potential, higher VT inducibility in vivo, higher cardiac NF-κB phosphorylation, and higher circulating IL-18 levels, as well as reduced voltage-gated potassium channel expression, which translates to reduced transient outward potassium current (Ito) in isolated cardiomyocytes. Administering IL-18 to isolated mouse hearts resulted in VT originating from the right ventricle and further reduced Ito in SCD mouse cardiomyocytes. Sustained IL-18 inhibition via IL-18-binding protein resulted in decreased cardiac fibrosis and NF-κB phosphorylation, improved diastolic function, normalized electrical remodeling, and attenuated IL-18-mediated VT in SCD mice. Patients with SCD and either myocardial fibrosis or increased QTc displayed greater IL18 gene expression in peripheral blood mononuclear cells (PBMCs), and QTc was strongly correlated with plasma IL-18 levels. PBMC-derived IL18 gene expression was increased in patients who did not survive compared with those who did. IL-18 is a mediator of sickle cell cardiomyopathy and VT in mice and a novel therapeutic target in patients at risk for sudden death.

Ampullary Adenocarcinoma, Version 1.2023, NCCN Clinical Practice Guidelines in Oncology.

Ampullary cancers refer to tumors originating from the ampulla of Vater (the ampulla, the intraduodenal portion of the bile duct, and the intraduodenal portion of the pancreatic duct), while periampullary cancers may arise from locations encompassing the head of the pancreas, distal bile duct, duodenum, or ampulla of Vater. Ampullary cancers are rare gastrointestinal malignancies, and prognosis varies greatly based on factors such as patient age, TNM classification, differentiation grade, and treatment modality received. Systemic therapy is used in all stages of ampullary cancer, including neoadjuvant therapy, adjuvant therapy, and first-line or subsequent-line therapy for locally advanced, metastatic, and recurrent disease. Radiation therapy may be used in localized ampullary cancer, sometimes in combination with chemotherapy, but there is no high-level evidence to support its utility. Select tumors may be treated surgically. This article describes NCCN recommendations regarding management of ampullary adenocarcinoma.

Statins Disrupt Macrophage Rac1 Regulation Leading to Increased Atherosclerotic Plaque Calcification.

OBJECTIVE: Calcification of atherosclerotic plaque is traditionally associated with increased cardiovascular event risk; however, recent studies have found increased calcium density to be associated with more stable disease. 3-hydroxy-3-methylglutaryl coenzymeA reductase inhibitors or statins reduce cardiovascular events. Invasive clinical studies have found that statins alter both the lipid and calcium composition of plaque but the molecular mechanisms of statin-mediated effects on plaque calcium composition remain unclear. We recently defined a macrophage Rac (Ras-related C3 botulinum toxin substrate)-IL-1ß (interleukin-1 beta) signaling axis to be a key mechanism in promoting atherosclerotic calcification and sought to define the impact of statin therapy on this pathway. Approach and Results: Here, we demonstrate that statin therapy is independently associated with elevated coronary calcification in a high-risk patient population and that statins disrupt the complex between Rac1 and its inhibitor RhoGDI (Rho GDP-dissociation inhibitor), leading to increased active (GTP bound) Rac1 in primary monocytes/macrophages. Rac1 activation is prevented by rescue with the isoprenyl precursor geranylgeranyl diphosphate. Statin-treated macrophages exhibit increased activation of NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells), increased IL-1ß mRNA, and increased Rac1-dependent IL-1ß protein secretion in response to inflammasome stimulation. Using an animal model of calcific atherosclerosis, inclusion of statin in the atherogenic diet led to a myeloid Rac1-dependent increase in atherosclerotic calcification, which was associated with increased serum IL-1ß expression, increased plaque Rac1 activation, and increased plaque expression of the osteogenic markers, alkaline phosphatase and RUNX2 (Runt-related transcription factor 2). CONCLUSIONS: Statins are capable of increasing atherosclerotic calcification through disinhibition of a macrophage Rac1-IL-1ß signaling axis.

Lung-RADS Version 1.1: Challenges and a Look Ahead, From the AJR Special Series on Radiology Reporting and Data Systems.

In 2014, the American College of Radiology (ACR) created Lung-RADS 1.0. The system was updated to Lung-RADS 1.1 in 2019, and further updates are anticipated as additional data become available. Lung-RADS provides a common lexicon and standardized nodule follow-up management paradigm for use when reporting lung cancer screening (LCS) low-dose CT (LDCT) chest examinations and serves as a quality assurance and outcome monitoring tool. The use of Lung-RADS is intended to improve LCS performance and lead to better patient outcomes. To date, the ACR's Lung Cancer Screening Registry is the only LCS registry approved by the Centers for Medicare & Medicaid Services and requires the use of Lung-RADS categories for reimbursement. Numerous challenges have emerged regarding the use of Lung-RADS in clinical practice, including the timing of return to LCS after planned follow-up diagnostic evaluation; potential substitution of interval diagnostic CT for future LDCT; role of volumetric analysis in assessing nodule size; assessment of nodule growth; assessment of cavitary, subpleural, and category 4X nodules; and variability in reporting of the S modifier. This article highlights the major updates between versions 1.0 and 1.1 of Lung-RADS, describes the system's ongoing challenges, and summarizes current evidence and recommendations.

New Lung-RADS Statement: A Talk With Committee Members Dr Jared Christensen and Dr Ashley Prosper.

In this video article, Lung-RADS committee members Dr. Jared Christensen (who also serves as chair) and Dr. Ashley Prosper discuss the most recent Lung-RADS update, including key changes and implications for clinical practice.

Efficacy and safety of an interleukin 6 monoclonal antibody for the treatment of systemic lupus erythematosus: a phase II dose-ranging randomised controlled trial.

OBJECTIVES: This phase II trial evaluated the efficacy and safety of an interleukin (IL) 6 monoclonal antibody for systemic lupus erythematosus (SLE). METHODS: Patients with active disease were randomised to placebo or PF-04236921 10 mg, 50 mg or 200 mg, subcutaneously, every 8 weeks with stable background therapy. SLE Responder Index (SRI-4; primary end point) and British Isles Lupus Assessment Group-based Composite Lupus Assessment (BICLA) were assessed at week 24. Post hoc analysis identified an enriched population based upon planned univariate analyses. RESULTS: 183 patients received treatment (placebo, n=45; 10 mg, n=45; 50 mg, n=47; 200 mg, n=46). The 200 mg dose was discontinued due to safety findings and not included in the primary efficacy analysis. The SRI-4 response rates were not significant for any dose compared with placebo; however, the BICLA response rate was significant for 10 mg (p=0.026). The incidence of severe flares was significantly reduced with 10 mg (n=0) and 50 mg (n=2) combined versus placebo (n=8; p<0.01). In patients with greater baseline disease activity (enriched population), the SRI-4 (p=0.004) and BICLA (p=0.012) response rates were significantly different with 10 mg versus placebo. Four deaths (200 mg, n=3; 10 mg, n=1) occurred. The most frequently reported adverse events included headache, nausea and diarrhoea. CONCLUSIONS: PF-04236921 was not significantly different from placebo for the primary efficacy end point in patients with SLE. Evidence of an effect with 10 mg was seen in a post hoc analysis. Safety was acceptable for doses up to 50 mg as the 200 mg dose was discontinued due to safety findings. TRIAL REGISTRATION NUMBER: NCT01405196; Pre-results.

Maximum-Intensity-Projection and Computer-Aided-Detection Algorithms as Stand-Alone Reader Devices in Lung Cancer Screening Using Different Dose Levels and Reconstruction Kernels.

OBJECTIVE: The objective of our study was to evaluate lung nodule detection rates on standard and microdose chest CT with two different computer-aided detection systems (SyngoCT-CAD, VA 20, Siemens Healthcare [CAD1]; Lung CAD, IntelliSpace Portal DX Server, Philips Healthcare [CAD2]) as well as maximum-intensity-projection (MIP) images. We also assessed the impact of different reconstruction kernels. MATERIALS AND METHODS: Standard and microdose CT using three reconstruction kernels (i30, i50, i70) was performed with an anthropomorphic chest phantom. We placed 133 ground-glass and 133 solid nodules (diameters of 5 mm, 8 mm, 10 mm, and 12 mm) in 55 phantoms. Four blinded readers evaluated the MIP images; one recorded the results of CAD1 and CAD2. Sensitivities for CAD and MIP nodule detection on standard dose and microdose CT were calculated for each reconstruction kernel. RESULTS: Dose for microdose CT was significantly less than that for standard-dose CT (0.1323 mSv vs 1.65 mSv; p < 0.0001). CAD1 delivered superior results compared with CAD2 for standard-dose and microdose CT (p < 0.0001). At microdose level, the best stand-alone sensitivity (97.6%) was comparable with CAD1 sensitivity (96.0%; p = 0.36; both with i30 reconstruction kernel). Pooled sensitivities for all nodules, doses, and reconstruction kernels on CAD1 ranged from 88.9% to 97.3% versus 49.6% to 73.9% for CAD2. The best sensitivity was achieved with standard-dose CT, i50 kernel, and CAD1 (97.3%) versus 96% with microdose CT, i30 or i50 kernel, and CAD1. MIP images and CAD1 had similar performance at both dose levels (p = 0.1313 and p = 0.48). CONCLUSION: Submillisievert CT is feasible for detecting solid and ground-glass nodules that require soft-tissue kernels for MIP and CAD systems to achieve acceptable sensitivities. MIP reconstructions remain a valuable adjunct to the interpretation of chest CT for increasing sensitivity and have the advantage of significantly lower false-positive rates.

Oral and inhaled p38 MAPK inhibitors: effects on inhaled LPS challenge in healthy subjects.

BACKGROUND: Inhaled LPS causes neutrophilic airway inflammation in healthy subjects. We compared the effects of p38 MAPK inhibitors and fluticasone propionate on the LPS response. METHODS: Three randomised, double-blind, placebo-controlled, single dose crossover studies were performed. Active treatments were the oral p38 MAPK inhibitor PH-797804 30 mg (study 1), PH-797804 30 mg and the inhaled p38 MAPK inhibitor PF-03715455 20 mg (study 2) and inhaled fluticasone propionate 500 µg (study 3). The primary endpoint was sputum neutrophil percentage. RESULTS: Sputum neutrophil percentage post-LPS challenge was significantly inhibited (15.1 and 15.3% reduction) by PH-797804 compared to placebo in studies 1 and 2 (p = 0.0096 and 0.0001, respectively), and by PF-03715455 (8.0% reduction, p = 0.031); fluticasone propionate had no effect. PH-797804 significantly inhibited the increase in inflammatory mediators (IL-6, MCP-1, MIP1ß and CC16) in sputum supernatant, while PF-03715455 had no effect. PH-797804 and PF-03715455 both inhibited IL-6, MCP-1, MIP1ß, CC16 and CRP levels in plasma, with PH-797804 having greater effects. Fluticasone propionate had no effect on sputum supernatant or plasma biomarkers. CONCLUSIONS: PH-797804 had the greatest impact on neutrophilic airway inflammation. Oral administration of p38 MAPK inhibitors may optimise pulmonary anti-inflammatory effects.

Tumor acquisition for biomarker research in lung cancer.

The biopsy collection data from two lung cancer trials that required fresh tumor samples be obtained for microarray analysis were reviewed. In the trial for advanced disease, microarray data were obtained on 50 patient samples, giving an overall success rate of 60.2%. The majority of the specimens were obtained through CT-guided lung biopsies (N = 30). In the trial for early-stage patients, 28 tissue specimens were collected from excess tumor after surgical resection with a success rate of 85.7%. This tissue procurement program documents the feasibility in obtaining fresh tumor specimens prospectively that could be used for molecular testing.

Assessment of vascular contrast and wall motion of the aortic root and ascending aorta on MDCT angiography: dual-source high-pitch vs non-gated single-source acquisition schemes.

OBJECTIVES: This retrospective study assessed whether dual-source high-pitch computed tomographic angiography (CTA) offered advantages over single-source standard-pitch techniques in the evaluation of the ascending aorta. METHODS: Twenty patients who received both thoracic dual-source high-pitch and single-source standard-pitch CTAs within 1 year were assessed. Dual-source CTAs were performed; standard-pitch imaging used dose-modulated 120 kVp/150 mAs and 0.8 pitch compared with high-pitch protocols employing dose-modulated 120 kVp/250 mAs and 2.4 target pitch. Radiation dose was documented. Contrast-to-noise ratios (CNRs) at sinuses of the Valsalva (CNRValsalva) and ascending aorta (CNRAorta) were calculated. Dose/CNR for each technique was compared with paired t-tests. Motion at aortic valve, aortic root and ascending aorta were assessed with four-point scales and Mann-Whitney U tests; longitudinal extension of motion was compared with paired t-tests. RESULTS: Significantly lower motion scores for high-pitch, compared with standard-pitch acquisitions for aortic annulus, 0 vs. 2, aortic root, 0 vs. 3, and ascending aorta, 0 vs. 2, were achieved. Significantly reduced longitudinal extension of motion at aortic root, 4.9 mm vs 15.7 mm, and ascending aorta, 4.9 mm vs 21.6 mm, was observed. Contrast was not impacted: CNRValsalva, 45.6 vs 46.3, and CNRAorta, 45.3 vs 47.1. CTDIvol was significantly decreased for high-pitch acquisitions, 13.9 mGy vs 15.8 mGy. CONCLUSIONS: Dual-source high-pitch CTAs significantly decreased motion artefact without negatively impacting vascular contrast and radiation dose. KEY POINTS: • Dual-source high-pitch CTA significantly decreased motion artefact of the ascending aorta. • Dual-source high-pitch CTA did not negatively impact on vascular contrast. • Dual-source high-pitch CTA significantly decreased radiation dose compared with single-source standard-pitch acquisitions.

Radiographic Imaging of Community-Acquired Pneumonia: A Case-Based Review.

The chest radiograph is the most common imaging examination performed in most radiology departments, and one of the more common indications for these studies is suspected infection. Radiologists must therefore be aware of less common radiographic patterns of pulmonary infection if they are to add value in the interpretation of chest radiographs for this indication. This review uses a case-based format to illustrate a range of imaging findings that can be associated with acute pulmonary infection and highlight findings that should prompt investigation for diseases other than community-acquired pneumonia to prevent misdiagnosis and delays in appropriate management.

Master protocols and other innovative trial designs in inflammation and immunology to expedite clinical drug development.

Master protocol designs, such as umbrella and basket studies, allow multiple compounds or multiple target populations to be evaluated simultaneously within a single protocol, and have been widely adopted in oncology clinical trials. These novel designs can also be applied in other therapeutic areas, where they could have several benefits over conducting traditional randomized controlled trials. Here, we detail Pfizer's recent implementations of master protocol designs in inflammation and immunology clinical studies, focusing on the opportunities for cost and resource savings and how these designs can expedite the time required to bring new treatments to patients in need.

ACR Lung-RADS v2022: Assessment Categories and Management Recommendations.

The ACR created the Lung CT Screening Reporting and Data System (Lung-RADS) in 2014 to standardize the reporting and management of screen-detected pulmonary nodules. Lung-RADS was updated to version 1.1 in 2019 and revised size thresholds for nonsolid nodules, added classification criteria for perifissural nodules, and allowed for short-interval follow-up of rapidly enlarging nodules that may be infectious in etiology. Lung-RADS v2022, released in November 2022, provides several updates including guidance on the classification and management of atypical pulmonary cysts, juxtapleural nodules, airway-centered nodules, and potentially infectious findings. This new release also provides clarification for determining nodule growth and introduces stepped management for nodules that are stable or decreasing in size. This article summarizes the current evidence and expert consensus supporting Lung-RADS v2022.

ACR Lung-RADS v2022: Assessment Categories and Management Recommendations.

The American College of Radiology created the Lung CT Screening Reporting and Data System (Lung-RADS) in 2014 to standardize the reporting and management of screen-detected pulmonary nodules. Lung-RADS was updated to version 1.1 in 2019 and revised size thresholds for nonsolid nodules, added classification criteria for perifissural nodules, and allowed for short-interval follow-up of rapidly enlarging nodules that may be infectious in etiology. Lung-RADS v2022, released in November 2022, provides several updates including guidance on the classification and management of atypical pulmonary cysts, juxtapleural nodules, airway-centered nodules, and potentially infectious findings. This new release also provides clarification for determining nodule growth and introduces stepped management for nodules that are stable or decreasing in size. This article summarizes the current evidence and expert consensus supporting Lung-RADS v2022.

PET/CT-Based Absorbed Dose Maps in 90Y Selective Internal Radiation Therapy Correlate with Spatial Changes in Liver Function Derived from Dynamic MRI.

Functional liver parenchyma can be damaged from treatment of liver malignancies with 90Y selective internal radiation therapy (SIRT). Evaluating functional parenchymal changes and developing an absorbed dose (AD)-toxicity model can assist the clinical management of patients receiving SIRT. We aimed to determine whether there is a correlation between 90Y PET AD voxel maps and spatial changes in the nontumoral liver (NTL) function derived from dynamic gadoxetic acid-enhanced MRI before and after SIRT. Methods: Dynamic gadoxetic acid-enhanced MRI scans were acquired before and after treatment for 11 patients undergoing 90Y SIRT. Gadoxetic acid uptake rate (k1) maps that directly quantify spatial liver parenchymal function were generated from MRI data. Voxel-based AD maps, derived from the 90Y PET/CT scans, were binned according to AD. Pre- and post-SIRT k1 maps were coregistered to the AD map. Absolute and percentage k1 loss in each bin was calculated as a measure of loss of liver function, and Spearman correlation coefficients between k1 loss and AD were evaluated for each patient. Average k1 loss over the patients was fit to a 3-parameter logistic function based on AD. Patients were further stratified into subgroups based on lesion type, baseline albumin-bilirubin scores and alanine transaminase levels, dose-volume effect, and number of SIRT treatments. Results: Significant positive correlations (ρ = 0.53-0.99, P < 0.001) between both absolute and percentage k1 loss and AD were observed in most patients (8/11). The average k1 loss over 9 patients also exhibited a significant strong correlation with AD (ρ ≥ 0.92, P < 0.001). The average percentage k1 loss of patients across AD bins was 28%, with a logistic function model demonstrating about a 25% k1 loss at about 100 Gy. Analysis between patient subgroups demonstrated that k1 loss was greater among patients with hepatocellular carcinoma, higher alanine transaminase levels, larger fractional volumes of NTL receiving an AD of 70 Gy or more, and sequential SIRT treatments. Conclusion: Novel application of multimodality imaging demonstrated a correlation between 90Y SIRT AD and spatial functional liver parenchymal degradation, indicating that a higher AD is associated with a larger loss of local hepatocyte function. With the developed response models, PET-derived AD maps can potentially be used prospectively to identify localized damage in liver and to enhance treatment strategies.

ACR Appropriateness Criteria® Sepsis.

Sepsis is defined as a life-threatening organ dysfunction caused by a dysregulated host response to infection. A search for the underlying cause of infection typically includes radiological imaging as part of this investigation. This document focuses on thoracic and abdominopelvic causes of sepsis. In 2017, the global incidence of sepsis was estimated to be 48.9 million cases, with 11 million sepsis-related deaths (accounting for nearly 20% of all global deaths); therefore, understanding which imaging modalities and types of studies are acceptable or not acceptable is imperative. The 5 variants provided include the most commonly encountered scenarios in the setting of sepsis along with recommendations and data for each imaging study. The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed annually by a multidisciplinary expert panel. The guideline development and revision process support the systematic analysis of the medical literature from peer reviewed journals. Established methodology principles such as Grading of Recommendations Assessment, Development, and Evaluation or GRADE are adapted to evaluate the evidence. The RAND/UCLA Appropriateness Method User Manual provides the methodology to determine the appropriateness of imaging and treatment procedures for specific clinical scenarios. In those instances where peer reviewed literature is lacking or equivocal, experts may be the primary evidentiary source available to formulate a recommendation.

Ascending thoracic aorta: postoperative imaging evaluation.

Advances in computed tomography (CT) scanners and electrocardiographic gating techniques have resulted in superior image quality of the ascending aorta and increased the use of CT angiography for evaluating the postoperative ascending aorta. Several abnormalities of the ascending aorta and aortic arch often require surgery, and various open techniques may be used to reconstruct the aorta, such as the Wheat procedure, in which both an ascending aortic graft and an aortic valve prosthesis are implanted; the Cabrol and modified Bentall procedures, in which a composite synthetic ascending aorta and aortic valve graft are placed; the Ross procedure, in which the aortic valve and aortic root are replaced with the patient's native pulmonary valve and proximal pulmonary artery; valve-sparing procedures such as the T. David-V technique, which leaves the native aortic valve intact; and more extensive arch repair procedures such as the elephant trunk and arch-first techniques, in which interposition or inclusion grafts are implanted, with or without replacement of the aortic valve. Normal postoperative imaging findings, such as hyperattenuating felt pledgets, prosthetic conduits, and reanastomosis sites, may mimic pathologic processes. Postoperative complications seen at CT angiography that require further intervention include pseudoaneurysms, anastomotic stenoses, dissections, and aneurysms. Radiologists must be familiar with these procedures and their imaging features to identify normal postoperative appearances and complications.

Computed tomography screening for lung cancer: where are we now?

Low-dose computed tomography (LDCT) screening has been shown to result in detection of earlier-stage lung cancers, with a 20% reduction in cancer-related deaths. LDCT screening offers significant potential benefits to selected patients; however, many questions remain, including questions about the applicability of lung cancer screening in clinical practice.