Targeting the liver clock improves fibrosis by restoring TGF-ß signaling.

BACKGROUND & AIMS: Liver fibrosis is the major driver for hepatocellular carcinoma and liver disease related death. Approved anti-fibrotic therapies are absent and compounds in development have limited efficacy. Increased TGF-ß signaling drives collagen deposition by hepatic stellate cells (HSC)/myofibroblasts. Here, we aimed to dissect the role of the circadian clock (CC) in controlling TGF-ß signaling and liver fibrosis. METHODS: Using CC-mutant mice, enriched HSCs and myofibroblasts obtained from healthy and fibrotic mice in different CC-phases and loss-of-function studies in human hepatocytes and myofibroblasts, we investigated the relationship between CC and TGF-ß signaling. We explored hepatocyte-myofibroblast communication through bioinformatic analyses of single-nuclei transcriptomes and validation in cell-based models. Using mouse models for MASH fibrosis and spheroids from patients with liver disease, we performed proof-of-concept studies to validate pharmacological targetability and clinical translatability. RESULTS: We discovered that the CC-oscillator temporally gates TGF-ß signaling and this regulation is broken in fibrosis. We demonstrate that HSCs and myofibroblasts contain a functional CC with rhythmic expression of numerous genes, including fibrogenic genes. Perturbation studies in hepatocytes and myofibroblasts revealed a reciprocal relationship between TGF-ß-activation and CC perturbation, which was confirmed in patient-derived ex vivo and in vivo models. Pharmacological modulation of CC-TGF-ß signaling inhibited fibrosis in mouse models in vivo as well as patient-derived liver spheroids. CONCLUSION: The CC regulates TGF-ß signaling, and the breakdown of this control is associated with liver fibrosis in patients. Pharmacological proof-of-concept studies across different models uncover the CC as a therapeutic candidate target for liver fibrosis - a rising global unmet medical need. IMPACT AND IMPLICATIONS: Liver fibrosis due to metabolic diseases is a global health challenge. Many liver functions are rhythmic throughout the day being controlled by the circadian clock (CC). Here we demonstrate that the regulation of the CC is perturbed upon chronic liver injury and this perturbation contributes to fibrotic disease. By showing that a compound targeting the CC improves liver fibrosis in patient-derived models, this study provides a novel therapeutic candidate strategy to treat fibrosis in patients. Additional studies will be needed for clinical translation. Since the findings uncovers a previously undiscovered profibrotic mechanism and therapeutic target, the study is of interest for scientists investigating liver disease, clinical hepatologists and drug developers.

Preoperative pancreatic radiologic characteristics predict pancreatic-specific complications before pancreaticoduodenectomy: the pancreatic acinar radiologic score.

BACKGROUND: High acinar pancreatic contents are associated with a higher rate of postpancreatectomy acute pancreatitis and pancreatic fistula formation (POPF). Predicting acinar contents preoperatively might identify those at high risk of developing postoperative complications. METHODS: A multivariable analysis was performed to identify radiological factors associated with high pancreatic acinar content at histology in patients undergoing pancreaticoduodenectomy. Clinical and radiological variables identified were used to build a composite score predicting low, moderate, and high acinar pancreatic contents. RESULTS: Pancreatic density, wirsung caliber, and pancreatic thickness on preoperative CT-scan predicted acinar contents. These three variables predicted low, moderate, and high acinar content in 94 (26%), 122 (33.6%), and 147 (40.5%) patients, respectively. Patients with high radiological acinar scores compared with patients with intermediate-low risk scores were more frequently male (73.4% vs. 54.1%; p = 0.0003), obese (14% vs. 6%; p = 0.01), and had a statistically significant higher rate of pancreatic-specific complications (23.8% vs. 8.33%; p = 0.01), POPF (12.9% vs. 4.63%; p = 0.005) and pancreaticogastrostomy bleeding (10.8% vs. 4.17%; p = 0.01). CONCLUSION: A simple radiological score combining pancreatic thickness, density, and wirsung caliber at CT scan preoperatively predicts patients with pancreatic parenchyma that are at higher risk of postoperative pancreatic-specific complications.

Management of a rare mandibular giant cell tumor of bone by neoadjuvant denosumab therapy and surgery: A 4-year follow-up case report.

INTRODUCTION: Giant cell tumor of bone (GCTB) is a very rare tumor encountered in the jaws and its histology is quite similar to the more common giant cell granuloma of the jaws (GCGJ). These two entities can be easily confused in maxillofacial region. They are classically managed surgically, but in some localizations and in specific medical-surgical contexts, neoadjuvant therapy with denosumab may be indicated. This report tends to reinforce existing evidence in favor of the use of a neoadjuvant approach, particularly for localization of GCTB in the orofacial region. PRESENTATION OF CASE: This is a 57-year-old female patient, an alcoholic smoker, in whom a voluminous mandibular radiolucent lesion was discovered during a routine X-ray by her dentist. After medical imaging assessment and incisional biopsy, diagnosis of GCTB was established. A neoadjuvant denosumab therapy was proposed first followed by a secondary surgical curettage. After 4 years' follow-up, complete healing was observed with no recurrence of the lesion. DISCUSSION: Surgical management of aggressive GCTB is risky particularly in localizations involving the sacrum, spine or craniofacial skeleton with a high residual recurrence rate. The use of denosumab to stop tumor progression and facilitate secondary excision surgery is a recent approach that is now well documented in the literature showing promising results with a low rate of side effects. CONCLUSION: This case of mandibular GCTB is to our knowledge the unique case described in this localization and treated by denosumab neoadjuvant therapy followed by surgery with a 4-year follow-up showing a complete healing.

p16 Immunohistochemical Expression as a Surrogate Assessment of CDKN2A Alteration in Gliomas Leading to Prognostic Significances.

CDKN2A is a tumor suppressor gene encoding the p16 protein, a key regulator of the cell cycle. CDKN2A homozygous deletion is a central prognostic factor for numerous tumors and can be detected by several techniques. This study aims to evaluate the extent to which immunohistochemical levels of p16 expression may provide information about CDKN2A deletion. A retrospective study was conducted in 173 gliomas of all types, using p16 IHC and CDKN2A fluorescent in situ hybridization. Survival analyses were performed to assess the prognostic impact of p16 expression and CDKN2A deletion on patient outcomes. Three patterns of p16 expression were observed: absence of expression, focal expression, and overexpression. Absence of p16 expression was correlated with worse outcomes. p16 overexpression was associated with better prognoses in MAPK-induced tumors, but with worse survival in IDH-wt glioblastomas. CDKN2A homozygous deletion predicted worse outcomes in the overall patient population, particularly in IDH-mutant 1p/19q oligodendrogliomas (grade 3). Finally, we observed a significant correlation between p16 immunohistochemical loss of expression and CDKN2A homozygosity. IHC has strong sensitivity and high negative predictive value, suggesting that p16 IHC might be a pertinent test to detect cases most likely harboring CDKN2A homozygous deletion.

Is It Possible to Replace Conventional Radiography (CR) with a Dose Neutral Computed Tomography (CT) of the Cervical Spine in Emergency Radiology-An Experimental Cadaver Study.

The purpose of this experimental study on recently deceased human cadavers was to investigate whether (I) the radiation exposure of the cervical spine CT can be reduced comparable to a dose level of conventional radiography (CR); and (II) whether and which human body parameters can be predictive for higher dose reduction potential (in this context). MATERIALS AND METHODS: Seventy serial CT scans of the cervical spine of 10 human cadavers undergoing postmortem virtual autopsy were taken using stepwise decreasing upper limits of the tube current (300 mAs, 150 mAs, 110 mAs, 80 mAs, 60 mAs, 40 mAs, and 20 mAs) at 120 kVp. An additional scan acquired at a fixed tube current of 300 mAs served as a reference. Images were reconstructed with filtered back projection and the upper (C1-4) and lower (C4-7) cervical spine were evaluated by three blinded readers for image quality, regarding diagnostic value and resolution of anatomical structures according to a semiquantitative three-point-scale. Dose values and individual physical parameters were recorded. The relationship of diagnostic IQ, dose reduction level, and patients' physical parameters were investigated. The high-contrast resolution of the applied CT protocols was tested in an additional phantom study. RESULTS: The IQ of the upper cervical spine was diagnostic at 1.69 ± 0.58 mGy (CTDI) corresponding to 0.20 ± 0.07 mSv (effective dose) in all cadavers. IQ of the lower cervical spine was diagnostic at 4.77 ± 1.86 mGy corresponding to 0.560 ± 0.21 mSv (effective dose) in seven cadavers and at 2.60 ± 0.93 mGy corresponding to 0.31 ± 0.11 mSv in four cadavers. Significant correlation was detected for BMI (0.8366; p = 0.002548) and the anteroposterior (a.p.) chest diameter (0.8363; p = 0.002566), shoulder positioning (0.79799; p = 0.00995), and radiation exposure. CONCLUSIONS: Conventional radiography can be replaced with a nearly dose-neutral CT scan of the cervical spine.

Bilateral and Optimistic Warning Paradigms Improve the Predictive Power of Intraoperative Facial Motor Evoked Potentials during Vestibular Schwannoma Surgery.

Facial muscle corticobulbar motor evoked potentials (FMcoMEPs) are used to monitor facial nerve integrity during vestibular schwannoma resections to increase maximal safe tumor resection. Established warning criteria, based on ipsilateral amplitude reduction, have the limitation that the rate of false positive alarms is high, in part because FMcoMEP changes occur on both sides, e.g., due to brain shift or pneumocephalus. We retrospectively compared the predictive value of ipsilateral-only warning criteria and actual intraoperative warnings with a novel candidate warning criterion, based on "ipsilateral versus contralateral difference in relative stimulation threshold increase, from baseline to end of resection" (BilatMT ≥ 20%), combined with an optimistic approach in which a warning would be triggered only if all facial muscles on the affected side deteriorated. We included 60 patients who underwent resection of vestibular schwannoma. The outcome variable was postoperative facial muscle function. Retrospectively applying BilatMT, with the optimistic approach, was found to have a significantly better false positive rate, which was much lower (9% at day 90) than the traditionally used ipsilateral warning criteria (>20%) and was also lower than actual intraoperative warnings. This is the first report combining the threshold method with an optimistic approach in a bilateral multi-facial muscle setup. This method could substantially reduce the rate of false positive alarms in FMcoMEP monitoring.

Radiation Dose and Fluoroscopy Time of Endovascular Treatment in Patients with Intracranial Lateral Dural Arteriovenous Fistulae.

PURPOSE: Intracranial lateral dural arteriovenous fistula (LDAVF) represents a specific subtype of cerebrovascular fistulae, harboring a potentially life-threatening risk of brain hemorrhage. Fluoroscopically guided endovascular embolization is the therapeutic gold standard. We provide detailed dosimetry data to suggest novel diagnostic reference levels (DRL). METHODS: Retrospective single-center study of LDAVFs treated between January 2014 and December 2019. Regarding dosimetry, the dose area product (DAP) and fluoroscopy time were analyzed for the following variables: Cognard scale grade, endovascular technique, angiographic outcome, and digital subtraction angiography (DSA) protocol. RESULTS: A total of 70 patients (19 female, median age 65 years) were included. Total median values for DAP and fluoroscopy time were 325 Gy cm2 (25%/75% percentile: 245/414 Gy cm2) and 110 min (68/142min), respectively. Neither median DAP nor fluoroscopy time were significantly different when comparing low-grade with high-grade LDAVF (Cognard I + IIa versus IIb-V; p > 0.05, each). Transvenous coil embolization yielded the lowest dosimetry values, with significantly lower median values when compared to a combined transarterial/transvenous technique (DAP 290 Gy cm2 versus 388 Gy cm2, p = 0.031; fluoroscopy time 85 min versus 170 min, p = 0.016). A significant positive correlation was found between number of arterial feeders treated by liquid embolization and both DAP (rs = 0.367; p = 0.010) and fluoroscopy time (rs = 0.295; p = 0.040). Complete LDAVF occlusion was associated with transvenous coiling (p = 0.001). A low-dose DSA protocol yielded a 20% reduction of DAP (p = 0.021). CONCLUSION: This LDAVF study suggests several local DRLs which varied substantially dependent on the endovascular technique and DSA protocol.

Radiation dose and image quality in intraoperative CT (iCT) angiography of the brain with stereotactic head frames.

OBJECTIVES: Intraoperative CT (iCT) angiography of the brain with stereotactic frames is an integral part of navigated neurosurgery. Validated data regarding radiation dose and image quality in these special examinations are not available. We therefore investigated two iCT protocols in this IRB-approved study. METHODS: Retrospective analysis of patients, who received a cerebral stereotactic iCT angiography on a 128 slice CT scanner between February 2016 and December 2017. In group A, automated tube current modulation (ATCM; reference value 410 mAs) and automated tube voltage selection (reference value 120 kV) were enabled, and only examinations with a selected voltage of 120 kV were included. In group B, fixed parameters were applied (300 mAs, 120 kV). Radiation dose was measured by assessing the volumetric CT dose index (CTDIvol), dose length product (DLP) and effective dose (ED). Signal-to-noise ratio (SNR) and image noise were assessed for objective image quality, visibility of arteries and grey-white differentiation for subjective image quality. RESULTS: Two hundred patients (n = 100 in each group) were included. In group A, median selected tube current was 643 mAs (group B, 300 mAs; p < 0.001). Median values of CTDIvol, DLP and ED were 91.54 mGy, 1561 mGy cm and 2.97 mSv in group A, and 43.15 mGy, 769 mGy cm and 1.46 mSv in group B (p < 0.001). Image quality did not significantly differ between groups (p > 0.05). CONCLUSIONS: ATCM yielded disproportionally high radiation dose due to substantial tube current increase at the frame level, while image quality did not improve. Thus, ATCM should preferentially be disabled. KEY POINTS: • Automated tube current modulation (ATCM) yields disproportionally high radiation dose in intraoperative CT angiography of the brain with stereotactic head frames. • ATCM does not improve overall image quality in these special examinations. • ATCM is not yet optimised for CT angiography of the brain with major extracorporeal foreign materials within the scan range.

Diagnostic yield and accuracy of coronary CT angiography after abnormal nuclear myocardial perfusion imaging.

We aimed to determine the diagnostic yield and accuracy of coronary CT angiography (CCTA) in patients referred for invasive coronary angiography (ICA) based on clinical concern for coronary artery disease (CAD) and an abnormal nuclear stress myocardial perfusion imaging (MPI) study. We enrolled 100 patients (84 male, mean age 59.6 ± 8.9 years) with an abnormal MPI study and subsequent referral for ICA. Each patient underwent CCTA prior to ICA. We analyzed the prevalence of potentially obstructive CAD (≥50% stenosis) on CCTA and calculated the diagnostic accuracy of ≥50% stenosis on CCTA for the detection of clinically significant CAD on ICA (defined as any ≥70% stenosis or ≥50% left main stenosis). On CCTA, 54 patients had at least one ≥50% stenosis. With ICA, 45 patients demonstrated clinically significant CAD. A positive CCTA had 100% sensitivity and 84% specificity with a 100% negative predictive value and 83% positive predictive value for clinically significant CAD on a per patient basis in MPI positive symptomatic patients. In conclusion, almost half (48%) of patients with suspected CAD and an abnormal MPI study demonstrate no obstructive CAD on CCTA.

Submillisievert Computed Tomography of the Chest Using Model-Based Iterative Algorithm: Optimization of Tube Voltage With Regard to Patient Size.

OBJECTIVE: The aim of this study was to define optimal tube potential for soft tissue and vessel visualization in dose-reduced chest CT protocols using model-based iterative algorithm in average and overweight patients. METHODS: Thirty-six patients receiving chest CT according to 3 protocols (120 kVp/noise index [NI], 60; 100 kVp/NI, 65; 80 kVp/NI, 70) were included in this prospective study, approved by the ethics committee. Patients' physical parameters and dose descriptors were recorded. Images were reconstructed with model-based algorithm. Two radiologists evaluated image quality and lesion conspicuity; the protocols were intraindividually compared with preceding control CT reconstructed with statistical algorithm (120 kVp/NI, 20). Mean and standard deviation of attenuation of the muscle and fat tissues and signal-to-noise ratio of the aorta were measured. RESULTS: Diagnostic images (lesion conspicuity, 95%-100%) were acquired in average and overweight patients at 1.34, 1.02, and 1.08 mGy and at 3.41, 3.20, and 2.88 mGy at 120, 100, and 80 kVp, respectively. Data are given as CT dose index volume values. CONCLUSIONS: Model-based algorithm allows for submillisievert chest CT in average patients; the use of 100 kVp is recommended.

Dose reduction in 64-row whole-body CT in multiple trauma: an optimized CT protocol with iterative image reconstruction on a gemstone-based scintillator.

OBJECTIVE: Evaluation of potential dose savings by implementing adaptive statistical iterative reconstruction (ASiR) on a gemstone-based scintillator in a clinical 64-row whole-body CT (WBCT) protocol after multiple trauma. METHODS: Dose reports of 152 WBCT scans were analysed for two 64-row multidetector CT scanners (Scanners A and B); the main scanning parameters were kept constant. ASiR and a gemstone-based scintillator were used in Scanner B, and the noise index was adjusted (head: 5.2 vs 6.0; thorax/abdomen: 29.0 vs 46.0). The scan length, CT dose index (CTDI) and dose-length product (DLP) were analysed. The estimated mean effective dose was calculated using normalized conversion factors. Student's t-test was used for statistics. RESULTS: Both the mean CTDI (mGy) (Scanner A: 53.8 ± 2.0, 10.3 ± 2.5, 14.4 ± 3.7; Scanner B: 48.7 ± 2.2, 7.1 ± 2.3, 9.1 ± 3.6; p < 0.001, respectively) and the mean DLP (mGy cm) (Scanner A: 1318.9 ± 167.8, 509.3 ± 134.7, 848.8 ± 254.0; Scanner B: 1190.6 ± 172.6, 354.6 ± 128.3, 561.0 ± 246.7; p < 0.001, respectively) for the head, thorax and abdomen were significantly reduced with Scanner B. There was no relevant difference in scan length. The total mean effective dose (mSv) was significantly decreased with Scanner B (24.4 ± 6.0, 17.2 ± 5.8; p < 0.001). CONCLUSION: The implementation of ASiR and a gemstone-based scintillator allows for significant dose savings in a clinical WBCT protocol. ADVANCES IN KNOWLEDGE: Recent technical developments can significantly reduce radiation dose of WBCT in multiple trauma. Dose reductions of 10-34% can be achieved.

Emergency radiology: straightening of the cervical spine in MDCT after trauma--a sign of injury or normal variant?

OBJECTIVE: To evaluate whether straightening of the cervical spine (C-spine) alignment after trauma can be considered a significant multidetector CT (MDCT) finding. METHODS: 160 consecutive patients after C-spine trauma admitted to a Level 1 trauma centre received MDCT according to Canadian Cervical Spine Rule and National Emergency X-Radiography Utilization Study indication rule; subgroups with and without cervical collar immobilization (CCI +/-) were compared with a control group (n = 20) of non-traumatized patients. Two independent readers evaluated retrospectively the alignment, determined the absolute rotational angle of the posterior surface of C2 and C7 (ARA C2-7) and grouped the results for lordosis (<-13°), straight (-13 to +6°) and kyphosis (>+6°). RESULTS: In the two CCI-/CCI+ study groups, the straight or kyphotic alignment significantly (p = 0.001) predominated over lordosis. The number of patients with straight C-spine alignment was higher in the CCI+ group (CCI+ 69% vs CCI- 49%, p = 0.05). A comparison of the CCI+ group vs the CCI- group revealed a slightly smaller number of kyphotic (10% vs 18%, p = 0.34) and lordotic (21% vs 33%, p = 0.33) alignments. Statistically, however, the differences were of no significance. The control group revealed no significant differences. CONCLUSION: Straightening of the C-spine alone is not a definitive sign of injury but is a biomechanical variation due to CCI and neck positioning during MDCT or active patient control. ADVANCES IN KNOWLEDGE: Straightening of the C-spine alignment in MDCT alone is not a definitive sign of injury. Straightening of the C-spine alignment is related to neck positioning and active patient control. CCI has a straightening effect on the cervical alignment.

Quantitative evaluation of beam-hardening artefact correction in dual-energy CT myocardial perfusion imaging.

OBJECTIVES: To assess quantitatively the impact of a novel reconstruction algorithm ("kernel") with beam-hardening correction (BHC) on beam-hardening artefacts of the myocardium at dual-energy CT myocardial perfusion imaging (DE-CTMPI). METHODS: Rest-series of DE-CTMPI examinations from 14 patients were retrospectively analyzed. Six image series were reconstructed for each patient: a) 100 kV, b) 140 kV, and c) linearly blended MIX0.5, each with BHC (D33f kernel) and without (D30f kernel). Seven hundred and fifty-six myocardial regions were assessed. Seven equal regions of interest divided the myocardium in the axial section. Three subdivisions were created within these regions in areas prone to BHA. Reports of SPECT studies performed within 30 days of CT examination were used to confirm the presence and location of true perfusion defects. Paired student t-test was used for statistical evaluation. RESULTS: Overall mean myocardial attenuation was lower using BHC (D30f: 87.3 ± 24.1 HU; D33f: 85.5 ± 21.5 HU; p = 0.009). Overall relative difference from average myocardial attenuation (RDMA) was more homogeneous using BHC (D30f: -0.3 ± 11.4 %; D33f: 0.1 ± 10.1 %; p < 0.001). Changes in RDMA were greatest in the posterobasal myocardium (D30f: -16.2 ± 10.0 %; D33f: 3.4 ± 10.7 %; p < 0.001). CONCLUSIONS: A dedicated reconstruction algorithm with BHC can significantly reduce beam-hardening artefacts in DE-CTMPI. KEY POINTS: • Beam-hardening artefacts (BHA) cause interference with attenuation-based CT myocardial perfusion assessment (CTMPI). • BHA occur mostly in the posterobasal left ventricular wall. • Beam-hardening correction homogenized and decreased mean myocardial attenuation. • BHC can help avoid false-positive findings and increase specificity of static CTMPI.

Radiological mass casualty incident (MCI) workflow analysis: single-centre data of a mid-scale exercise.

OBJECTIVE: The aim of the study was to analyse and interpret radiological mass casualty incident workflow data. METHODS: In a mid-scale mass casualty incident exercise, the on-site triage assigned 12 cases to the investigated institution (11 included in the study). Two out of five institutional multislice-CT-scanners were used and the whole CT workflow and radiological service process chain were simulated as close to realistic as possible. The respective time intervals for reaching defined milestones were measured. RESULTS: The average CT in-room time, i.e. from entering to leaving the CT room was 9.43 min [(standard deviation) SD: 2.27 min; 95% (confidence interval) CI: 7.90-10.95 min]. Time spent on CT table was 6.75 min (SD: 1.67; CI: 5.63-7.87), and the pure scan time was 4.22 min (SD: 0.64; CI: 3.79-4.65). The first images after entering the CT room were available at a dedicated CT workstation after 5.85 min (SD: 2.20; CI: 4.37-7.32) and institution wide via picture archiving system (PACS) after 7.85 min (SD: 1.27; CI: 7.00-8.71). However, the PACS archiving process, that is, transfer of standard reconstruction set of CT images into the PACS was finished after 20.85 min (SD: 2.97; CI: 18.85-22.84). CONCLUSION: Up to six patients may be served per hour and per CT scanner by using a standard whole body CT polytrauma protocol. Dedicated CT triage protocols may even increase this number. The time portion until images were available at end points was relatively long. A solution has to be developed in order to avoid scenarios of patients being faster at end points than their images.

Imaging minor head injury (MHI) in emergency radiology: MRI highlights additional intracranial findings after measurement of trauma biomarker S-100B in patients with normal CCT.

OBJECTIVE: To investigate whether MRI in emergency radiology can detect (a) additional trauma-related findings after minor head injury (MHI) or (b) structural, non-trauma-related intracranial lesions when trauma biomarker S-100B concentration is raised, or clinical symptoms are unexplained, or both. METHODS: 41 patients with MHI were included. Concentrations of S-100B in serum were measured and categorized using an established cut-off at 0.1 µg l(-1). Intracerebral trauma-related as well as non-trauma-related chronic structural findings (atrophy, microangiopathy and chronic parenchymal defects) were assessed by cranial CT (CCT) and MRI by two independent radiologists (UL and LLG). All CCT and MRI results were compared with biomarker S-100B. RESULTS: Compared with CCT, MRI detected 10 additional lesions. 5 patients had abnormal MRI with a total of 15 trauma-related lesions and showed elevated S-100B concentrations. Although sensitivity of S-100B was 100%, specificity was only 25%. Patients with structural brain lesions showed significantly higher S-100B serum levels (0.50 and 0.14 µg l(-1), p = 0.01). CONCLUSION: Biomarker S-100B has proven its high negative-predictive value to rule out intracranial bleeding in patients after MHI even if MRI is used as imaging modality. Regarding the low specificity of S-100B, structural lesions of the brain parenchyma not related to the acute trauma may be associated with increased serum concentrations of protein S-100B. ADVANCES IN KNOWLEDGE: Biomarker S-100B has a high negative-predictive value to rule out intracranial bleeding after MHI. Biomarker S-100B's low specificity may be associated with non-traumatic brain parenchyma lesions. MRI is superior to CCT in detecting subtle findings in neuroimaging after MHI. Biomarker S-100B can potentially reduce the large number of normal CCT studies after MHI.

State of the Art: Iterative CT Reconstruction Techniques.

Owing to recent advances in computing power, iterative reconstruction (IR) algorithms have become a clinically viable option in computed tomographic (CT) imaging. Substantial evidence is accumulating about the advantages of IR algorithms over established analytical methods, such as filtered back projection. IR improves image quality through cyclic image processing. Although all available solutions share the common mechanism of artifact reduction and/or potential for radiation dose savings, chiefly due to image noise suppression, the magnitude of these effects depends on the specific IR algorithm. In the first section of this contribution, the technical bases of IR are briefly reviewed and the currently available algorithms released by the major CT manufacturers are described. In the second part, the current status of their clinical implementation is surveyed. Regardless of the applied IR algorithm, the available evidence attests to the substantial potential of IR algorithms for overcoming traditional limitations in CT imaging.

Coexisting Prolactinoma and Primary Aldosteronism: Is There a Pathophysiological Link?

CONTEXT: Coexisting prolactinoma-primary aldosteronism (PA) is infrequently reported. OBJECTIVE: The objective of the study was to identify patients with prolactinoma-PA and test the hypothesis that elevated prolactin (PRL) concentrations play a role in PA pathogenesis. SETTING AND DESIGN: Hyperprolactinemia/prolactinoma was diagnosed in PA patients from two referral centers (Munich, Germany, and Turin, Italy) and in essential hypertensive (EH) patients from one center (Turin). PRL receptor (PRLR) gene expression was determined by microarrays on aldosterone-producing adenomas and normal adrenals and validated by real-time PCR. H295R adrenal cells were incubated with 100 nM PRL, and gene expression levels were determined by real-time PCR and aldosterone production was quantified. RESULTS: Seven patients with prolactinoma-PA were identified: four of 584 and three of 442 patients from the Munich and Turin PA cohorts, respectively. A disproportionate number presented with macroprolactinomas (five of seven). There were five cases of hyperprolactinemia with no cases of macroprolactinoma of 14 790 patients in a general EH cohort. In a population of PA patients case-control matched 1:3 with EH patients there were two cases of hyperprolactinemia of 270 PA patients and no cases in the EH cohort (n = 810). PRLR gene expression was significantly up-regulated in the aldosterone-producing adenomas compared with normal adrenals (1.7-fold and 1.5-fold by microarray and real-time PCR, respectively). In H295R cells, PRL treatment resulted in 1.3-fold increases in CYP11B2 expression and aldosterone production. CONCLUSION: Elevated PRL caused by systemic hyperprolactinemia may contribute to the development of PA in those cases in which the two entities coexist.

Low-volume contrast medium protocol for comprehensive cardiac and aortoiliac CT assessment in the context of transcatheter aortic valve replacement.

RATIONALE AND OBJECTIVES: To investigate the diagnostic performance of a comprehensive computed tomography (CT) protocol for both cardiac and aortoiliac evaluation of patients considered for transcatheter aortic valve replacement (TAVR) using a single, low-volume contrast medium (CM) injection. MATERIALS AND METHODS: Forty-four TAVR candidates were retrospectively analyzed. All underwent retrospectively electrocardiogram-gated cardiac CT followed by high-pitch CT angiography of the aortoiliac vasculature using one of two single injection protocols of 320 mgI/mL iodine CM: group A (n = 22), iodine delivery rate-based (1.28 gI/s), 60-mL CM volume, 4.0 mL/s flow rate; group B (n = 22), clinical routine protocol, 100-mL CM volume, 4.0 mL/s flow rate. Mean arterial attenuation, signal-to-noise ratio (SNR), and contrast-to-noise ratio (CNR) were calculated. Subjective image quality was assessed. RESULTS: Aortic root and iliofemoral dimensions could be analyzed in all cases. Patient characteristics showed no significant differences. Mean attenuation at the levels of the aortic root (285.8 ± 83.0 HU vs 327.5 ± 70.8 HU, P = .080) and the iliofemoral access route (256.8 ± 88.5 HU vs 307.5 ± 93.2 HU, P = .071), as well as SNR and CNR were nonsignificantly lower in group A compared to group B. Subjective image quality was equivalent. CONCLUSIONS: In multimorbid TAVR patients, the performance of a combined CT protocol using a single low-volume CM bolus is feasible with maintained image quality compared to a standard protocol.

ACTH after 15 min distinguishes between Cushing's disease and ectopic Cushing's syndrome: a proposal for a short and simple CRH test.

OBJECTIVE: The aim of the present study was to validate criteria of corticotropin-releasing hormone (CRH) stimulation and 8 mg dexamethasone suppression (high-dose dexamethasone suppression, HDDS) to distinguish the etiology of ACTH-dependent Cushing's syndrome. SUBJECTS AND METHODS: We retrospectively analyzed cortisol and ACTH after the injection of 100 µg human CRH in confirmed Cushing's disease (CD, n=78) and confirmed ectopic Cushing's syndrome (ECS, n=18). Cortisol and ACTH increase (in percentage above basal (%B)) at each time point, maximal increase (Δmax %B), and area under the curve (AUC %B) were analyzed using receiver operator characteristics (ROC) curve analyses. Cortisol suppression (%B) after 8 mg of dexamethasone was evaluated as a supplementary criterion. RESULTS: An increase in ACTH of ≥ 43%B at 15 min after CRH was the strongest predictor of CD, with a positive likelihood ratio of 14.0, a sensitivity of 83%, a specificity of 94%, a positive predictive value of 98% and a negative predictive value of 58%. All of the other criteria of stimulated ACTH and cortisol levels were not superior in predicting CD in response to CRH injection. The addition of cortisol suppression by dexamethasone did not increase the discriminatory power. However, the combination of a positive ACTH response at 15 min and a positive HDDS test excluded ECS in all cases. CONCLUSION: The present findings support the use of plasma ACTH levels 15 min after the injection of human CRH as a response criterion for distinguishing between CD and ECS. The addition of the HDDS test is helpful for excluding ECS when both tests are positive.

Influence of technical parameters on epicardial fat volume quantification at cardiac CT.

OBJECTIVES: To systematically analyze the influence of technical parameters on quantification of epicardial fat volume (EATV) at cardiac CT. METHODS: 153 routine cardiac CT data sets were analyzed using three-dimensional pericardial border delineation. Three image series were reconstructed per patient: (a) CTAD: coronary CT angiography (CTA), diastolic phase; (b) CTAS: coronary CTA, systolic phase; (c) CaScD: non-contrast CT, diastolic phase. EATV was calculated using three different upper thresholds (-15HU, -30 HU, -45HU). Repeated measures ANOVA, Spearman's rho, and Bland Altman plots were used. RESULTS: Mean EATV differed between all three image series at a -30HU threshold (CTAD 87.2 ± 38.5 ml, CTAS 90.9 ± 37.7 ml, CaScD 130.7 ± 49.5 ml, P<0.001). EATV of diastolic and systolic CTA reconstructions did not differ significantly (P=0.225). Mean EATV for contrast enhanced CTA at a -15HU threshold (CTAD15 102.4 ± 43.6 ml, CTAS15 105.3 ± 42.3 ml) could be approximated most closely by non-contrast CT at -45HU threshold (CaScD45 105.3 ± 40.8 ml). The correlation was excellent: CTAS15-CTAD15, rho=0.943; CTAD15-CaScD45, rho=0.905; CTAS15-CaScD45, rho=0.924; each P<0.001). Bias values from Bland Altman Analysis were: CTAS15-CTAD15, 4.9%; CTAD15-CaScD45, -4.3%; CTAS15-CaScD45, 0.6%. CONCLUSIONS: Measured EATV can differ substantially between contrast enhanced and non-contrast CT studies, which can be reconciled by threshold modification. Heart cycle phase does not significantly influence EATV measurements.