CD8+ T cells induce cachexia during chronic viral infection.

Cachexia represents a leading cause of morbidity and mortality in various cancers, chronic inflammation and infections. Understanding of the mechanisms that drive cachexia has remained limited, especially for infection-associated cachexia (IAC). In the present paper we describe a model of reversible cachexia in mice with chronic viral infection and identify an essential role for CD8+ T cells in IAC. Cytokines linked to cancer-associated cachexia did not contribute to IAC. Instead, virus-specific CD8+ T cells caused morphologic and molecular changes in the adipose tissue, which led to depletion of lipid stores. These changes occurred at a time point that preceded the peak of the CD8+ T cell response and required T cell-intrinsic type I interferon signaling and antigen-specific priming. Our results link systemic antiviral immune responses to adipose-tissue remodeling and reveal an underappreciated role of CD8+ T cells in IAC.

Evaluation of Hepatic Glucose and Palmitic Acid Metabolism in Rodents on High-Fat Diet Using Deuterium Metabolic Imaging.

BACKGROUND: One of the main features of several metabolic disorders is dysregulation of hepatic glucose and lipid metabolism. Deuterium metabolic imaging (DMI) allows for assessing the uptake and breakdown of 2H-labeled substrates, giving specific insight into nutrient processing in healthy and diseased organs. Thus, DMI could be a useful approach for analyzing the differences in liver metabolism of healthy and diseased subjects to gain a deeper understanding of the alterations related to metabolic disorders. PURPOSE: Evaluating the feasibility of DMI as a tool for the assessment of metabolic differences in rodents with healthy and fatty livers (FLs). STUDY TYPE: Animal Model. POPULATION: 18 male Sprague Dawley rats on standard (SD, n = 9, healthy) and high-fat diet (HFD, n = 9, FL disease). FIELD STRENGTH/SEQUENCE: Phase-encoded 1D pulse-acquire sequence and anatomy co-registered phase-encoded 3D pulse-acquire chemical shift imaging for 2H at 9.4T. ASSESSMENT: Localized and nonlocalized liver spectroscopy was applied at eight time points over 104 minutes post injection. The obtained spectra were preprocessed and quantified using jMRUI (v7.0) and the resulting amplitudes translated to absolute concentration (mM) according to the 2H natural abundance water peak. STATISTICAL TESTS: Two-way repeated measures ANOVA were employed to assess between-group differences, with statistical significance at P < 0.05. RESULTS: DMI measurements demonstrated no significant difference (P = 0.98) in the uptake of [6,6'-2H2]glucose between healthy and impaired animals (AUCSD = 1966.0 ± 151.5 mM - minutes vs. AUCHFD = 2027.0 ± 167.6 mM·minutes). In the diseased group, the intrahepatic uptake of palmitic acid d-31 was higher (AUCHFD = 57.4 ± 17.0 mM·minutes, AUCSD = 33.3 ± 10.5 mM·minutes), but without statistical significance owing to substantial in-group variation (P = 0.73). DATA CONCLUSION: DMI revealed higher concentrations of palmitic acid in rats with FL disease and no difference in hepatic glucose concentration between healthy and impaired animals. Thus, DMI appears to be a useful tool for evaluating metabolism in rodents with FL disease. LEVEL OF EVIDENCE: 2 TECHNICAL EFFICACY: Stage 3.

Positron Emission Tomography-Based Pharmacokinetic Analysis To Assess Renal Transporter-Mediated Drug-Drug Interactions of Antimicrobial Drugs.

Transporter-mediated drug-drug interactions (DDIs) are of concern in antimicrobial drug development, as they can have serious safety consequences. We used positron emission tomography (PET) imaging-based pharmacokinetic (PK) analysis to assess the effect of different drugs, which may cause transporter-mediated DDIs, on the tissue distribution and excretion of [18F]ciprofloxacin as a radiolabeled model antimicrobial drug. Mice underwent PET scans after intravenous injection of [18F]ciprofloxacin, without and with pretreatment with either probenecid (150 mg/kg), cimetidine (50 mg/kg), or pyrimethamine (5 mg/kg). A 3-compartment kidney PK model was used to assess the involvement of renal transporters in the examined DDIs. Pretreatment with probenecid and cimetidine significantly decreased the renal clearance (CLrenal) of [18F]ciprofloxacin. The effect of cimetidine (-86%) was greater than that of probenecid (-63%), which contrasted with previously published clinical data. The kidney PK model revealed that the decrease in CLrenal was caused by inhibition of basal uptake transporters and apical efflux transporters in kidney proximal tubule cells. Changes in the urinary excretion of [18F]ciprofloxacin after pretreatment with probenecid and cimetidine resulted in increased blood and organ exposure to [18F]ciprofloxacin. Our results suggest that multiple membrane transporters mediate the tubular secretion of ciprofloxacin, with possible species differences between mice and humans. Concomitant medication inhibiting renal transporters may precipitate DDIs, leading to decreased urinary excretion and increased blood and organ exposure to ciprofloxacin, potentially exacerbating adverse effects. Our study highlights the strength of PET imaging-based PK analysis to assess transporter-mediated DDIs at a whole-body level.

Residual fibroglandular breast tissue after mastectomy is associated with an increased risk of a local recurrence or a new primary breast cancer".

BACKGROUND: Residual fibroglandular breast tissue (RFGT) following a mastectomy has been claimed to be associated with the occurrence of an in-breast local recurrence (IBLR) or new primary tumor (NP). Yet, scientific evidence proving this assumption is lacking. The primary aim of the study was to verify whether RFGT following a mastectomy is a risk factor for an IBLR or NP. METHODS: This retrospective analysis included all patients that underwent a mastectomy and were followed up at the Department of Obstetrics and Gynecology of the Medical University of Vienna between 01.01.2015 and 26.02.2020. RFGT volume (assessed on magnetic resonance imaging) was correlated with the prevalence of an IBLR and a NP. RESULTS: A total of 105 patients (126 breasts) following a therapeutic mastectomy were included. After a mean follow-up of 46.0 months an IBLR had occurred in 17 breasts and a NP in 1 breast. A significant difference in RFGT volume was observed between the disease-free cohort and the subgroup with an IBLR or NP (p = .017). A RFGT volume of ≥ 1153 mm3 increased the risk by the factor 3.57 [95%CI 1.27; 10.03]. CONCLUSIONS: RFGT volume is associated with an increased risk for an IBLR or NP.

Breast PET/MRI Hybrid Imaging and Targeted Tracers.

The recent introduction of hybrid positron emission tomography/magnetic resonance imaging (PET/MRI) as a promising imaging modality for breast cancer assessment has prompted fervent research activity on its clinical applications. The current knowledge regarding the possible clinical applications of hybrid PET/MRI is constantly evolving, thanks to the development and clinical availability of hybrid scanners, the development of new PET tracers and the rise of artificial intelligence (AI) techniques. In this state-of-the-art review on the use of hybrid breast PET/MRI, the most promising advanced MRI techniques (diffusion-weighted imaging, dynamic contrast-enhanced MRI, magnetic resonance spectroscopy, and chemical exchange saturation transfer) are discussed. Current and experimental PET tracers (18 F-FDG, 18 F-NaF, choline, 18 F-FES, 18 F-FES, 89 Zr-trastuzumab, choline derivatives, 18 F-FLT, and 68 Ga-FAPI-46) are described in order to provide an overview on their molecular mechanisms of action and corresponding clinical applications. New perspectives represented by the use of radiomics and AI techniques are discussed. Furthermore, the current strengths and limitations of hybrid PET/MRI in the real world are highlighted. EVIDENCE LEVEL: 2 TECHNICAL EFFICACY: Stage 2.

Screening and diagnostic breast MRI: how do they impact surgical treatment? Insights from the MIPA study.

OBJECTIVES: To report mastectomy and reoperation rates in women who had breast MRI for screening (S-MRI subgroup) or diagnostic (D-MRI subgroup) purposes, using multivariable analysis for investigating the role of MRI referral/nonreferral and other covariates in driving surgical outcomes. METHODS: The MIPA observational study enrolled women aged 18-80 years with newly diagnosed breast cancer destined to have surgery as the primary treatment, in 27 centres worldwide. Mastectomy and reoperation rates were compared using non-parametric tests and multivariable analysis. RESULTS: A total of 5828 patients entered analysis, 2763 (47.4%) did not undergo MRI (noMRI subgroup) and 3065 underwent MRI (52.6%); of the latter, 2441/3065 (79.7%) underwent MRI with preoperative intent (P-MRI subgroup), 510/3065 (16.6%) D-MRI, and 114/3065 S-MRI (3.7%). The reoperation rate was 10.5% for S-MRI, 8.2% for D-MRI, and 8.5% for P-MRI, while it was 11.7% for noMRI (p ≤ 0.023 for comparisons with D-MRI and P-MRI). The overall mastectomy rate (first-line mastectomy plus conversions from conserving surgery to mastectomy) was 39.5% for S-MRI, 36.2% for P-MRI, 24.1% for D-MRI, and 18.0% for noMRI. At multivariable analysis, using noMRI as reference, the odds ratios for overall mastectomy were 2.4 (p < 0.001) for S-MRI, 1.0 (p = 0.957) for D-MRI, and 1.9 (p < 0.001) for P-MRI. CONCLUSIONS: Patients from the D-MRI subgroup had the lowest overall mastectomy rate (24.1%) among MRI subgroups and the lowest reoperation rate (8.2%) together with P-MRI (8.5%). This analysis offers an insight into how the initial indication for MRI affects the subsequent surgical treatment of breast cancer. KEY POINTS: • Of 3065 breast MRI examinations, 79.7% were performed with preoperative intent (P-MRI), 16.6% were diagnostic (D-MRI), and 3.7% were screening (S-MRI) examinations. • The D-MRI subgroup had the lowest mastectomy rate (24.1%) among MRI subgroups and the lowest reoperation rate (8.2%) together with P-MRI (8.5%). • The S-MRI subgroup had the highest mastectomy rate (39.5%) which aligns with higher-than-average risk in this subgroup, with a reoperation rate (10.5%) not significantly different to that of all other subgroups.

Preoperative breast MRI positively impacts surgical outcomes of needle biopsy-diagnosed pure DCIS: a patient-matched analysis from the MIPA study.

OBJECTIVES: To investigate the influence of preoperative breast MRI on mastectomy and reoperation rates in patients with pure ductal carcinoma in situ (DCIS). METHODS: The MIPA observational study database (7245 patients) was searched for patients aged 18-80 years with pure unilateral DCIS diagnosed at core needle or vacuum-assisted biopsy (CNB/VAB) and planned for primary surgery. Patients who underwent preoperative MRI (MRI group) were matched (1:1) to those who did not receive MRI (noMRI group) according to 8 confounding covariates that drive referral to MRI (age; hormonal status; familial risk; posterior-to-nipple diameter; BI-RADS category; lesion diameter; lesion presentation; surgical planning at conventional imaging). Surgical outcomes were compared between the matched groups with nonparametric statistics after calculating odds ratios (ORs). RESULTS: Of 1005 women with pure unilateral DCIS at CNB/VAB (507 MRI group, 498 noMRI group), 309 remained in each group after matching. First-line mastectomy rate in the MRI group was 20.1% (62/309 patients, OR 2.03) compared to 11.0% in the noMRI group (34/309 patients, p = 0.003). The reoperation rate was 10.0% in the MRI group (31/309, OR for reoperation 0.40) and 22.0% in the noMRI group (68/309, p < 0.001), with a 2.53 OR of avoiding reoperation in the MRI group. The overall mastectomy rate was 23.3% in the MRI group (72/309, OR 1.40) and 17.8% in the noMRI group (55/309, p = 0.111). CONCLUSIONS: Compared to those going directly to surgery, patients with pure DCIS at CNB/VAB who underwent preoperative MRI had a higher OR for first-line mastectomy but a substantially lower OR for reoperation. CLINICAL RELEVANCE STATEMENT: When confounding factors behind MRI referral are accounted for in the comparison of patients with CNB/VAB-diagnosed pure unilateral DCIS, preoperative MRI yields a reduction of reoperations that is more than twice as high as the increase in overall mastectomies. KEY POINTS: • Confounding factors cause imbalance when investigating the influence of preoperative MRI on surgical outcomes of pure DCIS. • When patient matching is applied to women with pure unilateral DCIS, reoperation rates are significantly reduced in women who underwent preoperative MRI. • The reduction of reoperations brought about by preoperative MRI is more than double the increase in overall mastectomies.

Mammography in combination with breast ultrasonography versus mammography for breast cancer screening in women at average risk.

BACKGROUND: Screening mammography can detect breast cancer at an early stage. Supporters of adding ultrasonography to the screening regimen consider it a safe and inexpensive approach to reduce false-negative rates during screening. However, those opposed to it argue that performing supplemental ultrasonography will also increase the rate of false-positive findings and can lead to unnecessary biopsies and treatments. OBJECTIVES: To assess the comparative effectiveness and safety of mammography in combination with breast ultrasonography versus mammography alone for breast cancer screening for women at average risk of breast cancer. SEARCH METHODS: We searched the Cochrane Breast Cancer Group's Specialised Register, CENTRAL, MEDLINE, Embase, the World Health Organization International Clinical Trials Registry Platform (WHO ICTRP), and ClinicalTrials.gov up until 3 May 2021. SELECTION CRITERIA: For efficacy and harms, we considered randomised controlled trials (RCTs) and controlled non-randomised studies enrolling at least 500 women at average risk for breast cancer between the ages of 40 and 75. We also included studies where 80% of the population met our age and breast cancer risk inclusion criteria. DATA COLLECTION AND ANALYSIS: Two review authors screened abstracts and full texts, assessed risk of bias, and applied the GRADE approach. We calculated the risk ratio (RR) with 95% confidence intervals (CI) based on available event rates. We conducted a random-effects meta-analysis. MAIN RESULTS: We included eight studies: one RCT, two prospective cohort studies, and five retrospective cohort studies, enrolling 209,207 women with a follow-up duration from one to three years. The proportion of women with dense breasts ranged from 48% to 100%. Five studies used digital mammography; one study used breast tomosynthesis; and two studies used automated breast ultrasonography (ABUS) in addition to mammography screening. One study used digital mammography alone or in combination with breast tomosynthesis and ABUS or handheld ultrasonography. Six of the eight studies evaluated the rate of cancer cases detected after one screening round, whilst two studies screened women once, twice, or more. None of the studies assessed whether mammography screening in combination with ultrasonography led to lower mortality from breast cancer or all-cause mortality. High certainty evidence from one trial showed that screening with a combination of mammography and ultrasonography detects more breast cancer than mammography alone. The J-START (Japan Strategic Anti-cancer Randomised Trial), enrolling 72,717 asymptomatic women, had a low risk of bias and found that two additional breast cancers per 1000 women were detected over two years with one additional ultrasonography than with mammography alone (5 versus 3 per 1000; RR 1.54, 95% CI 1.22 to 1.94). Low certainty evidence showed that the percentage of invasive tumours was similar, with no statistically significant difference between the two groups (69.6% (128 of 184) versus 73.5% (86 of 117); RR 0.95, 95% CI 0.82 to 1.09). However, positive lymph node status was detected less frequently in women with invasive cancer who underwent mammography screening in combination with ultrasonography than in women who underwent mammography alone (18% (23 of 128) versus 34% (29 of 86); RR 0.53, 95% CI 0.33 to 0.86; moderate certainty evidence). Further, interval carcinomas occurred less frequently in the group screened by mammography and ultrasonography compared with mammography alone (5 versus 10 in 10,000 women; RR 0.50, 95% CI 0.29 to 0.89; 72,717 participants; high certainty evidence). False-negative results were less common when ultrasonography was used in addition to mammography than with mammography alone: 9% (18 of 202) versus 23% (35 of 152; RR 0.39, 95% CI 0.23 to 0.66; moderate certainty evidence). However, the number of false-positive results and necessary biopsies were higher in the group with additional ultrasonography screening. Amongst 1000 women who do not have cancer, 37 more received a false-positive result when they participated in screening with a combination of mammography and ultrasonography than with mammography alone (RR 1.43, 95% CI 1.37 to 1.50; high certainty evidence). Compared to mammography alone, for every 1000 women participating in screening with a combination of mammography and ultrasonography, 27 more women will have a biopsy (RR 2.49, 95% CI 2.28 to 2.72; high certainty evidence). Results from cohort studies with methodological limitations confirmed these findings. A secondary analysis of the J-START provided results from 19,213 women with dense and non-dense breasts. In women with dense breasts, the combination of mammography and ultrasonography detected three more cancer cases (0 fewer to 7 more) per 1000 women screened than mammography alone (RR 1.65, 95% CI 1.0 to 2.72; 11,390 participants; high certainty evidence). A meta-analysis of three cohort studies with data from 50,327 women with dense breasts supported this finding, showing that mammography and ultrasonography combined led to statistically significantly more diagnosed cancer cases compared to mammography alone (RR 1.78, 95% CI 1.23 to 2.56; 50,327 participants; moderate certainty evidence). For women with non-dense breasts, the secondary analysis of the J-START study demonstrated that more cancer cases were detected when adding ultrasound to mammography screening compared to mammography alone (RR 1.93, 95% CI 1.01 to 3.68; 7823 participants; moderate certainty evidence), whilst two cohort studies with data from 40,636 women found no statistically significant difference between the two screening methods (RR 1.13, 95% CI 0.85 to 1.49; low certainty evidence). AUTHORS' CONCLUSIONS: Based on one study in women at average risk of breast cancer, ultrasonography in addition to mammography leads to more screening-detected breast cancer cases. For women with dense breasts, cohort studies more in line with real-life clinical practice confirmed this finding, whilst cohort studies for women with non-dense breasts showed no statistically significant difference between the two screening interventions. However, the number of false-positive results and biopsy rates were higher in women receiving additional ultrasonography for breast cancer screening. None of the included studies analysed whether the higher number of screen-detected cancers in the intervention group resulted in a lower mortality rate compared to mammography alone. Randomised controlled trials or prospective cohort studies with a longer observation period are needed to assess the effects of the two screening interventions on morbidity and mortality.

Effects of Salinomycin and Deferiprone on Lead-Induced Changes in the Mouse Brain.

Lead (Pb) is a highly toxic heavy metal that has deleterious effects on the central nervous system. This study aimed to investigate the effects of salinomycin (Sal) and deferiprone (DFP) on brain morphology and on the content of some essential elements in Pb-exposed mice. Adult male Institute of Cancer Research (ICR) mice were exposed to a daily dose of 80 mg/kg body weight ( b.w.) Pb(II) nitrate for 14 days and subsequently treated with Sal (16 mg/kg b.w.) or DFP (19 mg/kg b.w.) for another 14 days. At the end of the experimental protocol, the brains were processed for histological and inductively coupled plasma mass spectrometry (ICP-MS) analyses. Pb exposure resulted in a 50-fold increase in Pb concentration, compared with controls. Magnesium (Mg) and phosphorus (P) were also significantly increased by 22.22% and 17.92%, respectively. The histological analysis of Pb-exposed mice revealed brain pathological changes with features of neuronal necrosis. Brain Pb level remained significantly elevated in Sal- and DFP-administered groups (37-fold and 50-fold, respectively), compared with untreated controls. Treatment with Sal significantly reduced Mg and P concentrations by 22.56% and 18.38%, respectively, compared with the Pb-exposed group. Administration of Sal and DFP ameliorated brain injury in Pb-exposed mice and improved histological features. The results suggest the potential application of Sal and DFP for treatment of Pb-induced neurotoxicity.

Overlapping and Distinct Features of Cardiac Pathology in Inherited Human and Murine Ether Lipid Deficiency.

Inherited deficiency in ether lipids, a subgroup of glycerophospholipids with unique biochemical and biophysical properties, evokes severe symptoms in humans resulting in a multi-organ syndrome. Mouse models with defects in ether lipid biosynthesis have widely been used to understand the pathophysiology of human disease and to study the roles of ether lipids in various cell types and tissues. However, little is known about the function of these lipids in cardiac tissue. Previous studies included case reports of cardiac defects in ether-lipid-deficient patients, but a systematic analysis of the impact of ether lipid deficiency on the mammalian heart is still missing. Here, we utilize a mouse model of complete ether lipid deficiency (Gnpat KO) to accomplish this task. Similar to a subgroup of human patients with rhizomelic chondrodysplasia punctata (RCDP), a fraction of Gnpat KO fetuses present with defects in ventricular septation, presumably evoked by a developmental delay. We did not detect any signs of cardiomyopathy but identified increased left ventricular end-systolic and end-diastolic pressure in middle-aged ether-lipid-deficient mice. By comprehensive electrocardiographic characterization, we consistently found reduced ventricular conduction velocity, as indicated by a prolonged QRS complex, as well as increased QRS and QT dispersion in the Gnpat KO group. Furthermore, a shift of the Wenckebach point to longer cycle lengths indicated depressed atrioventricular nodal function. To complement our findings in mice, we analyzed medical records and performed electrocardiography in ether-lipid-deficient human patients, which, in contrast to the murine phenotype, indicated a trend towards shortened QT intervals. Taken together, our findings demonstrate that the cardiac phenotype upon ether lipid deficiency is highly heterogeneous, and although the manifestations in the mouse model only partially match the abnormalities in human patients, the results add to our understanding of the physiological role of ether lipids and emphasize their importance for proper cardiac development and function.

Contrast-enhanced Mammography versus Contrast-enhanced Breast MRI: A Systematic Review and Meta-Analysis.

Background Contrast-enhanced mammography (CEM) is a more accessible alternative to contrast-enhanced MRI (CE-MRI) in breast imaging, but a summary comparison of published studies is lacking. Purpose To directly compare the performance of CEM and CE-MRI regarding sensitivity, specificity, and negative predictive value in detecting breast cancer, involving all publicly available studies in the English language. Materials and Methods Two readers extracted characteristics of studies investigating the comparative diagnostic performance of CEM and CE-MRI in detecting breast cancer. Studies published until April 2021 were eligible. Sensitivity, specificity, negative predictive value, and positive and negative likelihood ratios were calculated using bivariate random effects models. A Fagan nomogram was used to identify the maximum pretest probability at which posttest probabilities of a negative CEM or CE-MRI examination were in line with the 2% malignancy rate benchmark for downgrading a Breast Imaging Reporting and Data System (BI-RADS) category 4 to a BI-RADS category 3 result. I 2 statistics, Deeks funnel plot asymmetry test for publication bias, and meta-regression were used. Results Seven studies investigating 1137 lesions (654 malignant, 483 benign) with an average cancer prevalence of 65.3% (range: 47.3%-82.2%) were included. No publication bias was found (P = .57). While the positive likelihood ratio was equal at a value of 3.1 for CE-MRI and 3.6 for CEM, the negative likelihood ratio of CE-MRI (0.04) was lower than that with CEM (0.12). CE-MRI had higher sensitivity for breast cancer than CEM (97% [95% CI: 86, 99] vs 91% [95% CI: 77, 97], respectively; P < .001) but lower specificity (69% [95% CI: 46, 85] vs 74% [95% CI: 52, 89]; P = .09). A Fagan nomogram demonstrated that the maximum pretest probability at which both tests could rule out breast cancer was 33% for CE-MRI and 14% for CEM. Furthermore, iodine concentration was positively associated with CEM sensitivity and negatively associated with its specificity (P = .04 and P < .001, respectively). Conclusion Contrast-enhanced MRI had superior sensitivity and negative likelihood ratios with higher pretest probabilities to rule out malignancy compared with contrast-enhanced mammography. © RSNA, 2022 Online supplemental material is available for this article. See also the editorial by Mann and Veldhuis in this issue.

Breast MRI: does a clinical decision algorithm outweigh reader experience?

OBJECTIVES: Due to its high sensitivity, DCE MRI of the breast (MRIb) is increasingly used for both screening and assessment purposes. The Kaiser score (KS) is a clinical decision algorithm, which formalizes and guides diagnosis in breast MRI and is expected to compensate for lesser reader experience. The aim was to evaluate the diagnostic performance of untrained residents using the KS compared to off-site radiologists experienced in breast imaging using only MR BI-RADS. METHODS: Three off-site, board-certified radiologists, experienced in breast imaging, interpreted MRIb according to the MR BI-RADS scale. The same studies were read by three residents in radiology without prior training in breast imaging using the KS. All readers were blinded to clinical information. Histology was used as the gold standard. Statistical analysis was conducted by comparing the AUC of the ROC curves. RESULTS: A total of 80 women (median age 52 years) with 93 lesions (32 benign, 61 malignant) were included. The individual within-group performance of the three expert readers (AUC 0.723-0.742) as well as the three residents was equal (AUC 0.842-0.928), p > 0.05, respectively. But, the rating of each resident using the KS significantly outperformed the experts' ratings using the MR BI-RADS scale (p ≤ 0.05). CONCLUSION: The KS helped residents to achieve better results in reaching correct diagnoses than experienced radiologists empirically assigning MR BI-RADS categories in a clinical "problem solving MRI" setting. These results support that reporting breast MRI benefits more from using a diagnostic algorithm rather than expert experience. KEY POINTS: • Reporting breast MRI benefits more from using a diagnostic algorithm rather than expert experience in a clinical "problem solving MRI" setting. • The Kaiser score, which provides a clinical decision algorithm for structured reporting, helps residents to reach an expert level in breast MRI reporting and to even outperform experienced radiologists using MR BI-RADS without further formal guidance.

One view or two views for wide-angle tomosynthesis with synthetic mammography in the assessment setting?

OBJECTIVES: To evaluate the diagnostic performance in the assessment setting of three protocols: one-view wide-angle digital breast tomosynthesis (WA-DBT) with synthetic mammography (SM), two-view WA-DBT/SM, and two-view digital mammography (DM). METHODS: Included in this retrospective study were patients who underwent bilateral two-view DM and WA-DBT. SM were reconstructed from the WA-DBT data. The standard of reference was histology and/or 2 years follow-up. Included were 205 women with 179 lesions (89 malignant, 90 benign). Four blinded readers randomly evaluated images to assess density, lesion type, and level of suspicion according to BI-RADS. Three protocols were evaluated: two-view DM, one-view (mediolateral oblique) WA-DBT/SM, and two-view WA-DBT/SM. Detection rate, sensitivity, specificity, and accuracy were calculated and compared using multivariate analysis. Reading time was assessed. RESULTS: The detection rate was higher with two-view WA-DBT/SM (p = 0.063). Sensitivity was higher for two-view WA-DBT/SM compared to two-view DM (p = 0.001) and one-view WA-DBT/SM (p = 0.058). No significant differences in specificity were found. Accuracy was higher with both one-view WA-DBT/SM and two-view WA-DBT/SM compared to DM (p = 0.003 and > 0.001, respectively). Accuracy did not differ between one- and two-view WA-DBT/SM. Two-view WA-DBT/SM performed better for masses and asymmetries. Reading times were significantly longer when WA-DBT was evaluated. CONCLUSIONS: One-view and two-view WA-DBT/SM can achieve a higher diagnostic performance compared to two-view DM. The detection rate and sensitivity were highest with two-view WA-DBT/SM. Two-view WA-DBT/SM appears to be the most appropriate tool for the assessment of breast lesions. KEY POINTS: • Detection rate with two-view wide-angle digital breast tomosynthesis (WA-DBT) is significantly higher than with two-view digital mammography in the assessment setting. • Diagnostic accuracy of one-view and two-view WA-DBT with synthetic mammography (SM) in the assessment setting is higher than that of two-view digital mammography. • Compared to one-view WA-DBT with SM, two-view WA-DBT with SM seems to be the most appropriate tool for the assessment of breast lesions.

Breast cancer screening in women with extremely dense breasts recommendations of the European Society of Breast Imaging (EUSOBI).

Breast density is an independent risk factor for the development of breast cancer and also decreases the sensitivity of mammography for screening. Consequently, women with extremely dense breasts face an increased risk of late diagnosis of breast cancer. These women are, therefore, underserved with current mammographic screening programs. The results of recent studies reporting on contrast-enhanced breast MRI as a screening method in women with extremely dense breasts provide compelling evidence that this approach can enable an important reduction in breast cancer mortality for these women and is cost-effective. Because there is now a valid option to improve breast cancer screening, the European Society of Breast Imaging (EUSOBI) recommends that women should be informed about their breast density. EUSOBI thus calls on all providers of mammography screening to share density information with the women being screened. In light of the available evidence, in women aged 50 to 70 years with extremely dense breasts, the EUSOBI now recommends offering screening breast MRI every 2 to 4 years. The EUSOBI acknowledges that it may currently not be possible to offer breast MRI immediately and everywhere and underscores that quality assurance procedures need to be established, but urges radiological societies and policymakers to act on this now. Since the wishes and values of individual women differ, in screening the principles of shared decision-making should be embraced. In particular, women should be counselled on the benefits and risks of mammography and MRI-based screening, so that they are capable of making an informed choice about their preferred screening method. KEY POINTS: • The recommendations in Figure 1 summarize the key points of the manuscript.

Magnetic resonance imaging before breast cancer surgery: results of an observational multicenter international prospective analysis (MIPA).

OBJECTIVES: Preoperative breast magnetic resonance imaging (MRI) can inform surgical planning but might cause overtreatment by increasing the mastectomy rate. The Multicenter International Prospective Analysis (MIPA) study investigated this controversial issue. METHODS: This observational study enrolled women aged 18-80 years with biopsy-proven breast cancer, who underwent MRI in addition to conventional imaging (mammography and/or breast ultrasonography) or conventional imaging alone before surgery as routine practice at 27 centers. Exclusion criteria included planned neoadjuvant therapy, pregnancy, personal history of any cancer, and distant metastases. RESULTS: Of 5896 analyzed patients, 2763 (46.9%) had conventional imaging only (noMRI group), and 3133 (53.1%) underwent MRI that was performed for diagnosis, screening, or unknown purposes in 692/3133 women (22.1%), with preoperative intent in 2441/3133 women (77.9%, MRI group). Patients in the MRI group were younger, had denser breasts, more cancers ≥ 20 mm, and a higher rate of invasive lobular histology than patients who underwent conventional imaging alone (p < 0.001 for all comparisons). Mastectomy was planned based on conventional imaging in 22.4% (MRI group) versus 14.4% (noMRI group) (p < 0.001). The additional planned mastectomy rate in the MRI group was 11.3%. The overall performed first- plus second-line mastectomy rate was 36.3% (MRI group) versus 18.0% (noMRI group) (p < 0.001). In women receiving conserving surgery, MRI group had a significantly lower reoperation rate (8.5% versus 11.7%, p < 0.001). CONCLUSIONS: Clinicians requested breast MRI for women with a higher a priori probability of receiving mastectomy. MRI was associated with 11.3% more mastectomies, and with 3.2% fewer reoperations in the breast conservation subgroup. KEY POINTS: • In 19% of patients of the MIPA study, breast MRI was performed for screening or diagnostic purposes. • The current patient selection to preoperative breast MRI implies an 11% increase in mastectomies, counterbalanced by a 3% reduction of the reoperation rate. • Data from the MIPA study can support discussion in tumor boards when preoperative MRI is under consideration and should be shared with patients to achieve informed decision-making.

Comparative Effects of Deferiprone and Salinomycin on Lead-Induced Disturbance in the Homeostasis of Intrarenal Essential Elements in Mice.

Lead (Pb) exposure induces severe nephrotoxic effects in humans and animals. Herein, we compare the effects of two chelating agents, salinomycin and deferiprone, on Pb-induced renal alterations in mice and in the homeostasis of essential elements. Adult male mice (Institute of Cancer Research (ICR)) were randomized into four groups: control (Ctrl)-untreated mice administered distilled water for 28 days; Pb-exposed group (Pb)-mice administered orally an average daily dose of 80 mg/kg body weight (BW) lead (II) nitrate (Pb(NO3)2) during the first two weeks of the experimental protocol followed by the administration of distilled water for another two weeks; salinomycin-treated (Pb + Sal) group-Pb-exposed mice, administered an average daily dose of 16 mg/kg BW salinomycin for two weeks; deferiprone-treated (Pb + Def) group-Pb-exposed mice, administered an average daily dose of 20 mg/kg BW deferiprone for 14 days. The exposure of mice to Pb induced significant accumulation of the toxic metal in the kidneys and elicited inflammation with leukocyte infiltrations near the glomerulus. Biochemical analysis of the sera revealed that Pb significantly altered the renal function markers. Pb-induced renal toxicity was accompanied by a significant decrease in the endogenous renal concentrations of phosphorous (P), calcium (Ca), copper (Cu) and selenium (Se). In contrast to deferiprone, salinomycin significantly improved renal morphology in Pb-treated mice and decreased the Pb content by 13.62% compared to the Pb-exposed group. There was also a mild decrease in the renal endogenous concentration of magnesium (Mg) and elevation of the renal concentration of iron (Fe) in the salinomycin-treated group compared to controls. Overall, the results demonstrated that salinomycin is a more effective chelating agent for the treatment of Pb-induced alterations in renal morphology compared to deferiprone.

Loss of the ribosomal RNA methyltransferase NSUN5 impairs global protein synthesis and normal growth.

Modifications of ribosomal RNA expand the nucleotide repertoire and thereby contribute to ribosome heterogeneity and translational regulation of gene expression. One particular m5C modification of 25S ribosomal RNA, which is introduced by Rcm1p, was previously shown to modulate stress responses and lifespan in yeast and other small organisms. Here, we report that NSUN5 is the functional orthologue of Rcm1p, introducing m5C3782 into human and m5C3438 into mouse 28S ribosomal RNA. Haploinsufficiency of the NSUN5 gene in fibroblasts from William Beuren syndrome patients causes partial loss of this modification. The N-terminal domain of NSUN5 is required for targeting to nucleoli, while two evolutionary highly conserved cysteines mediate catalysis. Phenotypic consequences of NSUN5 deficiency in mammalian cells include decreased proliferation and size, which can be attributed to a reduction in total protein synthesis by altered ribosomes. Strikingly, Nsun5 knockout in mice causes decreased body weight and lean mass without alterations in food intake, as well as a trend towards reduced protein synthesis in several tissues. Together, our findings emphasize the importance of single RNA modifications for ribosome function and normal cellular and organismal physiology.

Intestinal bacterial indicator phylotypes associate with impaired DNA double-stranded break sensors but augmented skeletal bone micro-structure.

Intestinal microbiota are considered a sensor for molecular pathways, which orchestrate energy balance, immune responses, and cell regeneration. We previously reported that microbiota restriction promoted higher levels of systemic radiation-induced genotoxicity, proliferative lymphocyte activation, and apoptotic polarization of metabolic pathways. Restricted intestinal microbiota (RM) that harbors increased abundance of Lactobacillus johnsonii (LBJ) has been investigated for bacterial communities that correlated radiation-induced genotoxicity. Indicator phylotypes were more abundant in RM mice and increased in prevalence after whole body irradiation in conventional microbiota (CM) mice, while none of the same ten most abundant phylotypes were different in abundance between CM mice before and after heavy ion irradiation. Muribaculum intestinale was detected highest in female small intestines in RM mice, which were lacking Ureaplasma felinum compared with males, and thus these bacteria could be contributing to the differential amounts of radiation-induced systemic genotoxicity between the CM and RM groups. Helicobacter rodentium and M.intestinale were found in colons in the radiation-resistant CM phenotype. While the expression of interferon-γ was elevated in the small intestine, and lower in blood in CM mice, high-linear energy transfer radiation reduced transforming growth factor-ß with peripheral interleukin (IL)-17 in RM mice, particularly in females. We found that female RM mice showed improved micro-architectural bone structure and anti-inflammatory radiation response compared with CM mice at a delayed phase 6 weeks postexposure to particle radiation. However, microbiota restriction reduced inflammatory markers of tumor necrosis factor in marrow, when IL-17 was reduced by intraperitoneal injection of IL-17 neutralizing antibody.

Low-Dose, Contrast-Enhanced Mammography Compared to Contrast-Enhanced Breast MRI: A Feasibility Study.

Contrast-enhanced MRI (CE-MRI) is the most sensitive technique for breast cancer detection. Contrast-enhanced mammography (CEM) is emerging as a possible alternative to CE-MRI. PURPOSE: To evaluate the diagnostic performance of a low radiation dose contrast-enhanced mammography (L-CEM) in women with suspicious findings on conventional imaging compared to CE-MRI of the breast. STUDY TYPE: Prospective, single center. POPULATION: Women with suspicious findings on mammography, tomosynthesis, or ultrasound, and no contraindications for L-CEM or CE-MRI. Eighty women were included. FIELD STRENGTH/SEQUENCE: 1.5 and 3T CE-MRI, standard protocol for breast, with dedicated coils, according to international guidelines. L-CEM was performed using a dedicated prototype. ASSESSMENT: Three, off-site, blinded readers evaluated the images according to the BI-RADS lexicon in a randomized order, each in two separate reading sessions. Histology served as a gold standard. STATISTICAL TEST: Lesion detection rate, sensitivity, specificity, and negative and positive predictive values (NPV, PPV) were calculated and compared with multivariate statistics. RESULTS: Included were 80 women (mean age, 54.3 years ±11.2 standard deviation) with 93 lesions (32 benign, 61 malignant). The detection rate was significantly higher with CE-MRI (92.5-94.6%; L-CEM 79.6-91.4%, P = 0.014). Sensitivity (L-CEM 65.6-90.2%; CE-MRI 83.6-93.4%, P = 0.086) and NPV (L-CEM 59.6-71.4%; CE-MRI 63.0-76.5%, P = 0.780) did not differ between the modalities. Specificity (L-CEM 46.9-96.9%; CE-MRI 37.5-53.1%, P = 0.001) and PPV (L-CEM 76.4-97.6%; CE-MRI 73.3-77.3%, P = 0.007) were significantly higher with L-CEM. Variations between readers were significant for sensitivity and NPV. The accuracy of L-CEM was as good as CE-MRI (75.3-76.3% vs. 72.0-75.3%, P = 0.514). DATA CONCLUSION: L-CEM showed a high sensitivity and accuracy in women with suspicious findings on conventional imaging. Compared to CE-MRI, L-CEM has the potential to increase specificity and PPV. L-CEM might help to reduce false-positive biopsies while obtaining sensitivity comparable to that of CE-MRI LEVEL OF EVIDENCE: 1 TECHNICAL EFFICACY STAGE: 2 J. Magn. Reson. Imaging 2020;52:589-595.

Maternal immune activation during pregnancy impacts on brain structure and function in the adult offspring.

Gestational infection constitutes a risk factor for the occurrence of psychiatric disorders in the offspring. Activation of the maternal immune system (MIA) with subsequent impact on the development of the fetal brain is considered to form the neurobiological basis for aberrant neural wiring and the psychiatric manifestations later in offspring life. The examination of validated animal models constitutes a premier resource for the investigation of the neural underpinnings. Here we used a mouse model of MIA based upon systemic treatment of pregnant mice with Poly(I:C) (polyriboinosinic-polyribocytidilic acid), for the unbiased and comprehensive analysis of the impact of MIA on adult offspring brain activity, morphometry, connectivity and function by a magnetic resonance imaging (MRI) approach. Overall lower neural activity, smaller brain regions and less effective fiber structure were observed for Poly(I:C) offspring compared to the control group. The corpus callosum was significantly smaller and presented with a disruption in myelin/ fiber structure in the MIA progeny. Subsequent resting-state functional MRI experiments demonstrated a paralleling dysfunctional interhemispheric connectivity. Additionally, while the overall flow of information was intact, cortico-limbic connectivity was hampered and limbic circuits revealed hyperconnectivity in Poly(I:C) offspring. Our study sheds new light on the impact of maternal infection during pregnancy on the offspring brain and identifies aberrant resting-state functional connectivity patterns as possible correlates of the behavioral phenotype with relevance for psychiatric disorders.