Central Actions of Leptin Induce an Atrophic Pattern and Improves Heart Function in Lean Normoleptinemic Rats via PPARß/δ Activation.

Leptin, acting centrally or peripherally, has complex effects on cardiac remodeling and heart function. We previously reported that central leptin exerts an anti-hypertrophic effect in the heart via cardiac PPARß/δ activation. Here, we assessed the impact of central leptin administration and PPARß/δ inhibition on cardiac function. Various cardiac properties, including QRS duration, R wave amplitude, heart rate (HR), ejection fraction (EF), end-diastolic left ventricular mass (EDLVM), end-diastolic volume (EDV), and cardiac output (CO) were analyzed. Central leptin infusion increased cardiac PPARß/δ protein content and decreased HR, QRS duration, and R wave amplitude. These changes induced by central leptin suggested a decrease in the ventricular wall growth, which was confirmed by MRI. In fact, the EDLVM was reduced by central leptin while increased in rats co-treated with leptin and GSK0660, a selective antagonist of PPARß/δ activity. In summary, central leptin plays a dual role in cardiac health, potentially leading to ventricular atrophy and improving heart function when PPARß/δ signaling is intact. The protective effects of leptin are lost by PPARß/δ inhibition, underscoring the importance of this pathway. These findings highlight the therapeutic potential of targeting leptin and PPARß/δ pathways to combat cardiac alterations and heart failure, particularly in the context of obesity.

Deep representation learning of tissue metabolome and computed tomography annotates NSCLC classification and prognosis.

The rich chemical information from tissue metabolomics provides a powerful means to elaborate tissue physiology or tumor characteristics at cellular and tumor microenvironment levels. However, the process of obtaining such information requires invasive biopsies, is costly, and can delay clinical patient management. Conversely, computed tomography (CT) is a clinical standard of care but does not intuitively harbor histological or prognostic information. Furthermore, the ability to embed metabolome information into CT to subsequently use the learned representation for classification or prognosis has yet to be described. This study develops a deep learning-based framework -- tissue-metabolomic-radiomic-CT (TMR-CT) by combining 48 paired CT images and tumor/normal tissue metabolite intensities to generate ten image embeddings to infer metabolite-derived representation from CT alone. In clinical NSCLC settings, we ascertain whether TMR-CT results in an enhanced feature generation model solving histology classification/prognosis tasks in an unseen international CT dataset of 742 patients. TMR-CT non-invasively determines histological classes - adenocarcinoma/squamous cell carcinoma with an F1-score = 0.78 and further asserts patients' prognosis with a c-index = 0.72, surpassing the performance of radiomics models and deep learning on single modality CT feature extraction. Additionally, our work shows the potential to generate informative biology-inspired CT-led features to explore connections between hard-to-obtain tissue metabolic profiles and routine lesion-derived image data.

Interval cancer in the Córdoba Breast Tomosynthesis Screening Trial (CBTST): comparison of digital breast tomosynthesis plus digital mammography to digital mammography alone.

PURPOSE: This work aims to compare the interval cancer rate and interval cancer characteristics between women screened with digital breast tomosynthesis (DBT) + digital mammography (DM) and those screened with DM alone. METHODS: The interval cancer rate and interval cancer characteristics of the study population included in the Córdoba Breast Tomosynthesis Screening Trial (CBTST) were compared to a contemporary control population screened with DM. The tumour characteristics of screen-detected and interval cancers were also compared. Contingency tables were used to compare interval cancer rates. The chi-square test and Fisher's exact test were used to compare the qualitative characteristics of the cancers whereas Student's t test and the Mann-Whitney U test were used to analyse quantitative features. RESULTS: A total of 16,068 screening exams with DBT + DM were conducted within the CBTST (mean age 57.59 ± 5.9 [SD]) between January 2015 and December 2016 (study population). In parallel, 23,787 women (mean age 58.89 ± 5.9 standard deviation [SD]) were screened with DM (control population). The interval cancer rate was lower in the study population than in the control population (15 [0.93‰; 95% confidence interval (CI): 0.73, 1.14] vs 43 [1.8‰; 95% CI: 1.58, 2.04] respectively; p = 0.045). The difference in rate was more marked in women with dense breasts (0.95‰ in the study population vs 3.17‰ in the control population; p = 0.031). Interval cancers were smaller in the study population than in the control population (p = 0.031). CONCLUSIONS: The interval cancer rate was lower in women screened with DBT + DM compared to those screened with DM alone. These differences were more pronounced in women with dense breasts. CLINICAL RELEVANCE STATEMENT: Women screened using tomosynthesis and digital mammography had a lower rate of interval cancer than women screened with digital mammography, with the greatest difference in the interval cancer rate observed in women with dense breasts. KEY POINTS: • The interval cancer rate was lower in the study population (digital breast tomosynthesis [DBT] + digital mammography [DM]) than in the control population (DM). • The difference in interval cancer rates was more pronounced in women with dense breasts. • Interval cancers were smaller in the study population (DBT + DM) than in the control population (DM).

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.

Impact of real-life use of artificial intelligence as support for human reading in a population-based breast cancer screening program with mammography and tomosynthesis.

OBJECTIVES: To evaluate the impact of using an artificial intelligence (AI) system as support for human double reading in a real-life scenario of a breast cancer screening program with digital mammography (DM) or digital breast tomosynthesis (DBT). MATERIAL AND METHODS: We analyzed the performance of double reading screening with mammography and tomosynthesis after implementarion of AI as decision support. The study group consisted of a consecutive cohort of 1 year screening between March 2021 and March 2022 where double reading was performed with concurrent AI support that automatically detects and highlights lesions suspicious of breast cancer in mammography and tomosynthesis. Screening performance was measured as cancer detection rate (CDR), recall rate (RR), and positive predictive value (PPV) of recalls. Performance in the study group was compared using a McNemar test to a control group that included a screening cohort of the same size, recorded just prior to the implementation of AI. RESULTS: A total of 11,998 women (mean age 57.59 years ± 5.8 [sd]) were included in the study group (5049 DM and 6949 DBT). Comparing global results (including DM and DBT) of double reading with vs. without AI support, we observed an increase in CDR, PPV, and RR by 3.2/‰ (5.8 vs. 9; p < 0.001), 4% (10.6 vs. 14.6; p < 0.001), and 0.7% (5.4 vs. 6.1; p < 0.001) respectively. CONCLUSION: AI used as support for human double reading in a real-life breast cancer screening program with DM and DBT increases CDR and PPV of the recalled women. CLINICAL RELEVANCE STATEMENT: Artificial intelligence as support for human double reading improves accuracy in a real-life breast cancer screening program both in digital mammography and digital breast tomosynthesis. KEY POINTS: • AI systems based on deep learning technology offer potential for improving breast cancer screening programs. • Using artificial intelligence as support for reading improves radiologists' performance in breast cancer screening programs with mammography or tomosynthesis. • Artificial intelligence used concurrently with human reading in clinical screening practice increases breast cancer detection rate and positive predictive value of the recalled women.

Ipsilesional Hippocampal GABA Is Elevated and Correlates With Cognitive Impairment and Maladaptive Neurogenesis After Cortical Stroke in Mice.

BACKGROUND: Cognitive dysfunction is a frequent stroke sequela, but its pathogenesis and treatment remain unresolved. Involvement of aberrant hippocampal neurogenesis and maladaptive circuitry remodeling has been proposed, but their mechanisms are unknown. Our aim was to evaluate potential underlying molecular/cellular events implicated. METHODS: Stroke was induced by permanent occlusion of the middle cerebral artery occlusion in 2-month-old C57BL/6 male mice. Hippocampal metabolites/neurotransmitters were analyzed longitudinally by in vivo magnetic resonance spectroscopy. Cognitive function was evaluated with the contextual fear conditioning test. Microglia, astrocytes, neuroblasts, interneurons, γ-aminobutyric acid (GABA), and c-fos were analyzed by immunofluorescence. RESULTS: Approximately 50% of mice exhibited progressive post-middle cerebral artery occlusion cognitive impairment. Notably, immature hippocampal neurons in the impaired group displayed more severe aberrant phenotypes than those from the nonimpaired group. Using magnetic resonance spectroscopy, significant bilateral changes in hippocampal metabolites, such as myo-inositol or N-acetylaspartic acid, were found that correlated, respectively, with numbers of glia and immature neuroblasts in the ischemic group. Importantly, some metabolites were specifically altered in the ipsilateral hippocampus suggesting its involvement in aberrant hippocampal neurogenesis and remodeling processes. Specifically, middle cerebral artery occlusion animals with higher hippocampal GABA levels displayed worse cognitive outcome. Implication of GABA in this setting was supported by the amelioration of ischemia-induced memory deficits and aberrant hippocampal neurogenesis after blocking pharmacologically GABAergic neurotransmission, an intervention which was ineffective when neurogenesis was inhibited. These data suggest that GABA exerts its detrimental effect, at least partly, by affecting morphology and integration of newborn neurons into the hippocampal circuits. CONCLUSIONS: Hippocampal GABAergic neurotransmission could be considered a novel diagnostic and therapeutic target for poststroke cognitive impairment.

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.

Clinical Presentation, Management, and Evolution of Lymphomas in Patients with Inflammatory Bowel Disease: An ENEIDA Registry Study.

An increased risk of lymphoma has been described in patients with inflammatory bowel disease (IBD). The aims of our study were to determine the clinical presentation, the previous exposure to immunosuppressive and biologic therapies, and the evolution of lymphomas in patients with IBD. IBD patients with diagnosis of lymphoma from October 2006 to June 2021 were identified from the prospectively maintained ENEIDA registry of GETECCU. We identified 52 patients (2.4 cases of lymphoma/1000 patients with IBD; 95% CI 1.8-3.1). Thirty-five were men (67%), 52% had ulcerative colitis, 60% received thiopurines, and 38% an anti-TNF drug before lymphoma diagnosis. Age at lymphoma was lower in those patients treated with thiopurines (53 ± 17 years old) and anti-TNF drugs (47 ± 17) than in those patients not treated with these drugs (63 ± 12; p < 0.05). Five cases had relapse of lymphoma (1.7 cases/100 patient-years). Nine patients (17%) died after 19 months (IQR 0-48 months). Relapse and mortality were not related with the type of IBD or lymphoma, nor with thiopurines or biologic therapies. In conclusion, most IBD patients had been treated with thiopurines and/or anti-TNF agents before lymphoma diagnosis, and these patients were younger at diagnosis of lymphoma than those not treated with these drugs. Relapse and mortality of lymphoma were not related with these therapies.

A cannabidiol aminoquinone derivative activates the PP2A/B55α/HIF pathway and shows protective effects in a murine model of traumatic brain injury.

BACKGROUND: Traumatic brain injury (TBI) is characterized by a primary mechanical injury and a secondary injury associated with neuroinflammation, blood-brain barrier (BBB) disruption and neurodegeneration. We have developed a novel cannabidiol aminoquinone derivative, VCE-004.8, which is a dual PPARγ/CB2 agonist that also activates the hypoxia inducible factor (HIF) pathway. VCE-004.8 shows potent antifibrotic, anti-inflammatory and neuroprotective activities and it is now in Phase II clinical trials for systemic sclerosis and multiple sclerosis. Herein, we investigated the mechanism of action of VCE-004.8 in the HIF pathway and explored its efficacy in a preclinical model of TBI. METHODS: Using a phosphoproteomic approach, we investigated the effects of VCE-004.8 on prolyl hydroxylase domain-containing protein 2 (PHD2) posttranslational modifications. The potential role of PP2A/B55α in HIF activation was analyzed using siRNA for B55α. To evaluate the angiogenic response to the treatment with VCE-004.8 we performed a Matrigel plug in vivo assay. Transendothelial electrical resistance (TEER) as well as vascular cell adhesion molecule 1 (VCAM), and zonula occludens 1 (ZO-1) tight junction protein expression were studied in brain microvascular endothelial cells. The efficacy of VCE-004.8 in vivo was evaluated in a controlled cortical impact (CCI) murine model of TBI. RESULTS: Herein we provide evidence that VCE-004.8 inhibits PHD2 Ser125 phosphorylation and activates HIF through a PP2A/B55α pathway. VCE-004.8 induces angiogenesis in vivo increasing the formation of functional vessel (CD31/α-SMA) and prevents in vitro blood-brain barrier (BBB) disruption ameliorating the loss of ZO-1 expression under proinflammatory conditions. In CCI model VCE-004.8 treatment ameliorates early motor deficits after TBI and attenuates cerebral edema preserving BBB integrity. Histopathological analysis revealed that VCE-004.8 treatment induces neovascularization in pericontusional area and prevented immune cell infiltration to the brain parenchyma. In addition, VCE-004.8 attenuates neuroinflammation and reduces neuronal death and apoptosis in the damaged area. CONCLUSIONS: This study provides new insight about the mechanism of action of VCE-004.8 regulating the PP2A/B55α/PHD2/HIF pathway. Furthermore, we show the potential efficacy for TBI treatment by preventing BBB disruption, enhancing angiogenesis, and ameliorating neuroinflammation and neurodegeneration after brain injury.

Heteroplasmy of Wild-Type Mitochondrial DNA Variants in Mice Causes Metabolic Heart Disease With Pulmonary Hypertension and Frailty.

BACKGROUND: In most eukaryotic cells, the mitochondrial DNA (mtDNA) is transmitted uniparentally and present in multiple copies derived from the clonal expansion of maternally inherited mtDNA. All copies are therefore near-identical, or homoplasmic. The presence of >1 mtDNA variant in the same cytoplasm can arise naturally or result from new medical technologies aimed at preventing mitochondrial genetic diseases and improving fertility. The latter is called divergent nonpathologic mtDNA heteroplasmy (DNPH). We hypothesized that DNPH is maladaptive and usually prevented by the cell. METHODS: We engineered and characterized DNPH mice throughout their lifespan using transcriptomic, metabolomic, biochemical, physiologic, and phenotyping techniques. We focused on in vivo imaging techniques for noninvasive assessment of cardiac and pulmonary energy metabolism. RESULTS: We show that DNPH impairs mitochondrial function, with profound consequences in critical tissues that cannot resolve heteroplasmy, particularly cardiac and skeletal muscle. Progressive metabolic stress in these tissues leads to severe pathology in adulthood, including pulmonary hypertension and heart failure, skeletal muscle wasting, frailty, and premature death. Symptom severity is strongly modulated by the nuclear context. CONCLUSIONS: Medical interventions that may generate DNPH should address potential incompatibilities between donor and recipient mtDNA.

Different dietary combinations of high/low starch and fat with or without bile acid supplementation on growth, liver histopathology, gene expression and fatty acid composition of largemouth bass, Micropterus salmoides.

High dietary levels of fat and/or starch can lower the growth and cause extensive liver inflammation that is linked to mortalities in largemouth bass, Micropterus salmoides. However, bile acids (BA) may mitigate these adverse effects. In a 2 × 2 × 2 factorial feeding trial, M. salmoides juveniles were fed different combinations of dietary high (HF), low fat (LF), high (HS) or low starch (LS) levels with or without BA supplementations at 1% for 8 weeks. A total of 8 isonitrogenous diets were formulated to include, HF/LS, HF/HS, LF/HS, LF/LS, HF/LS-BA, HF/HS-BA, LF/HS-BA and LF/LS-BA. Survival, growth performance, feeding efficiency, whole-body proximate composition, muscle/liver fatty acid composition, hepatic expression of growth regulator (GH/IGF1 axis), lipid metabolism (fatty acid synthase 'FASN' and cholesterol 7 alpha-hydroxylase 'CYP7A1') and antioxidant capacity (superoxide dismutase 'SOD') genes as well as liver histopathology were assessed. Results showed that among diets without BA, there was no significant effect on growth or feeding efficiency, but when BA was included this led to more variable effects including significantly higher weight gain in the LF/HS-BA group compared to all others fed BA. The HF, HS or their combination led to extensive hepatic inflammation, but BA appeared to partially mitigate this in the LF/HS group (i.e. LF/HS-BA). No abnormal liver histopathology was observed in the LF/LS and LF/LS-BA treatments. Muscle 22:6n-3 was significantly higher in the HF/LS and HF/HS-BA groups compared to those fed the HF/HS or LF/LS diets. Dietary fat had a significant effect on the moisture, crude lipid, and caloric content of M. salmoides. Hepatic expression of IGF-I and CYP7A1 were differentially modulated under different treatments. Overall, these results show that BA can alleviate some liver inflammation caused by high dietary starch; however the LF/LS diets led to a better balance between growth performance and liver health.

Stand-Alone Use of Artificial Intelligence for Digital Mammography and Digital Breast Tomosynthesis Screening: A Retrospective Evaluation.

Background Use of artificial intelligence (AI) as a stand-alone reader for digital mammography (DM) or digital breast tomosynthesis (DBT) breast screening could ease radiologists' workload while maintaining quality. Purpose To retrospectively evaluate the stand-alone performance of an AI system as an independent reader of DM and DBT screening examinations. Materials and Methods Consecutive screening-paired and independently read DM and DBT images acquired between January 2015 and December 2016 were retrospectively collected from the Tomosynthesis Cordoba Screening Trial. An AI system computed a cancer risk score (range, 1-100) for DM and DBT examinations independently. AI stand-alone performance was measured using the area under the receiver operating characteristic curve (AUC) and sensitivity and recall rate at different operating points selected to have noninferior sensitivity compared with the human readings (noninferiority margin, 5%). The recall rate of AI and the human readings were compared using a McNemar test. Results A total of 15 999 DM and DBT examinations (113 breast cancers, including 98 screen-detected and 15 interval cancers) from 15 998 women (mean age, 58 years ± 6 [standard deviation]) were evaluated. AI achieved an AUC of 0.93 (95% CI: 0.89, 0.96) for DM and 0.94 (95% CI: 0.91, 0.97) for DBT. For DM, AI achieved noninferior sensitivity as a single (58.4%; 66 of 113; 95% CI: 49.2, 67.1) or double (67.3%; 76 of 113; 95% CI: 58.2, 75.2) reader, with a reduction in recall rate (P < .001) of up to 2% (95% CI: -2.4, -1.6). For DBT, AI achieved noninferior sensitivity as a single (77%; 87 of 113; 95% CI: 68.4, 83.8) or double (81.4%; 92 of 113; 95% CI: 73.3, 87.5) reader, but with a higher recall rate (P < .001) of up to 12.3% (95% CI: 11.7, 12.9). Conclusion Artificial intelligence could replace radiologists' readings in breast screening, achieving a noninferior sensitivity, with a lower recall rate for digital mammography but a higher recall rate for digital breast tomosynthesis. Published under a CC BY 4.0 license. See also the editorial by Fuchsjäger and Adelsmayr in this issue.

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.

AI-based Strategies to Reduce Workload in Breast Cancer Screening with Mammography and Tomosynthesis: A Retrospective Evaluation.

Background The workflow of breast cancer screening programs could be improved given the high workload and the high number of false-positive and false-negative assessments. Purpose To evaluate if using an artificial intelligence (AI) system could reduce workload without reducing cancer detection in breast cancer screening with digital mammography (DM) or digital breast tomosynthesis (DBT). Materials and Methods Consecutive screening-paired and independently read DM and DBT images acquired from January 2015 to December 2016 were retrospectively collected from the Córdoba Tomosynthesis Screening Trial. The original reading settings were single or double reading of DM or DBT images. An AI system computed a cancer risk score for DM and DBT examinations independently. Each original setting was compared with a simulated autonomous AI triaging strategy (the least suspicious examinations for AI are not human-read; the rest are read in the same setting as the original, and examinations not recalled by radiologists but graded as very suspicious by AI are recalled) in terms of workload, sensitivity, and recall rate. The McNemar test with Bonferroni correction was used for statistical analysis. Results A total of 15 987 DM and DBT examinations (which included 98 screening-detected and 15 interval cancers) from 15 986 women (mean age ± standard deviation, 58 years ± 6) were evaluated. In comparison with double reading of DBT images (568 hours needed, 92 of 113 cancers detected, 706 recalls in 15 987 examinations), AI with DBT would result in 72.5% less workload (P < .001, 156 hours needed), noninferior sensitivity (95 of 113 cancers detected, P = .38), and 16.7% lower recall rate (P < .001, 588 recalls in 15 987 examinations). Similar results were obtained for AI with DM. In comparison with the original double reading of DM images (222 hours needed, 76 of 113 cancers detected, 807 recalls in 15 987 examinations), AI with DBT would result in 29.7% less workload (P < .001), 25.0% higher sensitivity (P < .001), and 27.1% lower recall rate (P < .001). Conclusion Digital mammography and digital breast tomosynthesis screening strategies based on artificial intelligence systems could reduce workload up to 70%. Published under a CC BY 4.0 license.

Preclinical Safety Evaluation of Intranasally Delivered Human Mesenchymal Stem Cells in Juvenile Mice.

Mesenchymal stem cell (MSC)-based therapy is a promising therapeutic approach in the management of several pathologies, including central nervous system diseases. Previously, we demonstrated the therapeutic potential of human adipose-derived MSCs for neurological sequelae of oncological radiotherapy using the intranasal route as a non-invasive delivery method. However, a comprehensive investigation of the safety of intranasal MSC treatment should be performed before clinical applications. Here, we cultured human MSCs in compliance with quality control standards and administrated repeated doses of cells into the nostrils of juvenile immunodeficient mice, mimicking the design of a subsequent clinical trial. Short- and long-term effects of cell administration were evaluated by in vivo and ex vivo studies. No serious adverse events were reported on mouse welfare, behavioral performances, and blood plasma analysis. Magnetic resonance study and histological analysis did not reveal tumor formation or other abnormalities in the examined organs of mice receiving MSCs. Biodistribution study reveals a progressive disappearance of transplanted cells that was further supported by an absent expression of human GAPDH gene in the major organs of transplanted mice. Our data indicate that the intranasal application of MSCs is a safe, simple and non-invasive strategy and encourage its use in future clinical trials.

Obliteration of gastric varices guided by eco-endoscopy with coils insertion coated with expandable hydrogel polymers.

INTRODUCTION: gastric varices hemorrhage is a severe complication of portal hypertension, with high mortality rates and few management alternatives, especially when there is a contraindication to transjugular intrahepatic portosystemic shunts (TIPS). The usual therapeutic options are the injection of cyanoacrylate, the insertion of coils or both. Hydrocoils are special coils coated with different types of expandable hydrogel polymers conventionally used in neurovascular interventionism. They allow rapid occlusion of vessel, forming a mesh that favors the local formation of thrombus and the development of a neointima on the gel cover. We consider the use of endoscopic ultrasound (EUS) guided hydrocoil insertion in gastric varices, without using cyanoacrylate. OBJECTIVE: this study aimed to evaluate the safety and effectivity of the application of EUS-guided hydrocoils in patients with gastric varices hemorrhage with TIPS contraindication. MATERIAL AND METHODS: this was a retrospective case series of four patients with TIPS contraindication after interventional radiologist evaluation. Linear echoendoscopes, fluoroscopy, 19G needles and hydrocoils (Azur®, Terumo) and Progreat® 3 Fr microcatheters were used. An interventional radiologist expert advised the procedures and endoscopic ultrasound confirmed the varix obliteration. RESULTS: technical and clinical success occurred in all patients involved in this study. There were no adverse effects related to the procedure or endoscopic equipment damage. CONCLUSIONS: the application of EUS-guided hydrocoils can be a safe and effective method in the short term for gastric varices bleeding in patients who are not candidates for TIPS. Besides, a complete obliteration of the vascular lumen could occur and thus, dispense with the use of cyanoacrylate. Further studies are needed to corroborate these preliminary results.

Endoscopic ultrasound-guided fine-needle aspiration of renal lesions: experience in a tertiary center.

INTRODUCTION: endoscopic ultrasound (EUS) allows the histological diagnosis of radiologically undetermined renal lesions, although few series have been described. OBJECTIVES: to describe the procedure, yield and complications of EUS-guided renal fine-needle aspiration (FNA). MATERIAL AND METHODS: a retrospective case series in a prospective database was used that consecutively included EUS procedures from March 2014 to August 2018. Data on complications, outcome and follow-up were collected. A successful FNA was defined as any FNA that allowed a histological diagnosis. Lesions were considered as malignant when surgically confirmed as such (the histological diagnosis was used for non-surgical patients) and benign when radiographically stable for ≥ 12 months. RESULTS: eight patients were identified with a median age of 61.6 years (57.3-71.9), and five (62.5 %) were female. Five FNA procedures involved the right kidney and three involved the left kidney. 22G cytology needles were used. Renal FNA was diagnostic in all cases, with no complications. CONCLUSIONS: EUS-guided FNA may represent an effective, safe procedure for the diagnosis of renal lesions of an uncertain origin.

Brain ventricular enlargement in human and murine acute intermittent porphyria.

The morphological changes that occur in the central nervous system of patients with severe acute intermittent porphyria (AIP) have not yet been clearly established. The aim of this work was to analyze brain involvement in patients with severe AIP without epileptic seizures or clinical posterior reversible encephalopathy syndrome, as well as in a mouse model receiving or not liver-directed gene therapy aimed at correcting the metabolic disorder. We conducted neuroradiologic studies in 8 severely affected patients (6 women) and 16 gender- and age-matched controls. Seven patients showed significant enlargement of the cerebral ventricles and decreased brain perfusion was observed during the acute attack in two patients in whom perfusion imaging data were acquired. AIP mice exhibited reduced cerebral blood flow and developed chronic dilatation of the cerebral ventricles even in the presence of slightly increased porphyrin precursors. While repeated phenobarbital-induced attacks exacerbated ventricular dilation in AIP mice, correction of the metabolic defect using liver-directed gene therapy restored brain perfusion and afforded protection against ventricular enlargement. Histological studies revealed no signs of neuronal loss but a denser neurofilament pattern in the periventricular areas, suggesting compression probably caused by imbalance in cerebrospinal fluid dynamics. In conclusion, severely affected AIP patients exhibit cerebral ventricular enlargement. Liver-directed gene therapy protected against the morphological consequences of the disease seen in the brain of AIP mice. The observational study was registered at Clinicaltrial.gov as NCT02076763.