Quantitative digital pathology enables automated and quantitative assessment of inflammatory activity in patients with autoimmune hepatitis.

Background: Chronic liver disease diagnoses depend on liver biopsy histopathological assessment. However, due to the limitations associated with biopsy, there is growing interest in the use of quantitative digital pathology to support pathologists. We evaluated the performance of computational algorithms in the assessment of hepatic inflammation in an autoimmune hepatitis in which inflammation is a major component. Methods: Whole-slide digital image analysis was used to quantitatively characterize the area of tissue covered by inflammation [Inflammation Density (ID)] and number of inflammatory foci per unit area [Focal Density (FD)] on tissue obtained from 50 patients with autoimmune hepatitis undergoing routine liver biopsy. Correlations between digital pathology outputs and traditional categorical histology scores, biochemical, and imaging markers were assessed. The ability of ID and FD to stratify between low-moderate (both portal and lobular inflammation ≤1) and moderate-severe disease activity was estimated using the area under the receiver operating characteristic curve (AUC). Results: ID and FD scores increased significantly and linearly with both portal and lobular inflammation grading. Both ID and FD correlated moderately-to-strongly and significantly with histology (portal and lobular inflammation; 0.36≤R≤0.69) and biochemical markers (ALT, AST, GGT, IgG, and gamma globulins; 0.43≤R≤0.57). ID (AUC: 0.85) and FD (AUC: 0.79) had good performance for stratifying between low-moderate and moderate-severe inflammation. Conclusion: Quantitative assessment of liver biopsy using quantitative digital pathology metrics correlates well with traditional pathology scores and key biochemical markers. Whole-slide quantification of disease can support stratification and identification of patients with more advanced inflammatory disease activity.

Increased glucose availability sensitizes pancreatic cancer to chemotherapy.

Pancreatic Ductal Adenocarcinoma (PDAC) is highly resistant to chemotherapy. Effective alternative therapies have yet to emerge, as chemotherapy remains the best available systemic treatment. However, the discovery of safe and available adjuncts to enhance chemotherapeutic efficacy can still improve survival outcomes. We show that a hyperglycemic state substantially enhances the efficacy of conventional single- and multi-agent chemotherapy regimens against PDAC. Molecular analyses of tumors exposed to high glucose levels reveal that the expression of GCLC (glutamate-cysteine ligase catalytic subunit), a key component of glutathione biosynthesis, is diminished, which in turn augments oxidative anti-tumor damage by chemotherapy. Inhibition of GCLC phenocopies the suppressive effect of forced hyperglycemia in mouse models of PDAC, while rescuing this pathway mitigates anti-tumor effects observed with chemotherapy and high glucose.

Segmenting pediatric optic pathway gliomas from MRI using deep learning.

Optic pathway gliomas are low-grade neoplastic lesions that account for approximately 3-5% of brain tumors in children. Assessing tumor burden from magnetic resonance imaging (MRI) plays a central role in its efficient management, yet it is a challenging and human-dependent task due to the difficult and error-prone process of manual segmentation of such lesions, as they can easily manifest different location and appearance characteristics. In this paper, we tackle this issue and propose a fully-automatic and reproducible deep learning algorithm built upon the recent advances in the field which is capable of detecting and segmenting optical pathway gliomas from MRI. The proposed training strategies help us elaborate well-generalizing deep models even in the case of limited ground-truth MRIs presenting example optic pathway gliomas. The rigorous experimental study, performed over two clinical datasets of 22 and 51 multi-modal MRIs acquired for 22 and 51 patients with optical pathway gliomas, and a public dataset of 494 pre-surgery low-/high-grade glioma patients (corresponding to 494 multi-modal MRIs), and involving quantitative, qualitative and statistical analysis revealed that the suggested technique can not only effectively delineate optic pathway gliomas, but can also be applied for detecting other brain tumors. The experiments indicate high agreement between automatically calculated and ground-truth volumetric measurements of the tumors and very fast operation of the proposed approach, both of which can increase the clinical utility of the suggested software tool. Finally, our deep architectures have been made open-sourced to ensure full reproducibility of the method over other MRI data.

Quantitative multiparametric MRI as a non-invasive stratification tool in children and adolescents with autoimmune liver disease.

Autoimmune hepatitis (AIH) and autoimmune sclerosing cholangitis (ASC) are two very closely related autoimmune liver diseases with overlapping clinical features and similar management strategies. The purpose of this study was to assess the utility of quantitative imaging markers to distinguish ASC from AIH in paediatrics. 66 participants (N = 52 AIH, N = 14 ASC) aged 14.4 ± 3.3 years scheduled to undergo routine biopsy and baseline serum liver biochemistry testing were invited to undergo MRI (non-contrast abdominal MRI and 3D fast spin-echo MRCP). Multiparametric MRI was used to measure fibro-inflammation with corrected T1 (cT1), while the biliary tree was modelled   using quantitative MRCP (MRCP +). Mann-Whitney U tests were performed to compare liver function tests with imaging markers between patient groups (ASC vs AIH). Receiver operating characteristic curves and stepwise logistic regressions were used to identify the best combination of markers to discriminate between ASC and AIH. Correlations between liver function tests and imaging markers were performed using Spearman's rank correlation. cT1 was significantly correlated with liver function tests (range 0.33 ≤ R ≤ 56, p < 0.05), as well as with fibrosis, lobular and portal inflammation (range 0.31 ≤ R ≤ 42, p < 0.05). 19 MRCP + metrics correlated significantly with liver function tests (range 0.29 ≤ R ≤ 0.43, p < 0.05). GGT and MRCP + metrics were significantly higher in ASC compared to those with AIH. The best multivariable model for distinguishing ASC from AIH included total number of ducts and the sum of relative severity of both strictures and dilatations AUC: 0.91 (95% CI 0.78-1). Quantitative MRCP metrics are a good discriminator of ASC from AIH.

Multiparametric MRI as a Noninvasive Monitoring Tool for Children With Autoimmune Hepatitis.

OBJECTIVES: Autoimmune hepatitis (AIH) is a progressive liver disease managed with corticosteroids and immunosuppression and monitored using a combination of liver biochemistry and histology. However, liver biopsy is invasive with risk of pain and bleeding. The aim of the present study was to investigate the utility of noninvasive imaging with multiparametric magnetic resonance imaging (MRI) (mpMRI) to provide clinically useful information on the presence and extent of hepatic inflammation, potentially guiding immunosuppression. METHODS: Eighty-one participants (aged 6-18), 21 healthy and 60 AIH patients, underwent multiparametric MRI to measure fibro-inflammation with iron-corrected T1 (cT1) at the Children's Memorial Health Institute in Warsaw alongside other clinical blood tests and liver biopsy at recruitment and after an average of 16-month follow-up (range 9-22 months). Correlation analyses were used to investigate the associations between cT1 with blood serum markers and histological scores. RESULTS: At recruitment, patients with AIH had a higher cT1 value than healthy controls (P < 0.01). cT1 correlated significantly with key histopathological features of disease. Treatment naïve AIH patients showed evidence of inflammation and heterogeneity across the liver compared to healthy controls.At follow-up, cT1 showed utility in monitoring disease regression as most patients showed significantly reduced fibro-inflammation with treatment (P < 0.0001) over the observational period. Six patients had histological fibrosis and clear fibro-inflammation on MR despite biochemical remission (normalized aspartate aminotransferase (AST), alanine aminotransferase (ALT), and immunoglobulin G [IgG]). CONCLUSIONS: Multiparametric MRI can measure disease burden in pediatric AIH and can show changes over time in response to therapy. Active disease can be seen even in biochemical remission in children.

Abnormal Cannabidiol Modulates Vitamin A Metabolism by Acting as a Competitive Inhibitor of CRBP1.

Cellular retinol-binding proteins (CRBPs) facilitate the uptake and intracellular transport of vitamin A. They integrate retinoid metabolism, playing an important role in regulating the synthesis of bioactive vitamin A metabolites. Thus, CRBPs constitute potential pharmacological targets to modulate cellular retinoid status that in turn may have applications in the treatment of certain immunological, metabolic, and ocular disorders. Here we identify abnormal cannabidiol (abn-CBD) as a nonretinoid inhibitor of cellular retinol-binding protein 1 (CRBP1). X-ray crystal structures of CRBP1 in complex with abn-CBD and its derivatives revealed a distinctive mode of protein-ligand interaction and provided a molecular basis for the high affinity and selectivity of this compound. We demonstrated that abn-CBD modulates the flux of retinoids via the retinoid cycle in vivo. Furthermore, the biological activity of abn-CBD was evidenced by its ability to protect against light-induced retinal damage in Balb/cJ mice. Altogether, our findings indicate that targeting selected CRBPs with a small-molecule inhibitor can potentially lead to the development of new therapeutic agents to counteract diseases with etiologies involving imbalance in retinoid metabolism or signaling.

Evaluation of brain lesions in patients after coronary artery bypass grafting using MRI with the emphasis on susceptibility-weighted imaging.

INTRODUCTION: Patients undergoing coronary artery bypass grafting (CABG) are at risk of strokes and neurocognitive disorders. THE AIM OF THE STUDY: The aim of the study was to assess the clinical utility of susceptibility-weighted imaging (SWI) MRI in detection of new brain lesions in patients after CABG. We assessed the incidence and types of brain lesions and correlated the data with neurological examinations in groups of patients who underwent on-pump and off-pump CABG. MATERIAL AND METHODS: Patients underwent a neurological examination and MRI before, 6-20 days after and 6 months after the CABG. Fifty-one patients (43 men, mean age 63.12 years) were analyzed. RESULTS: Fifteen (29.4%) patients underwent on-pump CABG, 36 (70.6%) off-pump CABG. On postoperative scans new lesions were detected in 12 (23.5%) patients. Ischemic lesions (visible on diffusion-weighted imaging [DWI]) were detected in 4 patients, in 6 lesions were visible on SWI, in 1 case lesions were visible on SWI and DWI. Hemorrhagic stroke was observed in 1 patient. In the group of patients who underwent on-pump CABG, new brain lesions were observed in 60.0% of patients vs. 8.3% of those who underwent off-pump CABG (p < 0.0001); these changes more frequently were multiple (p < 0.0013) and located infratentorially (p < 0.0218). Lesions visible on SWI were observed only in patients undergoing on-pump CABG (p = 0.00005). In all patients (except for 1 with stroke), lesions visible in MRI were clinically silent. CONCLUSIONS: The use of SWI enables one to detect lesions occurring in the brain after CABG, invisible in other sequences. On-pump CABG is associated with a greater risk of clinically silent brain damage compared to off-pump CABG.

[The role of fibrocytes in pulmonary fibrosis]. / Rola fibrocytów w procesach wlóknienia pluc.

Fibrocytes are bone-marrow derived mesenchymal progenitor cells. They express typical markers of leukocytes, hematopoietic stem cells and fibroblasts. They play a pivotal role in the tissue remodeling and fibrosis in both physiologic and pathologic settings. Fibrocytes are unique in that they are capable of differentiating into fibroblasts and myofibroblasts, as well as adipocytes. Circulating fibrocytes may play a role in pulmonary fibrosis and clinical outcomes. Recent data obtained from the clinical setting suggest that high numbers of circulating fibrocytes correlate with pulmonary function test parameters and disease activity in patients with different interstitial lung diseases. A greater understanding of the immunologic mediator that influence fibrocyte biology suggest new opportunities for therapeutic manipulation of these cells in fibrogenesis.

"Drop attacks" as first clinical symptoms in a child carrying MTTK m.8344A>G mutation.

UNLABELLED: We describe a child with dyslexia and difficulty in school who, at the age of 13 years, began to suffer from several head injuries resulting from falls of uncertain cause. Two years later, the patient developed symptoms of a severe mitochondrial disorder (involving bulbar-pyramidal paralysis, ophthalmoplegia, and hyperlactatemia) that coincided with VPA administration. Brain MR imaging revealed rapidly developing Leigh syndrome (LS), and muscle biopsy showed ragged blue fibres (RBF). A diminished expression of the E1α subunit of pyruvate dehydrogenase was found in muscle homogenate (signal 28.7% of normal). The accurate diagnosis of mitochondrially inherited LS (MILS) and the identification of an almost homoplasmic m.8344G>A mutation in the MTTK gene was delayed due to an initial incorrect diagnosis of epilepsy, misdiagnosis of neuroinfection, and failure to note LS on the first brain MRI. Periods of exacerbation or improvement were observed in association with the administration of certain drugs or procedures (VPA administration or intensive rehabilitation associated with worsening; ketogenic diet associated with remission). However, the random association of these factors with natural disease fluctuations cannot be excluded. CONCLUSIONS: 1) To improve the early detection of mitochondrial disorder, we recommend screening for mtDNA (and nDNA) mutations in all patients with LS present on brain MRI. 2) Brain MRI protocols should include diffusion-weighted and T2-weighted imaging, and LS-like changes should be analysed by a neuroradiologist experienced in the field. 3) Additional controlled studies are urgently needed to assess the causal relationship between management strategies and the natural history of the disease. Until the association between VPA and disease exacerbation can be ruled out, VPA should be avoided in patients with these symptoms unless the mitochondrial disorder has been excluded.

Infratentorial tumors in children - value of ADC in prediction of grade of neoplasms.

BACKGROUND: The purpose of this study was to evaluate ADC values in the preoperative grading of primary infratentorial brain tumors in children. MATERIAL /METHODS: We retrospectively reviewed 50 MR examinations of patients with infratentorial tumors. All children were operated on and tumors were histopathologically proved as low-grade - 25 (24 pilocytic astrocytomas, 1 ependymoma) and high-grade lesions - 25 (19 medulloblastomas, 6 anaplastic ependymomas). In all patients with contrast-enhanced tumors, ROIs were placed in the enhanced region. In patients with non-enhancing tumors, ROIs were placed in the solid part of the lesion. Cystic, hemorrhagic and necrotic areas of tumors were excluded. Statistical analysis was performed by using a Student's t-test. RESULTS: Statistically significant differences were found in the comparisons of mean ADC of pilocytic astrocytomas (1.54×10(-3)mm(2)/s ±0.2) with medulloblastomas (0.75×10(-3)mm(2)/s ±0.075) and pilocytic astrocytomas (1.54×10(-3)mm(2)/s ±0.2) with anaplastic ependymomas (0.99×10(-3)mm(2)/s ±0.25). Statistical analysis including ependymomas should be discussed, because of small number of these tumors and a non-homogenous group of lesions. CONCLUSIONS: DWI imaging and ADC map provide useful information for preoperative grading of infratentorial tumors in children.