OBJECTIVES: To develop a gadolinium-free MRI-based diagnosis prediction decision tree (DPDT) for adult-type diffuse gliomas and to assess the added value of gadolinium-based contrast agent (GBCA) enhanced images. MATERIALS AND METHODS: This study included preoperative grade 2-4 adult-type diffuse gliomas (World Health Organization 2021) scanned between 2010 and 2021. The DPDT, incorporating eleven GBCA-free MRI features, was developed using 18% of the dataset based on consensus readings. Diagnosis predictions involved grade (grade 2 vs. grade 3/4) and molecular status (isocitrate dehydrogenase (IDH) and 1p/19q). GBCA-free diagnosis was predicted using DPDT, while GBCA-enhanced diagnosis included post-contrast images. The accuracy of these predictions was assessed by three raters with varying experience levels in neuroradiology using the test dataset. Agreement analyses were applied to evaluate the prediction performance/reproducibility. RESULTS: The test dataset included 303 patients (age (SD): 56.7 (14.2) years, female/male: 114/189, low-grade/high-grade: 54/249, IDH-mutant/wildtype: 82/221, 1p/19q-codeleted/intact: 34/269). Per-rater GBCA-free predictions achieved ≥ 0.85 (95%-CI: 0.80-0.88) accuracy for grade and ≥ 0.75 (95%-CI: 0.70-0.80) for molecular status, while GBCA-enhanced predictions reached ≥ 0.87 (95%-CI: 0.82-0.90) and ≥ 0.77 (95%-CI: 0.71-0.81), respectively. No accuracy difference was observed between GBCA-free and GBCA-enhanced predictions. Group inter-rater agreement was moderate for GBCA-free (0.56 (95%-CI: 0.46-0.66)) and substantial for GBCA-enhanced grade prediction (0.68 (95%-CI: 0.58-0.78), p = 0.008), while substantial for both GBCA-free (0.75 (95%-CI: 0.69-0.80) and GBCA-enhanced (0.77 (95%-CI: 0.71-0.82), p = 0.51) molecular status predictions. CONCLUSION: The proposed GBCA-free diagnosis prediction decision tree performed well, with GBCA-enhanced images adding little to the preoperative diagnostic accuracy of adult-type diffuse gliomas. KEY POINTS: Question Given health and environmental concerns, is there a gadolinium-free imaging protocol to preoperatively evaluate gliomas comparable to the gadolinium-enhanced standard practice? Findings The proposed gadolinium-free diagnosis prediction decision tree for adult-type diffuse gliomas performed well, and gadolinium-enhanced MRI demonstrated only limited improvement in diagnostic accuracy. Clinical relevance Even inexperienced raters effectively classified adult-type diffuse gliomas using the gadolinium-free diagnosis prediction decision tree, which, until further validation, can be used alongside gadolinium-enhanced images to respect standard practice, despite this study showing that gadolinium-enhanced images hardly improved diagnostic accuracy.

• MeSH
• Adult MeSH
• Gadolinium MeSH
• Glioma * diagnostic imaging   MeSH
• Contrast Media * MeSH
• Middle Aged MeSH
• Humans MeSH
• Magnetic Resonance Imaging * methods   MeSH
• Brain Neoplasms * diagnostic imaging   MeSH
• Predictive Value of Tests MeSH
• Reproducibility of Results MeSH
• Decision Trees * MeSH
• Aged MeSH
• Neoplasm Grading * MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH

OBJECTIVES: Class imbalance in datasets is one of the challenges of machine learning (ML) in medical image analysis. We employed synthetic data to overcome class imbalance when segmenting bitewing radiographs as an exemplary task for using ML. METHODS: After segmenting bitewings into classes, i.e. dental structures, restorations, and background, the pixel-level representation of implants in the training set (1543 bitewings) and testing set (177 bitewings) was 0.03 % and 0.07 %, respectively. A diffusion model and a generative adversarial network (pix2pix) were used to generate a dataset synthetically enriched in implants. A U-Net segmentation model was trained on (1) the original dataset, (2) the synthetic dataset, (3) on the synthetic dataset and fine-tuned on the original dataset, or (4) on a dataset which was naïvely oversampled with images containing implants. RESULTS: U-Net trained on the original dataset was unable to segment implants in the testing set. Model performance was significantly improved by naïve over-sampling, achieving the highest precision. The model trained only on synthetic data performed worse than naïve over-sampling in all metrics, but with fine-tuning on original data, it resulted in the highest Dice score, recall, F1 score and ROC AUC, respectively. The performance on other classes than implants was similar for all strategies except training only on synthetic data, which tended to perform worse. CONCLUSIONS: The use of synthetic data alone may deteriorate the performance of segmentation models. However, fine-tuning on original data could significantly enhance model performance, especially for heavily underrepresented classes. CLINICAL SIGNIFICANCE: This study explored the use of synthetic data to enhance segmentation of bitewing radiographs, focusing on underrepresented classes like implants. Pre-training on synthetic data followed by fine-tuning on original data yielded the best results, highlighting the potential of synthetic data to advance AI-driven dental imaging and ultimately support clinical decision-making.

• MeSH
• Humans MeSH
• Image Processing, Computer-Assisted * methods   MeSH
• Machine Learning * MeSH
• Dental Implants MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH

Circular RNAs (circRNAs) make up approximately 10% of the human transcriptome. CircRNAs belong to the broad group of non-coding RNAs and characteristically are formed by backsplicing into a stable circular loop. Their main role is to regulate transcription through the inhibition of miRNAs' expression, termed miRNA sponging. CircRNAs promote tumorigenesis/lymphomagenesis by competitively binding to miRNAs at miRNA binding sites. In diffuse large B-cell lymphoma (DLBCL), several circRNAs have been identified and their expression is related to both progression and response to therapy. DLBCL is the most prevalent and aggressive subtype of B-cell lymphomas and accounts for about 25% to 30% of all non-Hodgkin lymphomas. DLBCL displays great heterogeneity concerning histopathology, biology, and genetics. Patients who have relapsed or have refractory disease after first-line therapy have a very poor prognosis, demonstrating an important unmet need for new treatment options. As more circRNAs are identified in the future, we will better understand their biological roles and potential use in treating cancer, including DLBCL. For example, circAmotl1 promotes nuclear translocation of MYC and upregulation of translational targets of MYC, thus enhancing lymphomagenesis. Another example is circAPC, which is significantly downregulated in DLBCL and correlates with disease aggressiveness and poor prognosis. CircAPC increases expression of the host gene adenomatous polyposis coli (APC), and in doing so inactivates the canonical Wnt/β-catenin signaling and restrains DLBCL growth. MiRNAs belong to the non-coding regulatory molecules that significantly contribute to lymphomagenesis through their target mRNAs. In DLBCL, among the highly expressed miRNAs, are miR-155-5p and miR-21-5p, which regulate NF-ĸB and PI3K/AKT signaling pathways. The aim of this review is to describe the function and mechanism of regulation of circRNAs on miRNAs' expression in DLBCL. This will help us to better understand the regulatory network of circRNA/miRNA/mRNA, and to propose novel therapeutic targets to treat DLBCL.

• Publication type
• Journal Article MeSH
• Review MeSH

BACKGROUND AND PURPOSE: CNS embryonal tumor with pleomorphic adenoma gene-like 1 (PLAGL1)/pleomorphic adenoma gene-like 2 (PLAGL2) amplification (ET, PLAGL) is a newly identified, highly malignant pediatric tumor. Systematic MRI descriptions of ET, PLAGL are currently lacking. MATERIALS AND METHODS: MRI data from 19 treatment-naïve patients with confirmed ET, PLAGL were analyzed. Evaluation focused on anatomic involvement, tumor localization, MRI signal characteristics, DWI behavior, and the presence of necrosis and hemorrhage. Descriptive statistics (median, interquartile range, percentage) were assessed. RESULTS: Ten patients had PLAGL1 and nine had PLAGL2 amplifications. The solid components of the tumors were often multinodular with heterogeneous enhancement (mild to intermediate in 47% and intermediate to strong in 47% of cases). Nonsolid components included cysts in 47% and necrosis in 84% of the cases. The tumors showed heterogeneous T2WI hyper- and isointensity (74%), relatively little diffusion restriction (ADC values less than contralateral normal-appearing WM in 36% of cases with available DWI), and tendencies toward hemorrhage/calcification (42%). No reliable distinction was found between PLAGL1- and PLAGL2-amplified tumors or compared with other embryonal CNS tumors. CONCLUSIONS: The study contributes to understanding the imaging characteristics of ET, PLAGL. It underscores the need for collaboration in studying rare pediatric tumors and advocates the use of harmonized imaging protocols for better characterization.

• MeSH
• Gene Amplification MeSH
• Child MeSH
• DNA-Binding Proteins genetics   MeSH
• Neoplasms, Germ Cell and Embryonal diagnostic imaging   pathology   MeSH
• Infant MeSH
• Humans MeSH
• Magnetic Resonance Imaging * methods   MeSH
• Adolescent MeSH
• Tumor Suppressor Proteins MeSH
• Central Nervous System Neoplasms diagnostic imaging   pathology   MeSH
• Brain Neoplasms diagnostic imaging   pathology   MeSH
• Child, Preschool MeSH
• Cell Cycle Proteins MeSH
• RNA-Binding Proteins MeSH
• Transcription Factors genetics   MeSH
• Check Tag
• Child MeSH
• Infant MeSH
• Humans MeSH
• Adolescent MeSH
• Male MeSH
• Child, Preschool MeSH
• Female MeSH
• Publication type
• Journal Article MeSH

Extracellular matrix (ECM) is a network of macromolecules which has two forms-perineuronal nets (PNNs) and a diffuse ECM (dECM)-both influence brain development, synapse formation, neuroplasticity, CNS injury and progression of neurodegenerative diseases. ECM remodeling can influence extrasynaptic transmission, mediated by diffusion of neuroactive substances in the extracellular space (ECS). In this study we analyzed how disrupted PNNs and dECM influence brain diffusibility. Two months after oral treatment of rats with 4-methylumbelliferone (4-MU), an inhibitor of hyaluronan (HA) synthesis, we found downregulated staining for PNNs, HA, chondroitin sulfate proteoglycans, and glial fibrillary acidic protein. These changes were enhanced after 4 and 6 months and were reversible after a normal diet. Morphometric analysis further indicated atrophy of astrocytes. Using real-time iontophoretic method dysregulation of ECM resulted in increased ECS volume fraction α in the somatosensory cortex by 35%, from α = 0.20 in control rats to α = 0.27 after the 4-MU diet. Diffusion-weighted magnetic resonance imaging revealed a decrease of mean diffusivity and fractional anisotropy (FA) in the cortex, hippocampus, thalamus, pallidum, and spinal cord. This study shows the increase in ECS volume, a loss of FA, and changes in astrocytes due to modulation of PNNs and dECM that could affect extrasynaptic transmission, cell-to-cell communication, and neural plasticity.

• MeSH
• Astrocytes metabolism   MeSH
• Chondroitin Sulfate Proteoglycans metabolism   MeSH
• Extracellular Matrix * metabolism   MeSH
• Extracellular Space * metabolism   MeSH
• Glial Fibrillary Acidic Protein metabolism   MeSH
• Hymecromone pharmacology   MeSH
• Rats MeSH
• Hyaluronic Acid MeSH
• Brain metabolism   MeSH
• Nerve Net drug effects   diagnostic imaging   MeSH
• Rats, Sprague-Dawley MeSH
• Animals MeSH
• Check Tag
• Rats MeSH
• Male MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH

BACKGROUND: The enhanced application of imaging techniques is resulting in the diagnosis of more patients with asymptomatic metastatic esophagogastric cancer (mEGC). We conducted a Delphi study to gather insights from European experts on the optimal timing for initiating palliative systemic therapy for these patients. METHODS: An online survey featured 14 scenarios where physicians chose their preferred timing for initiating systemic therapy: immediate(<3 weeks) or deferred. The standard scenario was a 65-year-old male, WHO/ECOG 0 with asymptomatic mEGC, 2 metastases in each lung, HER2 -, PDL1-CPS 2. In every subsequent case, one characteristic was modified. To investigate the fortitude of the physicians' preference for an immediate start, scenarios also included a patient who was motivated to start but preferred to defer if the physician deemed it judicious. Consensus was defined as ≥ 75 % agreement; scenarios without consensus were re-evaluated in Delphi round 2. RESULTS: Thirty-nine physicians participated in the first round, and 33 in the second round. Consensus to start treatment immediately was reached in 12 (86 %) scenarios. When patients preferred to defer, the consensus was to still advise to start palliative systemic treatment immediately in half (n = 7) of the scenarios. Only 2 scenarios (pre-existent WHO/ECOG 2 or 78 years old) reached the consensus that treatment could be deferred. CONCLUSIONS: In asymptomatic mEGC, immediate start of treatment is preferred by European experts. Consensus was established that treatment can be deferred for patients who prefer deferral and either have a pre-existent WHO/ECOG performance status of 2 or are of advanced age.

• MeSH
• Asymptomatic Diseases therapy   MeSH
• Time-to-Treatment MeSH
• Time Factors MeSH
• Delphi Technique * MeSH
• Consensus MeSH
• Middle Aged MeSH
• Humans MeSH
• Esophageal Neoplasms * pathology   drug therapy   MeSH
• Stomach Neoplasms * drug therapy   pathology   MeSH
• Palliative Care * methods   MeSH
• Aged MeSH
• Check Tag
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Geographicals
• Europe MeSH

BACKGROUND: Whole-body magnetic resonance imaging (wbMRI) allows general assessment of systemic cancers including lymphomas without radiation burden. AIM: To evaluate the diagnostic performance of wbMRI in the staging of diffuse large B-cell lymphoma (DLBCL), determine the value of individual MRI sequences, and assess patients' concerns with wbMRI. METHODS: In this single-center prospective study, adult patients newly diagnosed with systemic DLBCL underwent wbMRI on a 3T scanner [diffusion weighted images with background suppression (DWIBS), T2, short tau inversion recovery (STIR), contrast-enhanced T1] and fluorodeoxyglucose (18F-FDG) positron emission tomography/computed tomography (PET/CT) (reference standard). The involvement of 12 nodal regions and extranodal sites was evaluated on wbMRI and PET/CT. The utility of wbMRI sequences was rated on a five-point scale (0 = not useful, 4 = very useful). Patients received a questionnaire regarding wbMRI. RESULTS: Of 60 eligible patients, 14 (23%) were enrolled and completed the study. The sensitivity of wbMRI in the nodal involvement (182 nodal sites) was 0.84, with 0.99 specificity, positive predictive value of 0.96, negative predictive value of 0.97, and 0.97 accuracy. PET/CT and wbMRI were concordant both in extranodal involvement (13 instances) and staging (κ = 1.0). The mean scores of the utility of MRI sequences were 3.71 ± 0.73 for DWIBS, 2.64 ± 0.84 for T1, 2.14 ± 0.77 for STIR, and 1.29 ± 0.73 for T2 (P < 0.0001). Patients were mostly concerned about the enclosed environment and duration of the MRI examination (27% of patients). CONCLUSION: The wbMRI exhibited excellent sensitivity and specificity in staging DLBCL. DWIBS and contrast-enhanced T1 were rated as the most useful sequences. Patients were less willing to undergo wbMRI as a second examination parallel to PET/CT, especially owing to the long duration and the enclosed environment.

• Publication type
• Journal Article MeSH

The Sec translocon is a highly conserved membrane assembly for polypeptide transport across, or into, lipid bilayers. In bacteria, secretion through the core channel complex-SecYEG in the inner membrane-is powered by the cytosolic ATPase SecA. Here, we use single-molecule fluorescence to interrogate the conformational state of SecYEG throughout the ATP hydrolysis cycle of SecA. We show that the SecYEG channel fluctuations between open and closed states are much faster (~20-fold during translocation) than ATP turnover, and that the nucleotide status of SecA modulates the rates of opening and closure. The SecY variant PrlA4, which exhibits faster transport but unaffected ATPase rates, increases the dwell time in the open state, facilitating pre-protein diffusion through the pore and thereby enhancing translocation efficiency. Thus, rapid SecYEG channel dynamics are allosterically coupled to SecA via modulation of the energy landscape, and play an integral part in protein transport. Loose coupling of ATP-turnover by SecA to the dynamic properties of SecYEG is compatible with a Brownian-rachet mechanism of translocation, rather than strict nucleotide-dependent interconversion between different static states of a power stroke.

• MeSH
• Adenosine Triphosphate metabolism   MeSH
• Adenosine Triphosphatases genetics   metabolism   MeSH
• Bacterial Proteins * metabolism   MeSH
• Nucleotides metabolism   MeSH
• SecA Proteins metabolism   MeSH
• Escherichia coli Proteins * metabolism   MeSH
• SEC Translocation Channels chemistry   MeSH
• Protein Transport MeSH
• Publication type
• Journal Article MeSH

BACKGROUND: Chronic lymphocytic leukemia (CLL) is a common adult leukemia characterized by the accumulation of neoplastic mature B cells in blood, bone marrow, lymph nodes, and spleen. The disease biology remains unresolved in many aspects, including the processes underlying the disease progression and relapses. However, studying CLL in vitro poses a considerable challenge due to its complexity and dependency on the microenvironment. Several approaches are utilized to overcome this issue, such as co-culture of CLL cells with other cell types, supplementing culture media with growth factors, or setting up a three-dimensional (3D) culture. Previous studies have shown that 3D cultures, compared to conventional ones, can lead to enhanced cell survival and altered gene expression. 3D cultures can also give valuable information while testing treatment response in vitro since they mimic the cell spatial organization more accurately than conventional culture. METHODS: In our study, we investigated the behavior of CLL cells in two types of material: (i) solid porous collagen scaffolds and (ii) gel composed of carboxymethyl cellulose and polyethylene glycol (CMC-PEG). We studied CLL cells' distribution, morphology, and viability in these materials by a transmitted-light and confocal microscopy. We also measured the metabolic activity of cultured cells. Additionally, the expression levels of MYC, VCAM1, MCL1, CXCR4, and CCL4 genes in CLL cells were studied by qPCR to observe whether our novel culture approaches lead to increased adhesion, lower apoptotic rates, or activation of cell signaling in relation to the enhanced contact with co-cultured cells. RESULTS: Both materials were biocompatible, translucent, and permeable, as assessed by metabolic assays, cell staining, and microscopy. While collagen scaffolds featured easy manipulation, washability, transferability, and biodegradability, CMC-PEG was advantageous for its easy preparation process and low variability in the number of accommodated cells. Both materials promoted cell-to-cell and cell-to-matrix interactions due to the scaffold structure and generation of cell aggregates. The metabolic activity of CLL cells cultured in CMC-PEG gel was similar to or higher than in conventional culture. Compared to the conventional culture, there was (i) a lower expression of VCAM1 in both materials, (ii) a higher expression of CCL4 in collagen scaffolds, and (iii) a lower expression of CXCR4 and MCL1 (transcript variant 2) in collagen scaffolds, while it was higher in a CMC-PEG gel. Hence, culture in the material can suppress the expression of a pro-apoptotic gene (MCL1 in collagen scaffolds) or replicate certain gene expression patterns attributed to CLL cells in lymphoid organs (low CXCR4, high CCL4 in collagen scaffolds) or blood (high CXCR4 in CMC-PEG).

• MeSH
• Cell Culture Techniques methods   MeSH
• Leukemia, Lymphocytic, Chronic, B-Cell * pathology   metabolism   MeSH
• Gels chemistry   MeSH
• Collagen * chemistry   pharmacology   MeSH
• Humans MeSH
• Polyethylene Glycols * chemistry   MeSH
• Receptors, CXCR4 metabolism   MeSH
• Carboxymethylcellulose Sodium * chemistry   pharmacology   MeSH
• Cell Culture Techniques, Three Dimensional methods   MeSH
• Tissue Scaffolds * chemistry   MeSH
• Cell Survival drug effects   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH

Diffuse pediatric-type high-grade gliomas (pedHGG), H3- and IDH-wildtype, encompass three main DNA-methylation-based subtypes: pedHGG-MYCN, pedHGG-RTK1A/B/C, and pedHGG-RTK2A/B. Since their first description in 2017 tumors of pedHGG-RTK2A/B have not been comprehensively characterized and clinical correlates remain elusive. In a recent series of pedHGG with a Gliomatosis cerebri (GC) growth pattern, an increased incidence of pedHGG-RTK2A/B (n = 18) was observed. We added 14 epigenetically defined pedHGG-RTK2A/B tumors to this GC series and provided centrally reviewed radiological, histological, and molecular characterization. The final cohort of 32 pedHGG-RTK2A/B tumors consisted of 25 pedHGG-RTK2A (78%) and seven pedHGG-RTK2B (22%) cases. The median age was 11.6 years (range, 4-17) with a median overall survival of 16.0 months (range 10.9-28.2). Seven of 11 of the newly added cases with imaging available showed a GC phenotype at diagnosis or follow-up. PedHGG-RTK2B tumors exhibited frequent bithalamic involvement (6/7, 86%). Central neuropathology review confirmed a diffuse glial neoplasm in all tumors with prominent angiocentric features in both subclasses. Most tumors (24/27 with available data, 89%) diffusely expressed EGFR with focal angiocentric enhancement. PedHGG-RTK2A tumors lacked OLIG2 expression, whereas 43% (3/7) of pedHGG-RTK2B expressed this glial transcription factor. ATRX loss occurred in 3/6 pedHGG-RTK2B samples with available data (50%). DNA sequencing (pedHGG-RTK2A: n = 18, pedHGG-RTK2B: n = 5) found EGFR alterations (15/23, 65%; predominantly point mutations) in both subclasses. Mutations in BCOR (14/18, 78%), SETD2 (7/18, 39%), and the hTERT promoter (7/19, 37%) occurred exclusively in pedHGG-RTK2A tumors, while pedHGG-RTK2B tumors were enriched for TP53 alterations (4/5, 80%). In conclusion, pedHGG-RTK2A/B tumors are characterized by highly diffuse-infiltrating growth patterns and specific radiological and histo-molecular features. By comprehensively characterizing methylation-based tumors, the chance to develop specific and effective therapy concepts for these detrimental tumors increases.

• MeSH
• Child MeSH
• Phenotype MeSH
• Glioma * genetics   pathology   diagnostic imaging   MeSH
• Humans MeSH
• DNA Methylation * MeSH
• Adolescent MeSH
• Brain Neoplasms * genetics   pathology   diagnostic imaging   MeSH
• Neoplasms, Neuroepithelial * genetics   pathology   diagnostic imaging   MeSH
• Child, Preschool MeSH
• Check Tag
• Child MeSH
• Humans MeSH
• Adolescent MeSH
• Male MeSH
• Child, Preschool MeSH
• Female MeSH
• Publication type
• Journal Article MeSH