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Aim: Patients with multiple brain metastases (BM) benefit from hippocampal-avoiding whole brain radiotherapy (HA-WBRT), the challenging and less available form of WBRT. This study explores potential of pre-radiotherapy (pre-RT) hippocampal magnetic resonance spectroscopy (MRS) measuring hippocampal neuronal density as an imaging surrogate and predictive tool for assessing neurocognitive functions (NCF)., Methods: 43 BM patients underwent pre-RT hippocampal MRS. N-acetyl aspartate (NAA) concentration, a marker for neuronal density (weighted by creatine (Cr) and choline (Cho) concentrations), and neurocognitive function (NCF) tests (HVLT and BVMT) performed by certified psychologists were evaluated. Clinical variables and NAA concentrations were correlated with pre-RT NCFs., Results: HVLT and BVMT subtests showed pre-RT deterioration except for BVMT recognition. Significantly better NCFs were observed in women in HVLT subsets. Significantly higher NAA/Cr + Cho was measured in women (median 0.63 vs. 0.55; P=0.048) in the left hippocampus (no difference in the right hippocampus). In men, a positive correlation (0.51, P=0.018) between total brain volume and HVLT-TR, between left hippocampal NAA/Cr + Cho and HVLT-R (0.45, P=0.063), and between right hippocampal NAA/Cr + Cho and BVMT-recognition (0.49, P=0.054) was observed. In women, a borderline significant negative correlation was observed between left hippocampal NAA/Cr + Cho and BVMT-TR (-0.43, P=0.076) and between right NAA/Cr + Cho and HVLT-DR (-0.42, P=0.051)., Conclusion: Borderline statistically significant correlations were observed with speculative interpretation underlying the challenges of hippocampal MRS as a surrogate for neurocognitive impairment. Further studies need to be done to ascertain the opportunities for imaging predictors of benefit from memory sparing radiotherapy., Competing Interests: The authors report no conflicts of interest in this work.

Background: Changes in the hippocampus after brain metastases radiotherapy can significantly impact neurocognitive functions. Numerous studies document hippocampal atrophy correlating with the radiation dose. This study aims to elucidate volumetric changes in patients undergoing whole-brain radiotherapy (WBRT) or targeted stereotactic radiotherapy (SRT) and to explore volumetric changes in the individual subregions of the hippocampus., Method: Ten patients indicated to WBRT and 18 to SRT underwent brain magnetic resonance before radiotherapy and after 4 months. A structural T1-weighted sequence was used for volumetric analysis, and the software FreeSurfer was employed as the tool for the volumetry evaluation of 19 individual hippocampal subregions., Results: The volume of the whole hippocampus, segmented by the software, was larger than the volume outlined by the radiation oncologist. No significant differences in volume changes were observed in the right hippocampus. In the left hippocampus, the only subregion with a smaller volume after WBRT was the granular cells and molecular layers of the dentate gyrus (GC-ML-DG) region (median change -5 mm 3 , median volume 137 vs. 135 mm 3 ; P  = .027), the region of the presumed location of neuronal progenitors., Conclusions: Our study enriches the theory that the loss of neural stem cells is involved in cognitive decline after radiotherapy, contributes to the understanding of cognitive impairment, and advocates for the need for SRT whenever possible to preserve cognitive functions in patients undergoing brain radiotherapy., Competing Interests: The authors declare no conflict of interest. The funders had no role in the writing of the manuscript and in the decision to publish this article., (© The Author(s) 2024. Published by Oxford University Press, the Society for Neuro-Oncology and the European Association of Neuro-Oncology.)

Objectives: The study aims to analyze our first experience with direct percutaneous embolization of carotid body tumors (CBTs) using ethylene-vinyl alcohol copolymer (Onyx) along with balloon test occlusion (BTO)., Methods: A retrospective preliminary single-center study was conducted at the Otorhinolaryngology and Head and Neck Surgery Department and the Medical Imaging Department of the University Teaching Hospital. A consecutive series of three patients with CBTs was treated at the local institution between October 2018 and June 2019. All three patients underwent preoperative percutaneous embolization using ethylene-vinyl alcohol copolymer (Onyx 18) with the addition of BTO. Outcome measures were the percentage of tumor devascularization, intraoperative blood losses, and operation times. BTO was evaluated by clinical neurological examination and neurosonological transcranial Doppler examination of the middle cerebral artery (MCA)., Results: Devascularization of all three tumors was complete or near complete. All three tumors were surgically extirpated with excellent surgical outcomes. The blood losses were minimal, and the average operation time was 2 h and 8 min. BTO was positive in one patient, which was valuable additional information on carotid branches ligation limitations. The other two patients showed negative BTOs with the result of safety of eventual carotid arteries ligations., Conclusion: Preoperative direct percutaneous embolization of CBT with Onyx is a highly effective procedure that significantly facilitates surgery. BTO provides valuable additional information on the most appropriate and safe surgical approach., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Kelblová, Vaníček, Gál, Rottenberg, Bulik, Cimflová and Křivka.)

Objective: Systemic sclerosis-associated interstitial lung disease (SSc-ILD) is the leading cause of death in patients with SSc with unclear pathogenesis and limited treatment options. Evidence strongly supports an important role for profibrotic secreted phosphoprotein 1 (SPP1)-expressing macrophages in SSc-ILD. This study was undertaken to define the transcriptome and chromatin structural changes of SPP1 SSc-ILD macrophages in order to better understand their role in promoting fibrosis and to identify transcription factors associated with open chromatin driving their altered phenotype., Methods: We performed single-cell RNA sequencing (scRNA-Seq) on 11 explanted SSc-ILD and healthy control lung samples, as well as single-cell assay for transposase-accessible chromatin sequencing on 5 lung samples to define altered chromatin accessibility of SPP1 macrophages. We predicted transcription factors regulating SPP1 macrophages using single-cell regulatory network inference and clustering (SCENIC) and determined transcription factor binding sites associated with global alterations in SPP1 chromatin accessibility using Signac/Seurat., Results: We identified distinct macrophage subpopulations using scRNA-Seq analysis in healthy and SSc-ILD lungs and assessed gene expression changes during the change of healthy control macrophages into SPP1 macrophages. Analysis of open chromatin validated SCENIC predictions, indicating that microphthalmia-associated transcription factor, transcription factor EB, activating transcription factor 6, sterol regulatory element binding transcription factor 1, basic helix-loop-helix family member E40, Kruppel-like factor 6, ETS variant transcription factor 5, and/or members of the activator protein 1 family of transcription factors regulate SPP1 macrophage differentiation., Conclusion: Our findings shed light on the underlying changes in chromatin structure and transcription factor regulation of profibrotic SPP1 macrophages in SSc-ILD. Similar alterations in SPP1 macrophages may underpin fibrosis in other organs involved in SSc and point to novel targets for the treatment of SSc-ILD, specifically targeting profibrotic macrophages., (© 2022 American College of Rheumatology.)

Accumulation of excessive extracellular matrix (ECM) components from lung fibroblasts is a feature of systemic sclerosis-associated interstitial lung disease (SSc-ILD), and there is increasing evidence that innate immune signaling pathways contribute to these processes. Toll-like receptors (TLRs) are innate immune sensors activated by danger signals derived from pathogens or host molecular patterns. Several damage-associated molecular pattern (DAMP) molecules are elevated in SSc-ILD plasma, including ligands that activate TLR9, an innate immune sensor recently implicated in driving profibrotic responses in fibroblasts. Fibronectin and the isoform fibronectin-extra domain A (FN-EDA) are prominent in pathological extracellular matrix accumulation, but mechanisms promoting FN-EDA accumulation are only partially understood. Here, we show that TLR9 activation increases FN-EDA accumulation in MRC5 and SSc-ILD fibroblasts, but that this effect is independent of changes in FN-EDA gene transcription. Rather, we describe a novel mechanism where TLR9 activation inhibits FN-EDA turnover via reduced FN-EDA ubiquitination. TLR9 ligand ODN2006 reduces ubiquitinated FN-EDA destined for lysosomal degradation, an effect abrogated with TLR9 knockdown or inhibition. Taken together, these results provide rationale for disrupting the TLR9 signaling axis or FN-EDA degradation pathways to reduce FN-EDA accumulation in SSc-ILD fibroblasts. More broadly, enhancing intracellular degradation of ECM components through TLR9 inhibition or enhanced ECM turnover could be a novel strategy to attenuate pathogenic ECM accumulation in SSc-ILD.

Skin and lung fibrosis in systemic sclerosis (SSc) is driven by myofibroblasts, alpha-smooth muscle actin expressing cells. The number of myofibroblasts in SSc skin correlates with the modified Rodnan skin score, the most widely used clinical measure of skin disease severity. Murine fibrosis models indicate that myofibroblasts can arise from a variety of different cell types, but their origin in SSc skin has remained uncertain. Utilizing single cell RNA-sequencing, we define different dermal fibroblast populations and transcriptome changes, comparing SSc to healthy dermal fibroblasts. Here, we show that SSc dermal myofibroblasts arise in two steps from an SFRP2 hi /DPP4-expressing progenitor fibroblast population. In the first step, SSc fibroblasts show globally upregulated expression of transcriptome markers, such as PRSS23 and THBS1. A subset of these cells shows markers indicating that they are proliferating. Only a fraction of SFRP2 hi SSc fibroblasts differentiate into myofibroblasts, as shown by expression of additional markers, SFRP4 and FNDC1. Bioinformatics analysis of the SSc fibroblast transcriptomes implicated upstream transcription factors, including FOSL2, RUNX1, STAT1, FOXP1, IRF7 and CREB3L1, as well as SMAD3, driving SSc myofibroblast differentiation., (© 2021. The Author(s).)

Introduction: Hippocampi sparing whole brain radiotherapy (WBRT) is an evolving approach in the treatment of patients with multiple brain metastases, pursuing mitigation of verbal memory decline as a consequence of hippocampal radiation injury. Accumulating data are showing different postradiotherapy changes in the left and right hippocampus with a theoretical proposal of only unilateral (dominant, left) hippocampal sparing during WBRT., Method: The aim of this retrospective study is to describe spatial distribution of brain metastases on MRI in a cohort of 260 patients (2595 metastases) and to evaluate distribution separately in the left and right hippocampus and in respective hippocampal avoiding zones (HAZ, region with subtherapeutic radiation dose), including evaluation of location of metastatic mass centre., Results: The median number of brain metastases was three, with lung cancer being the most common type of primary tumour; 36% had single metastasis. Almost 8% of patients had metastasis within hippocampus (1.1% of all metastases) and 18.1% of patients within HAZ (3.3% of all metastases). No statistically significant difference was observed in the laterality of hippocampal involvement, also when the location of centre of metastases was analyzed. There were more patients presenting the centre of metastasis within left (15) versus right (6) HAZ approaching the borderline of statistical significance., Conclusion: No significant difference in the laterality of BM seeding within hippocampal structures was observed. The hypothesized unilateral sparing WBRT would have theoretical advantage in about 50% reduction in the risk of subsequent recurrence within spared regions.

Background and Purpose: The aim of this prospective study is to evaluate post-whole brain radiotherapy (WBRT) changes in hippocampal concentration of N-acetylaspartate (h-tNAA) as a marker of neuronal loss and to correlate those changes to neurocognitive function., Material and Methods: Thirty-five patients with brain metastases underwent baseline single slice multi-voxel MR spectroscopy (MRS) examination for measurement of hippocampal h-tNAA together with baseline battery of neurocognitive tests focused on memory (Auditory Verbal Learning Test and Brief Visuospatial Memory Test - Revised) as well as quality of life questionnaires (EORTC QLQ-C30 a EORTC QLQ-BN20). Eighteen patients completed follow-up evaluation four months after standard WBRT (2 laterolateral fields, 10×3.0Gy, 6MV photons) and were included in this analysis. MRS and cognitive examinations were repeated and compared to baseline measurements., Results: Statistically significant decreases in h-tNAA were observed in the right (8.52-7.42mM; -12.9%, 95%CI: -7.6 to -16.4%) as well as in the left hippocampus (8.64-7.60mM; -12%, 95%CI: -7.9 to -16.2%). Statistically significant decline was observed in all AVLT and BVMT-R subtests with exception of AVLT_Recognition. Quality of life declined after WBRT (mean Δ -14.1±20.3 points in transformed 0-100 point scale; p=0.018) with no correlation to changes in hippocampal metabolite concentrations. Moderate positive correlation was observed between left h-tNAA concentration decrease and AVLT_TR decline (r=+0.32; p=0.24) as well as with AVLT_DR (r=+0.33; p=0.22) decline. Changes in right h-tNAA/Cr negatively correlated with AVLT_DR (r=-0.48; p=0.061). No correlation between right hippocampus h-tNAA and memory decline (AVLT) was observed., Conclusions: Our results suggest hippocampal NAA concentrations decline after WBRT and MRS may be a useful biomarker for monitoring neuronal loss after radiotherapy., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

The accurate identification of glioblastoma progression remains an unmet clinical need. The aim of this prospective single-institutional study is to determine and validate thresholds for the main metabolite concentrations obtained by MR spectroscopy (MRS) and the values of the apparent diffusion coefficient (ADC) to enable distinguishing tumor recurrence from pseudoprogression. Thirty-nine patients after the standard treatment of a glioblastoma underwent advanced imaging by MRS and ADC at the time of suspected recurrence - median time to progression was 6.7 months. The highest significant sensitivity and specificity to call the glioblastoma recurrence was observed for the total choline (tCho) to total N-acetylaspartate (tNAA) concentration ratio with the threshold ≥ 1.3 (sensitivity 100.0% and specificity 94.7%). The ADCmean value higher than 1313 × 10(- 6) mm(2)/s was associated with the pseudoprogression (sensitivity 98.3%, specificity 100.0%). The combination of MRS focused on the tCho/tNAA concentration ratio and the ADCmean value represents imaging methods applicable to early non-invasive differentiation between a glioblastoma recurrence and a pseudoprogression. However, the institutional definition and validation of thresholds for differential diagnostics is needed for the elimination of setup errors before implementation of these multimodal imaging techniques into clinical practice, as well as into clinical trials.

Background: The hippocampus is considered as the main radiosensitive brain structure responsible for postradiotherapy cognitive decline. We prospectively assessed correlation of memory change to hippocampal N-acetylaspartate (h-tNAA) concentration, a neuronal density and viability marker, by (1)H-MR spectroscopy focused on the hippocampus., Methods: Patients with brain metastases underwent whole brain radiotherapy (WBRT) to a dose of 30 Gy in ten fractions daily. Pre-radiotherapy (1)H-MR spectroscopy focused on the h-tNAA concentration and memory testing was performed. Memory was evaluated by Auditory Verbal Learning Test (AVLT) and Brief Visuospatial Memory Test-Revised (BVMT-R). Total recall, recognition and delayed recall were reported. The both investigation procedures were repeated 4 months after WBRT and the h-tNAA and memory changes were correlated., Results: Of the 20 patients, ten passed whole protocol. The h-tNAA concentration significantly decreased from pre-WBRT 8.9, 8.86 and 8.88 [mM] in the right, left and both hippocampi to 7.16, 7.65 and 7.4 after WBRT, respectively. In the memory tests a significant decrease was observed in AVLT total-recall, BVMT-R total-recall and BVMT-R delayed-recall. Weak to moderate correlations were observed between left h-tNAA and AVLT recognition and all BVMT-R subtests and between the right h-tNAA and AVLT total-recall., Conclusions: A significant decrease in h-tNAA after WBRT was proven by (1)H-MR spectroscopy as a feasible method for the in vivo investigation of radiation injury. Continuing patient recruitment focusing on other cognitive tests and metabolites is needed.

Objective: To prospectively determine institutional cut-off values of apparent diffusion coefficients (ADCs) and concentration of tissue metabolites measured by MR spectroscopy (MRS) for early differentiation between glioblastoma (GBM) relapse and treatment-related changes after standard treatment., Materials and Methods: Twenty-four GBM patients who received gross total resection and standard adjuvant therapy underwent MRI examination focusing on the enhancing region suspected of tumor recurrence. ADC maps, concentrations of N-acetylaspartate, choline, creatine, lipids, and lactate, and metabolite ratios were determined. Final diagnosis as determined by biopsy or follow-up imaging was correlated to the results of advanced MRI findings., Results: Eighteen (75%) and 6 (25%) patients developed tumor recurrence and pseudoprogression, respectively. Mean time to radiographic progression from the end of chemoradiotherapy was 5.8 ± 5.6 months. Significant differences in ADC and MRS data were observed between those with progression and pseudoprogression. Recurrence was characterized by N-acetylaspartate ≤ 1.5 mM, choline/N-acetylaspartate ≥ 1.4 (sensitivity 100%, specificity 91.7%), N-acetylaspartate/creatine ≤ 0.7, and ADC ≤ 1300 × 10(-6) mm(2)/s (sensitivity 100%, specificity 100%)., Conclusion: Institutional validation of cut-off values obtained from advanced MRI methods is warranted not only for diagnosis of GBM recurrence, but also as enrollment criteria in salvage clinical trials and for reporting of outcomes of initial treatment.

Background: Multiple myeloma pathogenesis, pathology, symptoms and imaging techniques used in clinical diagnostic algorithm, the indications and the differences between currently available imaging methods., Design: The article describes advantages and disadvantages of basic X-ray imaging and recommended skeleton screening, as the method of first choice, followed by description of the most frequently affected areas and Mirels score. The present golden standard magnetic resonance (MR) imaging, its potential and also recommended MR indications. Concerning computer tomography (CT) imaging, mainly comparison between CT and MR and X-ray imaging its indications and benefits as the interventional instrument are mentioned. The arcticle also focuses on the role of skeleton scintigraphy with Tc-pyrophosphate, which is not recommended today, and the role of positron emission tomography with fluorodeoxyglucose (FDG-PET) in the assessment of the therapy effectiveness and prognosis for patients, its future and present limitations. The next commonly used radioisotope imaging with 99Tc-sestamibi (MIBI) and its comparison to other methods, especially to the FDG-PET and recommended indications for both techniques. Last aim is description of specification of bone tissue density with Dual Energy X-ray Absorption scanning method (DEXA)., Conclusion: These imaging methods are commonly used as additional diagnostic tests in initial diagnostic -work-up and in follow-up due to frequent relapses of multiple myeloma.

The popularity of permanent brachytherapy is now growing dramatically. The development of several new technologies has led to an improvement in dose distribution and results and can also return the patients to normal daily activities. The role of permanent brachytherapy in the treatment of localized prostate carcinoma is described in the present article. Indications and contraindications and a comparison of the results with other modalities of treatment are discussed. Emphasis is also placed on the morbidity of the treatment and the quality of life, which plays a very important role in the process of making a decision as to which therapy should be applied. Permanent brachytherapy is most often used separately, but in certain cases may be combined with external radiotherapy and hormonal treatment.