The FKBP51s Splice Isoform Predicts Unfavorable Prognosis in Patients with Glioblastoma.

The primary treatment for glioblastoma (GBM) is removing the tumor mass as defined by MRI. However, MRI has limited diagnostic and predictive value. Tumor-associated macrophages (TAM) are abundant in GBM tumor microenvironment (TME) and are found in peripheral blood (PB). FKBP51 expression, with its canonical and spliced isoforms, is constitutive in immune cells and aberrant in GBM. Spliced FKBP51s supports M2 polarization. To find an immunologic signature that combined with MRI could advance in diagnosis, we immunophenotyped the macrophages of TME and PB from 37 patients with GBM using FKBP51s and classical M1-M2 markers. We also determined the tumor levels of FKBP51s, PD-L1, and HLA-DR. Tumors expressing FKBP51s showed an increase in various M2 phenotypes and regulatory T cells in PB, indicating immunosuppression. Tumors expressing FKBP51s also activated STAT3 and were associated with reduced survival. Correlative studies with MRI and tumor/macrophages cocultures allowed to interpret TAMs. Tumor volume correlated with M1 infiltration of TME. Cocultures with spheroids produced M1 polarization, suggesting that M1 macrophages may infiltrate alongside cancer stem cells. Cocultures of adherent cells developed the M2 phenotype CD163/FKBP51s expressing pSTAT6, a transcription factor enabling migration and invasion. In patients with recurrences, increased counts of CD163/FKBP51s monocyte/macrophages in PB correlated with callosal infiltration and were accompanied by a concomitant decrease in TME-infiltrating M1 macrophages. PB PD-L1/FKBP51s connoted necrotic tumors. In conclusion, FKBP51s identifies a GBM subtype that significantly impairs the immune system. Moreover, FKBP51s marks PB macrophages associated with MRI features of glioma malignancy that can aid in patient monitoring. SIGNIFICANCE: Our research suggests that by combining imaging with analysis of monocyte/macrophage subsets in patients with GBM, we can enhance our understanding of the disease and assist in its treatment. We discovered a similarity in the macrophage composition between the TME and PB, and through association with imaging, we could interpret macrophages. In addition, we identified a predictive biomarker that drew more attention to immune suppression of patients with GBM.

Head CT Scans in the Emergency Department during the COVID-19 Pandemic: Use or Overuse?

BACKGROUND: The COVID-19 pandemic seemed to mainly involve the respiratory system, but it was realized that it could affect any organ, including the CNS. The pandemic has followed a wave-like trend, with its peaks being due to the COVID-19 different variants and the introduction of the vaccine, which led to an apparent reduction in hospitalizations but also brought about perplexities related to its adverse effects. The aim of this study was to analyze the changes in the use of head CT/contrast CT and their impacts on the onset of cerebrovascular disease in our emergency department during the COVID-19 period and the vaccine rollout. METHODS: Patients ≥ 18 years old admitted to our emergency department from January 2018 to September 2021 were enrolled. The patients were divided into three groups. The COVID-19 period included patients who visited our emergency department from 1 March 2020 to 31 January 2021; the vaccine period was considered to range from 1 February 2021 to 30 September 2021. The patients who visited the emergency department from 1 January 2018 to 31 January 2020 were considered the controls. RESULTS: We found an increase in head CT/contrast CT requests during the COVID-19 period and increase in head contrast CT during the vaccine period, without an increase in the incidence of cerebrovascular disease. CONCLUSIONS: The uncertainty regarding the possible thrombotic events associated with COVID-19 and its vaccine increased the relative use of head CT/contrast CT by about 20% compared to the control period.

Nerve MR in the Differential Diagnosis of Neuropathies: A Case Series from a Single Center.

In the present study, through a case series, we highlighted the role of magnetic resonance (MR) in the identification and diagnosis of peripheral neuropathies. MR neurography allows the evaluation of the course of nerves through 2D and 3D STIR sequences with an isotropic voxel, whereas the relationship between nerves, vessels, osteo-ligamentous and muscular structures can be appraised with T1 sequences. Currently, DTI and tractography are mainly used for experimental purposes. MR neurography can be useful in detecting subtle nerve alterations, even before the onset of symptoms. However, despite being sensitive, MR neurography is not specific in detecting nerve injury and requires careful interpretation. For this reason, MR information should always be supported by instrumental clinical tests.

Advanced Magnetic Resonance Imaging in the Evaluation of Treated Glioblastoma: A Pictorial Essay.

MRI plays a key role in the evaluation of post-treatment changes, both in the immediate post-operative period and during follow-up. There are many different treatment's lines and many different neuroradiological findings according to the treatment chosen and the clinical timepoint at which MRI is performed. Structural MRI is often insufficient to correctly interpret and define treatment-related changes. For that, advanced MRI modalities, including perfusion and permeability imaging, diffusion tensor imaging, and magnetic resonance spectroscopy, are increasingly utilized in clinical practice to characterize treatment effects more comprehensively. This article aims to provide an overview of the role of advanced MRI modalities in the evaluation of treated glioblastomas. For a didactic purpose, we choose to divide the treatment history in three main timepoints: post-surgery, during Stupp (first-line treatment) and at recurrence (second-line treatment). For each, a brief introduction, a temporal subdivision (when useful) or a specific drug-related paragraph were provided. Finally, the current trends and application of radiomics and artificial intelligence (AI) in the evaluation of treated GB have been outlined.

Scaffold proteins of cancer signaling networks: The paradigm of FK506 binding protein 51 (FKBP51) supporting tumor intrinsic properties and immune escape.

Scaffold proteins are crucial regulators of signaling networks, and their abnormal expression may favor the development of tumors. Among the scaffold proteins, immunophilin covers a unique role as 'protein-philin' (Greek 'philin' = friend) that interacts with proteins to guide their proper assembly. The growing list of human syndromes associated with the immunophilin defect underscores the biological relevance of these proteins that are largely opportunistically exploited by cancer cells to support and enable the tumor's intrinsic properties. Among the members of the immunophilin family, the FKBP5 gene was the only one identified to have a splicing variant. Cancer cells impose unique demands on the splicing machinery, thus acquiring a particular susceptibility to splicing inhibitors. This review article aims to overview the current knowledge of the FKBP5 gene functions in human cancer, illustrating how cancer cells exploit the scaffolding function of canonical FKBP51 to foster signaling networks that support their intrinsic tumor properties and the spliced FKBP51s to gain the capacity to evade the immune system.

Magnetic resonance imaging-derived parameters to predict response to regorafenib in recurrent glioblastoma.

PURPOSE: Regorafenib is a multikinase inhibitor, approved as a preferred regimen for recurrent glioblastoma (rGB). Although its effects on prolonging survival could seem modest, it is still unclear whether a subset of patients, potentially identifiable by imaging biomarkers, might experience a more substantial positive effect. Our aim was to evaluate the potential value of magnetic resonance imaging-derived parameters as non-invasive biomarkers to predict response to regorafenib in patients with rGB. METHODS: 20 patients with rGB underwent conventional and advanced MRI at diagnosis (before surgery), at recurrence and at first follow-up (3 months) during regorafenib. Maximum relative cerebral blood volume (rCBVmax) value, intra-tumoral susceptibility signals (ITSS), apparent diffusion coefficient (ADC) values, and contrast-enhancing tumor volumes were tested for correlation with response to treatment, progression-free survival (PFS), and overall survival (OS). Response at first follow-up was assessed according to Response Assessment in Neuro-Oncology (RANO) criteria. RESULTS: 8/20 patients showed stable disease at first follow-up. rCBVmax values of the primary glioblastoma (before surgery) significantly correlated to treatment response; specifically, patients with stable disease displayed higher rCBVmax compared to progressive disease (p = 0.04, 2-group t test). Moreover, patients with stable disease showed longer PFS (p = 0.02, 2-group t test) and OS (p = 0.04, 2-group t test). ITSS, ADC values, and contrast-enhancing tumor volumes showed no correlation with treatment response, PFS nor OS. CONCLUSION: Our results suggest that rCBVmax of the glioblastoma at diagnosis could serve as a non-invasive biomarker of treatment response to regorafenib in patients with rGB.

Magnetic Resonance Imaging of Primary Adult Brain Tumors: State of the Art and Future Perspectives.

MRI is undoubtedly the cornerstone of brain tumor imaging, playing a key role in all phases of patient management, starting from diagnosis, through therapy planning, to treatment response and/or recurrence assessment. Currently, neuroimaging can describe morphologic and non-morphologic (functional, hemodynamic, metabolic, cellular, microstructural, and sometimes even genetic) characteristics of brain tumors, greatly contributing to diagnosis and follow-up. Knowing the technical aspects, strength and limits of each MR technique is crucial to correctly interpret MR brain studies and to address clinicians to the best treatment strategy. This article aimed to provide an overview of neuroimaging in the assessment of adult primary brain tumors. We started from the basilar role of conventional/morphological MR sequences, then analyzed, one by one, the non-morphological techniques, and finally highlighted future perspectives, such as radiomics and artificial intelligence.

Orthopaedic surgeons can play important role in identifying victims of domestic violence in the emergency department - narrative review of Brazilian literature.

Over the last year, with the social isolation imposed by the coronavirus disease pandemic, there has been a significant increase in complaints associated with physical violence against women. In the present study, an exploratory literature review was carried out on the role of the on-call orthopedic surgeon when faced with a suspicion of domestic violence, in accordance with Brazilian legislation. The main objective of the study was to show the role of this specialist in identifying victims of domestic violence by recognizing their profiles and associated risk factors. The secondary objectives were to demonstrate the most common skeletal and non-skeletal injuries in this type of violence and to present a quick and practical guide on how to identify, approach, and manage cases of domestic violence against women. The findings revealed that the main aggressors were close partners, such as spouses and ex-spouses. Young adult women, black or multiracial, and low socioeconomic status are major risk factors for intimate partner violence. Head and neck injuries are the most frequently observed lesions in this population, with more than one-third of victims reporting falls. Musculoskeletal injuries are present in up to 42% of victims of domestic violence, occurring predominantly in the upper limbs and chest, and are the leading cause of death in women aged 1 to 34 years. A practical guide for orthopedic surgeons who work in emergency departments is proposed, with basic information about their role and responsibility in identifying potential victims of intimate partner violence.

Choice of imaging to evaluate carotid stenosis and guide management.

Carotid artery disease is a cause of ischemic stroke and is associated with cognitive decline. Besides the evaluation of the degree of stenosis, it is also crucial to assess the morphology of the atherosclerotic plaque, for a prompt and accurate diagnosis, and to make the best decision for the patient. On top of noninvasive duplex ultrasound (DUS) and invasive digital subtraction angiography (DSA), compute tomography angiography (CTA) and magnetic resonance angiography (MRA) are often used effectively as noninvasive imaging tools to study carotid stenoses. This review describes the fundamental characteristics of carotid artery plaques, and how they can be best evaluated with currently available imaging methods.

Neuro-Oncology Multidisciplinary Tumor Board: The Point of View of the Neuroradiologist.

BACKGROUND: The multi-disciplinary tumor board (MTB) is essential to quality cancer care and currently recommended to offer the best personalized clinical approach, but little has been published regarding MTBs in neuro-oncology (nMTBs). The aim of the present paper is to describe our nMTB, to evaluate its impact on clinical management decisions, and to assess the role of neuroradiologists. METHODS: The retrospective evaluation of the cases discussed at our nMTB from March 2017 to March 2020. From the electronic records, we extracted epidemiological, clinical and other specific data of nMTB. From the radiological records, we calculated data relating to the number, time for revision, and other specifications of MRI re-evaluation. Statistical analysis was performed. RESULTS: a total of 447 discussions were analyzed, representing 342 patients. The requests for case evaluations came from radiation oncologists (58.8%) and neurosurgeons (40.5%), and were mainly addressed to the neuroradiologist (73.8%). The most frequent questions were about the treatment's changes (64.4%). The change in patient treatment was reported in 40.5% of cases, 76.8% of these were based on the neuroradiologic assessment. A total of 1514 MRI examinations were re-evaluated, employing approximately 67 h overall. The median of the MRI exams reviewed per patient was 3 (min-max 1-12). CONCLUSIONS: Our study supported that the multidisciplinary approach to patient care can be particularly effective in managing brain tumors. A review by an expert neuroradiologist impacts patient management in the context of nMTBs, but has costs in terms of the time and effort spent preparing for it.

Reassessing the Role of Brain Tumor Biopsy in the Era of Advanced Surgical, Molecular, and Imaging Techniques-A Single-Center Experience with Long-Term Follow-Up.

Brain biopsy is the gold standard in order to establish the diagnosis of unresectable brain tumors. Few studies have investigated the long-term outcomes of biopsy patients. The aim of this single-institution-based study was to assess the concordance between radiological and histopathological diagnoses, and the long-term patient outcome. Ninety-three patients who underwent brain biopsy in the last 5 years were analyzed. We included patients treated with stereotactically guided needle, open, and neuroendoscopic biopsies. Most patients (86%) received needle biopsy. Gliomas and primary brain lymphomas comprised 88.2% of cases. The diagnostic yield was 95.7%. Serious complication and death rates were 3.2% and 2.1%, respectively. The concordance rate between radiological and histological diagnoses was 93%. Notably, the positive predictive value of radiological diagnosis of lymphoma was 100%. Biopsy allowed specific treatment in 72% of cases. Disease-related neurological worsening was the main reason that precluded adjuvant treatment. Adjuvant treatment, in turn, was the strongest prognostic factor, since the median overall survival was 11 months with vs. 2 months without treatment (p = 0.0002). Finally, advanced molecular evaluations can be obtained on glioma biopsy specimens to provide integrated diagnoses and individually tailored treatments. We conclude that, despite the huge advances in imaging techniques, biopsy is required when an adjuvant treatment is recommended, particularly in gliomas.

PD-L1 Expression Fluctuates Concurrently with Cyclin D in Glioblastoma Cells.

Despite Glioblastoma (GBM) frequently expressing programmed cell death ligand-1 (PD-L1), treatment with anti-programmed cell death-1 (PD1) has not yielded brilliant results. Intratumor variability of PD-L1 can impact determination accuracy. A previous study on mouse embryonic fibroblasts (MEFs) reported a role for cyclin-D in control of PD-L1 expression. Because tumor-cell growth within a cancer is highly heterogeneous, we looked at whether PD-L1 and its cochaperone FKBP51s were influenced by cell proliferation, using U251 and SF767 GBM-cell-lines. PD-L1 was measured by Western blot, flow cytometry, confocal-microscopy, quantitative PCR (qPCR), CCND1 by qPCR, FKBP51s by Western blot and confocal-microscopy. Chromatin-Immunoprecipitation assay (xChIp) served to assess the DNA-binding of FKBP51 isoforms. In the course of cell culture, PD-L1 appeared to increase concomitantly to cyclin-D on G1/S transition, to decrease during exponential cell growth progressively. We calculated a correlation between CCND1 and PD-L1 gene expression levels. In the temporal window of PD-L1 and CCND1 peak, FKBP51s localized in ER. When cyclin-D declined, FKBP51s went nuclear. XChIp showed that FKBP51s binds CCND1 gene in a closed-chromatin configuration. Our finding suggests that the dynamism of PD-L1 expression in GBM follows cyclin-D fluctuation and raises the hypothesis that FKBP51s might participate in the events that govern cyclin-D oscillation.

Combining Magnetic Resonance Imaging with Systemic Monocyte Evaluation for the Implementation of GBM Management.

Magnetic resonance imaging (MRI) is the gold standard for glioblastoma (GBM) patient evaluation. Additional non-invasive diagnostic modalities are needed. GBM is heavily infiltrated with tumor-associated macrophages (TAMs) that can be found in peripheral blood. FKBP51s supports alternative-macrophage polarization. Herein, we assessed FKBP51s expression in circulating monocytes from 14 GBM patients. The M2 monocyte phenotype was investigated by qPCR and flow cytometry using antibodies against PD-L1, CD163, FKBP51s, and CD14. MRI assessed morphologic features of the tumors that were aligned to flow cytometry data. PD-L1 expression on circulating monocytes correlated with MRI tumor necrosis score. A wider expansion in circulating CD163/monocytes was measured. These monocytes resulted in a dramatic decrease in patients with an MRI diagnosis of complete but not partial surgical removal of the tumor. Importantly, in patients with residual tumor, most of the peripheral monocytes that in the preoperative stage were CD163/FKBP51s- had turned into CD163/FKBP51s+. After Stupp therapy, CD163/FKBP51s+ monocytes were almost absent in a case of pseudoprogression, while two patients with stable or true disease progression showed sustained levels in such circulating monocytes. Our work provides preliminary but meaningful and novel results that deserve to be confirmed in a larger patient cohort, in support of potential usefulness in GBM monitoring of CD163/FKBP51s/CD14 immunophenotype in adjunct to MRI.

Regorafenib in Glioblastoma Recurrence: How to Deal With MR Imaging Treatments Changes.

The treatment of recurrent high-grade gliomas remains a major challenge of daily neuro-oncology practice, and imaging findings of new therapies may be challenging. Regorafenib is a multi-kinase inhibitor that has recently been introduced into clinical practice to treat recurrent glioblastoma, bringing with it a novel panel of MRI imaging findings. On the basis of the few data in the literature and on our personal experience, we have identified the main MRI changes during regorafenib therapy, and then, we defined two different patterns, trying to create a simple summary line of the main changes of pathological tissue during therapy. We named these patterns, respectively, pattern A (less frequent, similar to classical progression disease) and pattern B (more frequent, with decreased diffusivity and decrease contrast-enhancement). We have also reported MR changes concerning signal intensity on T1-weighted and T2-weighted images, SWI, and perfusion imaging, derived from the literature (small series or case reports) and from our clinical experience. The clinical implication of these imaging modifications remains to be defined, taking into account that we are still at the dawn in the evaluation of such imaging modifications.

ColorViz, a New and Rapid Tool for Assessing Collateral Circulation during Stroke.

Prognosis of patients with acute ischemic stroke is strictly related to the patency and prominence of the collateral leptomeningeal pathways distal to the arterial occlusion. The gold standard for assessment of collateral circulation is conventional angiography, but it is invasive and used in selected cases. To date, the most reliable technique is multiphase CTA; currently, the available classifications of collateral circles are often complex, time-consuming, and require a trained observer. The purpose of our work is to establish the effectiveness of a new semi-automatic post-processing software (ColorViz FastStroke, GE Healthcare, Milwaukee, Wisconsin) in evaluation of collateral circulation compared to the six-point classifications of multiphase CTA already validated in literature. We selected 86 patients with anterior ischemic stroke symptoms who underwent multiphasic CTA in our emergency department. Two radiologists separately evaluated the collateral leptomeningeal vessels, analyzing respectively, the multiphase CTA (using the six-point scale and its trichotomized form) and ColorViz (using a three-point scale). Then the results were matched. We found a good correlation between the two different analyses; the main advantage of ColorViz is that, while maintaining fast diagnostic times, it allows a simpler and more immediate evaluation of collateral circulation, especially for less experienced radiologists.

5-Aminolevulinic Acid and Contrast-Enhanced Ultrasound: The Combination of the Two Techniques to Optimize the Extent of Resection in Glioblastoma Surgery.

BACKGROUND: The survival benefit in maximizing resection in glioblastomas (GBMs) has been demonstrated by numerous studies. The true limit of infiltration of GBMs has been an overwhelming obstacle, and several technological advances have been introduced to improve the identification of residual tumors. OBJECTIVE: To evaluate whether the integration of 5-aminolevulinic acid (5-ALA) with microbubble contrast-enhanced ultrasound (CEUS) improves residual tumor identification and has an impact on the extent of resection (EOR), overall survival (OS), and progression-free survival (PFS). METHODS: A total of 230 GBM procedures were retrospectively studied. Cases were stratified according to the surgical procedure into 4 groups: 5-ALA- and CEUS-guided surgeries, 5-ALA-guided surgeries, CEUS-guided surgeries, and conventional microsurgical procedures. RESULTS: Patients undergoing conventional microsurgical procedures showed the worst EORs compared to the assisted techniques (5-ALA and CEUS procedures). Both 5-ALA and CEUS techniques improved the EOR compared to conventional microsurgical procedures. However, their combination gave the best results in terms of the EOR (P = .0003). The median EOR% and the number of supramarginal resections are hence superior in the 5-ALA + CEUS + group compared to the others; this observation had consequences on PFS and OS in our series. CONCLUSION: In terms of the EOR, the best results can be achieved through a combination of both techniques, where the 5-ALA-guided procedure is followed by a final survey with CEUS. Compared with other intraoperative imaging techniques, CEUS is a real-time, readily repeatable, safe, and inexpensive technique that provides valuable information to the surgeon before, during, and after resection.