Supramaximal resection: retrospective study on IDH-wildtype Glioblastomas based on the new RANO-Resect classification.

BACKGROUND: The prognostic value of the extent of resection in the management of Glioblastoma is a long-debated topic, recently widened by the 2022 RANO-Resect Classification, which advocates for the resection of the non-enhancing disease surrounding the main core of tumors (supramaximal resection, SUPR) to achieve additional survival benefits. We conducted a retrospective analysis to corroborate the role of SUPR by the RANO-Resect Classification in a single center, homogenous cohort of patients. METHODS: Records of patients operated for WHO-2021 Glioblastomas at our institution between 2007 and 2018 were retrospectively reviewed; volumetric data of resected lesions were computed and classified by RANO-Resect criteria. Survival and correlation analyses were conducted excluding patients below near-total resection. RESULTS: 117 patients met the inclusion criteria, encompassing 45 near-total resections (NTR), 31 complete resections (CR), and 41 SUPR. Median progression-free and overall survival were 11 and 15 months for NTR, 13 and 17 months or CR, 20 and 24 months for SUPR, respectively (p < 0.001), with inverse correlation observed between survival and FLAIR residual volume (r -0.28). SUPR was not significantly associated with larger preoperative volumes or higher rates of postoperative deficits, although it was less associated with preoperative neurological deficits (OR 3.37, p = 0.003). The impact of SUPR on OS varied between MGMT unmethylated (HR 0.606, p = 0.044) and methylated (HR 0.273, p = 0.002) patient groups. CONCLUSIONS: Results of the present study support the validity of supramaximal resection by the new RANO-Resect classification, also highlighting a possible surgical difference between tumors with methylated and unmethylated MGMT promoter.

Generative Adversarial Networks in Brain Imaging: A Narrative Review.

Artificial intelligence (AI) is expected to have a major effect on radiology as it demonstrated remarkable progress in many clinical tasks, mostly regarding the detection, segmentation, classification, monitoring, and prediction of diseases. Generative Adversarial Networks have been proposed as one of the most exciting applications of deep learning in radiology. GANs are a new approach to deep learning that leverages adversarial learning to tackle a wide array of computer vision challenges. Brain radiology was one of the first fields where GANs found their application. In neuroradiology, indeed, GANs open unexplored scenarios, allowing new processes such as image-to-image and cross-modality synthesis, image reconstruction, image segmentation, image synthesis, data augmentation, disease progression models, and brain decoding. In this narrative review, we will provide an introduction to GANs in brain imaging, discussing the clinical potential of GANs, future clinical applications, as well as pitfalls that radiologists should be aware of.

Precision Oncology in Lower-Grade Gliomas: Promises and Pitfalls of Therapeutic Strategies Targeting IDH-Mutations.

Mutations in isocitrate dehydrogenase (IDH)1 and its homolog IDH2 are considered an earliest "driver" genetic event during gliomagenesis, representing now the molecular hallmark of lower-grade gliomas (LGGs). IDH-mutated genes encode for a neomorphic enzyme that converts α-ketoglutarate to the oncometabolite D-2-hydroxyglutarate (2-HG), which accumulates to high concentrations and alters cellular epigenetics and metabolism. Targeting IDH mutations is the first attempt to apply "precision oncology" in LGGs. Two distinct strategies have been proposed so far and are under intense clinical investigation: (i) reducing the amount of intratumoral 2-HG by directly blocking the function of mutant IDH enzyme; (ii) exploiting the selective epigenetic and metabolic cellular vulnerabilities as a consequence of 2-HG accumulation. The present review describes the physiopathological mechanisms by which IDH mutations lead to tumorigenesis, discussing their prognostic significance and pivotal role in the gliomas diagnostic classification system. We critically review preclinical evidence and available clinical data of first-generation mutant-selective IDH inhibitors and novel IDH-targeted vaccines. Finally, as an alternative and attractive approach, we present the rationale to take advantage of selective 2-HG related epigenetic and metabolic weaknesses. The results of ongoing clinical trials will help us clarify the complex scenario of IDH-targeted therapeutic approaches in gliomas.

Re-irradiation for recurrent high grade glioma (HGG) patients: Results of a single arm prospective phase 2 study.

BACKGROUND AND PURPOSE: Standard of care for recurrent high grade glioma (HGG) is missing. Several treatment options have been investigated including re-irradiation (re-RT). Results are promising but provided by retrospective studies. We designed a single arm prospective phase II study aiming to evaluate efficacy, and toxicity of re-irradiation. MATERIALS AND METHODS: Adults patients with good performance status, HGG diagnosis reclassified according to the new 2021 fifth edition WHO CNS classification, an interval time (IT) from previous RT ≥ 6 months were included. Outcome was evaluated by MRI imaging at 1 month, and every 3 months thereafter. Toxicities were evaluated in terms of radionecrosis occurrence, and neurocognitive status. RESULTS: Ninety recurrent HGG patients were treated, 11 oligodendroglioma grade 3, 18 astrocytoma grade 3 and 4, and 61 glioblastoma grade 4. The median age was 54 years, and majority had KPS 90-100. The median IT between first-RT and re-RT was 24 months. Re-surgery has been performed in 56.6%, and chemotherapy in 53.3%. The median follow up time was 64 months; median overall survival (OS) time,1,2,3-year OS rates were 17 months (95%CI 14-19), 66.7%±4.9, 32.6%±5.0, and 22.2 ± 4.7. Prognostic factors impacting on survival were age (p = 0.0154), IT between first RT and re-RT (p = 0.0051), glioma grade (p = 0.0090), and IDH status (p = 0.0001). Radionecrosis grade 2-3 occurred in 9 (10%) patients; neurocognitive functions remained stable until disease progression. CONCLUSION: Re-RT proved to be a safe and feasible treatment option with low toxicity. Younger patients with grade 3 IDH mutated gliomas, and a longer IT had the better outcome. TRIAL REGISTRATION NUMBER: NCT02567539.

Virtual Biopsy for Diagnosis of Chemotherapy-Associated Liver Injuries and Steatohepatitis: A Combined Radiomic and Clinical Model in Patients with Colorectal Liver Metastases.

Non-invasive diagnosis of chemotherapy-associated liver injuries (CALI) is still an unmet need. The present study aims to elucidate the contribution of radiomics to the diagnosis of sinusoidal dilatation (SinDil), nodular regenerative hyperplasia (NRH), and non-alcoholic steatohepatitis (NASH). Patients undergoing hepatectomy for colorectal metastases after chemotherapy (January 2018-February 2020) were retrospectively analyzed. Radiomic features were extracted from a standardized volume of non-tumoral liver parenchyma outlined in the portal phase of preoperative post-chemotherapy computed tomography. Seventy-eight patients were analyzed: 25 had grade 2-3 SinDil, 27 NRH, and 14 NASH. Three radiomic fingerprints independently predicted SinDil: GLRLM_f3 (OR = 12.25), NGLDM_f1 (OR = 7.77), and GLZLM_f2 (OR = 0.53). Combining clinical, laboratory, and radiomic data, the predictive model had accuracy = 82%, sensitivity = 64%, and specificity = 91% (AUC = 0.87 vs. AUC = 0.77 of the model without radiomics). Three radiomic parameters predicted NRH: conventional_HUQ2 (OR = 0.76), GLZLM_f2 (OR = 0.05), and GLZLM_f3 (OR = 7.97). The combined clinical/laboratory/radiomic model had accuracy = 85%, sensitivity = 81%, and specificity = 86% (AUC = 0.91 vs. AUC = 0.85 without radiomics). NASH was predicted by conventional_HUQ2 (OR = 0.79) with accuracy = 91%, sensitivity = 86%, and specificity = 92% (AUC = 0.93 vs. AUC = 0.83 without radiomics). In the validation set, accuracy was 72%, 71%, and 91% for SinDil, NRH, and NASH. Radiomic analysis of liver parenchyma may provide a signature that, in combination with clinical and laboratory data, improves the diagnosis of CALI.

Sudden neck swelling with rash as late manifestation of COVID-19: a case report.

BACKGROUND: Although there are reports of otolaryngological symptoms and manifestations of CoronaVirus Disease 19 (COVID-19), there have been no documented cases of sudden neck swelling with rash in patients with Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection described in literature. CASE PRESENTATION: We report a case of a sudden neck swelling and rash likely due to late SARS-CoV-2 in a 64-year-old woman. The patient reported COVID-19 symptoms over the previous three weeks. Computed Tomography (CT) revealed a diffuse soft-tissue swelling and edema of subcutaneous tissue, hypodermis, and muscular and deep fascial planes. All the differential diagnoses were ruled out. Both the anamnestic history of the patient's husband who had died of COVID-19 with and the collateral findings of pneumonia and esophageal wall edema suggested the association with COVID-19. This was confirmed by nasopharyngeal swab polymerase chain reaction. The patient was treated with lopinavir/ritonavir, hydroxychloroquine and piperacillin/tazobactam for 7 days. The neck swelling resolved in less than 24 h, while the erythema was still present up to two days later. The patient was discharged after seven days in good clinical condition and with a negative swab. CONCLUSION: Sudden neck swelling with rash may be a coincidental presentation, but, in the pandemic context, it is most likely a direct or indirect complication of COVID-19.

Stroke management during the COVID-19 outbreak: challenges and results of a hub-center in Lombardy, Italy.

PURPOSE: We describe the reorganization carried out during the COVID-19 outbreak at one of the stroke centers in Italy and report on the clinical features and procedural variables of stroke patients in need of endovascular treatment. METHODS: From 1 March to 10 May 2020, we retrospectively analyzed data from stroke patients in need of urgent neurointerventional treatment. Clinical presentation, demographics, and clinical history were collected along with procedural variables (door-to-needle time, needle-to-mTiCi time). Each patient underwent a nasal swab (polymerase chain reaction test), clinical screening, and chest CT scan to assess the risk of SARS-CoV-2 infection. Technical success, procedural safety (including staff SARS-CoV-2 infection), and clinical outcome at discharge were retrieved. A comparison was made with the same patient population treated between 1 March and 10 May 2019 to highlight possible differences in the characteristics or outcomes of the patients. RESULTS: One hundred thirty-six ischemic stroke patients were admitted to our facility from 1 March to 10 May 2020. Of these, 12 patients (9%) were classified as "high risk" for SARS-CoV-2 infection. Radiological suspicion of COVID-19 was confirmed in all cases by pharyngeal swab. Five SARS-CoV-2 patients (42%) needed endovascular therapy. None of the staff members tested positive for IgG against SARS-CoV-2. Compared to the same period in 2019, an increase in the mean interval from the first symptoms to hospital arrival was observed (p < 0.05). CONCLUSION: Endovascular treatment of stroke presented several challenges during the COVID-19 outbreak. Within the hospital, special pathways can be used to maintain both procedural safety and procedural times.

Event-free survival in Desmoid-Type fibromatosis (DTF): A pre-post comparison of upfront surgery versus wait-and-see approach.

BACKGROUND: Desmoid-Type Fibromatosis (DTF) is a rare mesenchymal neoplasm with a locally invasive pattern and high risk of local recurrence after surgery. Historically, the standard treatment for DTF was surgical resection. However, considering the difficulty of achieving surgical eradication, the possible unnecessary morbidity and the unpredictability of the natural history, a wait-and-see approach has been proposed for asymptomatic DTF. METHODS: We analyzed 87 consecutive patients with histologically-proven sporadic primary DTF, first recurrence or residual disease managed at our institution between 2000 and 2018. Patients and tumor-related variables were reviewed and analyzed. Two different treatment strategies were adopted according to different time periods: in the "early period" (2000-2010) patients underwent surgical treatment irrespective of the clinical presentation, whereas in the "late period" (2012-2018) asymptomatic patients used to undergo a wait-and-see strategy. The event-free survival (EFS) was compared trough a pre-post comparison. RESULTS: In the early period, surgery was performed in 51 (94.4%) patients and watchful waiting in 3 (5.6%). In the late period, the watchful waiting group accounted for 24 (72.7%) patients and the surgical group for 9 (27.3%). No statistically independent prognostic factors were found. EFS did not show statistically significant differences between early and late period groups. CONCLUSION: Wait-and-see policy has shown to be equivalent to upfront surgery in terms of EFS; therefore, a conservative approach is recommended in asymptomatic patients diagnosed with DTF that can be followed through watchful waiting.

US-guided percutaneous irrigation of calcific tendinopathy of the rotator cuff in patients with or without previous external shockwave therapy.

OBJECTIVES: To compare the outcome of US-guided percutaneous irrigation of calcific tendinopathy (US-PICT) of the rotator cuff in patients with or without previous external shockwave therapy (ESWT). METHODS: We analyzed all patients treated with US-PICT from March 1, 2016, to October 1, 2019, with shoulder pain refractory to conservative management for rotator cuff calcific tendinopathy, diagnosed with ultrasound. Each patient was examined using the Constant-Murley Score (CMS) questionnaire (score 0-100) before and after treatment. We tested CMS differences using the Mann-Whitney U (Wilcoxon rank-sum) test in the two groups. US-PICT was performed placing two or multiple 14G needles, according to the calcification size, inserted under US guidance to create a circuit of irrigation in the calcified tendon. NaCl solution at 38 °C was then injected from the entry needle in a variable amount to hydrate and fragment the calcification, finally allowing for its expulsion through the exit needle. All patients also received an intrabursal steroid injection. RESULTS: From 2016 to 2019, 72 US-PICT treatments were performed on 70 patients (females = 46; males = 26) with a mean age of 49.7 years (SD = 8.7. Thirty-three (47%) underwent previous ESWT, while thirty-seven (53%) had no previous treatments. No treatment-related complications were observed. Follow-up was averagely 14.4 months (median = 11.6, SD = 11.9, range 1-45); 37 patients had a follow-up shorter than 12 months (1-11.6); 35 patients were visited after more than 1 year (12.2-45.6, Table W). Before treatment, the mean CMS was 35 (SD = 21); after treatment, it reached 75.4, with an average CMS improvement of 40.3 points (SD = 23.7, p < 0.001). The comparison of improvement between the ESWT and non-ESWT group yielded no significant difference (p = 0.3). CONCLUSIONS: US-PICT of the rotator cuff is an effective procedure to reduce shoulder pain and increase mobility in patients with calcific tendinopathy, both in short- and long-term time intervals. Previous unsuccessful ESWT does not affect the outcome of US-PICT.

Treatment of patients with glioma during the COVID-19 pandemic: what we learned and what we take home for the future.

OBJECTIVE: Coronavirus disease 2019 (COVID-19) has changed the way in which cancer is treated. Patients with high-grade glioma (HGG) are believed to be in a vulnerable category. The aim of this study was to describe the experience of a hub cancer center and the measures that were put in place for treatment of patients with newly diagnosed and recurrent glioma. METHODS: To prevent in-hospital contagion and preserve the safety of health professionals and patients, specific protocols and strict regulations were introduced. Physical distancing, use of surgical masks, and diligent hand hygiene were adopted. Each case was discussed in a multidisciplinary board meeting before treatment. All patient candidates for surgical procedures were tested for SARS-CoV-2 with a nasopharyngeal swab and a chest CT scan. Indications for surgery were the radiological suspicion of HGG in patients with a good performance status and/or the rapid and progressive occurrence of neurological deficits. Adjuvant treatments were performed only in cases of HGG. This therapy consisted of conventional fractional radiotherapy (RT; 60 Gy/30 fractions) with concomitant and adjuvant temozolomide chemotherapy (TMZCHT) in younger patients; in elderly patients, a short course of RT was employed (40.5 Gy/15 fractions). For recurrent HGG, treatments were assessed after a careful evaluation of the patient's general condition, neurological status, and risk of early impairment in neurological status if not treated. During simulation CT for the RT plan, each patient underwent a chest CT study. In cases in which an imaging study was suspicious for COVID-19 pneumonia, the patient was immediately isolated and rapidly underwent nasopharyngeal swab testing. RESULTS: Between March 1 and April 30, 2020, 23 HGGs were treated, and these cases are included in the present evaluation. Fifteen patients harboring newly diagnosed glioblastoma (GBM) underwent resection followed by a regimen of chemotherapy and RT, and 3 patients with newly diagnosed anaplastic oligodendroglioma underwent surgery followed by adjuvant RT. Five patients were treated for recurrent GBM, and they received surgery plus adjuvant RT. One patient in whom the simulation CT study was suspicious for COVID pneumonia was tested with a nasopharyngeal swab, which proved positive for SARS-CoV-2 infection. No patients contracted COVID-19 during hospitalization for surgery or during RT treatment. Corticosteroid therapy was administered to all patients beginning on the 1st day of RT. CONCLUSIONS: The authors' experience during the COVID-19 pandemic showed that patients with HGG can be treated in the most effective manner without a compromise in safety. Careful selection criteria and a multidisciplinary evaluation are pivotal to assessing the optimal therapeutic strategy.

Correction: Sarcopenia as a predictor of survival in patients undergoing bland transarterial embolization for unresectable hepatocellular carcinoma.

[This corrects the article DOI: 10.1371/journal.pone.0232371.].

Is IDH status the only factor predicting prognosis in newly diagnosed anaplastic glioma patients? Outcome evaluation and prognostic factor analysis in a single-institution large series.

OBJECTIVE: Anaplastic gliomas (AGs) are an extremely heterogeneous group of primary brain tumors. More recently, new discoveries have indicated that isocitrate dehydrogenase (IDH) mutation status is the most important parameter predicting survival. The primary aim of the present analysis was to identify prognostic factors, other than IDH status, that eventually impact survival. METHODS: Patients with available clinical, imaging, and molecular profile data who were amenable to resection were evaluated. The extent of resection (EOR) was defined as gross-total resection (GTR), near-total resection (NTR), subtotal resection (STR), or partial resection (PR). Residual tumor volume (RTV) was quantified. Following surgery, patients received adjuvant chemotherapy alone, radiation therapy plus concomitant and adjuvant temozolomide (TMZ), or sequential radio-chemotherapy. Clinical outcome was evaluated by neurological examination and MRI 1 month after treatment and every 4 months thereafter. Tumor progression was defined according to the Response Assessment in Neuro-Oncology (RANO) working group. RESULTS: Among 402 patients referred to the authors' institution for AG, 142 were included in the present analysis. Eighty-eight (62%) were male and 54 (38%) were female, with a median age of 43 years (range 19-70 years). At admission, most patients had a Karnofsky Performance Scale score of 90-100 (84.5%) and were symptomatic (93.7%). Forty-eight (33.8%) patients had newly diagnosed anaplastic oligodendrogliomas (AOs), and 94 (66.2%) had anaplastic astrocytomas (AAs). Most of them had mutant IDH tumors (67.6%) and methylated O 6-methylguanine-DNA-methyltransferase (MGMT) promoter status (71.8%). GTR was performed in more than half of the patients (56.3%). RTV was detected in 83 (58.5%) patients. Following surgery, 72 (50.7%) patients received radiotherapy with concomitant and adjuvant TMZ, 48 (33.8%) received sequential radio-chemotherapy, and 22 (15.5%) received adjuvant chemotherapy alone. The median follow-up time was 40 months (range 16-146 months). The median PFS time and the 1-, 3-, and 5-year PFS rates were 35 months (95% CI 27-76) and 78.9% ± 3.4%, 49.7% ± 4.6%, and 42.7% ± 5.4%, respectively. The median OS time and the 1-, 3-, and 5-year OS rates were 91 months (95% CI 66-95) and 90.1% ± 2.5%, 70.9% ± 4.2%, and 61.8% ± 4.9%, respectively. Prognostic factors predicting survival other than molecular profile were the EOR and the RTV (p < 0.0001). Sequential radio-chemotherapy was the more effective treatment administered. CONCLUSIONS: In addition to IDH status, EOR and the RTV have proved to statistically impact survival. The pivotal role of adjuvant radiotherapy has been recorded in all AG patients, regardless of tumor features.

Multimodality imaging of adult rhabdomyosarcoma: the added value of hybrid imaging.

Rhabdomyosarcoma (RMS) represents more than 50% of paediatric soft tissue tumours. Conversely, it is extremely rare among adults, where it shows peculiar biological and clinical features that are still poorly investigated. RMS patients should be referred to a Sarcoma Centre, where the contribution of experienced radiologists plays a relevant role in the diagnostic assessment of the disease, including precise localisation, staging, image-guided biopsy, response evaluation after treatment and follow-up. Besides CT and MRI, hybrid imaging including positron emission tomography (PET)/CT and PET/MRI are giving an increasing contribution to provide functional insights about tumour biology and to improve the diagnostic accuracy of the imaging work-up. This review paper provides a revision of the pathology, clinical and radiological features of adult RMS, with a particular focus on the growing role of hybrid PET-based imaging.

Sarcopenia as a predictor of survival in patients undergoing bland transarterial embolization for unresectable hepatocellular carcinoma.

Sarcopenia has been associated with lower overall survival in patients with cirrhosis and hepatocellular carcinoma (HCC) undergoing surgical resection, TACE, TARE, or transplantation. This monocentric study evaluated the prognostic significance of sarcopenia in patients affected by HCC who received bland transarterial embolization (TAE) therapy, by analyzing its impact on survival and treatment-related complications. All consecutive patients who underwent the 1st TAE between March 1st 2011 and July 1st 2019 in our Institution were retrospectively studied. To evaluate sarcopenia, the skeletal muscle index (SMI) was calculated by normalizing the cross-sectional muscle area at the level of L3 on an abdominal CT scan prior to embolization (cm2) by patient height (m2). SMI cut-off values for sarcopenia were considered ≤ 39 cm2/m2 for women and ≤55 cm2/m2 for men. Data about age, gender, body mass index (BMI), underlying liver disease, liver function, MELD score, Child-Pugh score, multifocal disease, performance status, previous interventions, length of stay (LOS), complications after the procedure, readmission rate within 30 days, survival time from TAE and total number and type of TAE received following the first procedure were collected. From 2011 to 2019, 142 consecutive patients underwent 305 TAEs. Observation time ranged from 1.4 to 100.5 months (median 20.1 SD = 22). Sarcopenia at baseline was present in 121 (85%) patients. Overall 87 (61.2%) patients died during follow-up with survival rates at 1-, 2-, 3-, 4-, and 5-year of 71%, 41%, 22%, 16% and 11% respectively. After multivariate analysis sarcopenia (HR = 2.22, p = 0.046), previous ablation/resection (HR = 0.51, p = 0.005) and multifocal disease (HR = 1.84, p = 0.02) were associated with reduced survival. Sarcopenia did not influence the safety of TAE in terms of LOS (2 days vs 1.5 days, p = 0.2), early complications rate (8% vs 5%, p = 0.5) and readmission rate within 30 days (7% vs 5%, p = 0.74). Sarcopenia, estimated by the L3SMI method, is an emerging prognostic factor in patients with HCC undergoing bland TAE therapy as it is associated with increased mortality, without impairing the safety of the locoregional treatment. Measures to ameliorate the SMI, such as nutritional support and physical exercise, should be evaluated in clinical trials for HCC patients receiving liver embolization to determine their impact on overall survival.

Quantitative chest CT analysis in COVID-19 to predict the need for oxygenation support and intubation.

OBJECTIVE: Lombardy (Italy) was the epicentre of the COVID-19 pandemic in March 2020. The healthcare system suffered from a shortage of ICU beds and oxygenation support devices. In our Institution, most patients received chest CT at admission, only interpreted visually. Given the proven value of quantitative CT analysis (QCT) in the setting of ARDS, we tested QCT as an outcome predictor for COVID-19. METHODS: We performed a single-centre retrospective study on COVID-19 patients hospitalised from January 25, 2020, to April 28, 2020, who received CT at admission prompted by respiratory symptoms such as dyspnea or desaturation. QCT was performed using a semi-automated method (3D Slicer). Lungs were divided by Hounsfield unit intervals. Compromised lung (%CL) volume was the sum of poorly and non-aerated volumes (- 500, 100 HU). We collected patient's clinical data including oxygenation support throughout hospitalisation. RESULTS: Two hundred twenty-two patients (163 males, median age 66, IQR 54-6) were included; 75% received oxygenation support (20% intubation rate). Compromised lung volume was the most accurate outcome predictor (logistic regression, p < 0.001). %CL values in the 6-23% range increased risk of oxygenation support; values above 23% were at risk for intubation. %CL showed a negative correlation with PaO2/FiO2 ratio (p < 0.001) and was a risk factor for in-hospital mortality (p < 0.001). CONCLUSIONS: QCT provides new metrics of COVID-19. The compromised lung volume is accurate in predicting the need for oxygenation support and intubation and is a significant risk factor for in-hospital death. QCT may serve as a tool for the triaging process of COVID-19. KEY POINTS: • Quantitative computer-aided analysis of chest CT (QCT) provides new metrics of COVID-19. • The compromised lung volume measured in the - 500, 100 HU interval predicts oxygenation support and intubation and is a risk factor for in-hospital death. • Compromised lung values in the 6-23% range prompt oxygenation therapy; values above 23% increase the need for intubation.

Enhanced SPARCL1 expression in cancer stem cells improves preclinical modeling of glioblastoma by promoting both tumor infiltration and angiogenesis.

Glioblastoma (GBM) is the most malignant brain tumor of adults and is characterized by extensive cell dissemination within the brain parenchyma and enhanced angiogenesis. Effective preclinical modeling of these key features suffers from several shortcomings. Aim of this study was to determine whether modulating the expression of extracellular matrix (ECM) modifiers in proneural (PN) and mesenchymal (MES) cancer stem cells (CSCs) and in conventional glioma cell lines (GCLs) might improve tumor invasion and vascularization. To this end, we selected secreted, acidic and rich in cysteine-like 1 (SPARCL1) as a potential mediator of ECM remodeling in GBM. SPARCL1 transcript and protein expression was assessed in PN and MES CSCs as well as GCLs, in their xenografts and in patient-derived specimens by qPCR, WB and IHC. SPARCL1 expression was then enforced in both CSCs and GCLs by lentiviral-based transduction. The effect of SPARCL1 gain-of-function on microvascular proliferation, microglia activation and advanced imaging features was tested in intracranial xenografts by IHC and MRI and validated by chorioallantoic membrane (CAM) assays. SPARCL1 expression significantly enhanced the infiltrative and neoangiogenic features of PN and MES CSC/GCL-induced tumors, with the concomitant activation of inflammatory responses associated with the tumor microenvironment, thus resulting in experimental GBMs that reproduced both the parenchymal infiltration and the increased microvascular density, typical of GBM. Overall, these results indicate that SPARCL1 overexpression might be instrumental for the generation of CSC-derived preclinical models of GBM in which the main pathognomonic hallmarks of GBMs are retrievable, making them suitable for effective preclinical testing of therapeutics.

18F-VC701-PET and MRI in the in vivo neuroinflammation assessment of a mouse model of multiple sclerosis.

BACKGROUND: Positron emission tomography (PET) using translocator protein (TSPO) ligands has been used to detect neuroinflammatory processes in neurological disorders, including multiple sclerosis (MS). The aim of this study was to evaluate neuroinflammation in a mouse MS model (EAE) using TSPO-PET with 18F-VC701, in combination with magnetic resonance imaging (MRI). METHODS: MOG35-55/CFA and pertussis toxin protocol was used to induce EAE in C57BL/6 mice. Disease progression was monitored daily, whereas MRI evaluation was performed at 1, 2, and 4 weeks post-induction. Microglia activation was assessed in vivo by 18F-VC701 PET at the time of maximum disease score and validated by radioligand ex vivo distribution and immunohistochemistry at 2 and 4 weeks post-immunization. RESULTS: In vivo and ex vivo analyses show that 18F-VC701 significantly accumulates within the central nervous system (CNS), particularly in the cortex, striatum, hippocampus, cerebellum, and cervical spinal cord of EAE compared to control mice, at 2 weeks post-immunization. MRI confirmed the presence of focal brain lesions at 2 weeks post-immunization in both T1-weighted and T2 images. Of note, MRI abnormalities attenuated in later post-immunization phase. Neuropathological analysis confirmed the presence of microglial activation in EAE mice, consistent with the in vivo increase of 18F-VC701 uptake. CONCLUSION: Increase of 18F-VC701 uptake in EAE mice is strongly associated with the presence of microglia activation in the acute phase of the disease. The combined use of TSPO-PET and MRI provided complementary evidence on the ongoing disease process, thus representing an attractive new tool to investigate neuronal damage and neuroinflammation at preclinical levels.

Neural Stem Cell Transplantation Induces Stroke Recovery by Upregulating Glutamate Transporter GLT-1 in Astrocytes.

Ischemic stroke is the leading cause of disability, but effective therapies are currently widely lacking. Recovery from stroke is very much dependent on the possibility to develop treatments able to both halt the neurodegenerative process as well as to foster adaptive tissue plasticity. Here we show that ischemic mice treated with neural precursor cell (NPC) transplantation had on neurophysiological analysis, early after treatment, reduced presynaptic release of glutamate within the ipsilesional corticospinal tract (CST), and an enhanced NMDA-mediated excitatory transmission in the contralesional CST. Concurrently, NPC-treated mice displayed a reduced CST degeneration, increased axonal rewiring, and augmented dendritic arborization, resulting in long-term functional amelioration persisting up to 60 d after ischemia. The enhanced functional and structural plasticity relied on the capacity of transplanted NPCs to localize in the peri-ischemic and ischemic area, to promote the upregulation of the glial glutamate transporter 1 (GLT-1) on astrocytes and to reduce peri-ischemic extracellular glutamate. The upregulation of GLT-1 induced by transplanted NPCs was found to rely on the secretion of VEGF by NPCs. Blocking VEGF during the first week after stroke reduced GLT-1 upregulation as well as long-term behavioral recovery in NPC-treated mice. Our results show that NPC transplantation, by modulating the excitatory-inhibitory balance and stroke microenvironment, is a promising therapy to ameliorate disability, to promote tissue recovery and plasticity processes after stroke. SIGNIFICANCE STATEMENT: Tissue damage and loss of function occurring after stroke can be constrained by fostering plasticity processes of the brain. Over the past years, stem cell transplantation for repair of the CNS has received increasing interest, although underlying mechanism remain elusive. We here show that neural stem/precursor cell transplantation after ischemic stroke is able to foster axonal rewiring and dendritic plasticity and to induce long-term functional recovery. The observed therapeutic effect of neural precursor cells seems to underlie their capacity to upregulate the glial glutamate transporter on astrocytes through the vascular endothelial growth factor inducing favorable changes in the electrical and molecular stroke microenvironment. Cell-based approaches able to influence plasticity seem particularly suited to favor poststroke recovery.

MRI Evidence of Cerebellar and Extraocular Muscle Atrophy Differently Contributing to Eye Movement Abnormalities in SCA2 and SCA28 Diseases.

PURPOSE: Spinocerebellar ataxias type 2 and 28 (SCA2, SCA28) are autosomal dominant disorders characterized by progressive cerebellar and oculomotor abnormalities. We aimed to investigate cerebellar, brainstem, and extraocular muscle involvement in the mitochondrial SCA28 disease compared with SCA2. METHODS: We obtained orbital and brain 1.5 T-magnetic resonance images (MRI) in eight SCA28 subjects, nine SCA2, and nine age-matched healthy subjects. Automated segmentation of cerebellum and frontal lobe was performed using Freesurfer software. Manual segmentations for midbrain, pons, and extraocular muscles were performed using OsiriX. RESULTS: Eye movement abnormalities in SCA2 subjects were characterized by slow horizontal saccades. Subjects with SCA28 variably presented hypometric saccades, saccadic horizontal pursuit, impaired horizontal gaze holding, and superior eyelid ptosis. Quantitative brain MRI demonstrated that cerebellar and pons volumes were significantly reduced in both SCA2 and SCA28 subjects compared with controls (P < 0.03), and in SCA2 subjects compared with SCA28 (P < 0.01). Midbrain and frontal lobe volumes were also significantly reduced in SCA2 compared to controls (P < 0.03), whereas these volumes did not differ between SCA2 and SCA28 and between SCA28 and control subjects. The extraocular muscle areas were 37% to 48% smaller in SCA28 subjects compared with controls (P < 0.002), and 14% to 36% smaller compared with SCA2 subjects (P < 0.03). Extraocular muscle areas did not differ between SCA2 and controls. CONCLUSIONS: Our MRI findings support the hypothesis of different cerebellar and extraocular myopathic contributions in the eye movement abnormalities in SCA2 and SCA28 diseases. In SCA28, a myopathic defect selectively involving the extraocular muscles supports a specific impairment of mitochondrial energy metabolism.