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Background: Brain tumor surgery is routinely supported by several intraoperative techniques, such as fluorescence, brain mapping and neuronavigation, which are often used independently. Efficacy of navigation is limited by the brain-shift phenomenon, particularly in cases of large or deep-sited lesions. Intraoperative imaging was introduced also to update neuronavigation data, to try and solve the brain-shift phenomenon-related pitfalls and increase overall safety. Nevertheless, each intraoperative imaging modality has some intrinsic limitations and technical shortcomings, making its clinical use challenging. We used a multimodal intraoperative imaging protocol to update neuronavigation, based on the combination of intraoperative Ultrasound (i-US) and intraoperative Computed Tomography (i-CT) integrated with 5-ALA fluorescence and neuromonitoring-guided resection., Methods: This is a pilot study on 52 patients (29 men), including four children, with a mean age of 57.67 years, suffering from brain low- (N.=10) or high-grade (N.=34) glioma or metastasis (N.=8), prospectively and consecutively enrolled. They underwent 5-ALA fluorescence-guided microsurgical tumor resection and neuromonitoring was used in cases of lesions located in eloquent areas, according to preoperative clinical and neuroradiological features. Navigated B-mode ultrasound acquisition was carried out after dural opening to identify the lesion. After tumor resection, i-US was used to identify residual tumor. Following further tumor resection or in cases of unclear US images, post-contrast i-CT was performed to detect and localize small tumor remnants and to allow further correction for brain shift. A final i-US check was performed to verify the completeness of resection. Clinical evaluation was based on comparison of pre- and postoperative Karnofsky Performance Score (KPS) and assessment of overall survival (OS) and progression-free survival (PFS). Extent of tumor resection (EOTR) was evaluated by volumetric postoperative Magnetic Resonance performed within 48 h after surgery., Results: Forty-one of the 52 (78.8%) patients were alive and still under follow-up in December 2017. 5-ALA was strongly or vaguely positive in 45 cases (86.5%). Seven lesions (four low-grade glioma, one high-grade glioma, and two metastases) were not fluorescent. i-US visualized residual tumor after resection of all fluorescent or pathological tissue in 22 cases (42.3%). After i-US guided resection, i-CT documented the presence of further residual tumor in 11 cases (21.1%). Mean EOTR was 98.79% in the low-grade gliomas group, 99.84% in the high-grade gliomas group and 100% in the metastases group. KPS changed from 77.88, preoperatively, to 72.5, postoperatively. At the last follow-up, mean KPS was 84.23., Conclusions: The combination of different intraoperative imaging modalities may increase brain tumor safety and extent of resection. In particular, i-US seems to be highly sensitive to detect residual tumors, but it may generate false positives due to artifacts. Conversely, i-CT is more specific to localize remnants, allowing a more reliable updating of navigation data.

Purpose: Magnetic resonance imaging (MRI) is the current standard for preoperative planning of glioblastoma (GBM) surgery. However, recent data on the use of 11  C-methionine positron emission tomography ( 11 [C]-MET PET) suggest its role in providing additional information beyond MRI. The purpose of this study is to establish if there is a correlation between anatomical and metabolic data., Methods: We retrieved all GBM cases treated from 2014 to January 2021. Preoperative MRI (Enhancing Nodule -EN-, FLAIR and Total Tumor Volume -TTV-), PET volumes and histological samples obtained from the different tumor regions were evaluated to analyze potential correlations between anatomical, metabolic and pathological data., Results: 150 patients underwent surgery for GBM and 49 of these were also studied preoperatively with 11 [C]-MET PET; PET volume was evaluated in 47 patients. In 33 patients (70.21%) preoperative 11 [C]-MET PET volume > preoperative EN volume and in 11 (23.4%) preoperative 11 [C]-MET PET volume > preoperative TTV. We found a significant correlation between preoperative TTVs and PET volumes (p = 0.016) as well as between preoperative EN volumes and PET volumes (p = < 0.001). Histologically, 109 samples were evaluated. ENs samples exhibited the conventional GBM morphology while samples from the FLAIR regions showed white matter tissue, with focal to diffuse tumor cells infiltration and areas of reactive astrogliosis., Conclusion: We submit that 11 [C]-MET PET volume generally overcome EN. The presence of neoplastic cells confirm these metabolic data. It should be considered in the surgical planning to achieve a Supra Total Resection (SupTR)., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

It is ge nerally accepted that glioblastoma (GBM) arise from cancer stem cells (CSC); however, there is little evidence on their anatomical distribution. We investigated the expression and distribution of SOX-2-positive and CD133-positive CSCs both in the enhancing nodule (EN) of GBM and in the FLAIR hyperintensity zones on a surgical, histopathological series of 33 GBMs. The inclusion criterion was the intraoperative sampling of different tumor regions individualized, thanks to neuronavigation and positivity to intraoperative fluorescence with the use of 5-aminolevulinic acid (5-ALA). Thirty-three patients (20 males and 13 females with a mean age at diagnosis of 56 years) met the inclusion criterion. A total of 109 histological samples were evaluated, 52 for ENs and 57 for FLAIR hyperintensity zone. Considering the quantitative distribution of levels of intensity of staining (IS), ES (extent score), and immunoreactivity score (IRS), no difference was found between ENs and FLAIR regions for both the SOX-2 biomarker (respectively, IS p = 0.851, ES p = 0.561, IRS p = 1.000) and the CD133 biomarker (IS p = 0.653, ES p = 0.409, IRS p = 0.881). This evidence suggests to recalibrate the target of surgery for FLAIRECTOMY and 5-ALA could improve the possibility to achieve this goal., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Glioblastoma (GBM) are among the most common malignant central nervous system (CNS) cancers, they are relatively rare. This evidence suggests that the CNS microenvironment is naturally equipped to control proliferative cells, although, rarely, failure of this system can lead to cancer development. Moreover, the adult CNS is innately non-permissive to glioma cell invasion. Thus, glioma etiology remains largely unknown. In this review, we analyze the anatomical and biological basis of gliomagenesis considering neural stem cells, the spatiotemporal diversity of astrocytes, microglia, neurons and glutamate transporters, extracellular matrix and the peritumoral environment. The precise understanding of subpopulations constituting GBM, particularly astrocytes, is not limited to glioma stem cells (GSC) and could help in the understanding of tumor pathophysiology. The anatomical fingerprint is essential for non-invasive assessment of patients' prognosis and correct surgical/radiotherapy planning.

Background/aim: Nowadays, Machine Learning (ML) algorithms have demonstrated remarkable progress in image-recognition tasks and could be useful for the new concept of precision medicine in order to help physicians in the choice of therapeutic strategies for brain tumours. Previous data suggest that, in the central nervous system (CNS) tumours, amino acid PET may more accurately demarcate the active disease than paramagnetic enhanced MRI, which is currently the standard method of evaluation in brain tumours and helps in the assessment of disease grading, as a fundamental basis for proper clinical patient management. The aim of this study is to evaluate the feasibility of ML on 11[C]-MET PET/CT scan images and to propose a radiomics workflow using a machine-learning method to create a predictive model capable of discriminating between low-grade and high-grade CNS tumours., Materials and Methods: In this retrospective study, fifty-six patients affected by a primary brain tumour who underwent 11[C]-MET PET/CT were selected from January 2016 to December 2019. Pathological examination was available in all patients to confirm the diagnosis and grading of disease. PET/CT acquisition was performed after 10 min from the administration of 11C-Methionine (401-610 MBq) for a time acquisition of 15 min. 11[C]-MET PET/CT images were acquired using two scanners (24 patients on a Siemens scan and 32 patients on a GE scan). Then, LIFEx software was used to delineate brain tumours using two different semi-automatic and user-independent segmentation approaches and to extract 44 radiomics features for each segmentation. A novel mixed descriptive-inferential sequential approach was used to identify a subset of relevant features that correlate with the grading of disease confirmed by pathological examination and clinical outcome. Finally, a machine learning model based on discriminant analysis was used in the evaluation of grading prediction (low grade CNS vs. high-grade CNS) of 11[C]-MET PET/CT., Results: The proposed machine learning model based on (i) two semi-automatic and user-independent segmentation processes, (ii) an innovative feature selection and reduction process, and (iii) the discriminant analysis, showed good performance in the prediction of tumour grade when the volumetric segmentation was used for feature extraction. In this case, the proposed model obtained an accuracy of ~85% (AUC ~79%) in the subgroup of patients who underwent Siemens tomography scans, of 80.51% (AUC 65.73%) in patients who underwent GE tomography scans, and of 70.31% (AUC 64.13%) in the whole patients' dataset (Siemens and GE scans)., Conclusions: This preliminary study on the use of an ML model demonstrated to be feasible and able to select radiomics features of 11[C]-MET PET with potential value in prediction of grading of disease. Further studies are needed to improve radiomics algorithms to personalize predictive and prognostic models and potentially support the medical decision process.

Background: Extent of tumor resection (EOTR) in glioblastoma surgery plays an important role in improving survival., Objective: To analyze the efficacy, safety and reliability of fluid-attenuated inversion-recovery (FLAIR) magnetic resonance (MR) images used to guide glioblastoma resection (FLAIRectomy) and to volumetrically measure postoperative EOTR, which was correlated with clinical outcome and survival., Methods: A total of 68 glioblastoma patients (29 males, mean age 65.8) were prospectively enrolled. Hyperintense areas on FLAIR images, surrounding gadolinium-enhancing tissue on T1-weighted MR images, were screened for signal changes suggesting tumor infiltration and evaluated for supramaximal resection. The surgical protocol included 5-aminolevulinic acid (5-ALA) fluorescence, neuromonitoring, and intraoperative imaging tools. 5-ALA fluorescence intensity was analyzed and matched with the different sites on navigated MR, both on postcontrast T1-weighted and FLAIR images. Volumetric evaluation of EOTR on T1-weighted and FLAIR sequences was compared., Results: FLAIR MR volumetric evaluation documented larger tumor volume than that assessed on contrast-enhancing T1 MR (72.6 vs 54.9 cc); residual tumor was seen in 43 patients; postcontrast T1 MR volumetric analysis showed complete resection in 64 cases. O6-methylguanine-DNA methyltransferase promoter was methylated in 8/68 (11.7%) cases; wild type Isocytrate Dehydrogenase-1 (IDH-1) was found in 66/68 patients. Progression free survival and overall survival (PFS and OS) were 17.43 and 25.11 mo, respectively. Multiple regression analysis showed a significant correlation between EOTR based on FLAIR, PFS (R2 = 0.46), and OS (R2 = 0.68)., Conclusion: EOTR based on FLAIR and 5-ALA fluorescence is feasible. Safety of resection relies on the use of neuromonitoring and intraoperative multimodal imaging tools. FLAIR-based EOTR appears to be a stronger survival predictor compared to gadolinium-enhancing, T1-based resection., (Copyright © 2020 by the Congress of Neurological Surgeons.)

Objective: No consensus exists on the best treatment for recurrent high-grade glioma (HGG), particularly in terms of surgical indications, and scant data are available on the integrated use of multiple technologies to overcome intraoperative limits and pitfalls related to artifacts secondary to previous surgery and radiotherapy. Here, the authors report on their experience with the integration of multiple intraoperative tools in recurrent HGG surgery, analyzing their pros and cons as well as their effectiveness in increasing the extent of tumor resection. In addition, they present a review of the relevant literature on this topic., Methods: The authors reviewed all cases in which recurrent HGG had been histologically diagnosed after a first surgery and the patient had undergone a second surgery involving neuronavigation with MRI, intraoperative CT (iCT), 11C-methionine-positron emission tomography (11C-MET-PET), 5-aminolevulinic acid (5-ALA) fluorescence, intraoperative neurophysiological monitoring (IONM), and intraoperative navigated ultrasound (iUS). All cases were classified according to tumor functional grade (1, noneloquent area; 2, near an eloquent area; 3, eloquent area)., Results: Twenty patients with recurrent HGG were operated on using a multimodal protocol. The recurrent tumor functional grade was 1 in 4 patients, 2 in 8 patients, and 3 in the remaining 8 patients. In all patients but 2, 100% EOTR was obtained. Intraoperative 5-ALA fluorescence and navigated iUS showed low specificity and sensitivity. iCT detected tumor remnants in 3 cases. Postoperatively, 6 patients (30%) had worsening neurological conditions: 4 recovered within 90 days, 1 partially recovered, and 1 experienced a permanent deficit. The median Karnofsky Performance Status remained substantially unchanged over the follow-up period. The mean progression-free survival after the second surgery was 7.7 months (range 2-11 months). The mean overall survival was 25.4 months (range 10-52 months), excluding 2 long survivors. Two patients died within 60 days after surgery, and 3 patients were still under follow-up at the end of this study., Conclusions: This is the first study reporting the integration of neuronavigation, 5-ALA fluorescence, iUS, iCT, 11C-MET-PET, and IOM during microsurgical resection of recurrent glioma. The authors believe that the proposed multimodal protocol is useful to increase the safety, effectiveness, and EOTR in patients with recurrent HGG and brain alterations secondary to radio- and chemotherapy.

Background: One of the greatest neuro-oncological concern remains the lack of knowledge about the etiopathogenesis and physiopathology of gliomas. Several studies reported a strict correlation between radiological features and biological behaviour of gliomas; in this way the velocity of diametric expansion (VDE) correlate with lower grade glioma aggressiveness. However, there are no the same strong evidences for high grade gliomas (HGG) because of the lack of several preoperative MRI., Patients and Methods: We describe a series of 4 patients affected by HGG followed from 2014 to January 2019. Two patients are male and two female; two had a pathological diagnosis of glioblastoma (GBM), one of anaplastic astrocytoma (AA) and one had a neuroradiological diagnosis of GBM. The VDE and the acceleration time (AT) was calculated for fluid attenuated inversion recovery (FLAIR) volume and for the enhancing nodule (EN). Every patients underwent sequential MRI study along a mean period of 413 days., Results: Mean VDE evaluated on FLAIR volume was 39.91 mm/year. Mean percentage ratio between peak values and mean value of acceleration was 282.7%. Median appearance time of EN after first MRI scan was 432 days. Mean VDE was 45.02 mm/year. Mean percentage ratio between peak values and mean value of acceleration was 257.52%., Conclusions: To our knowledge, this is the first report on VDE and acceleration growth in HGG confirming their strong aggressiveness. In a case in which we need to repeat an MRI, time between consecutive scans should be reduced to a maximum of 15-20 days and surgery should be executed as soon as possible., (© 2021 Roberto Altieri, Francesco Certo, Giuseppe La Rocca, Antonio Melcarne, Diego Garbossa, Alberto Bianchi, Salvatore Crimi, Alessandro Pluchino, Simone Peschillo, Giuseppe M.V. Barbagallo, published by Sciendo.)

Objective: Approximately half of glioblastoma (GBM) cases develop in geriatric patients, and this trend is destined to increase with the aging of the population. The optimal strategy for management of GBM in elderly patients remains controversial. The aim of this study was to assess the role of surgery in the elderly (≥ 65 years old) based on clinical, molecular, and imaging data routinely available in neurosurgical departments and to assess a prognostic survival score that could be helpful in stratifying the prognosis for elderly GBM patients., Methods: Clinical, radiological, surgical, and molecular data were retrospectively analyzed in 322 patients with GBM from 9 neurosurgical centers. Univariate and multivariate analyses were performed to identify predictors of survival. A random forest approach (classification and regression tree [CART] analysis) was utilized to create the prognostic survival score., Results: Survival analysis showed that overall survival (OS) was influenced by age as a continuous variable (p = 0.018), MGMT (p = 0.012), extent of resection (EOR; p = 0.002), and preoperative tumor growth pattern (evaluated with the preoperative T1/T2 MRI index; p = 0.002). CART analysis was used to create the prognostic survival score, forming six different survival groups on the basis of tumor volumetric, surgical, and molecular features. Terminal nodes with similar hazard ratios were grouped together to form a final diagram composed of five classes with different OSs (p < 0.0001). EOR was the most robust influencing factor in the algorithm hierarchy, while age appeared at the third node of the CART algorithm. The ability of the prognostic survival score to predict death was determined by a Harrell's c-index of 0.75 (95% CI 0.76-0.81)., Conclusions: The CART algorithm provided a promising, thorough, and new clinical prognostic survival score for elderly surgical patients with GBM. The prognostic survival score can be useful to stratify survival risk in elderly GBM patients with different surgical, radiological, and molecular profiles, thus assisting physicians in daily clinical management. The preliminary model, however, requires validation with future prospective investigations. Practical recommendations for clinicians/surgeons would strengthen the quality of the study; e.g., surgery can be considered as a first therapeutic option in the workflow of elderly patients with GBM, especially when the preoperative estimated EOR is greater than 80%.

Introduction: Glioblastoma treatment requires a multidisciplinary approach involving oncologists, radiotherapists and surgeons. Surgery constitutes the initial step of the therapeutic strategy and its efficacy is dependent on the extent of resection (EOR). Over the last decade, the goal of surgical treatment was the resection of the contrast enhancement on T1 MRI, defined as gross-total resection (GTR). More recently, an increasing number of studies reports a positive impact on survival parameters of a more aggressive surgical strategy aiming to resect all peri-tumoral infiltrated areas. These areas are histologically characterized by the presence of pathological cells infiltrating normal white matter and surround the neoplastic core of glioblastoma identified by gadolinium enhancement in T1-weighted MR. Intuitively, the major risk of the so called supramarginal resection is related to the possibility of resecting functionally eloquent brain tissue. Several strategies have been proposed to maximize the safety of resection and minimize the occurrence of postoperative functional deficits. The aim of this review was to focus on the clinical impact of supramarginal resection of glioblastomas, highlighting the role of image-guided surgery combined with neuromonitoring to increase surgical safety and efficacy., Evidence Acquisition: The MEDLINE database has been queried for the literature research., Evidence Synthesis: Ten studies matched the inclusion criteria, reporting a global number of 3221 patients., Conclusions: The current evidence suggests a positive correlation between a more extensive resection based on FLAIR abnormal areas and overall survival.

The first step of glioma treatment is surgery. Extent of resection (EOR) improves patient survival if surgery does not negatively impair a patient's neurological status. However, how surgery affects the patient's quality of life (QOL) has been less studied, especially as regards cognitive aspects. In our study, we retrospectively analyzed our cases with awake surgery. In all patients, surgical excision was stopped when active functions were intraoperatively identified. A neuropsychological assessment was performed both before and after surgery (5 days and 1 month after). Writing, motor speech, comprehension, expression, reading, pragmatics, attention, memory, problem solving and visuoperceptive functions were evaluated and scored with the NOMS scale. We found no differences in the median values of writing and motor speech, while there was a difference in the following variables: comprehension, expression, reading, pragmatics, attention, memory, problem solving and visuoperceptive functions. Moreover, the Dunn test did not show any difference between preoperative evaluation and evaluation performed 30 days after surgery regarding comprehension, expression, reading, pragmatics, attention, problem solving and visuoperceptive functions. However, there was a difference between preoperative and postoperative evaluation for memory. This retrospective study shows that awake surgery could be a reasonable possibility to preserve a patient's QOL achieving an EOR >82% of the Total Tumor Volume (Fluid-attenuated inversion recovery (FLAIR) hyperintense region in low-grade gliomas and enhancing nodules plus FLAIR hyperintense region in high-grade gliomas). In this series memory was the only aspect that had an impairment after surgery without a complete recovery at one month after surgery., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background: Angioleiomyoma (ALM) is a soft tissue neoplasm rarely described in the intracranial site. Because of their uncommon presentation, atypical neuroradiologic and pathologic features, ALMs are often misdiagnosed., Case Description: We describe the neuroradiologic, clinical, and pathologic data of a 37-year-old male patient suffering from a tentorial ALM. He was admitted at our hospital because of a posterior cranial fossa mass. Magnetic resonance imaging (MRI) showed a left tentorial tumor, hypointense on T1-weighted sequences, with heterogeneous contrast enhancement after gadolinium injection ("salt-and-pepper" fashion) and slightly hyperintense signal on T2-weighted sequence. After surgery, pathological examination showed a tumor composed of several thick-walled blood vessels mixed with a population of deeply eosinophilic spindle-shaped smooth muscle cells arranged in bundles. Necrosis was absent. Neither cellular pleomorphism nor mitoses were detected. Immuno-histochemical analysis confirmed the smooth muscle phenotype of the spindle cell component: diffuse and strong positivity for alpha-smooth muscle actin, desmin, and h-caldesmon. Based on both morphologic and immunohistochemical findings, a diagnosis of primary intracranial ALM was rendered., Conclusions: We add to the literature the tenth case of this exceedingly rare tumor and submit that ALM should be suspected when a tentorial mass with a "flame-like" time-dependent pattern of contrast enhancement on MRI, a "salt-and-pepper" post-contrast appearance on MRI T1-weighted sequences, and a relation with large intracranial feeding vessels are present., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Introduction: Colloid cysts are rare benign intracranial lesions classically described as "third ventricle colloid cysts" because of their location within the third ventricle. These lesions' clinical and diagnostic features are mainly related to intermittent or persistent obstruction of foramina of Monro causing cerebrospinal fluid (CSF) circulation impairment and symptoms of raised intracranial pressure. Few reports on colloid cysts located outside the third ventricle have been published over the years. This paper aims to review the existing literature on out-of-third ventricle colloid cysts, and introduces a new illustrative case of lateral ventricle colloid cyst surgically managed with endoscopic technique., Evidence Acquisition: A literature review was performed through a Medline web-search, using "colloid cysts," "lateral ventricle colloid cysts," "fourth ventricle colloid cysts," "brain colloid cyst," "spinal colloid cysts" as keywords. All retrieved abstracts were screened and full-length text of papers suitable for inclusion were examined. An illustrative case has been added to the existing literature. A 45-year-old man complaining of recurrent headache underwent conservative treatment for 4 years. The unusual headache features as well as the uncommon onset and association with episodic mental impairment led to an initial diagnosis of anxiety disorder triggering the headache. A further worsening of headache and the lack of significant clinical benefit prompted further investigation. Computed-tomography (CT) of the brain showed asymmetrical dilatation of the right lateral ventricle, due to the presence of a cystic mass obstructing the foramen of Monroe. Patient underwent endoscopic resection of the cyst., Evidence Synthesis: The literature review revealed 16 papers reported between 1952 and 2016. In all cases included histological diagnosis of colloid cyst had been obtained. Clinical and radiological features, as well as surgical management in each case have been analyzed. In the case here reported, histological examination documented a colloid cyst. The postoperative course was uneventful, with progressive resolution of headache., Conclusions: Despite third ventricle colloid cysts are related to typical clinical and diagnostic features, non-third ventricle colloid cysts may be responsible for unusual clinical presentation, so making a correct diagnostic approach challenging. We submit that in cases of recurrent headache with unusual features and lacking signs of neurological deficits, a rare neurosurgical condition as an "ectopic" colloid cyst should be included in the differential diagnosis.

Object: The objective of this study was to report the authors' experience with the long-term administration of temozolomide (TMZ; > 6 cycles, up to 101) in patients with newly diagnosed glioblastoma and to analyze its feasibility and safety as well as its impact on survival. The authors also compared data obtained from the group of patients undergoing long-term TMZ treatment with data from patients treated with a standard TMZ protocol., Methods: A retrospective analysis was conducted of 37 patients who underwent operations for glioblastoma between 2004 and 2012. Volumetric analysis of postoperative Gd-enhanced MR images, obtained within 48 hours, confirmed tumor gross-total resection (GTR) in all but 2 patients. All patients received the first cycle of TMZ at a dosage of 150 mg/m(2) starting on the second or third postsurgical day. Afterward, patients received concomitant radiochemotherapy according to the Stupp protocol. With regard to adjuvant TMZ therapy, the 19 patients in Group A, aged 30-72 years (mean 56.1 years), received 150 mg/m(2) for 5 days every 28 days for more than 6 cycles (range 7-101 cycles). The 18 patients in Group B, aged 46-82 years (mean 64.8 years), received the same dose, but for no more than 6 cycles. O(6)-methylguanine-DNA methyltransferase (MGMT) promoter methylation status was analyzed for both groups and correlated with overall survival (OS) and progression-free survival (PFS). The impact of age, sex, Karnofsky Performance Scale score, and Ki 67 staining were also considered., Results: All patients but 1 in Group A survived at least 18 months (range 18-101 months), and patients in Group B survived no more than 17 months (range 2-17 months). The long-term survivors (Group A), defined as patients who survived at least 12 months after diagnosis, were 51.3% of the total (19/37). Kaplan-Meier curve analysis showed that patients treated with more than 6 TMZ cycles had OS and PFS that was significantly longer than patients receiving standard treatment (median OS 28 months vs 8 months, respectively; p = 0.0001; median PFS 20 months vs 4 months, respectively; p = 0.0002). By univariate and multivariate Cox proportional hazard regression analysis, MGMT methylation status and number of TMZ cycles appeared to be survival prognostic factors in patients with glioblastoma. After controlling for MGMT status, highly significant differences related to OS and PFS between patients with standard and long-term TMZ treatment were still detected. Furthermore, in Group A and B, the statistical correlation of MGMT status to the number of TMZ cycles showed a significant difference only in Group A patients, suggesting that MGMT promoter methylation was predictive of response for long-term TMZ treatment. Prolonged therapy did not confer hematological toxicity or opportunistic infections in either patient group., Conclusions: This study describes the longest experience so far reported with TMZ in patients with newly diagnosed glioblastomas, with as many as 101 cycles, who were treated using GTR. Statistically significant data confirm that median survival correlates with MGMT promoter methylation status as well as with the number of TMZ cycles administered. Long-term TMZ therapy appears feasible and safe.

5-aminolevulinic acid (5-ALA) has been used for the last 5 years to increase the extent of resection in adult brain tumors, mostly glioblastomas, but it is not approved yet as standard adjuvant treatment in the pediatric population. We report three different cases of pediatric brain tumors (two glioblastomas and one medulloblastoma) recently operated using 5-ALA fluorescence guidance, highlighting how useful it is in pediatric high-grade glioma (but not in medulloblastoma) also and confirming the lack of 5-ALA-related side effects. The first glioma was a recurrent GBM, whilst the second was a primary tumor. In all children, 5-ALA was administrated after discussing its use, including pros and cons, with the parents. 5-ALA fluorescence was a very useful tool to better identify tumor tissue and achieve gross-total tumor resection in GBMs, as confirmed by postoperative magnetic resonance imaging (MRI). In the medulloblastoma case no useful 5-ALA fluorescence was identified. No hematological or dermatological complications nor other side effects related to use of 5-ALA were observed. We submit that 5-ALA fluorescence guided surgery can be safe and useful in pediatric high-grade glioma, although its use in children still remains an off-label indication and requires validation through larger studies.