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Glioblastoma is the most fatal and common malignant brain tumor, excluding metastasis and with a median survival of approximately one year. While solid tumors benefit from newly approved drugs, immunotherapy, and prevention, none of these scenarios are opening for glioblastoma. The key to unlocking the peculiar features of glioblastoma is observing its molecular and anatomical features tightly entangled with the host's central nervous system (CNS). In June 2024, we searched the PUBMED electronic database. Data collection and analysis were conducted independently by two reviewers. Results: A total of 215 articles were identified, and 192 were excluded based on inclusion and exclusion criteria. The remaining 23 were used for collecting divergent molecular pathways and anatomical features of glioblastoma. The analysis of the selected papers revealed a multifaced tumor with extreme variability and cellular reprogramming that are observable within the same patient. All the variability of glioblastoma could be clustered into three pillars to dissect the physiology of the tumor: 1. necrotic core; 2. vascular proliferation; 3. CNS infiltration. These three pillars support glioblastoma survival, with a pivotal role of the neurovascular unit, as supported by the most recent paper published by experts in the field.

Objectives: Dural based Marginal Zone MALT-type B-Cell Lymphoma (MZBCL) is an intracranial tumor that can mimicking meningioma both from a clinical and a radiological point of view. A standard treatment protocol is still lacking. Aim of the present work is to provide an update of the present literature regarding this rare neoplasia., Patients and Methods: We report the case of a patient with a dural-based lesion mimicking a meningioma of the tentorium. After surgical treatment, the diagnosis was of MZBCL. A literature review is performed to highlight the typical characteristics of this rare intracranial lesion and to define the best therapeutic approach., Results: Literature review included 38 articles describing 126 cases of intracranial dural-based MZBCL. No clinical trial has been found. Clinical and histopathological features are properly collected to provide a guide for future cases. Different treatment options have been attempted. Combination of surgery with adjuvant radiation therapy is the most used option., Conclusions: MZBCL should be considered in differential diagnosis for dural-based intracranial lesion. Surgery followed by radiation therapy is the most reported treatment. As a consequence of the rarity of this disease, of its indolent progression and of the lack of adequate follow-up, it is not possible to define it is the best treatment option.

The paucity of studies available in the literature on brain tumors demonstrates that liquid biopsy (LB) is not currently applied for central nervous system (CNS) cancers. The purpose of this systematic review focused on the application of machine learning (ML) to LB for brain tumors to provide practical guidance for neurosurgeons to understand the state-of-the-art practices and open challenges. The herein presented study was conducted in accordance with the PRISMA-P (preferred reporting items for systematic review and meta-analysis protocols) guidelines. An online literature search was launched on PubMed/Medline, Scopus, and Web of Science databases using the following query: "((Liquid biopsy) AND (Glioblastoma OR Brain tumor) AND (Machine learning OR Artificial Intelligence))". The last database search was conducted in April 2023. Upon the full-text review, 14 articles were included in the study. These were then divided into two subgroups: those dealing with applications of machine learning to liquid biopsy in the field of brain tumors, which is the main aim of this review (n = 8); and those dealing with applications of machine learning to liquid biopsy in the diagnosis of other tumors (n = 6). Although studies on the application of ML to LB in the field of brain tumors are still in their infancy, the rapid development of new techniques, as evidenced by the increase in publications on the subject in the past two years, may in the future allow for rapid, accurate, and noninvasive analysis of tumor data. Thus making it possible to identify key features in the LB samples that are associated with the presence of a brain tumor. These features could then be used by doctors for disease monitoring and treatment planning.

BackgroundFirst popularized by Dolenc, anterior clinoidectomies were performed with rongeurs, before the adoption of modern high-speed drills. We describe a novel application of the piezoelectric BoneScalpel™ in anterior skull base and posterior fossa surgeries. In the literature, to date, there are no mentions of anterior clinoidectomies performed with piezosurgical devices.MethodsWe reported a total of 12 patients, 8 affected by posterior fossa tumors and 4 treated for anterior skull base oncologic and vascular pathologies. This study aims to assess the safety and efficacy of the piezoelectric osteotomy in skull base and posterior fossa surgeries. In all patients, an ultrasonic bone dissector (BoneScalpel™ - Misonix) was used to perform the anterior clinoidectomy (AC) and craniotomy.ResultsA successful clinoidectomy was performed in 4 out of 12 patients (33.3%). We did not notice any heat damage to the surrounding soft tissue in critical areas such as paraclinoid structures. We documented only one durotomy in an oncologic patient, while no lesions of SSS or TS were detected.We recorded only a slightly increased surgery duration in the PIEZOSURGERY ® and BoneScalpel™ group, compared to standard surgery with an osteotome to perform craniotomies, but no time difference in performing the clinoidectomy between BoneScalpel™ and a conventional high-speed drill.ConclusionWe report the first experience with piezosurgery for anterior clinoidectomy. There is no time difference in performing the clinoidectomy between BoneScalpel™ and a conventional high-speed drill, and this is an undoubted advantage in critical contexts such as clinoid-paraclinoid surgeries, where the risk of dural sinuses tears is common., (© 2023. The Author(s), under exclusive license to Springer Nature Switzerland AG.)

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., (Copyright © 2020 by the Congress of Neurological Surgeons.)

Background: "Diffuse midline glioma H3K27M-mutant" (a mutation gene encoding H3 histone variants) represents a defined pathologic entity since the 2016 World Health Organization Central Nervous System classification and includes midline structures, namely the thalamus, brainstem, and spinal cord. H3K27M-mutant glioma responds more poorly and is associated with worse clinical outcome. Mutation detection is now diagnostic for "diffused midline gliomas." We report on a case arising in an atypical nonmidline localization with an exceedingly adverse course. The present case raises the question of the possible meaning of the H3K27M-mutation in high-grade gliomas arising from the cerebral hemispheres and its implications from prognostic and therapeutic views., Case Description: A 48-year-old woman was admitted with a mass arising from the splenium of the corpus callosum with bilateral hemispheric extension, displaying magnetic resonance imaging characteristics typical of a high-grade glioma. Needle biopsy confirmed the diagnosis of "diffuse astrocytic neoplasm, World Health Organization grade IV." Immunostaining of the tumor revealed the H3K27M-mutant nuclear expression. The patient was referred to adjuvant therapy and died 3 months after biopsy., Conclusions: This experience highlights the possible negative prognostic impact of H3K27M-m and possibility that H3K27M-m could be a reliable prognostic indicator to be considered in not only diffuse midline gliomas but also gliomas from the cerebral hemispheres. Because of the rarity and limited knowledge of this specific mutation in this experience, reports should be encouraged., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: Preoperative embolization is often considered mandatory in highly vascularized brain tumors to contain blood loss. However, not all lesions are amenable to endovascular preoperative embolization. In the literature, cases of preoperative and intraoperative embolization are described only by arterial catheterization, whereas experiences of tumor embolization through direct puncture of the lesion are anecdotal; furthermore these cases lack an intraoperative control method to assess the effects of the embolizing procedure itself., Methods: We describe the association of contrast enhanced ultrasonography (CEUS) and color Doppler ultrasonography (CDUS) to perform intraoperative embolization in an illustrative case of a posterior cranial fossa hemangioblastoma not amenable to a preoperative endovascular procedure. The combination of CEUS and CDUS was tested as an option for the intraoperative devascularization of tumors in which preoperative embolization is considered risky or not possible., Results: The association of CEUS and CDUS provided real-time intraoperative data that directly guided the intraoperative embolization and provided reliable data about the hemodynamic effects produced after the direct injection of an embolizing agent. The technique offered a true real-time definition of the anatomic characteristics of the lesion and its relationships with the adjacent structures while distinguishing feeding from draining vessels., Conclusions: This technique has been proved to be a valuable tool in the surgical resection of highly vascularized tumors and in the treatment of intracranial and spinal vascular lesions and can be considered an option in those cases in which preoperative embolization is not possible. It is a feasible, modern, and cost-effective intraoperative imaging technique that allows identification of unexposed anatomic structures, hence minimizing surgical exposition and surgical manipulation., (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: It is becoming well-established that increasing extent of resection with decreasing residual volume is associated with delayed recurrence and prolonged survival for patients with glioblastoma (GBM). These prior studies are based on evaluating the contrast-enhancing (CE) tumour and not the surrounding fluid attenuated inversion recovery (FLAIR) volume. It therefore remains unclear if the resection beyond the CE portion of the tumour if it translates into improved outcomes for patients with GBM., Methods: Adult patients who underwent resection of a primary glioblastoma at a tertiary care institution between January 1, 2007 and December 31, 2012 and underwent radiation and temozolomide chemotherapy were retrospectively reviewed. Pre and postoperative MRI images were measured for CE tumour and FLAIR volumes. Multivariate proportional hazards were used to assess associations with both time to recurrence and death. Values with p < 0.05 were considered statistically significant., Results: 245 patients met the inclusion criteria. The median [IQR] preoperative CE and FLAIR tumour volumes were 31.9 [13.9-56.1] cm 3 and 78.3 [44.7-115.6] cm 3 , respectively. Following surgery, the median [IQR] postoperative CE and FLAIR tumour volumes were 1.9 [0-7.1] cm 3 and 59.7 [29.7-94.2] cm 3 , respectively. In multivariate analyses, the postoperative FLAIR volume was not associated with recurrence and/or survival (p > 0.05). However, the postoperative CE tumour volume was significantly associated with both recurrence [HR (95%CI); 1.026 (1.005-1.048), p = 0.01] and survival [HR (95%CI); 1.027 (1.007-1.032), p = 0.001]. The postoperative FLAIR volume was also not associated with recurrence and/or survival among patients who underwent gross total resection of the CE portion of the tumour as well as those who underwent supratotal resection., Conclusions: In this study, the volume of CE tumour remaining after resection is more important than FLAIR volume in regards to recurrence and survival for patients with GBM.

Glioblastoma (GBM) is the most common glioma in adults, with incidence increasing by 3% per year. According to the World Health Organization Classification of Central Nervous System Tumors, GBM is considered a grade IV tumor due to its malignant behavior. The aim of this review is to summarize the main biological aspects of GBM. In particular, we focused our attention on those alterations which have been proven to have an impact on patients' outcome, mainly in terms of overall survival (OS), or on the tumor response to therapies. We have also analyzed the cellular biology and the interactions between GBM and the surrounding environment., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Expression of type 5 phosphodiesterase (PDE5), a cGMP-specific hydrolytic enzyme, is frequently altered in human cancer, but its specific role in tumorigenesis remains controversial. Herein, by analyzing a cohort of 69 patients affected by glioblastoma multiforme (GBM) who underwent chemo- and radiotherapy after surgical resection of the tumor, we found that PDE5 was strongly expressed in cancer cells in about 50% of the patients. Retrospective analysis indicated that high PDE5 expression in GBM cells significantly correlated with longer overall survival of patients. Furthermore, silencing of endogenous PDE5 by short hairpin lentiviral transduction (sh-PDE5) in the T98G GBM cell line induced activation of an invasive phenotype. Similarly, pharmacological inhibition of PDE5 activity strongly enhanced cell motility and invasiveness in T98G cells. This invasive phenotype was accompanied by increased secretion of metallo-proteinase 2 (MMP-2) and activation of protein kinase G (PKG). Moreover, PDE5 silencing markedly enhanced DNA damage repair and cell survival following irradiation. The enhanced radio-resistance of sh-PDE5 GBM cells was mediated by an increase of poly(ADP-ribosyl)ation (PARylation) of cellular proteins and could be counteracted by poly(ADP-ribose) polymerase (PARP) inhibitors. Conversely, PDE5 overexpression in PDE5-negative U87G cells significantly reduced MMP-2 secretion, inhibited their invasive potential and interfered with DNA damage repair and cell survival following irradiation. These studies identify PDE5 as a favorable prognostic marker for GBM, which negatively affects cell invasiveness and survival to ionizing radiation. Moreover, our work highlights the therapeutic potential of targeting PKG and/or PARP activity in this currently incurable subset of brain cancers.

Background: As the early detection and total destruction of gliomas are essential for longer survival, we attempted to synthesize a quantum dot (QD) that is capable of recognizing glioma cells for imaging and photodynamic therapy., Methods: Using a one-pot aqueous approach, near infrared-emitting CdTe was produced. After detection of its physicochemical characteriistics, it was conjugated with RGD. The emission images were observed with confocal microscopy. To test its toxicity, CdTe-RGD at various concentrations was separately added to a human glioma cell line (U251) and a mouse embryo fibroblast cell line (3T3) (control) for incubation in dark conditions. To test its photodynamic effect, the U251 and 3T3 cells were then irradiated for 5-60 min, using a 632.8-nm laser., Results: This QD (Φ = 3.75 nm, photoluminescence (PL) peak wavelength = 700 nm, photoluminescence quantum yield (PLQY) = 20 %), was a spherical crystal with excellent monodispersity. Under a confocal microscope, U251 cells were visualized, but not the 3T3 cells. In dark conditions, the survival rates of both U251 and 3T3 cells were above 85 %. After laser irradiation, the survival rate of U251 cells decreased to 37 ± 1.6 % as the irradiation time and the CdTe-RGD concentration were increased., Conclusions: With good physicochemical characteriistics and low toxicity, this QD-RGD has broad prospects for use in the biomedical imaging and photodynamic therapy of gliomas.

Background: Surgery of low-grade gliomas (LGGs) in eloquent areas still presents a challenge. New technologies have been introduced to enable the performance of "functional", customized preoperative planning aimed at maximal resection, while reducing the risk of postoperative deficits. We describe our experience in the surgery of LGGs in eloquent areas using preoperative planning based on navigated transcranial magnetic stimulation (nTMS) and diffusion tensor imaging (DTI) tractography., Methods: Sixteen patients underwent preoperative planning, using nTMS and nTMS-based DTI tractography. Motor and language functions were mapped. Preoperative data allowed for tailoring of the surgical strategy. The impact of these modalities on surgical planning was evaluated. Influence on functional outcome was analyzed in comparison with results in a historical control group., Results: In 12 patients (75 %), nTMS added useful information on functional anatomy and surgical risks. Surgical strategy was modified in 9 of 16 cases (56 %). The nTMS "functional approach" provided a good outcome at discharge, with a decrease in postoperative motor and/or language deficits, as compared with controls (6 vs. 44 %; p = 0.03)., Conclusions: The functional preoperative mapping of speech and motor pathways based on nTMS and DTI tractography provided useful information, allowing us to plan the best surgical strategy for radical resection; this resulted in improved postoperative neurological results.

Background: Cerebral radiation necrosis (RN) is a severe complication of radiotherapy for cerebral pathologies. This study discusses the radiographic and pathological features of 12 patients with RN and investigates the management strategy., Methods: Eleven patients with brain tumors, and one with cerebral cavernous angioma, treated by surgical resection or Gamma Knife alone before radiotherapy developed RN during follow-up. Surgical resection for the cerebral RN was performed in nine patients, and the other three patients received medical treatment. The clinical features, magnetic resonance imaging (MRI), surgical findings, and pathological sections are reviewed., Results: The diagnosis of RN was confirmed by histological study in all the patients; those with surgical and medical treatment recovered., Conclusion: As a major complication of radiotherapy, from the clinical and neuroradiological points of view, RN may simulate tumor recurrence. Due to the increasing number of patients with RN who will need to be treated in future years, the definite diagnosis and appropriate treatment of RN remain critical.

Introduction: Functional MRI (fMRI) can assess language lateralization in brain tumor patients; however, this can be limited if the primary language area-Broca's area (BA)-is affected by the tumor. We hypothesized that the middle frontal gyrus (MFG) can be used as a clinical indicator of hemispheric dominance for language during presurgical workup., Methods: Fifty-two right-handed subjects with solitary left-hemispheric primary brain tumors were retrospectively studied. Subjects performed a verbal fluency task during fMRI. The MFG was compared to BA for fMRI voxel activation, language laterality index (LI), and the effect of tumor grade on the LI., Results: Language fMRI (verbal fluency) activated more voxels in MFG than in BA (MFG = 315, BA = 216, p < 0.001). Voxel activations in the left-hemispheric MFG and BA were positively correlated (r = 0.69, p < 0.001). Mean LI in the MFG was comparable to that in BA (MFG = 0.48, BA = 0.39, p = 0.06). LIs in MFG and BA were positively correlated (r = 0.62, p < 0.001). Subjects with high-grade tumors demonstrate lower language lateralization than those with low-grade tumors in both BA and MFG (p = 0.02, p = 0.02, respectively)., Conclusion: MFG is comparable to BA in its ability to indicate hemispheric dominance for language using a measure of verbal fluency and may be an adjunct measure in the clinical determination of language laterality for presurgical planning.

A description is given of the clinical, neuropsychological, and neuroimaging evolution of a 12-year-old boy (CG) who presented with bilateral thalamic astrocytoma (World Health Organization Grade 2). CG underwent an extensive neuropsychological assessment immediately after biopsy prior to any medical therapies and was followed up for 3 years until death. Neuropsychological functioning was thoroughly investigated by means of a detailed battery that included intelligence and cognitive functions. Evolution was characterized by cognitive deterioration that preceded neuroimaging signs of tumor progression. Starting from normal cognitive organization, the child exhibited visuospatial memory deficits and, afterward, diffuse cognitive impairment. The role of neuropsychological assessment in detecting early disease progression is discussed, mainly for rare pathologies whose evolution may be extremely variable.

Glioblastoma multiforme (GBM) is the most common and malignant primary brain tumour, with very poor prognosis. The high recurrence rate and failure of conventional treatments are expected to be related to the presence of radio-resistant cancer stem cells (CSCs) inside the tumour mass. CSCs can both self-renew and differentiate into the heterogeneous lineages of cancer cells. Recent evidence showed a higher effectiveness of C-ions and protons in inactivating CSCs, suggesting a potential advantage of Hadrontherapy compared with conventional radiotherapy for GBM treatment. To investigate the mechanisms involved in the molecular and cellular responses of CSCs to ionising radiations, two GBM stem cell (GSC) lines, named lines 1 and 83, which were derived from patients with different clinical outcomes and having different metabolic profiles (as shown by NMR spectroscopy), were irradiated with (137)Cs photons and with protons or C-ions of 62 MeV u(-1) in the dose range of 5-40 Gy. The biological effects investigated were: cell death, cell cycle progression, and DNA damage induction and repair. Preliminary results show a different response to ionising radiation between the two GSC lines for the different end points investigated. Further experiments are in progress to consolidate the data and to get more insights on the influence of radiation quality., (© The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

High-grade gliomas are the main cause of death in children with brain tumours. Despite recent advances in cancer therapy, their prognosis remains poor and the treatment is still challenging. To date, surgery followed by radiotherapy and temozolomide is the standard therapy. However, increasing knowledge of glioma biology is starting to impact drug development towards targeted therapies. The identification of agents directed against molecular targets aims at going beyond the traditional therapeutic approach in order to develop a personalized therapy and improve the outcome of pediatric high-grade gliomas. In this paper, we critically review the literature regarding the genetic abnormalities implicated in the pathogenesis of pediatric malignant gliomas and the current development of molecularly targeted therapies. In particular, we analyse the impact of molecular biology on the prognosis and treatment of pediatric high-grade glioma, comparing it to that of adult gliomas.

A 52-year-old woman displayed a brain-MRI depicting a left lateral ventricle mass, associated with cystic component, extending controlaterally. Histological examination revealed neuronal differentiation with neurocytes and small ganglionic cells and the tumour was graded as a ganglioneurocytoma. We report the first case of a cystic ganglioneurocytoma with an intraventricular location.

In this brief report we have described eight children affected by optic pathway/hypothalamus gliomas and treated with carboplatin and/or cisplatin, which developed a derangement of sodium and water metabolism, due to diabetes insipidus (DI) or to syndrome of inappropriate antidiuretic hormone secretion (SIADH) after surgical resection. In four out of these eight patients the treatment with platinum compounds produced prolonged haematological toxicity and in five out of them it caused neurosensorial bilateral hypoacusia. In addition cisplatin worsened electrolytes disturbances. Hence children with DI or SIADH should be carefully monitored before, during and after the treatment with platinum compounds.

The treatment of children with malignant glioma remains challenging. The aim of this multicenter phase I study is to establish the recommended dose (RD) of the combination therapy with temozolomide (TMZ) and oral etoposide (VP-16) in children with relapsed or refractory malignant glioma and brainstem glioma at diagnosis. A phase I trial was conducted to establish the maximum tolerated dose (MTD) of TMZ and oral VP-16. This orally administered combination was investigated by a classical 3 + 3 design. Cohorts of patients were enrolled at 4 different levels: (1) TMZ 120 mg/m(2) on days 1-5 and VP-16 50 mg/m(2) on days 1-8; (2) TMZ 150 mg/m(2) on days 1-5 and VP-16 50 mg/m(2) on days 1-8; (3) TMZ 150 mg/m(2) on days 1-5 and VP-16 50 mg/m(2) on days 1-10; (4) TMZ 150 mg/m(2) on days 1-5 and VP-16 50 mg/m(2) on days 1-12. Therapy was administered in 28-day courses. A total of 118 courses were administered to 18 patients with a median age of 11.2 years. At dose level 1, none displayed toxicity. Of the 6 patients at dose level 2, 1 patient had dose limiting toxicity (DLT). None of the 3 patients at dose level 3 had DLT. At dose level 4, grade III/IV thrombocytopenia and neutropenia were observed in 2 out of the 6 patients enrolled. Therefore, the MTD was established at dose level 3. The RD for phase II trial in children with malignant glial is TMZ 150 mg/m(2) for 5 days and VP-16 50 mg/m(2) for 10 days every 28 days.

We report on glioblastoma multiple spinal intraaxial metastases with primary disease radiologically under control. The case highlights glioblastoma biological behavior and spread mechanisms; dissemination may have occurred initially and been controlled by chemotherapy, or more likely, is an indicator that even if radiologically dormant, disease is unlikely biologically inactive.

The gene expression pattern of glioblastoma (GBM) is well documented but the expression profile of brain adjacent to tumor is not yet analysed. This may help to understand the oncogenic pathway of GBM development. We have established the genome-wide expression profiles of samples isolated from GBM tumor mass, white matter adjacent to tumor (apparently free of tumor cells), and white matter controls by using the Affymetrix HG-U133 arrays. Array-CGH (aCGH) was also performed to detect genomic alterations. Among genes dysregulated in peritumoral white matter, 15 were over-expressed, while 42 were down-regulated when compared to white matter controls. A similar expression profile was detected in GBM cells. Growth, proliferation and cell motility/adhesion-associated genes were up-regulated while genes involved in neurogenesis were down-regulated. Furthermore, several tumor suppressor genes along with the KLRC1 (a member of natural killer receptor) were also down-regulated in the peritumoral brain tissue. Several mosaic genomic lesions were detected by aCGH, mostly in tumor samples and several GBM-associated mosaic genomic lesions were also present in the peritumoral brain tissue, with a similar mosaicism pattern. Our data could be explained by a dilution of genes expressed from tumor cells infiltrating the peritumour tissue. Alternatively, these findings could be substained by a relevant amount of "apparently normal" cells presenting a gene profile compatible with a precancerous state or even "quiescent" cancer cells. Otherwise, the recurrent tumor may arise from both infiltrating tumor cells and from an interaction and recruitment of apparently normal cells in the peritumor tissue by infiltrating tumor cells.

Two main varieties of recognition disorders are distinguished in neuropsychology: agnosias and semantic disorders. The term agnosias is generally used to denote recognition defects limited to a single perceptual modality (which is itself apparently intact), whereas the term semantic disorders is used to denote recognition defects involving all the sensory modalities in a roughly similar manner. Brain tumors can be one of the aetiologies underlying agnosias and semantic disorders. However, due to the heterogeneity and the rarity of recognition disorders, their investigation can be useful only to suggest or exclude the oncological nature of a brain lesion, but not to systematically monitor the clinical outcome in tumor patients. Furthermore, the relevance of recognition disorders as a hint toward a diagnosis of brain tumor varies according to the type of agnosia and of semantic disorder and the localization of the underlying brain pathology. The hypothesis that a variety of agnosia (or of semantic disorder) may be due to a neoplastic lesion can, therefore, be advanced if it is consistent with our knowledge about the usual localization and the growing patterns of different types of brain tumors.

The exceptional case of a 19-month-old boy with an apparently isolated frontal lesion and a huge holocord neoplastic involvement, presenting with a subtly indolent preoperative course and a particularly tumultuous evolution, is reported. The diagnosis of embryonal tumour with abundant neuropil and true rosettes was posed.

Background: The prognosis of patients with advanced neuroblastoma (NB) remains poor. Major and early responses have an important bearing on treatment outcome. Iodine-131-metaiodobenzylguanidine (¹³¹I-MIBG) has the potential to deliver large doses of radiation specifically to NB cells. We evaluated the toxicity of, and response to, a novel induction regimen that included ¹³¹I-MIBG combined with cisplatin, cyclophosphamide, etoposide, vincristine, and doxorubicin., Procedure: Thirteen children over 1 year of age with advanced NB at diagnosis were investigated extensively. ¹³¹I-MIBG was administered on day 10; this was preceded by chemotherapy in the five patients in group 1 (described in our previous study), and both preceded and followed by chemotherapy in the eight patients in group 2. The final induction regimen (used for group 2) lasted 1 month. Evaluation was performed 40 days after the start of treatment., Results: In both groups 1 and 2, the extent of hematologic toxicity, which was the only side effect, was similar to that seen with chemotherapy alone. Doses of ¹³¹I-MIBG as high as 16.6 mCi/kg showed no evidence of toxicity, even in patients with extensive bone marrow infiltration. Overall, we recorded two patients with a complete response (CR), six very good partial responses (VGPR), four partial responses (PR), and one mixed response (MR). In group 2, CR/VGPR were observed in patients treated with higher doses of ¹³¹I-MIBG., Conclusions: The results of this pilot study show that ¹³¹I-MIBG, in combination with chemotherapy, appears to play an important role in a new and effective induction regimen for advanced NB., (Copyright © 2011 Wiley-Liss, Inc.)

Temozolomide (TMZ) is an oral alkylating agent with proven antitumoral activity in preclinical and clinical studies in adults with high-grade glioma (HGG). However, only limited efficacy has been reported in children with HGG using the 5-day schedule. This study investigated the safety of administering TMZ to children and adolescents with brain tumors over an extended period. Extended schedules have been proven to overcome chemoresistance without any major toxicity. The toxicity of TMZ, administered at 70 mg/m(2)/day orally for 21 consecutive days every 28 days, was assessed in children with brain tumors. A total of 156 courses of TMZ were given to 17 patients (median age 12.5 years, range 1-17 years), who were recruited into the study. Eleven patients had progressive or relapsing disease, and six patients were newly diagnosed. In this cohort no cases of toxic death or nonhematological toxicity were reported. In comparison with the 5-day schedule, thrombocytopenia and neutropenia were noted to be less frequent. Grades 3 and 4 lymphopenia occurred in 10.8 and 22.4% of courses, respectively; among the lymphopenic patients there was one case of disseminated zoster (meningoencephalitis and cutaneous involvement), one case of rotavirus gastroenteritis, and two cases of herpetic stomatitis reported. The objective response rate was 11.8%. Overall, 82.3% of patients showed stable disease. The prolonged TMZ schedule appeared to be well tolerated, with few cases of neutropenia or thrombocytopenia recorded. Nevertheless, prolonged exposure to TMZ was associated with lymphopenia and may lead to a higher rate of viral infections.

Purpose: Cancer stem cells (CSC) are thought to represent the population of tumorigenic cells responsible for tumor development. The stem cell antigen CD133 identifies such a tumorigenic population in a subset of glioblastoma patients. We conducted a prospective study to explore the prognostic potential of CSC analysis in glioblastoma patients., Experimental Design: We investigated the relationship between the in vitro growth potential of glioblastoma CSCs and patient death or disease progression in tumors of 44 consecutive glioblastoma patients treated with complete or partial tumorectomy followed by radiotherapy combined with temozolomide treatment. Moreover, we evaluated by immunohistochemistry and immunofluorescence the prognostic value of the relative presence of CD133+ and CD133+/Ki67+ cells in patient tumors., Results: In vitro CSC generation and the presence of > or = 2% CD133+ cells in tumor lesions negatively correlated with overall (P = 0.0001 and 0.02, respectively) and progression-free (P = 0.0002 and 0.01, respectively) survival of patients. A very poor overall (P = 0.007) and progression-free (P = 0.001) survival was observed among patients whose tumors contained CD133+ cells expressing Ki67. Taking into account symptom duration, surgery type, age, O6-methylguanine-DNA methyltransferase promoter methylation, and p53 status, generation of CSCs and CD133/Ki67 coexpression emerged as highly significant independent prognostic factors, with an adjusted hazard ratio of 2.92 (95% confidence interval, 1.37-6.2; P = 0.005) and 4.48 (95% confidence interval, 1.68-11.9; P = 0.003), respectively., Conclusions: The analysis of CSCs may predict the survival of glioblastoma patients. In vitro CSC generation and presence of CD133+/Ki67+ cells are two considerable prognostic factors of disease progression and poor clinical outcome.

Objects: Radiation-induced cerebral tumours constitute a significant risk for subjects undergoing radiotherapy for the management of cerebral neoplasms. Age-related cerebral vulnerability could be a specific factor in the genesis of these complications., Methods: The pertinent literature of both paediatric and adult series has been reviewed. Three personal cases were added., Results: One hundred forty-two paediatric second brain tumours were evaluated. Out of them, 69 were malignant gliomas, 33 meningiomas, 8 sarcomatous lesions and 13 low-grade astrocytomas. The average latency period for the appearance of the second tumour was 8 years. Among the second tumours occurring in adults, meningioma is the most common. In this subgroup, the latency period ranged between 16 and 30 years., Conclusion: Paediatric radiation-induced brain tumours differ from the adult counterpart for both the histological subtypes. These figures indicate a specific vulnerability of the infantile brain demonstrated by the most frequent occurrence of highly malignant lesions.

Object: The aim in this study was to assess the state and trait types of anxiety as well as current depression before and after surgery in patients affected by brain tumors. The relationships between these affective disorders and the patient's sex, tumor histology, and laterality of the tumor were also evaluated., Methods: A total of 72 patients affected by a primary brain tumor were enrolled in the study. Histological grades were assigned according to the World Health Organization classification. State and trait anxiety were assessed using the State and Trait Anxiety Inventory; current depression was assessed using the Zung Self-Rating Depression Scale. Cognitive impairment was assessed using the 10-item Short Portable Mental Status Questionnaire. Psychometric evaluation was assessed before surgery and at 1, 3, 6, and 12 months after surgery., Results: Before brain surgery, 62.5% of patients showed state anxiety, 50% of patients showed trait anxiety, and 9.7% of patients showed current depression. During the follow-up period there was no significant variation in the percentage of patients with state anxiety (p=0.416) and trait anxiety (p=0.7), whereas a significant increase in the percentage of those with current depression was found (p<0.0001), in particular at 1 month (p=0.002) and 3 months (p=0.039) after surgical treatment. The tumor's laterality and histology showed no correlation with psychometric variables, whereas a relationship between the presence of trait anxiety at the enrollment and current depression after surgery (p<0.0001) was found., Conclusions: Patients affected by brain tumors frequently experience affective disorders. After brain surgery, a depressive state can develop. The psychometric assessment could be useful in these patients for quick recognition of psychological disorders.

FEATURES OF TEMOZOLOMIDE: Temozolomide (TMZ) belongs to the imidazotetrazine class and it is a DNA-methylating agent that has a good antitumor activity. Despite of dacarbazine, TMZ is spontaneously converted into its active metabolite 5-(3-methyltriazen-l-yl)imidazole-4-carboxamide at physiologic pH, so it is not required in enzymatic demethylation in the liver. TMZ is able to cross the blood brain barrier and is stable at gastric acid pH so it has almost 100% oral bioavailability and is rapidly absorbed after it is taken orally., Temozolomide in Cancer Patients: On the basis of the relatively safe toxicity and the findings achieved in adult malignant gliomas, phase I and II clinical trials were set up to evaluate the opportunity of using this novel drug in pediatric cancer, too. In this review, we evaluate the antitumor activity of TMZ against high-grade gliomas, low-grade-gliomas, and medulloblastoma/primitive neuroectodermal tumors analyzing several phases I and II clinical trials in children., Conclusions: In spite of the poor activity of TMZ against pediatric brain tumors, the use of the drug in combination with other compounds should be evaluated in phases I and II clinical trials. Moreover, the evaluation of the methylation status of the O6-methylguanine DNA methyltransferase promoter in glioblastoma biopsy specimens could be assayed as a predictive factor of TMZ efficacy.

Background: Prevention of meningeal recurrence achieved by intrathecal methotrexate (MTX) and systemic chemotherapy is part of standard acute lymphoblastic leukemia (ALL) treatment. Cranial irradiation has been a routine part of past protocol treatment but is currently reserved only for select subsets of patients. Central nervous system (CNS) prophylaxis may cause brain abnormalities such as intracerebral calcifications, cerebral atrophy, and white matter alterations. In addition, long-term neuropsychologic sequelae following CNS prophylaxis have been investigated marginally in children cured for ALL., Methods: To explore possible correlations between neuroimaging findings and neuropsychologic outcome, we used detailed cognitive tests to evaluate 21 children with ALL who received cranial irradiation (range, 18-24 Gy) plus intrathecal MTX as CNS prophylaxis. All children were followed prospectively once a year by cerebral computed tomographic scan and magnetic resonance imaging. All patients had continuous complete disease remission for at least 4 years and cognitive tests were performed after neuroradiologic examinations., Results: White matter abnormalities were associated with poor performance only in a task exploring visual motor integration in about 50% of patients. Intracerebral calcifications correlate with the number of intrathecal MTX doses and with low scores in total intellectual quotient, performance intellectual quotient, and significant impairment in attention and visual motor integration tests. Girls are more vulnerable to the effects of CNS prophylaxis, whereas age at treatment and radiotherapy dose are not relevant to neuropsychologic outcome., Conclusions: Our results indicate the need for careful follow-up of children's cognitive abilities because global intellectual measures often fail to detect specific disorders that may cause learning difficulties. Moreover, as the clinical implications of neuroimaging findings are often limited, periodic extensive evaluation by specific neurocognitive tests of mental abilities is recommended to detect early signs of cognitive impairment., (Copyright 2002 American Cancer Society.DOI 10.1002/cncr.10997)

Hypersensitivity reactions to carboplatin are rare but sometimes life-threatening events may occur requiring discontinuation of treatment. In our study, we describe clinical features and diagnostic procedures of carboplatin-associated reactions in children affected by low-grade astrocytoma and treated with multiple courses of carboplatin. In 6 out of 29 children, we reported allergic events. We also report a desensitization protocol for carboplatin administration, which allowed the patients to receive effective treatment without adverse reactions.

Objective: The prognosis of non-small cell lung cancer (NSCLC) with brain metastasis is very poor, with median survival rate below 6 months, even if treated with palliative radio and/or chemotherapy. To assess the effectiveness of surgical treatment for this kind of patients we reviewed our experience., Methods: From January 1989 to October 1999, 30 patients (26 males and four females; mean age: 58.7 years) with NSCLC and single brain metastasis underwent surgical treatment of both primary lung cancer and secondary cerebral lesion. Patients (pts) were divided into two major groups. In group 1 (G1) 20 pts (18 males and two females) presented a synchronous brain metastasis. In group 2 (G2) 10 pts (eight males and two females) presented a metachronous brain metastasis during the follow-up period (range 3-24 months since the primary tumor). Patients selected in G1 had T1-2, N0-1 clinical staging, good 'performance status' (ECOG:0--1; Karnofsky index > 70%), age < 75 years. Craniotomy has always been the first approach. In G2 also patients with locally advanced tumors (T3 and/or N2) were included. Whole brain radiotherapy and/or chemotherapy was the post-operative choice treatment., Results: Histologic findings have shown: adenocarcinoma in 17 cases (12 in G1; five in G2), squamous cell carcinoma in 10 cases (six in G1; four in G2), large cell carcinoma in 2 (one in G1; one in G2) and large cell neuroendocrine carcinoma in one (G1). Survival analysis (Kaplan--Meier method) has shown an overall value of 80% at 1 year (95% in G1; 50% in G2), 41% at 2 years (47% in G1; 30% in G2) and 17% at 3 years (14% in G1; 20% in G2). Overall median survival is 23 months (23 in G1; 11 in G2); mean survival 27.8 months (30.3 months in G1; 22.8 months in G2). According to univariate analysis prognosis is definitively better in N0 tumors compared to N1-2 tumors and in adenocarcinoma cases compared to other histotypes (P < 0.05)., Conclusions: We can conclude that combined surgical therapy is, nowadays, the choice treatment for this kind of patients, even though restricted to selected cases. The knowledge of prognostic factors may optimize indications for surgery.

Sixteen patients with high risk MB/PNET at diagnosis were included in a pilot study employing carboplatin (CBDCA) as a single drug prior to conventional therapy. The main goal of the study was to identify in a short-term trial a significant response that would predict further response to CBDCA in the single patient. Exploration of CBDCA activity was focused on response after the first course as compared to the response following the second course. A course consisted of CBDCA 600 mg/m2 on days 1 and 2 administered in a 1 h infusion to be repeated 3-4 weeks later. After two cycles we observed 1 CR and 9 PR, that is a 62% response rate. The first course resulted in 5 PR, 5 MR, 5 SD, and 1 PD; after the subsequent course in all responding patients, response persisted or improved whereas in no patient with SD any improvement was observed. The correlation of response to the first course with response to the second course was statistically significant (P = 0.0009). The main toxicity of the single course was hematologic and consisted of rapidly reversible grade 3-4 neutropenia and thrombocytopenia in 94% of patients. Pharmacokinetic studies showed a very limited interpatient variability of both Cmax 57.6 +/- 9.9 micrograms/ml) and AUC (15.3 +/- 1.5 mg/ml.min) of free CBDCA, which eliminates an important variable in the evaluation of response. In conclusion, this "in vivo test" appears effective, reasonably safe, and reproducible in identifying patients likely to benefit from CBCDA: after a period of time as short as 3-4 weeks following the first course, multidrug chemotherapy including CBDCA may be employed in the responding patients, whereas an alternative regimen would be indicated in the non-responding patients.