Prognostic role and interaction of TERT promoter status, telomere length and MGMT promoter methylation in newly diagnosed IDH wild-type glioblastoma patients.

BACKGROUND: The clinical relevance of promoter mutations and single nucleotide polymorphism rs2853669 of telomerase reverse transcriptase (TERT) and telomere length in patients with isocitrate dehydrogenase (IDH) wild-type glioblastoma (GBM) patients remains unclear. Moreover, some studies speculated that TERT promoter status might influence the prognostic role of O6-methylguanine DNA methyltransferase (MGMT) promoter methylation in newly diagnosed GBM. We carried out a large study to investigate their clinical impact and their interaction in newly diagnosed GBM patients. PATIENTS AND METHODS: We included 273 newly diagnosed IDH wild-type GBM patients who started treatment at Veneto Institute of Oncology IOV - IRCCS (Padua, Italy) from December 2016 to January 2020. TERT promoter mutations (-124 C>T and -146 C>T) and SNP rs2853669 (-245 T>C), relative telomere length (RTL) and MGMT methylation status were retrospectively assessed in this prospective cohort of patients. RESULTS: Median overall survival (OS) of 273 newly diagnosed IDH wild-type GBM patients was 15 months. TERT promoter was mutated in 80.2% of patients, and most had the rs2853669 single nucleotide polymorphism as T/T genotype (46.2%). Median RTL was 1.57 (interquartile range 1.13-2.32). MGMT promoter was methylated in 53.4% of cases. At multivariable analysis, RTL and TERT promoter mutations were not associated with OS or progression-free survival (PFS). Notably, patients C carrier of rs2853669 (C/C+C/T genotypes) showed a better PFS compared with those with the T/T genotype (hazard ratio 0.69, P = 0.007). In terms of OS and PFS, all interactions between MGMT, TERT and RTL and between TERT and rs2853669 genotype were not statistically significant. CONCLUSIONS: Our findings suggest the presence of the C variant allele at the rs2853669 of the TERT promoter as an attractive independent prognostic biomarker of disease progression in IDH wild-type GBM patients. RTL and TERT promoter mutational status were not correlated to survival regardless of MGMT methylation status.

Multishell Diffusion MRI-Based Tractography of the Facial Nerve in Vestibular Schwannoma.

BACKGROUND AND PURPOSE: Tractography of the facial nerve based on single-shell diffusion MR imaging is thought to be helpful before surgery for resection of vestibular schwannoma. However, this paradigm can be vitiated by the isotropic diffusion of the CSF, the convoluted path of the facial nerve, and its crossing with other bundles. Here we propose a multishell diffusion MR imaging acquisition scheme combined with probabilistic tractography that has the potential to provide a presurgical facial nerve reconstruction uncontaminated by such effects. MATERIALS AND METHODS: Five patients scheduled for vestibular schwannoma resection underwent multishell diffusion MR imaging (b-values = 0, 300, 1000, 2000 s/mm2). Facial nerve tractography was performed with a probabilistic algorithm and anatomic seeds located in the brain stem, cerebellopontine cistern, and internal auditory canal. A single-shell diffusion MR imaging (b-value = 0, 1000 s/mm2) subset was extrapolated from the multishell diffusion MR imaging data. The quality of the facial nerve reconstruction based on both multishell diffusion MR imaging and single-shell diffusion MR imaging sequences was assessed against intraoperative videos recorded during the operation. RESULTS: Single-shell diffusion MR imaging-based tractography was characterized by failures in facial nerve tracking (2/5 cases) and inaccurate facial nerve reconstructions displaying false-positives and partial volume effects. In contrast, multishell diffusion MR imaging-based tractography provided accurate facial nerve reconstructions (4/5 cases), even in the presence of ostensibly complex patterns. CONCLUSIONS: In comparison with single-shell diffusion MR imaging, the combination of multishell diffusion MR imaging-based tractography and probabilistic algorithms is a more valuable aid for surgeons before vestibular schwannoma resection, providing more accurate facial nerve reconstructions, which may ultimately improve the postsurgical patient's outcome.

Multi-option therapy vs observation for small acoustic neuroma: hearing-focused management.

The current treatment options for acoustic neuromas (AN) - observation, microsurgery and radiotherapy - should assure no additional morbidity on cranial nerves VII and VIII. Outcomes in terms of disease control and facial function are similar, while the main difference lies in hearing. From 2012 to 2016, 91 of 169 patients (54%) met inclusion criteria for the present study, being diagnosed with unilateral, sporadic, intrameatal or extrameatal AN up to 1 cm in the cerebello-pontine angle; the remaining 78 patients (46%) had larger AN and were all addressed to surgery. The treatment protocol for small AN included observation, translabyrinthine surgery, hearing preservation surgery (HPS) and radiotherapy. Hearing function was assessed according to the Tokyo classification and the American Academy of Otolaryngology-Head and Neck Surgery (AAO-HNS) classification. Sixty-one patients (71%) underwent observation, 19 (22%) HPS and 6 (7%) translabyrinthine surgery; 5 patients were lost to follow-up. Median follow-up was 25 months. In the observation group, 24.6% of patients abandoned the wait-and-see policy for an active treatment; the risk of switching from observation to active treatment was significant for tumour growth (p = 0.0035) at multivariate analysis. Hearing deteriorated in 28% of cases without correlation with tumour growth; the rate of hearing preservation for classes C-D was higher than for classes A-B (p = 0.032). Patients submitted to HPS maintained an overall preoperative hearing class of Tokyo and AAO-HNS in 63% and 68% of cases, respectively. Hearing preservation rate was significantly higher for patients presenting with preoperative favourable conditions (in-protocol) (p = 0.046). A multi-option management for small AN appeared to be an effective strategy in terms of hearing outcomes.

Cognitive Rehabilitation in Patients with Gliomas and Other Brain Tumors: State of the Art.

Disease prognosis is very poor in patients with brain tumors. Cognitive deficits due to disease or due to its treatment have an important weight on the quality of life of patients and caregivers. Studies often take into account quality of life as a fundamental element in the management of disease and interventions have been developed for cognitive rehabilitation of neuropsychological deficits with the aim of improving the quality of life and daily-life autonomy of patients. In this literature review, we will consider the published studies of cognitive rehabilitation over the past 20 years.

Cell Therapy for Parkinson's Disease: A Translational Approach to Assess the Role of Local and Systemic Immunosuppression.

Neural transplantation is a promising therapeutic approach for neurodegenerative diseases; however, many patients receiving intracerebral fetal allografts exhibit signs of immunization to donor antigens that could compromise the graft. In this context, we intracerebrally transplanted mesencephalic pig xenografts into primates to identify a suitable strategy to enable long-term cell survival, maturation, and differentiation. Parkinsonian primates received WT or CTLA4-Ig transgenic porcine xenografts and different durations of peripheral immunosuppression to test whether systemic plus graft-mediated local immunosuppression might avoid rejection. A striking recovery of spontaneous locomotion was observed in primates receiving systemic plus local immunosuppression for 6 mo. Recovery was associated with restoration of dopaminergic activity detected both by positron emission tomography imaging and histological examination. Local infiltration by T cells and CD80/86+ microglial cells expressing indoleamine 2,3-dioxigenase were observed only in CTLA4-Ig recipients. Results suggest that in this primate neurotransplantation model, peripheral immunosuppression is indispensable to achieve the long-term survival of porcine neuronal xenografts that is required to study the beneficial immunomodulatory effect of local blockade of T cell costimulation.

Spontaneous involution of diffuse fibrous dysplasia of paranasal sinuses.

We report the case of a 25-year-old patient, diagnosed at age 10, with diffuse fibrous dysplasia of the paranasal sinuses, an extremely rare idiopathic condition. This diagnosis is possible only by cerebral computed tomography (CT), cerebral and anterior skull base magnetic resonance imaging (MRI), and histopathology. Surgical treatment is common. This boy had mild symptoms: moderate headache in the morning that did not affect his daily activity, and rhinitis, partially responsive to medication. The neurologic examination was abnormal. Radiographs, CT, and MRI showed a diffuse mass in the paranasal sinuses which had a histopathological diagnosis of fibrous dysplasias. The family refused to refer the patient to surgery. The boy has been monitored annually for 15 years. He has remained asymptomatic without headache since age 11, with normal, general and neurologic examinations. Serial MRIs showed a spontaneous partial involution of the mass.

Cognitive outcome as part and parcel of clinical outcome in brain tumor surgery.

Although validated tools (neuropsychological tests, patient reported outcomes, mood and psychological profile) were first introduced many years ago in clinical practice, the impact of the tumor itself on patient cognition has not been extensively studied. Furthermore, while outcome research is evolving in an attempt to adapt the use of different tools to the preoperative and postoperative phases, the standard guidelines for evaluating outcome after brain surgery, by neurological examination and complication assessment, are frequently neglected in the current literature. This article attempts to provide an appraisal of the evidence for the impact of surgical treatment on cognitive function of brain tumor patients within the context of general outcome.

Hydrocephalus in infants less than six months of age: effectiveness of endoscopic third ventriculostomy.

OBJECTIVE: Although endoscopic third ventriculostomy (ETV) is a well established procedure for the treatment of congenital and acquired hydrocephalus, there is still a controversy with regard to the higher risk of failure in younger infants compared to older children after such a procedure. The aim of this article is to define the effectiveness of third ventriculostomy for hydrocephalus in infants less than 6 months of age better and to determine possible positive predictive factors. MATERIALS AND METHODS: In a series of 126 consecutive patients who underwent ETV between January 2000 and December 2002, 21 procedures were performed on infants ranging in age from 23 to 180 days, and without a previous history of shunting. The follow-up period was 49 to 82 months. RESULTS: The overall success rate of ETV was 67% (14/21). All failures occurred in the early postoperative period (average 38 days, range 25-88 days). The success rate varied with the etiology of the patient's hydrocephalus. The best results were obtained in patients with acqueductal stenosis, Dandy-Walker malformation and myelomeningocele. The least favorable results (50% failure rate) occurred in infants treated for post-hemorrhagic and post-meningitic hydrocephalus. CONCLUSION: This study does not demonstrate a correlation between the age of the infants and the ETV success rate. The specific etiology of hydrocephalus is the most relevant prognostic factor in infants under six months of age.

Hypophyseal triplication: case report and embryologic considerations.

SUMMARY: Hypophyseal triplication is malformation that has not been described previously. We present a child with midline abnormalities who underwent epignathus excision at birth. Brain MR imaging revealed 2 paired lateral pituitary glands and an oval midline gland, each with an independent stalk, connected to a thickened third ventricle floor. Because malformations represent a failure in embryogenesis, this case may provide interesting clues on the normal development of the hypophysis.

Venous stroke can be the unusual clinical presentation of an arising naso-ethmoidal encephalo-meningocele in adulthood.

Trans-ethmoidal encephalo-meningocele is an extremely rare event among the adult population. It mainly affects young people who have previously reported a head injury. Even though early treatment is mandatory to avoid septic complications, the diagnosis is usually late because of the misleading symptomatology. We describe the unusual clinical history of an adult patient with a giant trans-ethmoidal encephalo-meningocele. A 61-year-old woman presented progressively more intense headache and rhinorrhea. No trauma was reported. We learned that she had a history of misunderstood spontaneous rhinorrhea beginning two years before, followed one year later by a lateral sinus thrombosis which worsened the cerebrospinal fluid leakage. Some months after stroke a new cerebral magnetic resonance scan revealed a giant trans-ethmoidal encephalo-meningocele. The brain herniation was surgically removed by a subfrontal intradural approach through a frontal craniotomy. Even rare, giant naso-ethmoidal encephalo-meningocele has to be considered in adult patients presenting with rhinorrhea even without a history of meningitis or neurological defects. Venous stroke can affect patients in whom prolonged CSF leakage occurs because of misunderstood cerebrospinal fistula. These patients must be monitored after stroke for the possible onset of an encephalo-meningocele.

Endoscopic treatment of hydrocephalus due to aneurysm of the vein of Galen: case report and literature review.

Aneurysms of the vein of Galen are uncommon vascular malformations. They are most frequently seen in infants and children, leading to heart failure and hydrocephalus. Exceptionally, they are detected in adults. Several theories have been proposed to explain hydrocephalus in these patients: obstruction of the cerebral aqueduct, impaired absorption of CSF after subarachnoid hemorrhage, passive ex-vacuo mechanism, or thrombosis of an aneurysm. Hydrocephalus has been treated mainly with cerebrospinal shunt procedures, but also direct surgery, radiosurgery and embolisation of the malformation have proved to be effective. We report the case of a partially thrombosed ectasia of the vein of Galen in a 44-year-old male, with huge hydrocephalus successfully treated with an endoscopic third ventriculostomy.

Traumatic acute subdural haematomas of the posterior fossa: clinicoradiological analysis of 24 patients.

BACKGROUND: We report 24 patients with a traumatic acute subdural haematoma of the posterior fossa managed between 1997 and 1999 at 8 Italian neurosurgical centres. METHOD: Each centre provided data about patients' clinico-radiological findings, management, and outcomes, which were retrospectively reviewed. FINDINGS: A poor result occurred in 14 patients (58.3%). Ten patients (41.7%) had favourable results. Patients were divided into two groups according to their admission Glasgow Coma Scale (GCS) scores. In Group 1 (12/24 cases; GCS score, > or =8), the outcome was favourable in 75% of cases. In Group 2 (12/12 cases; GCS score, <8), the outcome was poor in 91.6% of cases. Nineteen patients underwent posterior fossa surgery. Factors correlating to outcome were GCS score, status of the basal cisterns and the fourth ventricle, and the presence of supratentorial hydrocephalus. Multivariate analysis showed significant independent prognostic effect only for GCS score (P<0.05). INTERPRETATION: acute posterior fossa subdural haematomas can be divided into two distinct groups: those patients admitted in a comatose state and those with a moderate/mild head injury on admission. Comatose patients present usually with signs of posterior fossa mass effect and have a high percentage of bad outcomes. On the contrary, patients admitted with a GCS of 8 or higher are expected to recover. In these patients the thickness of the haematoma (<1 cm) seems to be a guide to indicate surgical evacuation of the haematoma.

Large sphenocavernous meningiomas: is there still a role for the intradural approach via the pterional-transsylvian route?

BACKGROUND: Large-sized sphenocavernous meningiomas represent a surgical challenge. Although the role of skull base techniques with combined extra- and intradural steps has been recently emphasized, pure intradural resection tactics via the pterional route constitute the traditional microsurgical approach for resection of such tumours. METHOD: We report the application of the pterional-transsylvian approach in 13 patients with sphenocavernous meningiomas. This series is unique because it includes only patients with tumours exceeding 5 cm in their greatest dimension. FINDINGS: A gross total resection was accomplished in 10 patients (77%). Eight patients had a good outcome, one had a persistent mild hemiparesis, and one died. No recurrences occurred in this group. Three patients (23%) had subtotal resections owing to invasion of the cavernous sinus in one instance and encasement of the middle cerebral artery in the others. Two had a good outcome and one died. In these patients minimal asymptomatic tumour progression was seen 3 and 6 years after surgery. The overall surgical outcome was good in 10 patients (77%), fair in one, and death in two. INTERPRETATION: In our experience, large sphenocavernous meningiomas may be operated on adopting pure intradural resection tactics via the pterional-transsylvian route with rates of gross total removal and surgical complications related to brain retraction or vascular manipulation comparable to those of extensive skull base approaches. The traditional intradural pterional transsylvian approach continues to have a place in the treatment of these lesions.

Immunohistochemical TRF1 expression in human primary intracranial tumors.

BACKGROUND: The telomeric-repeat binding factor (TRF1) participates in a physiological homeostatic mechanism controlling telomere shortening by inhibiting telomerase activity: down-regulation of TRF1 expression results in telomere elongation and may be involved in cell immortalization. PATIENTS AND METHODS: To determine the TRF1 expression by immunohistochemistry (IHC) in human brain tumors, a cohort of 20 consecutive flash-frozen surgical specimens (14 meningiomas and 6 anaplastic astrocytomas (AA)) were collected. RESULTS: Variable levels of TRF1 expression in 12 out of the 14 (87.5%) meningioma samples were observed. By contrast, no expression of TRF1 in tissue samples from AA (p = 0.008) was detected. Positive TRF1 cells were usually more differentiated (less atypical features) and Ki67 negative (inverse statistical association, chi2 = p < 0.001). CONCLUSION: We demonstrated, for the first time, that routine IHC techniques are capable of identifying TRF1 expression in intracranial tumors, which is heterogeneously expressed in meningiomas, but absent in AA. Although these preliminary observations need confirmation from larger studies, the TRF1 status in intracranial tumors might become of prognostic value.

Traumatic intracerebellar hemorrhagic contusions and hematomas.

BACKGROUND: Traumatic intracerebellar hemorrhagic contusions and hematomas (TIHC) are unusual lesions and their surgical management remains controversial. METHODS: From January 1990 to July, 1998, 3290 patients underwent computed tomography for acute head trauma at our Institution. Eighteen patients (0.54%) were retrospectively identified as harboring TIHC. Patients were divided into two groups. In Group I (n=78) GCS at admission was > or = 9. Seven patients presented with isolated TIHC and one with an associated supratentorial lesion. Three patients exhibited an evolving clinico-radiological course. In Group II patients (n=10) GCS at admission was < or = 7. All but one presented with severe supratentorial lesions and associated brainstem signs. RESULTS: In group I six patients had their TIHC managed conservatively, and two were operated on, and all recovered completely. In group II, two patients were operated on. The outcome was poor in 90% of cases. CONCLUSIONS: TIHC constitute a protean clinico-pathological entity. Non-comatose patients with intracerebellar clots less than 3 cm in diameter should be treated conservatively and expected to make a good recovery. Surgery is indicated for larger hematomas causing cisternal and IV ventricle compression ab initio or as a result of their secondary evolution. In severely ill patients admitted comatose, it is generally the primary brain stem damage and the concomitant severe supratentorial lesions to dictate the prognosis. In these cases obliteration of the posterior fossa cisterns is the most reliable indicator of poor outcome.

Guidelines for the treatment of adults with severe head trauma (part I). Initial assessment; evaluation and pre-hospital treatment; current criteria for hospital admission; systemic and cerebral monitoring.

If pragmatic recommendations for treatment of severely head-injured patients could really be applied, they would probably have a considerable impact in terms of reduction in mortality and disability. Since 1995 a Group of Italian Neurointensivists and Neurosurgeons belonging to the Italian Societies of Neurosurgery (SINch) and Anesthesiology & Intensive Care (SIAARTI) has produced this first part of recommendations that are completed by Medical treatment (Part II) and Surgical treatment criteria (Part III). These recommendations reflect a multidisciplinary consent but are based on scientific evidence, when available, and take origin mainly from expert opinions and the current clinical and organizational situation. For this aspect they differ from other American and European guidelines, which are strictly based on criteria of proven efficacy. These recommendations aim at providing a practical reference for all those dealing with severe head injuries from first-aid to intensive care units, setting out the minimal goals of management to be reached throughout the country. For these reasons they need continual critical review and updating. Main clinical aims are: 1) to prevent secondary cerebral damage by continuous and meticulous maintenance of systemic homeostasis 2) to standardize methods of neurological evaluation and CT scan classification and scheduling; 3) to give simple indications for systemic and cerebral monitoring 4) to pragmatically discuss the organizational scenarios and specify the minimal safe clinical approach when patients are treated in non-specialized settings. Briefly, smooth tracheal intubation and ventilation in all comatose patients, administration of rapidly metabolized sedative and analgesic drugs to permit frequent neurological evaluation, restoration of volemia and systolic blood pressure above 110 mm Hg, oxygen saturation >95% and normocapnia, are all recommended from the very early treatment and transport. Homogeneity of language, reliable and correctly tested Glasgow Coma Score and pupillary reflexes, and a simple CT scan classification are recommended to improve communications and clinical decisions in the multidisciplinary setting of management. In comatose patients, cerebral perfusion pressure, intracranial pressure and oxygen jugular saturation must be monitored according to specific criteria, which are described. Therapy with hyperventilation and mannitol should be used only in case of clinical deterioration and uncal herniation. This therapy could be useful to gain time to reach neurosurgery. The aim of these recommendations is to achieve safer management of severely brain injured patients, immediate diagnosis of clinical deterioration and successful identification and treatment of surgical lesions. The impact of these guidelines requires further verification.

Guidelines for the treatment of adults with severe head trauma (part II). Criteria for medical treatment.

Since 1995 a Group of Italian Neurointensivists and Neurosurgeons belonging to the Italian Societies of Neurosurgery (SINch) and Anesthesia & Intensive Care (SIAARTI) has produced some recommendations for treatment of adults with severe head trauma. They have been published in 3 parts: Part I (Initial assessment, Evaluation and pre-hospital treatment, Criteria for hospital admission, Systemic and cerebral monitoring), Part II (Medical treatment) and Part III (Surgical treatment criteria). These recommendations reflect a multidisciplinary consent and are mostly based on expert opinion. The main aim is to provide a practical reference for all those dealing with severe head injuries from first-aid to intensive care units, setting out the minimal goals of management to be reached throughout the Country. These recommendations need a continuous critical review and updating. Medical treatment is aimed at preventing or minimizing secondary brain damage following acute brain injury, provided that surgical masses have been promptly identified and removed. In order to assure cerebral perfusion, systemic hemodynamics and respiratory exchanges should be normal. Volemia is crucial, and mean arterial pressure should remain above 90 mmHg. Good general intensive care, including gastroprotection, water-electrolyte balance, infection control, nutrition and physiotherapy, is assumed as the basis for brain-oriented therapy. Intracranial hypertension requires an approach based on various steps. First, factors that can directly rise intracranial pressure (ICP) such as venous outflow obstruction, fever, pain etc. should be checked and corrected. Second, Mannitol, CSF withdrawal, sedation and moderate hyperventilation should be applied. This can be done by targeting specific problems with specific treatment (which is possible when the cause of ICP rise is known) or in a step-wise approach, by using less aggressive interventions before than more aggressive ones, with a higher risk of complications. Third, extreme treatment, such as barbiturates, should be reserved to cases with refractory intracranial hypertension. The main goal of ICP treatment is not simply ICP reduction, but the maintenance of adequate cerebral perfusion pressure.