Selective cell cycle arrest in glioblastoma cell lines by quantum molecular resonance alone or in combination with temozolomide.

BACKGROUND: Glioblastoma is the most aggressive form of brain cancer, characterised by high proliferation rates and cell invasiveness. Despite advances in surgery and radio-chemotherapy, patients continue to have poor prognoses, with a survival rate of 14-15 months. Thus, new therapeutic strategies are needed. Non-ionising electromagnetic fields represent an emerging option given the potential advantages of safety, low toxicity and the possibility to be combined with other therapies. METHODS: Here, the anticancer activity of quantum molecular resonance (QMR) was investigated. For this purpose, three glioblastoma cell lines were tested, and the QMR effect was evaluated on cancer cell proliferation rate and aggressiveness. To clarify the QMR mechanism of action, the proteomic asset after stimulation was delineated. Mesenchymal stromal cells and astrocytes were used as healthy controls. RESULTS: QMR affected cancer cell proliferation, inducing a significant arrest of cell cycle progression and reducing cancer tumorigenicity. These parameters were not altered in healthy control cells. Proteomic analysis suggested that QMR acts not only on DNA replication but also on the machinery involved in the mitotic spindle assembly and chromosome segregation. Moreover, in a combined therapy assessment, QMR significantly enhanced temozolomide efficacy. CONCLUSIONS: QMR technology appears to be a promising tool for glioblastoma treatment.

Clipping versus coiling for treatment of middle cerebral artery aneurysms: a retrospective Italian multicenter experience.

Endovascular treatment has emerged as the predominant approach in intracranial aneurysms. However, surgical clipping is still considered the best treatment for middle cerebral artery (MCA) aneurysms in referral centers. Here we compared short- and long-term clinical and neuroradiological outcomes in patients with MCA aneurysms undergoing clipping or coiling in 5 Italian referral centers for cerebrovascular surgery. We retrospectively reviewed 411 consecutive patients admitted between 2015 and 2019 for ruptured and unruptured MCA aneurysm. Univariate and multivariate analyses of the association between demographic, clinical, and radiological parameters and ruptured status, type of surgical treatment, and clinical outcome at discharge and follow-up were performed. Clipping was performed in 340 (83%) cases, coiling in 71 (17%). Clipping was preferred in unruptured aneurysms and in those showing collateral branches originating from neck/dome. Surgery achieved a higher rate of complete occlusion at discharge and follow-up. Clipping and coiling showed no difference in clinical outcome in both ruptured and unruptured cases. In ruptured aneurysms age, presenting clinical status, intracerebral hematoma at onset, and treatment-related complications were significantly associated with outcome at both short- and long-term follow-up. The presence of collaterals/perforators originating from dome/neck of the aneurysms also worsened the short-term clinical outcome. In unruptured cases, only treatment-related complications such as ischemia and hydrocephalus were associated with poor outcome. Clipping still seems superior to coiling in providing better short- and long-term occlusion rates in MCA aneurysms, and at the same time, it appears as safe as coiling in terms of clinical outcome.

Transethmoidal encephalocele endoscopically treated in a newborn: a case report.

Congenital encephalocele is a very rare entity, with herniation of normal brain or gliotic tissue through a defect in the skull. The objective is to present a newborn child diagnosed with transethmoidal encephaloceles at birth. She developed respiratory problems, feeding difficulties, and failure to thrive since the first days of life and so required early surgery at her 33th day of life, through an endoscopic nasal approach. Technical difficulties encountered, complications, and management are discussed. To the best of our knowledge, this is the first report of endoscopic treatment of transethmoidal encephalocele in a newborn. Further studies are needed to understand the best way to repair the dural defect in this rare condition.

Neurosurgery in times of a pandemic: a survey of neurosurgical services during the COVID-19 outbreak in the Veneto region in Italy.

OBJECTIVE: The purpose of this study was to analyze the effect of the coronavirus disease 2019 (COVID-19) outbreak and of the subsequent lockdown on the neurosurgical services of the Veneto region in Italy compared to the previous 4 years. METHODS: A survey was conducted in all 6 neurosurgical departments in the Veneto region to collect data about surgical, inpatient care and endovascular procedures during the month of March for each year from 2016 to 2020. Safety measures to avoid infection from SARS-CoV-2 and any COVID-19 cases reported among neurosurgical patients or staff members were considered. RESULTS: The mean number of neurosurgical admissions for the month of March over the 2016-2019 period was 663, whereas in March 2020 admissions decreased by 42%. Emergency admissions decreased by 23%. The average number of neurosurgical procedures was 697, and declined by 30% (range -10% to -51% in individual centers). Emergency procedures decreased in the same period by 23%. Subarachnoid hemorrhage and spontaneous intracerebral hemorrhage both decreased in Veneto-by 25% and 22%, respectively. Coiling for unruptured aneurysm, coiling for ruptured aneurysm, and surgery for ruptured aneurysm or arteriovenous malformation diminished by 49%, 27%, and 78%, respectively. Endovascular procedures for acute ischemic stroke (AIS) increased by 33% in 2020 (28 procedures in total). There was a slight decrease (8%) in brain tumor surgeries. Neurosurgical admissions decreased by 25% and 35% for head trauma and spinal trauma, respectively, while surgical procedures for head trauma diminished by 19% and procedures for spinal trauma declined by 26%. Admissions and surgical treatments for degenerative spine were halved. Eleven healthcare workers and 8 patients were infected in the acute phase of the pandemic. CONCLUSIONS: This multicenter study describes the effects of a COVID-19 outbreak on neurosurgical activities in a vast region in Italy. Remodulation of neurosurgical activities has resulted in a significant reduction of elective and emergency surgeries compared to previous years. Most likely this is a combined result of cancellation of elective and postponable surgeries, increase of conservative management, increase in social restrictions, and in patients' fear of accessing hospitals. Curiously, only endovascular procedures for AIS have increased, possibly due to reduced physical activity or increased thrombosis in SARS-CoV-2. The confounding effect of thrombectomy increase over time cannot be excluded. No conclusion can be drawn on AIS incidence. Active monitoring with nasopharyngeal swabs, wearing face masks, and using separate pathways for infected patients reduce the risk of infection.

Utility of 3D rotational angiography road map in flow diverter deployment in a distal dissecting MCA aneurysm.

Distal, dissecting, middle cerebral artery (MCA) aneurysms are changing surgically and endovascularly. Endovascular treatment requires flow diverter stenting. A good vessel visualization is crucial for safe navigation. Three-dimensional rotational digital subtraction angiography (3D-DSA) is used routinely in diagnostic imaging. The utilization of the 3D-DSA road map in vessel navigation and stent deployment is novel. An illustrative video of a distal, dissecting left MCA aneurysm treated with flow diverter stenting is presented. The technical issues were distal location, dissecting nature with double lumen, proximal stenosis, and vessel curves. The 3D-DSA road map helped to enhance visualization with a safer procedure.The video can be found here: https://youtu.be/sS3o1Z0P8WE.

Complete embolization of jugular paragangliomas by direct puncture. Technical note.

Objective: Intra-arterial embolization of jugular paragangliomas is an established endovascular technique. Intratumoral embolization by direct puncture has been proposed, prior to surgical treatment or radiosurgery to reduce the risk of cranial nerve deficits. Methods: We examined the technical aspects of two patients with jugular paragangliomas embolized with liquid embolic agent by direct puncture of the lesion, as sole treatment. Results: Two patients with jugular paragangliomas presented with lower cranial nerve deficits. The first patient showed an extended lesion (55-mm) and was treated with partial intra-arterial embolization plus direct puncture and injection of Squid 18 and a second staged embolization by direct puncture and filling of the remainder of the lesion. The second patient with a smaller jugular paraganglioma (33-mm) was treated by single embolization by direct puncture of the tumor and injection of Squid 12 and Squid 18 obtaining complete filling of the lesion. No procedural complications were observed. Both patients showed no residual and initial improvement of the neurological deficits. Conclusion: The intratumoral embolization by direct puncture of jugular paragangliomas, under accurate radiological control is a safe procedure, and complete exclusion of the lesion can be obtained in selected cases. A staged particle embolization of the lesion by direct puncture can be proposed for large lesions. Only further studies with larger series and long-term follow-up will be able to define, if this strategy can be curative avoiding additional surgical or radio-surgical treatment.

Role of MGMT Methylation Status at Time of Diagnosis and Recurrence for Patients with Glioblastoma: Clinical Implications.

BACKGROUND: MGMT methylation status represents a powerful prognostic factor in newly diagnosed glioblastoma (GBM). Recently, its role in recurrent tumors has also been suggested; however, few data investigating the stability of this biomarker during the clinical course of the disease are available. In this study, we evaluated the rate of change of MGMT methylation status between diagnosis and first recurrence in patients who received tumor resection for recurrent GBM. METHODS: We included patients who received temozolomide concurrent with and adjuvant to radiotherapy after diagnosis of GBM and had a second surgery performed at least 3 months after radiotherapy completion. Other eligibility criteria were age ≥18 years and Eastern Cooperative Oncology Group performance status 0-2. We evaluated the MGMT methylation status by methylation-specific polymerase chain reaction. RESULTS: From our institutional data warehouse, 295 patients with recurrent GBM who underwent second surgery were evaluated. MGMT methylation status at both first and second surgery was available for 108 patients. MGMT was methylated in both surgeries in 38 patients (35.2%), while it was unmethylated in 43 patients (39.8%). We found a significant concordance between the first and the second MGMT methylation assessments (K = 0.500, p < .001), MGMT methylation being stable in 75% of the cases. CONCLUSION: MGMT methylation presents relative stability during the clinical course of GBM. The Oncologist 2017;22:432-437 IMPLICATIONS FOR PRACTICE: MGMT methylation is a prognostic factor in newly diagnosed glioblastoma. In this study, we evaluated the rate of change of MGMT methylation during the clinical course of the disease, and we found a significant concordance between the first and the second MGMT methylation assessments, with MGMT methylation being stable in 75% of the cases. Thus, re-testing this biomarker at recurrence does not provide further information for clinicians. MGMT methylation at first surgery, extent of resection at second surgery, and time between first and second surgery are significantly correlated with overall survival. Age and extent of resection are correlated with post-progression survival.

Patient outcomes following second surgery for recurrent glioblastoma.

BACKGROUND: The most appropriate management of recurrent glioblastoma is still controversial. In particular, the role of surgery at recurrence remains uncertain. PATIENTS & METHODS: From our Institutional data warehouse we analyzed 270 consecutive patients who received second surgery for recurrent glioblastoma, to assess survival after second surgery, and to evaluate prognostic factors. RESULTS: Complete resection was found in 128 (47.4%) and partial resection in 142 patients (52.6%). Median survival from second surgery was 11.4 months (95% CI: 10.0-12.7). Multivariate analysis showed that age (p = 0.001), MGMT methylation (p = 0.021) and extent of surgery (p < 0.001) are associated with better survival. CONCLUSION: A complete resection should be the goal for second resection and younger age and MGMT methylation status might be considered in the selection of patients.

Geometry and Symmetry of Willis' Circle and Middle Cerebral Artery Aneurysms Development.

Background: A relationship between the geometry and symmetry of Willis' circle and intracranial aneurysms was reported for anterior communicating and posterior communicating (PCom) aneurysms. A similar association with the middle cerebral artery (MCA) aneurysms instead appeared weaker. Methods: We reviewed 432 patients from six Italian centers with unilateral MCA aneurysms, analyzing the relationship between the caliber and symmetry of Willis' circle and the presence of ruptured and unruptured presentation. CT-angiograms were evaluated to assess Willis' circle geometrical characteristics and the MCA aneurysm side, dimension and rupture status. Results: The hypoplasia of the first segment of the anterior cerebral artery (A1) was in approximately one-quarter of patients and PCom hypoplasia was in almost 40%. About 9% had a fetal PCom ipsilaterally to the aneurysm. By comparing the aneurysmal and healthy sides, only the PCom hypoplasia appeared significantly higher in the affected side. Finally, the caliber of the internal carotid artery (ICA) and the first segment of MCA (M1) caliber were significantly greater in patients with unruptured aneurysms, and PCom hypoplasia appeared related to the incidence of an ipsilateral MCA aneurysm and its risk of rupture. Conclusions: Although according to these findings asymmetries of Willis' circle are shown to be a risk factor for MCA aneurysm formation and rupture, the indifferent association with ipsilateral or contralateral hypoplasia remains a datum of difficult hemodynamic interpretation, thereby raising the concern that this association may be more casual than causal.

Comparison Between Intrasylvian and Intracerebral Hematoma Associated with Ruptured Middle Cerebral Artery Aneurysms: Clinical Implications, Technical Considerations, and Outcome Evaluation.

BACKGROUND: Subarachnoid hemorrhage (SAH) due to a middle cerebral artery (MCA) aneurysm rupture is often associated with an intracerebral hematoma (ICH) or intrasylvian hematoma (ISH). METHODS: We reviewed 163 patients with ruptured MCA aneurysms associated with pure SAH or SAH plus ICH or ISH. The patients were first dichotomized according to the presence of a hematoma (ICH or ISH). Next, we performed a subgroup analysis comparing ICH versus ISH to explore their relationship with the most relevant demographic, clinical, and angioarchitectural features. RESULTS: Overall, 85 patients (52%) had a pure SAH, and 78 (48%) had presented with an associated ICH or ISH. No significant differences were observed in the demographics or angioarchitectural features between the 2 groups. However, the Fisher grade and Hunt-Hess score were higher for the patients with hematomas. A good outcome was observed in a higher percentage of patients with pure SAH compared with those with an associated hematoma (76% vs. 44%), although the mortality rates were comparable. Age, Hunt-Hess score, and treatment-related complications were the main outcome predictors on multivariate analysis. Patients with ICH appeared worse clinically compared with those with ISH. We also found that older age, a higher Hunt-Hess score, larger aneurysms, decompressive craniectomy, and treatment-related complications were associated with poor outcomes among the patients with an ISH, but not an ICH, which appeared, per se, as a more severe clinical condition. CONCLUSIONS: Our study has confirmed that age, Hunt-Hess score, and treatment-related complications influence the outcome of patients with ruptured MCA aneurysms. However, in the subgroup analysis of patients with SAH associated with an ICH or ISH, only the Hunt-Hess score at onset appeared as an independent predictor of the outcome.

Transcallosal approach for intraventricular gliomas: neuropsychological outcome and functionality of the corpus callosum.

The transcallosal approach is commonly used for surgery of lateral and third ventricle lesions. Cognitive deficits due to the transcallosal approach still remain controversial. Even if enormous efforts have been made in order to understand specific functions of the corpus callosum, still little is known. The present study was aimed to evaluate the neuropsychological results and the functionality of the corpus callosum in transferring visual, auditory and tactile information between the two hemispheres in a group of patients who were treated using the transcallosal approach. The study evaluated the neuropsychological status of five selected patients presenting low-grade lesions of lateral ventricles that had not previously undergone surgical treatments and that did not receive radiotherapy and chemotherapy. All patients were administered an extensive neuropsychological testing postoperatively and the interhemispheric transfer of visual, auditory and tactile information was also evaluated. Two patients were tested preoperatively. Incisions of 2.4 cm maximum of the corpus callosum length were operated. The postoperative cognitive profile was normal. In some patients, a postoperative subnormal performance in memory functions was found but it cannot be attributable to the surgical approach given that it was altered even pre-surgically. Small incisions of the corpus callosum preserved the integrity of this anatomical structure in transferring lateralized information between the two hemispheres. The transcallosal approach is a safe surgical route to lateral ventricles lesions and the neuropsychological evaluation of these cases could give new insights in the comprehension of corpus callosum functions.

A Survey on Pituitary Surgery in Italy.

BACKGROUND: Pituitary tumors are a heterogeneous group of lesions that are usually benign. Therefore, a proper understanding of the anatomy, physiology, and pathology is mandatory to achieve favorable outcomes. Accordingly, diagnostic tests and treatment guidelines should be determined and implemented. Thus, we decided to perform a multicenter study among Italian neurosurgical centers performing pituitary surgery to provide an actual depiction from the neurosurgical standpoint. METHODS: On behalf of the SINch (Società Italiana di Neurochirurgia), a survey was undertaken with the participants to explore the activities in the field of pituitary surgery within 41 public institutions. RESULTS: Of the 41 centers, 37 participated in the present study. The total number of neurosurgical procedures performed in 2016 was 1479. Most of the procedures were performed using the transsphenoidal approach (1320 transsphenoidal [1204 endoscopic, 53 microscopic, 53 endoscope-assisted microscopic] vs. 159 transcranial). A multidisciplinary tumor board is convened regularly in 32 of 37 centers, and a research laboratory is present in 18 centers. CONCLUSIONS: Diagnosing pituitary/hypothalamus disorders and treating them is the result of teamwork, composed of several diverse experts. Regarding neurosurgery, our findings have confirmed the central role of the transsphenoidal approach, with preference toward the endoscopic technique. Better outcomes can be expected at centers with a multidisciplinary team and a full, or part of a, residency program, with a greater surgical caseload.

The effect of re-operation on survival in patients with recurrent glioblastoma.

BACKGROUND: Treatment options for glioblastoma (GBM) at recurrence have limited efficacy. Re-surgery has been used for confirmation of recurrent disease and to provide relief of symptoms but the real impact on survival is unknown. PATIENTS AND METHODS: A retrospective analysis was performed for GBM patients followed between 01/2005 and 06/2010 at our Institution. RESULTS: Two hundred and thirty-two patients with recurrent GBM were evaluated. One hundred and two patients (44%) were treated with re-surgery followed by chemotherapy and 130 patients (56%) with chemotherapy alone. In multivariate analysis, no significant effect of re-surgery was found, with age (p=0.001), MGMT methylation (p=0.002) and PFS at 6 months (p=0.0001) being significant prognostic factors. CONCLUSION: Second surgery might have a limited impact in the clinical course of recurrent GBM patients.

New perspectives in the treatment of adult medulloblastoma in the era of molecular oncology.

Medulloblastoma is the most common central nervous system tumor in children, while it is extremely rare in adults. Multimodal treatment involving surgery, radiotherapy and chemotherapy can improve the prognosis of this disease, and recent advances in molecular biology have allowed the identification of molecular subgroups (WNT, SHH, Groups 3 and 4), each of which have different cytogenetic, mutational and gene expression signatures, demographics, histology and prognosis. The present review focuses on the state of the art for adult medulloblastoma treatment and on novel molecular advances and their future implications in the treatment of this disease.

The treatment of adults with medulloblastoma: a prospective study.

PURPOSE: To assess in a prospective trial the value of prognostic factors and the outcome of medulloblastoma in adults. METHODS AND MATERIALS: Patients (> or =18 years) with a histologic diagnosis of medulloblastoma were staged according to Chang et al.'s classification (low risk: T1, T2, T3a, M0, and no residual disease after surgery; high risk: T3b-T4, any M+ or postoperative presence of residual tumor). In low-risk patients, treatment consisted of 36 Gy to the craniospinal axis, supplemented by a local tumor dose of 18.8 Gy (total dose of 54.8 Gy). In high-risk patients, 2 cycles of "up-front chemotherapy" were delivered before the same radiation therapy, followed by maintenance chemotherapy if M1, M2, or M3 disease was present. RESULTS: Over a 12-year period, 36 evaluable patients were enrolled. Progression-free survival (PFS) at 5 years was higher in low-risk patients compared to the high-risk group: 76% +/- 14% (95% confidence interval [CI] = 52%-100%) vs. 61% +/- 11% (95% CI = 42%-87%). Patients with M- disease showed a significantly better outcome than M+ patients, with 75% showing PFS at 5 years vs. 45% (p = 0.01). CONCLUSION: The overall PFS observed is comparable to that obtained in pediatric series and suggests that a more effective therapy must be developed for high-risk patients.

Drug-resistant cluster headache: long-term evaluation of pain control by posterior hypothalamic deep-brain stimulation.

OBJECTIVE: On the basis of recent findings about the pathophysiology of cluster headache and through the experience reported in recent literature, we have reviewed the outcome of four patients affected by drug-resistant cluster headache treated in our department by posterior hypothalamic deep brain stimulation with a follow-up of more than 5 years. METHODS: Between 2004 and 2006, we selected four patients affected by cluster headache. The diagnosis was based on the International Classification of Headache Disorders II criteria, and all patients were refractory to drug therapy. Under local anesthesia they underwent stereotactic positioning of a stimulation electrode within the posterior hypothalamus, ipsilateral to the site of pain. An intraoperative neurophysiological test stimulation was performed to assess possible side effects and symptoms related to hypothalamic neuronal activity. A second surgery was then performed with the patient under general anesthesia to implant the extension cable and the implantable pulse generator. RESULTS: After 5 years of follow up, all patients had a valuable benefit with a reduction in episode frequency from 90% to 50% associated with a decrease in pain intensity perception. CONCLUSION: The long-lasting pain reduction and the improvement in the patients' symptoms should be considered a real positive prospective, not only because there was uncertainty about the persistence of the beneficial effects at a long-term follow-up, but also for the improvement of the quality of life. The stimulation can restore important aspects concerning the psychic condition that very often constitutes an important limiting factor in normal daily life for this type of patient.