O-(2-18F-fluoroethyl)-L-tyrosine (18F-FET) PET as a potential selection tool for second surgery in glioblastoma patients.

BACKGROUND: Treatment-related changes still represent a diagnostic challenge in the management of patients with suspect of recurrent glioblastoma. The specificity of conventional MRI in detecting recurrence remains limited. Brain PET imaging provides information on tumor metabolism and can contribute to improving the diagnostic accuracy of cerebral neoplasms. We performed a retrospective analysis to evaluate the clinical value of O-(2-18F-fluoroethyl)-L-tyrosine (18F-FET) PET in the diagnosis of glioblastoma recurrence. METHODS: A retrospective analysis on patients considered suitable for salvage surgery for recurrence glioblastoma was performed. 18F-FET-PET was performed to investigate gadolinium enhancement suspected for recurrence. Static and kinetic 18F-FET parameters were analyzed and related to O-6-methylguanine-DNA methyltransferase (MGMT) status. RESULTS: Forty-two of the 51 patients who underwent 18F-FET-PET were re-operated. In each case, neuropathological diagnosis of tumor recurrence was confirmed. pMGMT hypermethylation was detected in 21 patients. Mean tumor-to-brain ratios (TBR) max was 3.87 (range 2.6-6.0). Static and kinetic 18F-FET parameters were similar according to MGMT status. CONCLUSIONS: 18FET-PET can be a reliable tool to improve the selection of patients suitable for salvage surgery for glioblastoma recurrence.

Innovative Approach to Isolate and Characterize Glioblastoma Circulating Tumor Cells and Correlation with Tumor Mutational Status.

Circulating tumor cells (CTCs) are one of the most important causes of tumor recurrence and distant metastases. Glioblastoma (GBM) has been considered restricted to the brain for many years. Nevertheless, in the past years, several pieces of evidence indicate that hematogenous dissemination is a reality, and this is also in the caseof GBM. Our aim was to optimize CTCs' detection in GBM and define the genetic background of single CTCs compared to the primary GBM tumor and its recurrence to demonstrate that CTCs are indeed derived from the parental tumor. We collected blood samples from a recurrent IDH wt GBM patient. We genotyped the parental recurrent tumor tissue and the respective primary GBM tissue. CTCs were analyzed using the DEPArray system. CTCs Copy Number Alterations (CNAs) and sequencing analyses were performed to compare CTCs' genetic background with the same patient's primary and recurrent GBM tissues. We identified 210 common mutations in the primary and recurrent tumors. Among these, three somatic high-frequency mutations (in PRKCB, TBX1, and COG5 genes) were selected to investigate their presence in CTCs. Almost all sorted CTCs (9/13) had at least one of the mutations tested. The presence of TERT promoter mutations was also investigated and C228T variation was found in parental tumors and CTCs (C228T heterozygous and homozygous, respectively). We were able to isolate and genotype CTCs from a patient with GBM. We found common mutations but also exclusive molecular characteristics.

Surgical management of skull base meningiomas and vestibular schwannomas.

PURPOSE OF REVIEW: The aim of this study is to discuss surgical management of meningiomas and schwannomas of skull base. RECENT FINDINGS: Meningiomas and schwannomas are typically benign neoplasm with a good prognosis after surgery. Patients should be treated individually related to several features: size and localization of tumor and its proximity with deep critical neurovascular structures, neurological status, age and comorbidity. Also, the widespread use of neuroimaging and the progressive and constant aging of the populations inevitably result in the increase of detection rate of incidental (asymptomatic) neoplasm.Nowadays, there are still controversies about the correct management strategy. SUMMARY: Surgery represents the gold standard treatment, with the objective of gross total resection; however, it is not always feasible due to localization, encasement of neuro-vascular structure, invasion of cranial nerve and brain parenchyma. Stereotactic radiosurgery and radiation therapy are important to achieve a satisfactory functional outcome and tumor control in case of residue or recurrence. A multidisciplinary approach is pivotal.

Aneurismal subarachnoid hemorrhage during the COVID-19 outbreak in a Hub and Spoke system: observational multicenter cohort study in Lombardy, Italy.

BACKGROUND: Lombardy was the most affected Italian region by the first phase of the COVID-19 pandemic and underwent urgent reorganization for the management of emergencies, including subarachnoid hemorrhage from a ruptured cerebral aneurysm (aSAH). The aim of the study was to define demographics, clinical, and therapeutic features of aSAH during the COVID-19 outbreak and compare these with a historical cohort. METHODS: In this observational multicenter cohort study, patients aged 18 years or older, who were diagnosed with aSAH at the participating centers in Lombardy from March 9 to May 10, 2020, were included (COVID-19 group). In order to minimize bias related to possible SAH seasonality, the control group was composed of patients diagnosed with aSAH from March 9 to May 10 of the three previous years, 2017-2018-2019 (pre-pandemic group). Twenty-three demographic, clinical, and therapeutic features were collected. Statistical analysis was performed. RESULTS: Seventy-two patients during the COVID-19 period and 179 in the control group were enrolled at 14 centers. Only 4 patients were positive for SARS-CoV-2. The "diagnostic delay" was significantly increased (+ 68%) in the COVID-19 group vs. pre-pandemic (1.06 vs. 0.63 days, respectively, p-value = 0.030), while "therapeutic delay" did not differ significantly between the two periods (0.89 vs. 0.74 days, p-value = 0.183). Patients with poor outcome (GOS at discharge from 1 to 3) were higher during the COVID-19 period (54.2%) compared to pre-pandemic (40.2%, p = 0.044). In logistic regression analysis, in which outcome was the dichotomized Glasgow Outcome Scale (GOS), five variables showed p-values < 0.05: age at admission, WFNS grade, treatment (none), days in ICU, and ischemia. CONCLUSIONS: We documented a significantly increased "diagnostic delay" for subarachnoid hemorrhages during the first COVID-19 outbreak in Lombardy. However, despite the dramatic situation that the healthcare system was experiencing, the Lombardy regional reorganization model, which allowed centralization of neurosurgical emergencies such as SAHs, avoided a "therapeutic delay" and led to results overall comparable to the control period.

Fronto-orbito-ethmoidal intradiploic meningiomas: A case study with systematic review.

BACKGROUND: Primary intradiploic meningiomas, extra-axial tumors arising primarily in the skull, are rare. The authors reported a complex case of intradiploic intraosseous metaplastic meningioma of the left medial wall and orbital roof with the left frontal sinus invasion and left ethmoidal body bone substitution. The authors also conducted a systematic review concerning diagnosis and management of patients affected by purely calvarial intradiploic meningiomas along with a focus on fronto-orbito-ethmoidal ones. METHODS: A literature search was conducted using PubMed and Scopus databases according to preferred reporting items for systematic reviews and meta-analysis statement and with the following Mesh terms: Intradiploic, intraosseous, calvarial, and meningioma. Eligibility criteria were limited by the nature of existing literature on intradiploic meningiomas, consisting of only case series, and case reports. RESULTS: A total of 128 published studies were identified through our search. 41 studies were included in this systematic review, 59 patients with a female/male ratio of 1.2/1. The mean age of the patients is of 47.69 years (range 3-84 years). Only seven out of 59 patients (11.9%) presented a complex intradiploic meningioma located in fronto-orbito-ethmoidal region like our case. In almost all patients, a gross-total resection was performed (96.6%) and only in two patients (3.4%) a subtotal resection was achieved. CONCLUSION: The authors shared this successfully treated case to add to the overall clinical experience in the management of this rare subtype tumor, with the hope that more studies are conducted to further address the mechanism of intradiploic meningiomas development.

Natura non facit saltus: a phase 2 proposal to manage brain tumors cases from the Neuro-oncology section of the Italian Society of Neurosurgery (SINch®).

The Coronavirus (COVID-19) pandemic has fast spread throughout the world in more than 200 countries, resulting in the need for a de-prioritization of elective medical care to face the demands of the global health crisis. Although the acute and catastrophic phase of the pandemic seems to have been left behind, it is also clear that the virus will not disappear soon, and we must live with it for a period of unpredictable length, the COVID-19 era. In this setting, a common coordinated approach to treat patients harboring brain tumors is urgently required to guarantee the best updated oncological care and to reduce the risk of viral infection during hospitalization. The study group on Neuro-oncology of Italian Society of Neurosurgery, SINCh gathered pieces of evidence and data and would like to suggest a practice protocol of care for neurosurgical oncologic procedures in the COVID-19 era. The present document aimed at summarizing current evidence and expert opinions to help neurosurgeons in taking decisions on their patients harboring different brain tumors.

Low penetrance COL5A1 variants in a young patient with intracranial aneurysm and very mild signs of Ehlers-Danlos syndrome.

Spontaneous cervical artery dissection (CeAD) is a major cause of ischemic stroke in young adults, whose genetic susceptibility factors are still largely unknown. Nevertheless, subtle ultrastructural connective tissue alterations (especially in the collagen fibril morphology) are recognized in a large proportion of CeAD patients, in which recent genetic investigations reported an enrichment of variants in genes associated with known connective tissue disorders. In this regard, COL5A1 variants have been reported in a small subset of CeAD patients, with or without classical Ehlers-Danlos syndrome (cEDS) features. We investigated a 22-year-old patient with intracranial aneurysm and mild connective tissue manifestations reminiscent of EDS. Whole-exome sequencing identified two COL5A1 missense variants in trans configuration: NM_000093.5:c.[1588G>A];[4135C>T], NP_000084.3:p.[(Gly530Ser)];[(Pro1379Ser)]. Functional assays demonstrated a significant decrease of collagen α1(V) chain expression in both heterozygous parents compared to control cells, and an additive effect of these two variants in the proband. Interestingly, both parents manifested very subtle EDS signs, such as atrophic scars, recurrent bone fractures, colonic diverticulosis, varicose veins, and osteoarthritis. Our findings emphasize the involvement of COL5A1 in the predisposition to vascular phenotypes and provide novel insights on the c.1588G>A variant, whose functional significance has not been definitely established. In fact, it was previously reported as both "disease modifying", and as a biallelic causative mutation (with heterozygous individuals showing subtle clinical signs of cEDS). We speculated that the c.1588G>A variant might lead to overt phenotype in combination with additional genetic "hits" lowering the collagen α1(V) chain expression below a hypothetical disease threshold.

A modified park bench position: the "Dormeuse" position.

BACKGROUND: Because of the restricted volume of the cisternal space, proper patient positioning on the operating table is of utmost importance during surgery by retrosigmoid approaches. Three positions are commonly used: supine, with the head rotated to the side contralateral to the lesion; the semi-sitting position; and the park bench position. Each position has advantages and disadvantages, and the surgeon should choose the one best suited to the individual patient and the pathology to be treated. METHODS: We describe a modified park bench position that we call the Dormeuse position. CONCLUSION: The Dormeuse position guarantees decrease in the posterior fossa pressure and allows optimal neural and vascular manipulation and control of any aspect of the cerebellopontine angle.

Polymethyl Methacrylate Cranioplasty Is an Effective Ultrasound Window to Explore Intracranial Structures: Preliminary Experience and Future Perspectives.

OBJECTIVE: To evaluate the feasibility of transcranial sonography in patients harboring polymethylmethacrylate cranioplasties (PMMA-CP) and explore whether this material is a valid sonic window to explore intracerebral structures. METHODS: In 6 patients, we performed transcranial sonography (TCS), using the PMMA-CP as sonic window. To test the reliability of ultrasound images, we collected several quantitative and qualitative measurements of intracranial structures and compared these sonographic images with standard computed tomography (CT) scan images. RESULTS: We found that PMMA-CP is a very good sonic window and allowed us to obtain very good quality echographic images of intracranial structures, as shown by the comparison of measurements with CT scan, which were very reliable. The main drawback was related to the shape (i.e., the curvature) of the cranial flap, which hindered the ultrasound probe from correctly adhering to the scalp. CONCLUSIONS: Although limited by the restricted number of cases, this preliminary experience represents the first available data about the serial use of TCS using PMMA-CP as window. These results open the path to the routine use of TCS to longitudinally control patients already harboring PMMA-CP. More, we here discuss its potential role in globally reducing the number of follow-up CT and magnetic resonance imaging scans required in different type of patients and pathologies.

It Is Time to Reduce Free-Hand Manipulation: Case Report of Our Proposal for an Innovative 1-Step Cranioplasty.

BACKGROUND: Cranioplasty is a well-known procedure, and autologous graft bone is usually considered the best choice in this procedure, but it cannot be used in conditions such as bone-infiltrating tumors, spheno-orbital en plaque meningiomas, and bone infections. Polymethylmethacrylate (PMMA) offers great possibility of intraoperative adaption. We describe a case of 1-step cranioplasty performed in a patient with a meningeal fibrosarcoma using a custom-made silicon mold. CASE DESCRIPTION: A 48-year-old man was admitted to our department for a left temporo-parietal subcutaneous tumefaction that grew for a few months on the site of a previous osteodural decompression. After a biopsy that was diagnostic for meningeal fibrosarcoma, we planned tumor asportation, considering the bone infiltration of the tumor and the necessity of a cranioplasty. Before the intervention, we performed the craniotomy on a gypsum powder head phantom created based on a computed tomography scan. Then, using a computer-assisted design technique, a silicon mold was created and sterilized for the intervention. The edges of the preoperative simulated craniectomy were reproduced during the intervention using a rigid rail on the patient's scalp. The craniectomy was performed, and the tumor was removed. Then, a PMMA bone flap was made using a silicon mold and was fixed to the skull by miniscrews. Aesthetic results were considered excellent by the patient. CONCLUSIONS: We performed a 1-step cranioplasty after resection of a meningeal fibrosarcoma that infiltrated bone with a new technique to reproduce during intervention a preoperative simulated craniectomy and a computer-assisted design PMMA flap.

Pattern of care and outcome in elderly patients with glioblastoma: Data in 151 patients from 3 Lombardia Hospitals.

The appropriate treatment approach for elderly patients with glioblastoma multiforme (GBM) is unclear, although different studies suggest survival benefit in fit patients treated with radiotherapy and chemiotherapy after surgery. We performed a retrospective analysis of 151 patients older than 65years with GBM treated in 3 Lombardia Hospitals. In univariate regression analysis higher KPS (p=0.02), macroscopical total resection (p<0.003), radiotherapy (p<0.0001), chemotherapy (p<0.0001) and second line chemotheraphy (p=0.02) were of positive prognostic value. On the contrary older age (>70years), presence of seizure at onset and additional resection after tumor recurrence did not influence OS. Multivariate analysis revealed radiotherapy (HR 0.2 p<0.0001) and extent of surgery (HR 0.3, p=0,0063) as positive independent prognostic factors. Patients receiving radio-chemiotherapy displayed more treatment-related toxicities with a slightly prolonged OS versus those receiving hypofractionated radiotherapy. With the limits of a retrospective study, our data suggest that in elderly fit patients extensive surgery should be considered, moreover adjuvant treatments led to an increase in OS. Randomized controlled study are needed to develop treatment guidelines for elderly GBM patients and to assess whether the combination of post-surgical radio and chemiotherapy may be superior to hypofractionated radiotherapy and chemiotherapy in fit patients.

Valproate induced hyperammonemic encephalopathy successfully treated with levocarnitine.

Valproate-induced hyperammonemic encephalopathy is an unusual but serious adverse effect that is usually characterized by the acute onset of impaired consciousness, focal neurological symptoms and increased seizure frequency. It has been reported to occur at therapeutic valproate levels. We report a patient who developed valproate-induced hyperammonemic encephalopathy after a short treatment with valproate and was successfully treated with levocarnitine. We discuss this patient and review the literature regarding the use of levocarnitine in similar patients.

Collagen-only biomatrix as dural substitute: What happened after a 5-year observational follow-up study.

OBJECTIVES: To assess long-term efficacy of the collagen-only biomatrix as a dural substitute in a large case series. PATIENTS AND METHODS: We reviewed a prospectively acquired database of patients who underwent neurosurgical surgeries in whom the dural substitute was used and who were the subject of two previous studied with shorter follow-ups. RESULTS: The present study was conducted on 111 subjects of the original 209 patients. No late complications, nor local or systemic toxicity were observed during the observational period. As a matter of facts, 5 patients (4.5%) underwent reoperation for different reasons and 2 out of 5 experienced subcutaneous fluid collections; another case (0.9%), already reported in our previous studies, developed a CSF leak after an endoscopic endonasal operation for an intra-suprasellar arachnoid cyst. CONCLUSIONS: Our data further confirm that the collagen-only biomatrix derived from horse equine tendon is a safe and effective dural substitute for routine neurosurgical procedures.

Decompressive surgery in malignant dural sinus thrombosis: report of 3 cases and review of the literature.

Cerebral venous and dural sinus thrombosis (CVDST) is a rare cause of stroke in young and middle-aged adults. When the clinical course is complicated by uncontrollable intracranial hypertension and brainstem compression due to edema or cerebral hemorrhage, the prognosis is poor. The authors evaluated the therapeutic role of surgical decompression in patients with clinical signs of impending herniation. Cerebral venous and dural sinus thrombosis complicated by impending brain herniation a very rare, life-threatening but potentially treatable clinical condition. Three patients with pupillary signs of transtentorial herniation due to brain edema and hemorrhage caused by CVDST (superior sagittal sinus in 1 patient and transverse and sigmoid sinus in 2 patients) were treated surgically. The intervention consisted of clot removal, infarcted tissue resection, and frontotemporoparietooccipital craniectomy with duraplasty. According to the Glasgow Outcome Scale, 2 patients were classified as having good recovery and 1, moderate disability. The results of neuropsychological assessment were normal in 2 patients and demonstrated a partial neuropsychological deficit (neglect) in the other. Surgery may be indicated in selected patients with CVDST whose condition is deteriorating because of intractable intracranial hypertension and impending brain herniation.