Electrochemotherapy in Spine Metastases: A Case Series Focused on Technical Aspects, Surgical Strategies and Results.

Metastases are complications of primary tumors due to prolonged cancer survival and have become an important issue for oncological patients and the most frequent cause of death and disability. Bone metastases occur at a later stage of cancer disease, and the spine is the most frequent site. To date, the aim of the treatment of metastases remains to be the control of disease and provide a satisfactory quality of life. The decision making of treatment is influenced by several factors such as the status of the primary disease, the number of metastases, site involvement, and the performance status of the patients. For this reason, the treatment of metastases is challenging and undergoes constant development. Therefore, alternative techniques with respect to surgery, which is the first option but not always practicable, and radiochemotherapy are attractive. Lately, electrochemotherapy has emerged as an innovative method for treating various primary and metastatic solid tumors, showing promising outcomes in terms of inducing tumor tissue necrosis and alleviating symptoms. This technique uses electric pulses to increase the uptake of chemotherapy by tumor cells. Despite the initial enthusiasm and good results in the treatment of bone tumors, relatively few papers have described its use in spine metastases. Therefore, we conducted a systemic review of this intriguing topic while also reporting our experience in the use of electrochemotherapy for the treatment of spine metastases.

Indirect functional connectivity does not predict overall survival in glioblastoma.

BACKGROUND: Lesion network mapping (LNM) is a popular framework to assess clinical syndromes following brain injury. The classical approach involves embedding lesions from patients into a normative functional connectome and using the corresponding functional maps as proxies for disconnections. However, previous studies indicated limited predictive power of this approach in behavioral deficits. We hypothesized similarly low predictiveness for overall survival (OS) in glioblastoma (GBM). METHODS: A retrospective dataset of patients with GBM was included (n = 99). Lesion masks were registered in the normative space to compute disconnectivity maps. The brain functional normative connectome consisted in data from 173 healthy subjects obtained from the Human Connectome Project. A modified version of the LNM was then applied to core regions of GBM masks. Linear regression, classification, and principal component (PCA) analyses were conducted to explore the relationship between disconnectivity and OS. OS was considered both as continuous and categorical (low, intermediate, and high survival) variable. RESULTS: The results revealed no significant associations between OS and network disconnection strength when analyzed at both voxel-wise and classification levels. Moreover, patients stratified into different OS groups did not exhibit significant differences in network connectivity patterns. The spatial similarity among the first PCA of network maps for each OS group suggested a lack of distinctive network patterns associated with survival duration. CONCLUSIONS: Compared with indirect structural measures, functional indirect mapping does not provide significant predictive power for OS in patients with GBM. These findings are consistent with previous research that demonstrated the limitations of indirect functional measures in predicting clinical outcomes, underscoring the need for more comprehensive methodologies and a deeper understanding of the factors influencing clinical outcomes in this challenging disease.

Epidemiology of Spondylolisthesis: A Nationwide Study From 2001 to 2016 in the Italian Population.

STUDY DESIGN: Epidemiological study. OBJECTIVE: This study aimed to evaluate the annual incidence of spondylolisthesis requiring surgery in Italy and the epidemiological characteristics of the patients. BACKGROUND: The health care system continues to incur considerable costs as a result of low-back pain. Segmental instability of the lumbar spine has attracted significant interest from researchers as a potential mechanism leading to mechanical low back pain. MATERIALS AND METHODS: The Italian Ministry of Health's National Hospital Discharge Reports database in the 2001-2016 period was considered. RESULTS: A total of 55,804 hospital admissions for spondylolisthesis were performed in Italy. The cumulative incidence was 6.8 interventions for every 100,000 Italian adult residents. The highest amount of procedures was recorded in the 65-69 years of age group. The overall patient's age was 56.8 ± 15.1 years. The 62.2% of patients were females. The average hospital stay length was 8.1 ± 7.3 days. On average, older patients require more days of hospital stay. Over the study period, it was observed a decreasing trend in the average number of days of hospital stay. The main primary diagnoses included were "acquired spondylolisthesis" [International Classification of Diseases (ICD) code: 738.4; 57.8%] and "spondylolisthesis" (ICD code: 756.12; 42.2%). By far, the main primary procedure performed was "lumbar and lumbosacral fusion of the anterior column, posterior technique" (ICD code: 81.08; 60.3%). CONCLUSIONS: Spondylolisthesis is a problem in Italy and a leading cause requiring spine surgery. Females were the majority of patients requiring surgery for spondylolisthesis. However, for younger age groups, males showed superior or equal need for spine surgery. The socioeconomic impact of spondylolisthesis in Italy is relevant, affecting patients still in the working population. The increasing trend of spine surgery for spondylolisthesis in Italy may be attributable to the widespread diffusion of modern diagnostic and surgical technologies. LEVEL OF EVIDENCE: Level II.

HER2 expression and genOmic characterization of rESected brain metastases from colorectal cancer: the HEROES study.

BACKGROUND: Little is known about prognostic factors of brain metastases (BM) from colorectal cancer (CRC). HER2 amplification/overexpression (HER2+) was previously described; its impact on prognosis remains uncertain. METHODS: In the translational study HEROES, extensive molecular analysis was performed on primary CRC (prCRC) and their matched resected BM by means of NGS comprehensive genomic profiling and HER2 status as assessed by immunohistochemical/ in situ hybridization. Count of tumour-infiltrating lymphocytes (TILs) was also performed. PRIMARY OBJECTIVE: to describe the molecular landscape of paired BM/prCRC. SECONDARY OBJECTIVES: to search for new prognostic biomarkers of outcome after BM resection: intracranial-only Progression-Free Survival (BM-iPFS), Progression-Free Survival (BM-PFS), and Overall Survival (BM-OS). RESULTS: Out of 22 patients having paired samples of prCRC and BM, HER2+ was found on 4 (18%) BM, 3 (75%) of which also HER2+ in matched prCRC. Lower tumour mutation burden (HR 3.08; 95%CI 1.06-8.93; p = 0.0386) and HER2-negative BM (HER2neg) (HR 7.75;95%CI 1.97-30.40; p = 0.0033) were associated with longer BM-iPFS; HER2neg BM (HR 3.44; 95%CI 1.03-11.53; p = 0.0449) and KRASmut BM (HR 0.31; 95%CI 0.12-0.80; p = 0.0153) conferred longer BM-PFS. Longer BM-OS was found in pts with TILs-enriched (≥1.6/HPF) BM (HR 0.11; 95%CI0.01-0.91; p = 0.0403). CONCLUSIONS: This study shows HER2+ enrichment in both BM and their prCRC. TILs-enriched BM conferred better BM-OS.

Role of Vagus Nerve Stimulation in Refractory and Super Refractory Status Epilepticus: A Pediatric Case Series.

BACKGROUND: Status epilepticus is a life-threatening condition that is defined as refractory (RSE) when the seizure activity continues despite treatment with benzodiazepine and a second appropriate treatment. Super refractory status epilepticus (SRSE) is an RSE that persists or recurs for ≥24 h. Few papers have reported the outcomes of pediatric patients affected by RSE and SRSE and treated with neuromodulation therapies. Vagus nerve stimulation (VNS) is an approved treatment for drug-resistant epilepsy. We present our findings of pediatric patients treated with VNS for RSE/SRSE. METHODS: We present a case series of seven consecutive pediatric patients treated with VNS for SRSE since 2012 by a single surgeon in Monza and Padua. A rapid titration was started soon after implantation. We considered electroclinical data before and after VNS implantation and at the last follow-up. RESULTS: We achieved the resolution of SRSE in five out of seven patients in a mean time of two weeks. At the last follow-up, these patients had a significant reduction of seizure burden without any relapse of SE. DISCUSSION AND CONCLUSIONS: Based on our limited findings, we discuss the potential role of VNS therapy in similar but distinct clinical contexts. For patients with drug-resistant epilepsy and RSE/SRSE, prompt VNS consideration is suggested, offering rapid responses and potentially reducing pharmacological load. Meanwhile, in NORSE/FIRES, we suggest early neuromodulation during the acute phase if standard treatments prove ineffective or not tolerated. This approach may leverage VNS's potential anti-inflammatory effects and neuromodulation, enhancing patient-specific treatments. Expanding case studies and prolonged follow-ups are recommended to strengthen these clinical insights.

Thalamopeduncular Tumors in Pediatric Age: Advanced Preoperative Imaging to Define Safe Surgical Planning: A Multicentric Experience.

Background: Thalamopeduncular tumors are challenging lesions arising at the junction between the thalamus and the cerebral peduncle. They represent 1-5% of pediatric brain tumors, are mainly pilocytic astrocytoma and occur within the first two decades of life. To date, the optimal treatment remains unclear. Methods: We retrospectively reviewed pediatric patients who underwent surgery for thalamopeduncular tumors in the Academic Pediatric Neurosurgery Unit of Padova and Verona from 2005 to 2022. We collected information on age, sex, symptoms, preoperative and postoperative neuroradiological studies, histological specimens, surgical approaches, and follow-up. Results: We identified eight patients with a mean age of 9 years. All lesions were pilocytic astrocytoma. The main symptoms were spastic hemiparesis, cranial nerve palsy, headache, and ataxia. The corticospinal tract was studied in all patients using diffusion-tensor imaging brain MRI and in two patients using navigated transcranial magnetic stimulation. The transsylvian approach was the most frequently used. A gross total resection was achieved in two patients, a subtotal resection in five and a partial resection in one. In three patients, a second treatment was performed due to the regrowth of the tumor, performing an additional surgery in two cases and a second-look surgery followed by adjuvant therapy in one. After the surgery, four patients maintained stability in their postoperative neurological exam, two patients improved, and two worsened but in one of them, an improvement during recovery occurred. At the last follow-up available, three patients were disease-free, four had a stable tumor residual, and only one patient died from the progression of the disease. Conclusions: Advanced preoperative tools allow one to define a safe surgical strategy. Due to the indolent behavior of thalamopeduncular tumors, surgery should be encouraged.

Aesthetic transaxillary subpectoral placement of vagus nerve stimulator in children and young adults: A technical note.

INTRODUCTION: Vagus nerve stimulation (VNS) is a neuromodulation therapy for drug-resistant epilepsy (DRE), refractory status epilepticus, and treatment-resistant depression. The lead is tunneled into the subcutaneous space and connected to the generator, which is usually implanted in a subcutaneous pocket below the clavicle. Surgical complications in the chest region include skin breakdown or infection. An alternative approach is to perform a subclavear subpectoral implantation. In our surgical series, we report a new aesthetic implantation method for VNS generators in children and young patients: the transaxillary subpectoral placement. MATERIALS AND METHODS: From May 2021 to May 2023, 10 vagus nerve stimulation generators were placed subpectorally with a transaxillary approach by the authors. We considered operative time, surgical complications such as blood loss, infections, device migration, pain, and adverse events at follow-up. RESULTS: In this surgical series, we reviewed all cases of subpectoral implantation of VNS generators in children and young adults at our institution in the last 2 years. All patients were treated with subpectoral Sentiva 1000 (Livanova PLC) insertion with axillary access by a neurosurgeon and a pediatric surgeon. The operative time was slightly longer compared to the traditional subcutaneous implant. All generators reported impedances within the optimal range. Blood loss was not significant and no other perioperative complications were reported. Patients and families were highly satisfied with the outcomes in terms of comfort and aesthetic results after surgery and at the last follow-up. No cases of infection occurred, and no malfunctions or displacements of the generator were registered at clinical follow-up. CONCLUSION: The transaxillary subpectoral placement of theVNS generator is an aesthetic and anatomic approach, which provides several benefits to children and young adults.

Patterns of gray and white matter functional networks involvement in glioblastoma patients: indirect mapping from clinical MRI scans.

Background: Resting-state functional-MRI studies identified several cortical gray matter functional networks (GMNs) and white matter functional networks (WMNs) with precise anatomical localization. Here, we aimed at describing the relationships between brain's functional topological organization and glioblastoma (GBM) location. Furthermore, we assessed whether GBM distribution across these networks was associated with overall survival (OS). Materials and methods: We included patients with histopathological diagnosis of IDH-wildtype GBM, presurgical MRI and survival data. For each patient, we recorded clinical-prognostic variables. GBM core and edema were segmented and normalized to a standard space. Pre-existing functional connectivity-based atlases were used to define network parcellations: 17 GMNs and 12 WMNs were considered in particular. We computed the percentage of lesion overlap with GMNs and WMNs, both for core and edema. Differences between overlap percentages were assessed through descriptive statistics, ANOVA, post-hoc tests, Pearson's correlation tests and canonical correlations. Multiple linear and non-linear regression tests were employed to explore relationships with OS. Results: 99 patients were included (70 males, mean age 62 years). The most involved GMNs included ventral somatomotor, salient ventral attention and default-mode networks; the most involved WMNs were ventral frontoparietal tracts, deep frontal white matter, and superior longitudinal fasciculus system. Superior longitudinal fasciculus system and dorsal frontoparietal tracts were significantly more included in the edema (p < 0.001). 5 main patterns of GBM core distribution across functional networks were found, while edema localization was less classifiable. ANOVA showed significant differences between mean overlap percentages, separately for GMNs and WMNs (p-values<0.0001). Core-N12 overlap predicts higher OS, although its inclusion does not increase the explained OS variance. Discussion and conclusion: Both GBM core and edema preferentially overlap with specific GMNs and WMNs, especially associative networks, and GBM core follows five main distribution patterns. Some inter-related GMNs and WMNs were co-lesioned by GBM, suggesting that GBM distribution is not independent of the brain's structural and functional organization. Although the involvement of ventral frontoparietal tracts (N12) seems to have some role in predicting survival, network-topology information is overall scarcely informative about OS. fMRI-based approaches may more effectively demonstrate the effects of GBM on brain networks and survival.

Complications and mortality of Cushing's disease: report on data collected over a 20-year period at a referral centre.

CONTEXT: Cushing's disease (CD) is rare condition burdened by several systemic complications correlated to higher mortality rates. The primary goal of clinicians is to achieve remission, but it is unclear if treatment can also increase life expectancy. AIM: To assess the prevalence of cortisol-related complications and mortality in a large cohort of CD patients attending a single referral centre. MATERIALS AND METHODS: The clinical charts of CD patients attending a referral hospital between 2001 and 2021 were reviewed. RESULTS: 126 CD patients (median age at diagnosis 39 years) were included. At the last examination, 78/126 (61.9%) of the patients were in remission regardless of previous treatment strategies. Patients in remission showed a significant improvement in all the cardiovascular (CV) comorbidities (p < 0.05). The CV events were more frequent in older patients (p = 0.003), smokers and persistent CD groups (p < 0.05). Most of the thromboembolic (TE) and infective events occurred during active stages of the disease. The CV events were the most frequent cause of death. The standardized mortality ratio (SMR) resulted increased in persistent cases at the last follow-up (SMR 4.99, 95%CI [2.15; 9.83], p < 0.001) whilst it was not higher in those in remission (SMR 1.66, 95%CI [0.34; 4.85], p = 0.543) regardless of the timing or number of treatments carried out. A younger age at diagnosis (p = 0.005), a microadenoma (p = 0.002), and remission status at the last follow-up (p = 0.027) all increased survival. Furthermore, an elevated number of comorbidities, in particular arterial hypertension, increased mortality rates. CONCLUSIONS: Patients with active CD presented a poor survival outcome. Remission restored the patients' life expectancy regardless of the timing or the types of treatments used to achieve it. Persistent CD-related comorbidities remained major risk factors.

The Methylation Analysis of the Glucose-Dependent Insulinotropic Polypeptide Receptor (GIPR) Locus in GH-Secreting Pituitary Adenomas.

The glucose-dependent insulinotropic polypeptide receptor (GIPR) is aberrantly expressed in about one-third of GH-secreting pituitary adenomas (GH-PAs) and has been associated with a paradoxical increase of GH after a glucose load. The reason for such an overexpression has not yet been clarified. In this work, we aimed to evaluate whether locus-specific changes in DNA methylation patterns could contribute to this phenomenon. By cloning bisulfite-sequencing PCR, we compared the methylation pattern of the GIPR locus in GIPR-positive (GIPR+) and GIPR-negative (GIPR-) GH-PAs. Then, to assess the correlation between Gipr expression and locus methylation, we induced global DNA methylation changes by treating the lactosomatotroph GH3 cells with 5-aza-2'-deoxycytidine. Differences in methylation levels were observed between GIPR+ and GIPR- GH-PAs, both within the promoter (31.9% vs. 68.2%, p < 0.05) and at two gene body regions (GB_1 20.7% vs. 9.1%; GB_2 51.2% vs. 65.8%, p < 0.05). GH3 cells treated with 5-aza-2'-deoxycytidine showed a ~75% reduction in Gipr steady-state level, possibly associated with the observed decrease in CpGs methylation. These results indicate that epigenetic regulation affects GIPR expression in GH-PAs, even though this possibly represents only a part of a much more complex regulatory mechanism.

Association between thyroid function and regorafenib efficacy in patients with relapsed wild-type IDH glioblastoma: a large multicenter study.

PURPOSE: Regorafenib demonstrated encouraging results in recurrent glioblastoma patients. Some studies showed that changes in circulating thyroid hormones (fT3, fT4, fT3/fT4 ratio) can be considered as prognostic factors in patients with various types of tumors. We designed this study to investigate the relationship between baseline thyroid variables and outcome in IDH-wild type GBM patients who were treated with regorafenib. METHODS: This multicenter retrospective study included recurrent IDH-wild-type glioblastoma patients treated with regorafenib. Only patients with baseline thyroid function values (TSH, fT3, fT4, fT3/fT4 ratio) available were evaluated. RANO criteria were used to analyze neuroradiological response. Survival curves were estimated using the Kaplan-Meier method. The relationships between baseline thyroid variables (TSH, fT3, fT4, fT3/fT4) and survival (PFS, OS) were investigated with Cox regression models. RESULTS: From November 2015 to April 2022, 134 recurrent IDH-wildtype GBM patients were treated with regorafenib and 128 of these had information on baseline thyroid function value. Median follow-up was 8 months (IQR 4.7-14.0). Objective Response Rate was 9% and Disease Control Rate was 40.9%. Median PFS was 2.7 months (95%CI 2.2-3.6) and median OS was 10.0 months (95%CI 7.0-13.0). Lower baseline TSH value in the blood was correlated with a higher rate of disease progression to regorafenib (p = 0.04). Multivariable analyses suggested a non-linear relationship between PFS (p = 0.01) and OS (p = 0.03) with baseline fT3/fT4 ratio. CONCLUSION: In recurrent wild-type IDH glioblastoma patients, baseline fT3/fT4 ratio showed a non-linear relationship with survival, with different impacts across the spectrum of fT3/fT4 ratio. Moreover, baseline TSH may be a predictor of regorafenib activity.

Navigated Transcranial Magnetic Stimulation Motor Mapping and Diffusion Tensor Imaging Tractography for Diencephalic Tumor in Pediatric Patients.

Background. In deep-seated brain tumors, adequate preoperative planning is mandatory to assess the best surgical corridor to obtain maximal safe resection. Functional diffusor tensor imaging (DTI) tractography based on navigated transcranial magnetic stimulation (nTMS) motor mapping has proven to be a valid preoperative examination method in adults. The aim of this paper is to present the application of nTMS and functional DTI tractography in a series of pediatric diencephalic tumors. Material and methods. Three patients affected by thalamic (one) and thalamopeduncular tumor (two) were successfully examined with nTMS motor mapping and DTI tractography between October 2020 and October 2021 (F:M 3:0, mean age 12 years ± 0.8). Cortical representation of leg, hand and mouth were determined in the affected hemisphere and the positive stimulation spots were set as seeds point for tractography. Results. Mapping of the motor cortex and tracts reconstruction for leg and hand were successful in all patients, while facial function was properly mapped in one patient only. In all cases, the procedure was well tolerated and no adverse events were recorded. Spatial relationships between tumor and functional tissue guided the surgical planning. Extent of the resection varied from 96.1% to 100% with a postoperative new motor deficit in one patient. Conclusions. nTMS and DTI fiber tracking is a feasible, effective and well-tolerated method to identify motor pathway in deep-seated lesion in pediatric population.

Selective Stimulus Intensity during Hotspot Search Ensures Faster and More Accurate Preoperative Motor Mapping with nTMS.

INTRODUCTION: Navigated transcranial magnetic stimulation (nTMS) has emerged as one of the most innovative techniques in neurosurgical practice. However, nTMS motor mapping involves rigorous steps, and the importance of an accurate execution method has not been emphasized enough. In particular, despite strict adherence to procedural protocols, we have observed high variability in map activation according to the choice of stimulation intensity (SI) right from the early stage of hotspot localization. We present a retrospective analysis of motor mappings performed between March 2020 and July 2022, where the SI was only chosen with rigorous care in the most recent ones, under the guide of an expert neurophysiologist. MATERIALS AND METHODS: In order to test the ability to reduce inaccurate responses and time expenditure using selective SI, data were collected from 16 patients who underwent mapping with the random method (group A) and 15 patients who underwent mapping with the proposed method (group B). The parameters considered were resting motor threshold (%), number of stimuli, number of valid motor evoked potentials (MEPs), number of valid MEPs considered true positives (TPs), number of valid MEPs considered false positives (FPs), ratio of true-positive MEPs to total stimuli, ratio of true-positive MEPs to valid MEPs, minimum amplitude, maximum amplitude and mapping time for each patient. RESULTS: The analysis showed statistically significant reductions in total stimulus demand, procedural time and number of false-positive MEPs. Significant increases were observed in the number of true-positive MEPs, the ratio of true-positive MEPs to total stimuli and the ratio of true-positive MEPs to valid MEPs. In the subgroups analyzed, there were similar trends, in particular, an increase in true positives and a decrease in false-positive responses. CONCLUSIONS: The precise selection of SI during hotspot search in nTMS motor mapping could provide reliable cortical maps in short time and with low employment of resources. This method seems to ensure that a MEP really represents a functionally eloquent cortical point, making mapping more intuitive even in less experienced centers.

Acute hydrocephalus following post-traumatic peri-mesencephalic subarachnoid hemorrhage: an uncommon and potentially fatal event in children.

PURPOSE: In pediatric, head trauma acute hydrocephalus is an uncommon but possible complication. Association with a subarachnoid hemorrhage is poorly described. METHODS: We described a case of an 8-year-old girl with acute hydrocephalus secondary to peri-mesencephalic subarachnoid hemorrhage after mild head trauma resolved with external ventricular drainage. Furthermore, we have conducted a review of the literature about this complication in pediatric head trauma. DISCUSSION AND CONCLUSION: Acute hydrocephalus related to post-traumatic peri-mesencephalic subarachnoid hemorrhage (tSAH) is an unknown entity in pediatric head trauma. According to our experience, traumatic peri-mesencephalic SAH should be under close clinical monitoring to identify post-traumatic hydrocephalus (PTH), a potentially fatal complication in pediatric mild head trauma.

Acquired Chiari type I malformation: a late and misunderstood supratentorial over-drainage complication.

PURPOSE: Acquired Chiari I malformation is an uncommon but possible late complication of supratentorial shunting in children. This condition can be caused by an abnormal thickening of the cranial vault and consequent reduction of the posterior cranial fossa (PCF) volume especially in children with already a small PCF volume. The management of Acquired Chiari I malformation is very challenging, and several options have been proposed for this condition. These are aimed to expand the PCF volume both through decompression and PCF remodeling in order to relieve symptoms of acquired Chiari I malformation. A cranial vault remodeling or a standard Chiari decompression is two proposed techniques aimed to expand the PCF volume thus relieving symptoms . METHODS: We describe the case of a 16-year-old girl undergone surgical removal of sellar-suprasellar glioneuronal tumor and ventriculo-peritoneal shunting, who developed an acquired symptomatic Chiari type I malformation some years after ventricular-peritoneal shunting. For this condition, she underwent successful standard Chiari decompression with C0-C1 craniectomy and duroplasty. RESULTS: We retrospectively analyzed MRI and CT scan performed during follow-up, in order to evaluate the volume of the posterior cranial fossa and to measure the variation of skull thickness at different periods. MRI and CT scan analysis showed a progressive thickening of the calvaria, in particular of the occipital bone, leading to a progressive reduction of PCF volume with the establishment of acquired Chiari type I malformation. In this case, standard C0-C1 Chiari decompression was effective in restoring PCF volume and relieving symptoms. CONCLUSION: Acquired Chiari I malformation due to chronic overhunting could be a severe and late complication in patient undergone supratentorial shunting. These patients require careful clinical and radiological follow-up to avoid over-drainage. According to our analysis, a careful selection of pediatric patients for supratentorial shunting should be made according to pre-operative PCF volume in order to foresee higher odds of possible late complications from over-drainage.

Impressive response to dabrafenib and trametinib plus silybin in a heavily pretreated IDH wild-type glioblastoma patient with BRAFV600E -mutant and SOX2 amplification.

Isocitrate dehydrogenase wild-type glioblastoma is the most frequent primary brain tumor in adult patients and its prognosis is still dismal with a median survival of about 1 year. BRAF V600E mutation, an important target for personalized therapy, has been identified in about 3% of these patients, but few data are available from prospective studies on the role of anti-BRAF drugs in adult glioblastoma patients. Moreover, SOX2 gene amplification and overexpression can represent an important mechanism of resistance to BRAF inhibitors by STAT3 gene activation. We present the case of a heavily pretreated 42-year-old man with BRAF V600E mutant and SOX2 amplification glioblastoma having a radiologic and metabolic [analyzed by a brain 18F-fluoro-ethyl-tyrosine([18F]FET) PET/MRI] complete response to the combination therapy with dabrafenib plus trametinib and silybin, a potent STAT3 inhibitor. The patient is currently undergoing treatment after a total of 24 months of continuation therapy with a good safety profile. In conclusion, we showed a promising activity of the personalized treatment of BRAF and MEK inhibitors in patient with BRAF V600E mutant glioblastoma; silybin can play an important role in decreasing drug resistance during BRAF inhibitor therapy, especially in patients with SOX2 amplification.

Vagus Nerve Stimulation in Treatment-Resistant Depression: A Case Series of Long-Term Follow-up.

OBJECTIVES: Vagus nerve stimulation (VNS) has been shown to be effective for treatment-resistant depression (TRD). However, long-term (>5 years) studies on the efficacy and tolerability of this treatment have been lacking. Here, we report a long-term clinical follow-up of 5 patients with severe and long-standing TRD, who received a VNS implant. METHODS: Of the initial 6 patients with TRD implanted with VNS at our center, 5 of them were followed for 6 to 12 years after implantation. Primary efficacy outcomes were clinical response and improved functioning at follow-up visits. The primary safety outcome was all-cause discontinuation, and the secondary safety outcomes were the number and the severity of adverse events. RESULTS: The VNS implant was associated with a sustained response (>10 years) in terms of clinical response and social, occupational, and psychological functioning in 3 patients. Two patients dropped out after 6 and 7 years of treatment, respectively. Vagus nerve stimulation was well tolerated by all patients, who reported only mild adverse effects. One patient, who discontinued concomitant drug treatment, had a hypomanic episode in the 10th year of treatment. The parameters of the VNS device were fine-tuned when life stressors or symptom exacerbation occurred. CONCLUSIONS: Our case series showed that VNS can have long-term and durable effectiveness in patients with severe multiepisode chronic depression, and this could be associated with its neuroplastic effects in the hippocampus. In light of good general tolerability, our findings support VNS as a viable treatment option for TRD.

Trends in Hospitalization and Economic Impact of Percutaneous Kyphoplasty in Italy.

Vertebral Fractures (VFs) caused by osteoporosis are the most typical reason for performing Percutaneous Kyphoplasty (PK). Globally, VF prevalence is not well described in the literature. In Europe, only Sweden has an accurate record of the incidence of this type of fracture. Moreover, the exact incidence of the PK procedure is not reported. Therefore, the annual patterns and financial burden of PK in Europe is not well known, and it could be may better understood by examining national registers. For surgeons, lawmakers, hospital administrators, and the healthcare system, determining the annual national costs of this treatment is helpful. The National Hospital Discharge Reports (SDOs) submitted to the Italian Ministry of Health during the years covered by this study (2009-2015) were used. A total of 13,113 kyphoplasties were performed in Italy, with a prevalence of 3.6 procedures for every 100,000 Italian inhabitants over 15 years. The average age of patients was 68.28 (±12.9). Females represented the majority of patients undergoing PK procedures (68.6%). The median length of hospital stay was 5.33 days. The prevalence of PK procedures increased from 2009 to 2015, while the average days of hospitalization decreased. Older patients were most at risk in undergoing PK procedures. Reporting the national data on PK in Italy could also help compare the findings across nations. The current study aims to determine the trends of PK hospitalisation and patient features in Italy.

Early surgery and definitive cure in small sporadic vestibular schwannoma.

Objective: To report surgical outcomes of a cohort of small sporadic vestibular schwannoma and discuss the role of early surgery. Methods: Retrospective descriptive analysis of 234 consecutive patients with small vestibular schwannoma operated on with translabyrinthine or hearing preservation surgical approaches. Outcome measures were control of disease, postoperative facial nerve function, complications and hearing outcome. Results: A translabyrinthine approach was performed in 59% of cases, hearing preservation surgery in 40% and transmeatal approach in 1%, respectively. Complete resection was achieved in 100% of cases. Overall, postoperative major and minor complications were 8.5% in the series, with complete recovery and no sequalae. Facial nerve function at one year postoperatively was House-Brackmann scale (HB) 1-2 in 95% of cases. The rate of hearing preservation was 70% A-B-C classes of Tokyo classification and 77% AB classes of AAOHNS classification. Conclusions: Early surgery in small vestibular schwannoma is a valid option, due to good functional outcomes, low morbidity and definitive cure. Early surgery is associated with better outcomes when considered in relation to non-surgical treatments reported in the literature.

Intraoperative Evaluation of Brain-Tumor Microvascularization through MicroV IOUS: A Protocol for Image Acquisition and Analysis of Radiomic Features.

Microvascular Doppler (MicroV) is a new-generation Doppler technique developed by Esaote (Esaote s.p.a., Genova, Italy), which is able to visualize small and low-flow vessels through a suppression of interfering signals. MicroV uses advanced filters that are able to differentiate tissue artifacts from low-speed blood flows; by exploiting the space-time coherence information, these filters can selectively suppress tissue components, preserving the signal coming from the microvascular flow. This technique is clinically applied to the study of the vascularization of parenchymatous lesions, often with better diagnostic accuracy than color/power Doppler techniques. The aim of this paper is to develop a reproducible protocol for the recording and collection of MicroV intraoperative ultrasound images by the use of a capable intraoperative ultrasound machine and post-processing aimed at evaluation of brain-tumor microvascularization through the analysis of radiomic features. The proposed protocol has been internally validated on eight patients and will be firstly applied to patients affected by WHO grade IV astrocytoma (glioblastoma-GBM) candidates for craniotomy and lesion removal. In a further stage, it will be generally applied to patients with primary or metastatic brain tumors. IOUS is performed before durotomy. Tumor microvascularization is evaluated using the MicroV Doppler technique and IOUS images are recorded, stored, and post-processed. IOUS images are remotely stored on the BraTIoUS database, which will promote international cooperation and multicentric analysis. Processed images and texture radiomic features are analyzed post-operatively using ImageJ, a free scientific image-analysis software based on the Sun-Java platform. Post-processing protocol is further described in-depth. The study of tumor microvascularization through advanced IOUS techniques such as MicroV could represent, in the future, a non-invasive and real-time method for intraoperative predictive evaluation of the tumor features. This evaluation could finally result in a deeper knowledge of brain-tumor behavior and in the on-going adaptation of the surgery with the improvement of surgical outcomes.