CD8+CD103+PD1+TIM3+ T cells in glioblastoma microenvironment correlate with prognosis.

Glioblastoma, isocitrate dehydrogenase-wildtype (GB), is the most common and aggressive primary brain malignancy with poor outcome. Immune checkpoint inhibitors (ICIs) have been tested in GB and, despite disappointing results, the identification of a small subgroup of responders underlies the need to improve our understanding of the tumour microenvironment (TME) immunity. This study aimed to determine whether the expression of selected immune checkpoints on tissue-resident memory T cells (Trm) may predict patient outcome. We conducted a single cohort observational study. Tumour samples were collected from 45 patients with histologically confirmed GB (WHO grade 4) and processed to obtain single-cell suspensions. Patients were assessed for the correlation of Trm phenotype with overall survival (OS) or progression-free survival (PFS) using multiparametric flow cytometry and uni/multivariate analyses. Levels of Trm expressing programmed cell death protein 1 (PD1) and T cell immunoglobulin and mucin domain-containing protein 3 (TIM3) were found to be linked to clinical outcome. Low frequency of Trm expressing PD1 or TIM3 or both markers defined subgroups as independent positive prognostic factors for patient survival. On multivariate analysis, low CD8+CD103+PD1+TIM3+ Trm and Karnofsky performance status (KPS) ≥70 were confirmed to be the most predictive independent factors associated with longer OS (hazard ratios-HR [95%CI]: 0.14 [0.04-0.52] p < 0.001, 0.39 [0.16-0.96] p = 0.04, respectively). The CD8+CD103+ Trm subgroups were also age-related predictors for survival in GB.

Bone health and skeletal fragility in second- and third-line medical therapies for acromegaly: preliminary results from a pilot single center experience.

INTRODUCTION: Skeletal fragility is a clinically relevant and not-reversible complication of acromegaly, involving around 30-40% of patients since the disease diagnosis. Few studies have investigated the effects on skeletal health of medical therapies for acromegaly. In this retrospective longitudinal monocentre study, we investigated the outcome of skeletal fragility in patients treated with Pasireotide Lar in combination with Pegvisomant (Pasi-Lar + Peg-V), also comparing those observed in patients treated with conventional therapies. RESULTS: We included 6 patients treated with Pasi-Lar + Peg-V, 5 patients treated with Peg-V in monotherapy (m-Peg-V), 16 patients treated with Peg-V plus first-generation somatostatin receptor ligands (fg-SRLs + Peg-V), 9 patients treated with Pasi-Lar. None of the patients treated with Pasi-Lar + Peg-V experienced worsening of spine and femoral bone mineral density (BMD) and incident vertebral fractures (i-VFs). Eight patients experienced i-VFs. The frequency of i-VFs was significantly lower in patients treated with the Pasi-Lar + Peg-V (0/8; 0%), as compared to those observed in m-Peg-V treated patients (4/8; 50%, p = 0.02). The frequency of i-VFs was slightly but not significantly higher in Pasi-Lar treated patients (1/8; 12.5% p = 0.6) and in fg-SRLs + Peg-V treated patients (3/8; 37.5% p = 0.364), concerning those treated with Pasi-Lar + Peg-V (0/8; 0%). I-VFs occurred more frequently in patients with higher GH levels at acromegaly diagnosis (p < 0.001), and in patients who experienced a BMD worsening (p = 0.005). CONCLUSION: Our preliminary data suggested that in conventional and multi-drug resistant acromegaly, the combination therapy Pasi-Lar + Peg-V may prevent the worsening of BMD and the occurrence of i-VFs. Prospective and translational studies should further validate these results and ascertain underlying physiopathology mechanisms.

Telomerase inhibition in malignant gliomas: a systematic review.

Glioblastoma (GBM) is the most frequent adult malignant brain tumour and despite different therapeutic efforts, the median overall survival still ranges from 14 to 18 months. Thus, new therapeutic strategies are urgently needed. However, the identification of cancer-specific targets is particularly challenging in GBM, due to the high heterogeneity of this tumour in terms of histopathological, molecular, genetic and epigenetic features. Telomerase reactivation is a hallmark of malignant glioma. An activating mutation of the hTERT gene, encoding for the active subunit of telomerase, is one of the molecular criteria to establish a diagnosis of GBM, IDH-wildtype, in the 2021 WHO classification of central nervous system tumours. Telomerase inhibition therefore represents, at least theoretically, a promising strategy for GBM therapy: pharmacological compounds, as well as direct gene expression modulation therapies, have been successfully employed in in vitro and in vivo settings. Unfortunately, the clinical applications of telomerase inhibition in GBM are currently scarce. The aim of the present systematic review is to provide an up-to-date report on the studies investigating telomerase inhibition as a therapeutic strategy for malignant glioma in order to foster the future translational and clinical research on this topic.

MRI and Trouillas' grading system of pituitary tumors: the usefulness of T2 signal intensity volumetric values.

PURPOSE: To classify pituitary macroadenomas according to the Trouillas' grading system; to compare this grading system with T2 values of volumetric signal intensity to determine T2 values able to predict the final grade. METHODS: A total of 106 patients with macroadenomas were grouped according to the grading system score combining proliferation and invasiveness criteria of Trouillas' classification. Normalized volumetric signal intensity values were extracted from coronal T2-weighted images (nT2mean, nT2Max, nT2min) and were compared with the final grading score system. RESULTS: Thirty-three patients were in grade 1a (non-invasive, non-proliferative tumors), 17 patients in grade 1b (non-invasive, proliferative tumors), 36 patients in grade 2a (invasive, non-proliferative tumors), and 20 patients in grade 2b (invasive, proliferative tumors). No patient was in grade 3 (metastatic tumors). nT2Max and nT2min were the best quantitative values to discriminate invasive from non-invasive grades; in invasive grades, nT2Max intensity values were higher, and nT2min intensity values were lower than in non-invasive grades. Receiver operating characteristic analysis of nT2 values showed that nT2min values had a better diagnostic performance than nT2Max values because they allowed differentiating with a moderate accuracy invasive tumors (2a or 2b grades) from both non-invasive proliferative tumors (1b) and non-invasive-non proliferative tumors (1a) (2a vs 1b: AUCnT2min = 0.78, 2b vs 1b: AUCnT2min = 0.72, 2a vs 1a: AUCnT2min = 0.72, 2b vs 1a AUCnT2min = 0.69). CONCLUSION: Volumetric nT2Max and nT2min values of MRI might be practical and non-invasive markers for assessing tumor invasiveness although nT2 min signal intensity values have more effects in discriminating tumor's invasive behavior.

Resection versus biopsy for management of primary central nervous system lymphoma: a meta-analysis.

The role of surgery in the management of primary central nervous system lymphomas (PCNSL) is currently confined to diagnosis. However, over recent years, an increasing number of papers have suggested a possible positive prognostic impact of surgery in selected cases. The present work aims to perform a meta-analysis of the available literature evidence. A meta-analysis with meta-regression on the role of surgical resection compared to biopsy in the management of PCNSL was conducted according to the PRISMA statement, searching MEDLINE via PubMed and Embase. The random effect model was used. The quality of evidence was assessed using the GRADE framework. After screening 1395 records, we included 11 papers in our analysis. Patients who underwent surgical resection harbored superficial and single-lesion tumors. At 1-, 2-, and 5-year follow-up, progression-free survival did not differ between the two groups, while overall survival favored resection, even if in a non-significant fashion. Meta-regression analysis showed that the overall survival rate at 2 years, but not at 1 or 5 years, was significantly influenced by tumor location. There were no differences in terms of age, sex, Karnofsky performance status, adjuvant therapy, or procedure-related complications. Overall, the quality of evidence is low. The results of the present meta-analysis do not change the current standard of care for PCNSL. However, surgery could be non-inferior to biopsy with an acceptable risk profile in selected patients harboring single and superficial lesions. The low quality of evidence prompts future randomized studies.

Training models and simulators for endoscopic transsphenoidal surgery: a systematic review.

Endoscopic transsphenoidal surgery is a novel surgical technique requiring specific training. Different models and simulators have been recently suggested for it, but no systematic review is available. To provide a systematic and critical literature review and up-to-date description of the training models or simulators dedicated to endoscopic transsphenoidal surgery. A search was performed on PubMed and Scopus databases for articles published until February 2023; Google was also searched to document commercially available. For each model, the following features were recorded: training performed, tumor/arachnoid reproduction, assessment and validation, and cost. Of the 1199 retrieved articles, 101 were included in the final analysis. The described models can be subdivided into 5 major categories: (1) enhanced cadaveric heads; (2) animal models; (3) training artificial solutions, with increasing complexity (from "box-trainers" to multi-material, ct-based models); (4) training simulators, based on virtual or augmented reality; (5) Pre-operative planning models and simulators. Each available training model has specific advantages and limitations. Costs are high for cadaver-based solutions and vary significantly for the other solutions. Cheaper solutions seem useful only for the first stages of training. Most models do not provide a simulation of the sellar tumor, and a realistic simulation of the suprasellar arachnoid. Most artificial models do not provide a realistic and cost-efficient simulation of the most delicate and relatively common phase of surgery, i.e., tumor removal with arachnoid preservation; current research should optimize this to train future neurosurgical generations efficiently and safely.

Reliability of intraoperative visual evoked potentials (iVEPs) in monitoring visual function during endoscopic transsphenoidal surgery.

OBJECTIVE: To refine a reliable and reproducible intraoperative visual evoked potentials (iVEPs) monitoring protocol during endoscopic transsphenoidal surgery. To assess the reliability of baseline iVEPs in predicting preoperative visual status and perioperative iVEP variation in predicting postoperative visual outcome. METHODS: Sixty-four patients harboring tumors of the pituitary region were included. All patients underwent endoscopic endonasal approach (EEA) with iVEPs monitoring, using a totally intravenous anesthetic protocol. Ophthalmological evaluation included visual acuity and visual field studies. RESULTS: Preoperatively, visual acuity was reduced in 86% and visual field in 76.5% of cases. Baseline iVEPs amplitude was significantly correlated with preoperative visual acuity and visual field (p = 0.001 and p = 0.0004, respectively), confirming the reliability of the neurophysiological/anesthetic protocol implemented. Importantly, perioperatively the variation in iVEPs amplitude was significantly correlated with the changes in visual acuity (p < 0.0001) and visual field (p = 0.0013). ROC analysis confirmed that iVEPs are an accurate predictor of perioperiative visual acuity improvement, with a 100% positive predictive value in patients with preoperative vision loss. CONCLUSIONS: iVEPs during EEA is highly reliable in describing preoperative visual function and can accurately predict postoperative vision improvement. SIGNIFICANCE: iVEPs represent a promising resource for carrying out a more effective and safe endoscopic transsphenoidal surgery.

Neuromodulation for Brain Tumors: Myth or Reality? A Narrative Review.

In recent years, research on brain cancers has turned towards the study of the interplay between the tumor and its host, the normal brain. Starting from the establishment of a parallelism between neurogenesis and gliomagenesis, the influence of neuronal activity on the development of brain tumors, particularly gliomas, has been partially unveiled. Notably, direct electrochemical synapses between neurons and glioma cells have been identified, paving the way for new approaches for the cure of brain cancers. Since this novel field of study has been defined "cancer neuroscience", anticancer therapeutic approaches exploiting these discoveries can be referred to as "cancer neuromodulation". In the present review, we provide an up-to-date description of the novel findings and of the therapeutic neuromodulation perspectives in cancer neuroscience. We focus both on more traditional oncologic approaches, aimed at modulating the major pathways involved in cancer neuroscience through drugs or genetic engineering techniques, and on electric stimulation proposals; the latter is at the cutting-edge of neuro-oncology.

Aggressive PitNETs and Potential Target Therapies: A Systematic Review of Molecular and Genetic Pathways.

Recently, advances in molecular biology and bioinformatics have allowed a more thorough understanding of tumorigenesis in aggressive PitNETs (pituitary neuroendocrine tumors) through the identification of specific essential genes, crucial molecular pathways, regulators, and effects of the tumoral microenvironment. Target therapies have been developed to cure oncology patients refractory to traditional treatments, introducing the concept of precision medicine. Preliminary data on PitNETs are derived from preclinical studies conducted on cell cultures, animal models, and a few case reports or small case series. This study comprehensively reviews the principal pathways involved in aggressive PitNETs, describing the potential target therapies. A search was conducted on Pubmed, Scopus, and Web of Science for English papers published between 1 January 2004, and 15 June 2023. 254 were selected, and the topics related to aggressive PitNETs were recorded and discussed in detail: epigenetic aspects, membrane proteins and receptors, metalloprotease, molecular pathways, PPRK, and the immune microenvironment. A comprehensive comprehension of the molecular mechanisms linked to PitNETs' aggressiveness and invasiveness is crucial. Despite promising preliminary findings, additional research and clinical trials are necessary to confirm the indications and effectiveness of target therapies for PitNETs.

Comparison of combined anterior-posterior and posterior-only approaches for lumbosacral chordomas: a systematic review and meta-analysis of surgical and clinical outcomes.

Lumbosacral chordoma is a slow-growing but locally aggressive tumor, resistant to adjuvant treatments and endowed with dismal prognosis. Surgery is the mainstay of treatment but the choice of surgical approach (the posterior-only approach or the combined anterior-posterior approach) remains an open question due to the need of both pursuing a surgical radicality and preserving the neurologic function. The aim of the study was to compare the surgical and clinical outcomes of these approaches in the management of lumbosacral chordomas. A systematic review and meta-analysis in agreement with the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-analyses) guidelines of papers comparing the outcomes of the two approaches was performed. Ten papers met the inclusion criteria. The combined anterior-posterior approach was more frequently performed for tumors with an upper level beyond S2 (p = 0.012). The 5-year progression-free survival was significantly higher in posterior-only approach compared with the combined anterior-posterior approach (44.7% vs 27.1%, p = 0.049). Adjuvant radiotherapy was added more frequently after a posterior-only approach (p = 0.036) and the rate of complications was significantly lower after a posterior-only approach (p = 0.040). No significant differences in sex, age, tumor diameter, entity of resection, and overall survival were observed. Posterior-only surgical approach may be a reasonable option for lumbosacral chordoma, being associated with comparable entity of surgical resection, reduced complication rate and increased 5-year progression-free survival rate as compared with combined anterior-posterior approach.

Dissecting Stemness in Aggressive Intracranial Meningiomas: Prognostic Role of SOX2 Expression.

Meningiomas are mostly benign tumors that, at times, can behave aggressively, displaying recurrence despite gross-total resection (GTR) and progression to overt malignancy. Such cases represent a clinical challenge, particularly because they are difficult to recognize at first diagnosis. SOX2 (Sex-determining region Y-box2) is a transcription factor with a key role in stem cell maintenance and has been associated with tumorigenesis in a variety of cancers. The purpose of the present work was to dissect the role of SOX2 in predicting the aggressiveness of meningioma. We analyzed progressive/recurrent WHO grade 1−2 meningiomas and WHO grade 3 meningiomas; as controls, non-recurring WHO grade 1 and grade 2 meningioma patients were enrolled. SOX2 expression was evaluated using both immunohistochemistry (IHC) and RT-PCR. The final analysis included 87 patients. IHC was able to reliably assess SOX2 expression, as shown by the good correlation with mRNA levels (Spearman R = 0.0398, p = 0.001, AUC 0.87). SOX2 expression was an intrinsic characteristic of any single tumor and did not change following recurrence or progression. Importantly, SOX2 expression at first surgery was strongly related to meningioma clinical behavior, histological grade and risk of recurrence. Finally, survival data suggest a prognostic role of SOX2 expression in the whole series, both for overall and for recurrence-free survival (p < 0.0001 and p = 0.0001, respectively). Thus, SOX2 assessment could be of great help to clinicians in informing adjuvant treatments during follow-up.

Comparison between VII-to-VII and XII-to-VII coaptation techniques for early facial nerve reanimation after surgical intra-cranial injuries: a systematic review and pooled analysis of the functional outcomes.

The surgical injury of the intracranial portion of the facial nerve (FN) is a severe complication of many skull base procedures, and it represents a relevant issue in terms of patients' discomfort, social interactions, risk for depression, and social costs. The aim of this study was to investigate the surgical and functional outcomes of the most common facial nerve rehabilitation techniques. The present study is a systematic review of the pertinent literature, according to the PRISMA guidelines. Two different online medical databases (PubMed, Scopus) were screened for studies reporting the functional outcome, measured by the House-Brackman (HB) scale, and complications, in FN early reanimation, following surgical injuries on its intracranial portion. Data on the VII-to-VII and XII-to-VII coaptation, the surgical technique, the use of a nerve graft, the duration of the deficit, and complications were collected and pooled. The XII-to-VII end-to-side coaptation seems to provide higher chances for functional restoration (HB 1-3) than the VII-to-VII (68.8% vs 60.6%), regardless of the duration of the palsy deficit, the use or not of a nerve graft, and the use of stitches or glues. However, its complication rate was as high as 28.6%, and a second procedure is then often needed. The XII-to-VII side-to-end coaptation is the most effective in providing a functional outcome (HB 1-3), even though it is associated to a higher complication rate. Further trials are needed to better investigate this relevant topic, in terms of health-related social costs and patients' quality of life.

Sural nerve biopsy in peripheral neuropathies: 30-year experience from a single center.

INTRODUCTION: Nerve biopsy has been widely used to investigate patients with peripheral neuropathy, and in many centers, it is still a useful diagnostic tool in this setting. In this study, we reviewed the histopathological spectrum of the nerve biopsies performed in our center in a 30-year period and we analyzed their relevance in the clinical setting. MATERIALS AND METHODS: Retrospective analysis of the retrieved data was done for cases of nerve biopsies performed in our institute between 1988 and 2018. Surgical technique and histopathological analysis were done accordingly to standard protocol. RESULTS: Complete clinical and pathological data were available only for 717 cases. The procedure was generally safe, with only 0.3% superimposed infection. Main pathological results were "unspecific" axonal polyneuropathy (49.8%), vasculitis neuropathy (9.3%), acquired demyelinating neuropathy (8.9%), and Charcot-Marie-Tooth (8.2%). Considering clinical-neurophysiological suspicion of vasculitis, nerve biopsy confirmed the diagnosis in 60.9% of cases. DISCUSSION: In conclusion, for inherited neuropathies, we do not recommend this invasive procedure, but we strongly suggest a genetic test. Conversely, in vasculitic neuropathies or in dysimmune neuropathies not clearly confirmed by neurophysiological examination, nerve biopsy continues to represent a useful and irreplaceable tool.

Eight-year survival of a recurrent glioblastoma patient treated with molecularly tailored therapy: a case report.

Treatment options for recurrent glioblastoma are scarce; targeted therapy trials were disappointing, probably due to enrollment of patients without molecular selection. We treated with bevacizumab and erlotinib a 66-year-old male suffering from recurrent glioblastoma, IDH-wildtype and MGMT unmethylated, after three neurosurgeries. Treatment was tailored on molecular profile of recurrent tumor-namely, EGFRvIII positivity, VEGF overexpression, normal PTEN, low total VEGF and VEGF-121 mRNA-and resulted in complete, exceptionally durable response (51-month progression-free survival). Notably, histology of further recurrence after therapy was reminiscent of sarcoma. We suggest a thorough molecular screening for personalization of targeted therapy in recurrent glioblastoma.

Skin glomic tumors referred for local pain and cured by surgical removal.

BACKGROUND: Under the definition "glomus tumors" are often erroneously enclosed neoplasms that are absolutely unlike for origin, location, and behavior. Glomus tumors (GTs) are small but extremely painful skin tumors of mesenchymal origin. GTs derive from the neuromyoarterial glomus in adults of middle-age and are generally benign. Due to their small size, diagnosis is often difficult and patients harboring these tumors usually consult many physicians, including sometimes neurosurgeons. More familiar to neurosurgeons are neoplasms as glomus jugular, glomus vagale, and glomus tympanicum that instead all belong to the family of paragangliomas (PGs) and for this reason should not be confused with the aforementioned skin tumors. METHOD AND RESULTS: Here we present a brief review of these two different classes of tumors and also the clarification of any misunderstanding that may derive from an improper use of the terminology. In order to illustrate why skin tumors may interest neurosurgeons, we have reviewed our institutional series of outpatient surgical procedures. Differential diagnosis with other tumors that appear as cutaneous nodules is also discussed. From January 2012 to May 2015, seven patients harboring a GT (six male and one female) were treated. The age ranged from 34 to 71 years (mean, 54.1). The clinical suspect of GT, was validated by ultrasound (US) and, if necessary, by magnetic resonance imaging (MRI). All patients underwent surgery for total tumor removal. Immediate pain relief was obtained in all the patients, and no recurrences were observed during follow-up. Histology confirmed the diagnosis of GT. CONCLUSIONS: Subcutaneous painful nodules, originating from the glomus body, are properly called GTs. Unlikely from other tumors, as schwannomas or neurofibromas, GTs are the cause of pain that is disproportionate to their tiny size and that is not associated to neurological disturbances. Surgical treatment allows a complete regression of pain with significant patient satisfaction. Neoplasms originating from neuroepithelial cells, on the contrary, should not be defined as GTs.

Ultrasound evaluation in traumatic peripheral nerve lesions: from diagnosis to surgical planning and follow-up.

Surgical treatment of traumatic nerve lesions is a matter of debate, mostly about the timing and technical aspects of the procedure. In deciding about and planning the operation, it is often necessary to repeat the electrophysiological and neuroradiological studies several times. Here we present our experience with ultrasonography taken before and after surgery: this simple and handy tool allowed clear visualization of the preoperative anatomy, thorough preparation and fast carrying out of surgery, and accurate postoperative monitoring of the graft's vitality at follow-up. Though this is a limited series, the importance of ultrasonographic evaluation in traumatic peripheral nerve lesions appears remarkable.

Personalized Medicine in Brain Tumors.

Personalizing clinical, diagnostic and therapeutic approaches in neuro-oncology is a huge challenge [...].

Neuralgic Amyotrophy and Hourglass Nerve Constriction/Nerve Torsion: Two Sides of the Same Coin? A Clinical Review.

Neuralgic amyotrophy, also called Parsonage-Turner syndrome, in its classic presentation is a brachial plexopathy or a multifocal neuropathy, involving mainly motor nerves of the upper limb with a monophasic course. Recently, a new radiological entity was described, the hourglass constriction, which is characterized by a very focal constriction of a nerve, or part of it, usually associated with nerve thickening proximally and distally to the constriction. Another condition, which is similar from a radiological point of view to hourglass constriction, is nerve torsion. The pathophysiology of neuralgic amyotrophy, hourglass constriction and nerve torsion is still poorly understood, and a generic role of inflammation is proposed for all these conditions. It is now widely accepted that nerve imaging is necessary in identifying hourglass constrictions/nerve torsion pre-surgically in patients with an acute mononeuropathy/plexopathy. Ultrasound and MRI are useful tools for diagnosis, and they are consistent with intraoperative findings. The prognosis is generally favorable after surgery, with a high rate of good motor recovery.