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The majority of patients with glioblastoma (GBM) experience disease progression. At recurrence, treatment options have limited efficacy. Many studies report a limited and short duration response rate. Although clinical trials represent the "gold standard" for providing evidence on efficacy of specific treatment strategies, real-world data can be considered more representative of the "real" GBM population.To describe the management of GBM recurrence in a large real-world sample.We analysed retrospectively the data stored in the database of the Neuro-oncology Unit, IRCCS "Regina Elena" National Cancer Institute, Rome, Italy. We considered only data of patients with histological diagnosis of GBM and disease recurrence during their follow-up. We excluded patients who did not receive treatment after the diagnosis.We analysed 422 patients (64% males, 36% females) with a mean age of 59.6 (range 16-87) years. At GBM recurrence, 135 (32.0%) patients underwent palliative care, and 287 (68.0%) underwent other treatments. Patients on palliative care were older, had a worse performance status, and a shorter time between GBM diagnosis and its recurrence. Patients who received chemotherapy in combination with other treatments (surgery and/or radiation therapy) at GBM recurrence had a longer survival than those in palliative care (p 0.001). Surgery or radiation therapy alone did not have any effect on survival as compared with palliative care (p 0.001).This study confirms the importance of a multidisciplinary approach even at GBM recurrence, suggesting that combination treatments play a key role in management of disease.

BACKGROUND AND PURPOSE Amyotrophic lateral sclerosis (ALS) patients exhibit dysfunctional energy metabolism and weight loss, which is negatively correlated with survival, together with neuroinflammation. However, the possible contribution of neuroinflammation to deregulations of feeding behaviour in ALS has not been studied in detail. We here investigated if microglial KCa 3.1 is linked to hypothalamic neuroinflammation and affects feeding behaviours in ALS mouse models. EXPERIMENTAL APPROACH hSOD1G93A and TDP43A315T mice were treated daily with 120 mg·kg-1 of TRAM-34 or vehicle by intraperitoneal injection from the presymptomatic until the disease onset phase. Body weight and food intake were measured weekly. The later by weighing food provided minus that left in the cage. RT-PCR and immunofluorescence analysis were used to characterize microglia phenotype and the main populations of melanocortin neurons in the hypothalamus of hSOD1G93A and age-matched non-tg mice. The cannabinoid-opioid interactions in feeding behaviour of hSOD1G93A mice were studied using an inverse agonist and an antagonist of the cannabinoid receptor CB1 (rimonabant) and μ-opioid receptors (naloxone), respectively. KEY RESULTS We found that treatment of hSOD1G93A mice with the KCa 3.1 inhibitor TRAM-34 (i), attenuates the pro-inflammatory phenotype of hypothalamic microglia, (ii) increases food intake and promotes weight gain, (iii) increases the number of healthy pro-opiomelanocortin (POMC) neurons and (iv), changes the expression of cannabinoid receptors involved in energy homeostasis. CONCLUSION AND IMPLICATIONS Using ALS mouse models, we describe defects in the hypothalamic melanocortin system that affect appetite control. These results reveal a new regulatory role for KCa 3.1 to counteract weight loss in ALS.

Amyotrophic lateral sclerosis (ALS) patients exhibit dysfunctional energy metabolism and weight loss, which is negatively correlated with survival, together with neuroinflammation. However, the possible contribution of neuroinflammation to deregulations of feeding behaviour in ALS has not been studied in detail. We here investigated if microglial KhSOD1We found that treatment of hSOD1Using ALS mouse models, we describe defects in the hypothalamic melanocortin system that affect appetite control. These results reveal a new regulatory role for K

Nectin2 is a member of immunoglobulin-like cell adhesion molecules and plays a prominent role in the establishment of adherens and tight junctions. It is also upregulated on the surface of tumor and virus-infected cells where it functions as a ligand for the activating receptor CD226, thus contributing to cytotoxic lymphocyte-mediated recognition and killing of damaged cells. Little is currently known about the regulation of Nectin2 expression and, in particular, whether posttranscriptional and posttranslational mechanisms are involved. Here, we analyzed Nectin2 expression on a panel of human tumor cell lines and primary cultures and we found that Nectin2 is mainly expressed in cytoplasmic pools. Moreover, we demonstrated that ubiquitination of Nectin2 promotes its degradation and is responsible for protein intracellular retention. Indeed, inhibition of the ubiquitin pathway results in increased Nectin2 surface expression and enhances tumor cell susceptibility to NK cell cytotoxicity. Our results demonstrate a previously unknown mechanism of Nectin2 regulation revealing that the ubiquitin pathway represents a potential target of intervention in order to increase susceptibility to NK cell-mediated lysis.

CD155 is an adhesion molecule belonging to the Nectin/Nectin-like family often overexpressed on tumor cells and involved in many different processes such as cell adhesion, migration and proliferation. In contrast to these pro-tumorigenic functions, CD155 is also a ligand for the activating receptor DNAM-1 expressed on cytotoxic lymphocytes including Natural Killer (NK) cells and involved in anti-tumor immune response. However, during tumor progression inhibitory receptors for CD155 are up-regulated on the surface of effector cells, contributing to an impairment of their cytotoxic capacity. In this review we will focus on the roles of CD155 as a ligand for the activating receptor DNAM-1 regulating immune surveillance against cancer and as pro-oncogenic molecule favoring tumor proliferation, invasion and immune evasion. A deeper understanding of the multiple roles played by CD155 in cancer development contributes to improving anti-tumor strategies aimed to potentiate immune response against cancer.

Natural Killer cells are innate lymphocytes involved in tumor immunosurveillance. They express activating receptors able to recognize self-molecules poorly expressed on healthy cells but up-regulated upon stress conditions, including transformation. Regulation of ligand expression in tumor cells mainly relays on transcriptional mechanisms, while the involvement of ubiquitin or ubiquitin-like modifiers remains largely unexplored. Here, we focused on the SUMO pathway and demonstrated that the ligand of DNAM1 activating receptor, PVR, undergoes SUMOylation in multiple myeloma. Concurrently, we found that PVR is preferentially located in intracellular compartments in human multiple myeloma cell lines and malignant plasma cells and that inhibition of the SUMO pathway promotes its translocation to the cell surface, increasing tumor cell susceptibility to NK cell-mediated cytolysis. Our findings provide the first evidence of an innate immune activating ligand regulated by SUMOylation, and confer to this modification a novel role in impairing recognition and killing of tumor cells.

Background Patients affected by tuberous sclerosis (TS) have a greater incidence of tumors than the healthy population. Spinal tumours in TS are reported very rarely and consist mainly of sacrococcygeal and cervical chordomas. Method Case report. Findings A 21-year-old man, affected by TS, presented a spinal dorsal T2 tumor that caused medullary compression. He underwent decompressive laminectomy and microsurgical excision of a giant cell tumor and an associated aneurysmal bone cyst. Postoperative hypofractionated radiotherapy was performed on the surgical field. At 2.4 years of follow-up the patient reported total recovery of neurological deficits and was free from tumor recurrence. Conclusion Considering this association, which is the first reported in the literature, spinal magnetic resonance imaging with gadolinium should be performed at the onset of spinal pain in patients affected by TS.

Boron neutron capture therapy (BNCT) is a promising binary modality used to treat malignant brain gliomas. To optimize BNCT effectiveness a non-invasive method is needed to monitor the spatial distribution of BNCT carriers in order to estimate the optimal timing for neutron irradiation. In this study, in vivo spatial distribution mapping and pharmacokinetics evaluation of the (19)F-labelled boronophenylalanine (BPA) were performed using (19)F magnetic resonance imaging ((19)F MRI) and (19)F magnetic resonance spectroscopy ((19)F MRS). Characteristic uptake of (19)F-BPA in C6 glioma showed a maximum at 2.5 h after compound infusion as confirmed by both (19)F images and (19)F spectra acquired on blood samples collected at different times after infusion. This study shows the ability of (19)F MRI to selectively map the bio-distribution of (19)F-BPA in a C6 rat glioma model, as well as providing a useful method to perform pharmacokinetics of BNCT carriers.

Radiosurgery (RS) and hypofractionated stereotactic radiotherapy (HSRT) were performed in 23 and 22 patients respectively for the treatment of trigeminal neuralgia. RS and HSRT were performed with a dedicated linear accelerator (LINAC): an invasive frame (for RS) or a relocatable stereotactic frame fitted with a thermoplastic mask and bite blocks (HSRT) were used for positioning patients. The RS treatment delivered 40 Gy in a single fraction, or for HSRT, the equivalent radiobiological fractionated dose – a total of 72 Gy in six fractions. The target (the retrogasserian cisternal portion of the trigeminal nerve) was identified by fusion of CT scans with 1-mm-thick T2-weighted MRI, and the radiant dose was delivered by a 10-mm-diameter cylindrical collimator. The results were evaluated using the Barrow Neurological Institute pain scale during follow-up (mean 3.9 years). The 95% isodose was applied to the entire target volume. After RS (23 patients), Class 1 results were observed in 10 patients; Class II in nine, Class IIIa in two, Class IIIb in one, and Class V results in one patient. Facial numbness occurred in two (8.7%) patients, and the trigeminal neuralgia recurred in two patients (8.7%). Following HSRT (22 patients), Class I results were achieved in eight patients, Class II in eight, Class IIIa in four, and Class IIIb in two patients; recurrence occurred in six (27.5%), and there were no complications. Thus, both RS and HSRT provided effective and safe therapy for the treatment of trigeminal neuralgia. Patients who underwent RS experienced better pain relief and a lower recurrence rate, whereas those who underwent HRST had no side effects, and in particular, no facial numbness.

a b s t r a c t Objective: A modified transsphenoidal technique to remove huge pituitary adenomas with marked suprasellar extension (4.5-8 cm of maximum diameter) is presented. Methods: The technique allowed to avoid the occurrence of a precocious descent of the suprasellar cister- nal plane into the sellar plane during tumour removal and its related consequences (incomplete tumour removal, occurrence of cerebrospinal fluid leak, prolonged time of postoperative stay in hospital). Tech- nique is performed opening at the beginning only the lateral parts of peritumoral dura mater, leaving the central part of the dura mater in support of the central part of tumour and suprasellar cisternal plane. After removal of lateral parts of the tumour, the central part of peritumoral dura mater is opened and the central intra- and supra-sellar parts of the tumour are removed. Results: Total removal was accomplished in 64% and 45% in groups two and one respectively. Intraopera- tive CSF leak occurred in 2.4% and 22.5% respectively in groups two and one. Postoperative CSF fistula did not occur in group two, while it occurred in 7.4% of patients of group one. Average time of postoperative stay in hospital was 4.3 and 8.2 days in groups two and one respectively. Conclusion: The presented modified transsphenoidal microsurgical technique for removal of huge pitu- itary adenomas allowed to achieve better results than patients operated by standard transsphenoidal surgery.

Introduction: Trigeminal neuralgia is a common cause of facial pain. Many therapies are accomplishable; purpose of the study is to evaluate the role and the indications, in our experience, of peripheral alcohol injections, controlled radiofrequency thermocoagulation, gasserian ganglion compression with balloon and microvascular decompression in posterior cranial fossa. Methods: A series of 437 patients treated with various surgical methods for idiopathic trigeminal neuralgia refractory to medical therapy is presented. The treatments were performed according to the interested trigeminal division, the gravity of the neuralgia, the age and the general conditions of the patients. Moreover, the role of radiosurgery is underlined. Results: Peripheral alcohol injections resulted very effective for temporary control of dolorific attacks. Thermocoagulation resulted a very effective and stable method for isolated III division trigeminal neuralgia; balloon compression was very effective for pain control but entire hemifacial anesthesia was necessary to obtain a good outcome; microvascular decompression resulted affective but was reserved for young healthy patients (trigeminal neuralgia is predominant in advanced age). Conclusions: In our opinion, each treatment should be indicated according to neuralgia (interested trigeminal division, gravity) and patient (age, general conditions) characteristics, to perform the best treatment for each patient.

The aim of this study was to evaluate in vivo the boron biodistribution and pharmacokinetics of 4-borono-2-fluorophenylalanine ((19)F-BPA) using (19)F MR Imaging ((19)F MRI) and Spectroscopy ((19)F MRS). The correlation between the results obtained by both techniques, (19)F MRI on rat brain and (19)F MRS on blood samples, showed the maximum (19)F-BPA uptake in C6 glioma model at 2.5 h after infusion determining the optimal irradiation time. Moreover, the effect of L-DOPA as potential enhancer of (19)F-BPA turnout intake was assessed using (19)F MRI.