Second surgery for relapsed glioblastoma: an observational study on criteria for patient selection in real life.

Aim: There is little consensus on salvage management of glioblastoma after recurrence, for lack of evidence. Materials & methods: A retrospective study of treatments in patients with recurrent glioblastoma. Results: Surgery at recurrence was related to better overall survival (OS) and progression-free survival (PFS). Surgery at recurrence, Karnofsky index, MGMT methylation status, younger age at diagnosis and number of chemotherapy cycles were positive factors for OS and PFS. The benefit of OS was relevant for a second surgery performed at least 9 months after the first one. Systemic treatments after the second surgery were linked to an improved PFS. Conclusion: Younger age, Karnofsky index, MGMT methylation status and a median time between surgeries ≥9 months may be criteria for eligibility for surgery at recurrence.

[Box: see text].

The Glioma-IRE project - Molecular profiling in patients with glioma: steps toward an individualized diagnostic and therapeutic approach.

BACKGROUND: This study aimed to characterize the genetic profile of patients with glioma and discuss the impact of next-generation sequencing in glioma diagnosis and treatment. METHODS: Between 2019 and 2022, we analyzed the genetic profile of 99 patients with glioma through the Oncomine Focus Assay. The assay enables the detection of mutations in 52 driver genes, including single nucleotide variants (SNVs), copy number variants (CNVs), and gene fusions. We also collected and analyzed patients' clinic characteristics and treatment outcomes. RESULTS: Over a period of 35 months, 700 patients with glioma followed by our neuro-oncology unit were screened, and 99 were enrolled in the study; most of the patients were excluded for inadequate non-morphological MRI or lack/inadequacy of the tissue samples. Based on our findings, most patients with glioma present mutations, such as SNVs, CNVs or gene fusions. Our data were similar to those reported by The Cancer Genome Atlas Program in terms of frequency of SNVs and CNVs, while we observed more cases of gene fusions. Median overall survival, progression-free survival, and time to progression were significantly lower for patients with grade VI glioblastoma than those with other gliomas. Only four patients were offered a targeted treatment based on the mutation detected; however, only one received treatment, the others could not receive the selected treatment because of worsening clinical status. CONCLUSION: Routine timely molecular profiling in patients with glioma should be implemented to offer patients an individualized diagnostic approach and provide them with advanced targeted therapy options if available.

Recurrent glioblastoma: which treatment? A real-world study from the Neuro-oncology Unit "Regina Elena" National Cancer Institute.

BACKGROUND: 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. OBJECTIVE: To describe the management of GBM recurrence in a large real-world sample. METHODS: 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. RESULTS: 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). CONCLUSION: 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.

The Ubiquitin-proteasome pathway regulates Nectin2/CD112 expression and impairs NK cell recognition and killing.

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.

FcεRI Signaling in the Modulation of Allergic Response: Role of Mast Cell-Derived Exosomes.

Mast cells (MCs) are immune cells that act as environment resident sentinels playing a crucial role in Th2-mediated immune responses, including allergic reactions. Distinguishing features of MCs are the presence of numerous cytoplasmic granules that encapsulate a wide array of preformed bio-active molecules and the constitutive expression of the high affinity receptor of IgE (FcεRI). Upon FcεRI engagement by means of IgE and multivalent antigens, aggregated receptors trigger biochemical pathways that ultimately lead to the release of granule-stored and newly synthesized pro-inflammatory mediators. Additionally, MCs are also able to release exosomes either constitutively or upon stimulation. Exosomes are nanosized vesicles of endocytic origin endowed with important immunoregulatory properties, and represent an additional way of intercellular communication. Interestingly, exosomes generated upon FcεRI engagement contain co-stimulatory and adhesion molecules, lipid mediators, and MC-specific proteases, as well as receptor subunits together with IgE and antigens. These findings support the notion that FcεRI signaling plays an important role in influencing the composition and functions of exosomes derived by MCs depending on their activation status.

CD155: A Multi-Functional Molecule in Tumor Progression.

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.

Monocenter Experience with 532 Nm-Laser Photoselective-Vaporization of the Prostate by GreenLight XPS™ Laser: Is It Really an Endourological Joker Card?

INTRODUCTION: In our study, we reported on our monocenter experience with GreenLight (GL) Xcelerated Performance System (XPS)™ /MoXy™ laser fiber (American Medical Systems Inc., Minnetonka, Minnesota), examining its efficacy, safety, and its ability to effectively treat lower urinary tract symptoms (LUTS) in benign prostate obstruction (BPO). We also explored and compared the three different endoscopic approaches used for GL treatment of benign prostatic hyperplasia (BPH), standard photovaporization (PVP), anatomical PVP, and GreenLight XPS™ enucleation of the prostate. MATERIALS AND METHODS: Between February 2013 and April 2017, 140 patients, with an average age of 67.7 years (range 47-85), were treated using the XPS™/MoXy™ system in a single-operative urologic center. The data were retrospectively analyzed with an assessment of the main intra- and postoperative outcomes at three, six, 12, and 18 months comparing both subjective (international prostate symptom score [IPSS]) and objective (uroflow [Qmax] parameters and prostate volume) parameters to the preoperative data. Patients underwent standard PVP, anatomical PVP, or prostate photo-selective en-bloc enucleation (PEBE) according to surgeon preferences. RESULTS: Median prostate volume (MPV) and prostate-specific antigen (PSA) were 69cc and 3.24 ng/dl, respectively. An indwelling catheter, at the time of surgery, was observed in 15% of men. Median operative-laser time and energy applied were 56.4 minutes, 26.5 minutes, and 245813 kJ. Outpatient surgery was feasible with median length of stay at 48 hours. Significant improvement in IPSS and Qmax are observed at all endpoints. No significant intraoperative complications were reported. When stratifying postoperative complications according to the Cavien-Dindo classification, only two cases of high-degree emerged (grades III-IV). CONCLUSION: Our data confirm that in treating men with symptomatic benign prostate disease, the GreenLight XPS™/MoXy™ laser fiber is safe and able to achieve challenging results in terms of clinical outcomes and prostate volume reduction. Balance between functional outcomes and complications was great without statistically significant differences, in terms of outcomes, between the different surgical techniques.

Visuospatial, oculomotor, and executive reading skills evolve in elementary school, and errors are significant: a topological RAN study.

We investigate the development of visuospatial and oculomotor reading skills in a cohort of elementary school children. Employing a longitudinal methodology, the study applies the Topological serial digit Rapid Automated Naming (Top-RAN) battery, which evaluates visuospatial reading skills leveraging metrics addressing crowding, distractors, and voluntary attention orientation. The participant pool comprises 142 students (66 males, 76 females), including 46 non-native speakers (21 males, 25 females), representing a diverse range of ethnic backgrounds. The Top-RAN dataset encompasses performance, error, and self-correction metrics for each subtest and student, underscoring the significance of these factors in the process of reading acquisition. Analytical methods include dimensionality reduction, clustering, and classification algorithms, consolidated into a Python package to facilitate reproducible results. Our results indicate that visuospatial reading abilities vary according to the task and demonstrate a marked evolution over time, as seen in the progressive decrease in execution times, errors, and self-corrections. This pattern supports the hypothesis that the growth of oculomotor, attentional, and executive skills is primarily fostered by educational experiences and maturation. This investigation provides valuable insights into the dynamic nature of these skills during pivotal educational stages.

Spinal giant cell tumor in tuberous sclerosis: case report and review of the literature.

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.

SCF and IL-33 regulate mouse mast cell phenotypic and functional plasticity supporting a pro-inflammatory microenvironment.

Mast cells (MCs) are multifaceted innate immune cells often present in the tumor microenvironment (TME). Several recent findings support their contribution to the transition from chronic inflammation to cancer. However, MC-derived mediators can either favor tumor progression, inducing the spread of the tumor, or exert anti-tumorigenic functions, limiting tumor growth. This apparent controversial role likely depends on the plastic nature of MCs that under different microenvironmental stimuli can rapidly change their phenotype and functions. Thus, the exact effect of unique MC subset(s) during tumor progression is far from being understood. Using a murine model of colitis-associated colorectal cancer, we initially characterized the MC population within the TME and in non-lesional colonic areas, by multicolor flow cytometry and confocal microscopy. Our results demonstrated that tumor-associated MCs harbor a main connective tissue phenotype and release high amounts of Interleukin (IL)-6 and Tumor Necrosis Factor (TNF)-α. This MC phenotype correlates with the presence of high levels of Stem Cell Factor (SCF) and IL-33 inside the tumor. Thus, we investigated the effect of SCF and IL-33 on primary MC cultures and underscored their ability to shape MC phenotype eliciting the production of pro-inflammatory cytokines. Our findings support the conclusion that during colonic transformation a sustained stimulation by SCF and IL-33 promotes the accumulation of a prevalent connective tissue-like MC subset that through the secretion of IL-6 and TNF-α maintains a pro-inflammatory microenvironment.

The feeding behaviour of Amyotrophic Lateral Sclerosis mouse models is modulated by the Ca2+ -activated KCa 3.1 channels.

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.

In vivo (19)F MRI and (19)F MRS of (19)F-labelled boronophenylalanine-fructose complex on a C6 rat glioma model to optimize boron neutron capture therapy (BNCT).

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.

Innate immune activating ligand SUMOylation affects tumor cell recognition by NK cells.

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.

Transsphenoidal removal of huge pituitary adenomas with marked suprasellar extension: results with modified surgical technique.

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 cisternal 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). Technique 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. Intraoperative 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 pituitary adenomas allowed to achieve better results than patients operated by standard transsphenoidal surgery.

Preliminary results of 45 patients with trigeminal neuralgia treated with radiosurgery compared to hypofractionated stereotactic radiotherapy, using a dedicated linear accelerator.

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.