Francesco Zenga

Solid lipid nanoparticles: could they help to improve the efficacy of pharmacologic treatments for brain tumors?

Abstract Objectives: Brain malignant neoplasms are still characterized by poor prognosis due to their peculiar hallmarks that severely limit aggressive multimodal therapeutic approaches. The optimization of the intratumoral drug delivery, directed to achieve effective concentrations and to reduce systemic undesired toxicity, is one of the primary goals of the brain tumors therapeutic strategies. Different passive and active delivery carriers allowing to a better control of drug distribution, metabolism, and elimination after parenteral administration have been developed. In the present review we will describe general characteristics and evaluate the efficacy of Solid Lipid Nanoparticles (SLN) as carriers of different drugs in experimental brain malignant tumor therapy. Methods: SLN vehiculating different illustrative types of antineoplastic agents (conventional cytotoxic drugs such as doxorubicin and paclitaxel, the prodrug Cholesteryl butyrate, and anti VEGF antisense oligonucleotides) have been tested in experimental animal models of cerebral gliomas. Results: SLN proved to successfully vehiculate into the brain different types of cytotoxic and gene therapeutical agents (otherwise unable to pass through the Blood-Brain Barrier) and to induce effective anti-tumoral therapeutical response. Discussion: Compared to other vehicules, SLN seem to offer more advantages (such as higher physical stability, greater protection from degradation and better release profile of incorporated drugs, good tolerability and possibility of site-specific targeting) and could be regarded as an effective carrier for chemotherapeutic drugs, gene therapeutical agents, and diagnostic tools in neuro-oncology.

Extradural Motor Cortex Stimulation in Advanced Parkinson's Disease: The Turin Experience: Technical Case Report

OBJECTIVE AND IMPORTANCE: At our institution, extradural motor cortex stimulation (EMCS) has recently been applied for treating Parkinson’s disease symptoms. We report our results and review the literature supporting this application of EMCS. CLINICAL PRESENTATION: Since 1998, six patients affected by advanced Parkinson’s disease and not fulfilling inclusion criteria for deep brain stimulation underwent EMCS. INTERVENTION: A quadripolar electrode was introduced in the extradural space over the motor cortex, opposite to the side on which parkinsonian symptoms had begun. Bipolar chronic electrostimulation was delivered at 2.5 to 6 V, 150 to 180 microseconds, and 25 to 40 Hz. Preoperative and postoperative clinical status was assessed by the Unified Parkinson’s Disease Rating Scale (UPDRS) and recorded on videotapes. The follow-up of this series varied from 4 months to 2.5 years. After EMCS, the overall UPDRS score decreased by 42 to 62%; Section III UPDRS score (motility evaluation) by 32 to 83%; and Section IV UPDRS score (therapy complications) by 100% in two patients, by 50 to 67% in four patients, and by 33% in one patient. l-Dopa therapy was reduced by 11 to 33% in three patients and by 70 to 73% in the other two patients. No postoperative complications or negative side effects of electrostimulation were recorded, except for a misplacement of the electrodes in one patient. CONCLUSION: Unilateral EMCS relieves, at least partially, but sometimes dramatically, the whole spectrum of symptoms in advanced Parkinson’s disease. l-Dopa may be reduced up to 70%. The symptoms of long-term l-dopa syndrome are usually markedly improved. The neurophysiological mechanisms involved are still under debate. Our clinical experience adds favorable data to enlarge the series of parkinsonian patients treated by EMCS.

Results by motor cortex stimulation in treatment of focal dystonia, Parkinson’s disease and post-ictal spasticity. The experience of the Italian Study Group of the Italian Neurosurgical Society

Extradural motor cortex stimulation has been employed in cases of Parkinsons disease (PD), fixed dystonia (FD) and spastic hemiparesis (SH) following cerebral stroke. Symptoms of PD are improved by EMCS: results were evaluated on the basis of the UPDRS and statistically analysed. In PD EMCS is less efficacious than bilateral subthalamic nucleus (STN) stimulation, but it may be safely employed in patients not eligible for deep brain stimulation (DBS). The most rewarding effect is the improvement, in severely affected patients, of posture and gait. FD, unresponsive to bilateral pallidal stimulation, has been relieved by EDMS. In SH reduction of spasticiy by EMCS allows improvement of the motor function.

Prevention and treatment of post-traumatic epilepsy

Post-traumatic epilepsy is reported after 2–5% of closed head injuries but up to 50% or more following penetrating head injury. Despite several studies, no drug strategy has been able, to date, to quench the biochemical events leading to epileptogenesis. One possibility is that treatment with available antiepileptic drugs has been implemented too late, and thus, ultra-early treatment might still be able to stop the neurochemical epileptogenic cascade dead in its tracks. However, currently drug therapy should be instituted only after the first late unprovoked seizure.

Primary and secondary reconstruction of complex craniofacial defects using polyetheretherketone custom-made implants

PURPOSE The aim of this study was to evaluate the surgical outcomes using polyetheretherketone (PEEK) patient-specific prostheses produced by computer-aided design and manufacturing for primary and secondary reconstruction in patients with craniofacial defects. MATERIAL AND METHODS The study included 13 patients who underwent reconstruction for craniofacial defects using PEEK patient-specific implants (PSI). Eight patients underwent single-step primary reconstruction using individual custom-made surgical guides and custom-made prostheses during the same surgery; five patients underwent delayed reconstruction. The material used to manufacture the implants was PEEK in 13 cases. All patients underwent esthetic examination, ophthalmological examination, and radiological evaluation during the preoperative and follow-up periods. The operation duration and short- and long-term complications were recorded. RESULTS The shape and global position of the implants were satisfactory in each case. Fitting of the implant during surgery required extensive adaptation in 1 case and minor in 11 cases. Of 13 implants, 11 adequately restored a morphological complex area with satisfactory cosmetic results. No complications related to the implants were reported. CONCLUSION Reconstruction for cranio-facial defects using PEEK computer-aided designed and manufactured implants is a promising new technique that allows for accurate restoration of the complex 3D anatomy of the craniofacial region.

Endoscopic Endonasal Approach to the Odontoid Pathologies.

BACKGROUND Surgical anterior decompression represents the treatment of choice for symptomatic irreducible ventral craniovertebral junction (CVJ) compression. With the refinement of the endoscopic techniques, the endonasal route has been proposed as alternative to the classic transoral approach to CVJ. Some reports assess the effectiveness and safety of endoscopic endonasal approaches to CVJ pathologies. MATERIALS AND METHODS From July 2011 to February 2014, 12 patients with symptomatic nonreducible ventral spinal cord compression underwent purely 3-dimensional endoscopic endonasal odontoidectomy in our department. The surgical technique is described. RESULTS A good brainstem-medullary decompression was achieved in all patients. In 10 of 12 patients the endotracheal tube was removed just after the procedure with good recovery of the respiratory function. We report no cases of velopharyngeal insufficiency. In 5 of 12 patients the preservation of C1 anterior was achieved, without the need for posterior cervical fixation. DISCUSSION AND CONCLUSIONS Endoscopic endonasal odontoidectomy has proven to be safe and effective in selected patients. Soft and hard palate preservation dramatically reduces the risk of postoperative velopharyngeal insufficiency. Moreover, the endonasal endoscopic approach provides a direct access to the dens. Three-dimensional high-definition endoscope, laser, and ultrasound bony curettes revealed to be useful tools for this approach that, however, remains a demanding one.

Characterization of biological features of a rat F98 GBM model: a PET-MRI study with [18F]FAZA and [18F]FDG.

INTRODUCTION The prognosis of malignant gliomas remains largely unsatisfactory for the intrinsic characteristics of the pathology and for the delayed diagnosis. Multimodal imaging based on PET and MRI may assess the dynamics of disease onset and progression allowing the validation of preclinical models of glioblastoma multiforme (GBM). The aim of this study was the characterization of a syngeneic rat model of GBM using combined in vivo imaging and immunohistochemistry. METHODS Four groups of Fischer rats were implanted in a subcortical region with increasing concentration of rat glioma F98 cells and weekly monitored with Gd-MR, [(18)F]FDG- and [(18)F]FAZA-PET starting one week after surgery. Different targets were evaluated on post mortem brain specimens using immunohistochemistry: VEGF, GFAP, HIF-1α, Ki-67 and nestin. RESULTS Imaging results indicated that tumor onset but not progression was related to the number of F98 cells. Hypoxic regions identified with [(18)F]FAZA and high-glucose metabolism regions recognized with [(18)F]FDG were located respectively in the core and in external areas of the tumor, with partial overlap and remodeling during disease progression. Histological and immunohistochemical analysis confirmed PET/MRI results and revealed that our model resumes biological characteristics of human GBM. IHC and PET studies showed that necrotic regions, defined on the basis of [(18)F]FDG uptake reduction, may include hypoxic clusters of vital tumor tissue identified with [(18)F]FAZA. This last information is particularly relevant for the identification of the target volume during image-guided radiotherapy. CONCLUSIONS In conclusion, the combined use of PET and MRI allows in vivo monitoring of the biological modification of F98 lesions during tumor progression.

Evaluation of variation in the course of the facial nerve, nerve adhesion to tumors, and postoperative facial palsy in acoustic neuroma.

Objective To investigate the variation in the course of the facial nerve (FN) in patients undergoing acoustic neuroma (AN) surgery, its adhesion to tumors, and the relationship between such adhesions and postoperative facial palsy. Methods The subjects were 356 patients who underwent AN surgery in whom the course of the FN could be confirmed. Patients were classified into six groups: ventro-central surface of the tumor (VCe), ventro-rostral (VR), ventro-caudal (VCa), rostral (R), caudal (C), and dorsal (D). Results The FN course was VCe in 185 cases, VR in 137, VCa in 19, R in 10, C in 4, and D in one. For tumors < 1.5 cm, VCe was most common. For tumors ≥ 1.5 cm, the proportion of VR increased. No significant difference was observed between the course patterns of the FN in terms of postoperative FN function, but for tumors > 3.0 cm, there was an increasing tendency for the FN to adhere strongly to the tumor capsule, and postoperative facial palsy was more severe in patients with stronger adhesions. Conclusions The VCe pattern was most common for small tumors. Strong or less strong adhesion to the tumor capsule was most strongly associated with postoperative FN palsy.

Say “no” to spinal cord injury: is nitric oxide an option for therapeutic strategies?

Purpose: a literature review was made to investigate the role of nitric oxide (NO) in spinal cord injury, a pathological condition that leads to motor, sensory, and autonomic deficit. Besides, we were interested in potential therapeutic strategies interfering with NO mechanism of secondary damage. Materials: A literature search using PubMed Medline database has been performed. Results: excessive NO production after spinal cord injury promotes oxidative damage perpetuating the injury causing neuronal loss at the injured site and in the surrounding area. Conclusion: different therapeutic approaches for contrasting or avoiding NO secondary damage have been studied, these include nitric oxide synthase inhibitors, compounds that interfere with inducible NO synthase expression, and molecules working as antioxidant. Further studies are needed to explain the neuroprotective or cytotoxic role of the different isoforms of NO synthase and the other mediators that take part or influence the NO cascade. In this way, it would be possible to find new therapeutic targets and furthermore to extend the experimentation to humans.

Three-dimensional endoscopy in transnasal transsphenoidal approach to clival chordomas

The purpose of this prospective, observational study was to evaluate the management of skull base chordomas surgically resected via a 3D‐endoscopic transnasal approach.