Rosaria Viola Abbritti

ROS and Brain Gliomas: An Overview of Potential and Innovative Therapeutic Strategies

Reactive oxygen species (ROS) represent reactive products belonging to the partial reduction of oxygen. It has been reported that ROS are involved in different signaling pathways to control cellular stability. Under normal conditions, the correct function of redox systems leads to the prevention of cell oxidative damage. When ROS exceed the antioxidant defense system, cellular stress occurs. The cellular redox impairment is strictly related to tumorigenesis. Tumor cells, through the generation of hydrogen peroxide, tend to the alteration of cell cycle phases and, finally to cancer progression. In adults, the most common form of primary malignant brain tumors is represented by gliomas. The gliomagenesis is characterized by numerous molecular processes all characterized by an altered production of growth factor receptors. The difficulty to treat brain cancer depends on several biological mechanisms such as failure of drug delivery through the blood-brain barrier, tumor response to chemotherapy, and intrinsic resistance of tumor cells. Understanding the mechanisms of ROS action could allow the formulation of new therapeutic protocols to treat brain gliomas.

Aggressive Pituitary Adenomas: The Dark Side of the Moon.

BACKGROUND Although pituitary adenomas are considered benign lesions, a small group may show clinically aggressive behavior, sometimes independently from the classic markers of aggressiveness, including the Ki67 labeling index or p53 expression. METHODS We selected 7 patients harboring a pituitary tumor with clinical features of aggressiveness. Patients underwent a full preoperative and postoperative endocrinologic and neuroradiologic workup. Two were nonfunctioning, 2 prolactin-secreting, 2 adrenocorticotrophic hormone-secreting, and 1 a growth hormone-secreting adenoma. RESULTS The 7 patients underwent a total of 17 surgical procedures. At the first surgical procedure, gross total removal was achieved in none of the patients, whereas subtotal removal (>90% of tumor removed) was achieved in 4/7 cases and partial removal (<90% of tumor removed) in 3/7 cases. At first operation, 4/7 patients showed a Ki67 index ≤3% and 2/7 >3%; this information was not available for 1 patient. Postoperatively, all patients underwent radiation therapy. Three patients received chemotherapy with temozolomide. Three patients underwent peptide receptor radionuclide therapy. To date, 1 patient has died of tumor progression, and 2 patients are in a poor general condition. The remaining 4 patients are in a fair/good condition, without any major complaints. The mean follow-up is 43.42 months. CONCLUSIONS Aggressive pituitary adenomas represent a specific and still underestimated entity, often diagnosed late. Clinical and neuroradiologic rapid progression is often the only marker of aggressiveness. Surgical debulking remains the first therapeutic option. Multidisciplinary management is mandatory to offer these patients targeted therapeutic options.

The Impact of Diffusion Tensor Imaging Fiber Tracking of the Corticospinal Tract Based on Navigated Transcranial Magnetic Stimulation on Surgery of Motor-Eloquent Brain Lesions

BACKGROUND Navigated transcranial magnetic stimulation (nTMS) enables preoperative mapping of the motor cortex (M1). The combination of nTMS with diffusion tensor imaging fiber tracking (DTI-FT) of the corticospinal tract (CST) has been described; however, its impact on surgery of motor-eloquent lesions has not been addressed. OBJECTIVE To analyze the impact of nTMS-based mapping on surgery of motor-eloquent lesions. METHODS In this retrospective case-control study, we reviewed the data of patients operated for suspected motor-eloquent lesions between 2012 and 2015. The patients underwent nTMS mapping of M1 and, from 2014, nTMS-based DTI-FT of the CST. The impact on the preoperative risk/benefit analysis, surgical strategy, craniotomy size, extent of resection (EOR), and outcome were compared with a control group. RESULTS We included 35 patients who underwent nTMS mapping of M1 (group A), 35 patients who also underwent nTMS-based DTI-FT of the CST (group B), and a control group composed of 35 patients treated without nTMS (group C). The patients in groups A and B received smaller craniotomies (P = .01; P = .001), had less postoperative seizures (P = .02), and a better postoperative motor performance (P = .04) and Karnofsky Performance Status (P = .009) than the controls. Group B exhibited an improved risk/benefit analysis (P = .006), an increased EOR of nTMS-negative lesions in absence of preoperative motor deficits (P = .01), and less motor and Karnofsky Performance Status worsening in case of preoperative motor deficits (P = .02, P = .03) than group A. CONCLUSION nTMS-based mapping enables a tailored surgical approach for motor-eloquent lesions. It may improve the risk/benefit analysis, EOR and outcome, particularly when nTMS-based DTI-FT is performed.

Fully Endoscopic Freehand Evacuation of Spontaneous Supratentorial Intraparenchymal Hemorrhage

OBJECTIVE A modification of other reported endoscopic techniques for intracerebral clot evacuation is described and illustrated. METHODS From January 2014 to December 2014, we operated on 6 patients harboring a spontaneous supratentorial intracerebral hemorrhage using a fully endoscopic freehand technique. Clinical chart and surgical videos were analyzed. Volumetric evaluation of the clot preoperatively and the residual hematoma postoperatively was performed. Clinical outcome was measured using the modified Rankin Scale and Glasgow Outcome Scale. RESULTS The mean operative time was 96 minutes (range, 72-125 minutes). Clot evacuation was >90% in all patients. No patient experienced rebleeding after surgery. Two patients died. The Glasgow Outcome Scale score at 6 months was 4 in 2 patients, 3 in 2 patients, and 1 (death) in 2 patients. The modified Rankin Scale score at 6 months was 6 (death) in 2 patients, 4 in 2 patients, 3 in 1 patient and 2 in 1 patient. CONCLUSIONS The proposed minimally invasive technique allows a good rate of hematoma evacuation and intraoperative bleeding control. Further studies in large series are needed to confirm the role of this freehand endoscopic technique.

Microvascular Decompression for Trigeminal Neuralgia: Technical Refinement for Complication Avoidance

BACKGROUND Microvascular decompression (MVD) represents the most effective and safe surgical option for the treatment of trigeminal neuralgia since it was first popularized by Jannetta 50 years ago. Despite several advances, complications such as cerebellar and vascular injury, hearing loss, muscular atrophy, cerebrospinal fluid (CSF) leak, postoperative cutaneous pain, and sensory disturbances still occur and may negatively affect the outcome. We propose some technical nuances of the surgical procedure that were used in our recent series. METHODS We used a novel hockey stick-shaped retromastoid skin incision, preserving the major nerves of the occipital and temporal areas. Microsurgical steps were performed without the use of retractors. CSF leakage was prevented with a watertight dural closure and multilayer osteodural reconstruction. RESULTS The refined surgical steps were perfected in the last consecutive 15 cases of our series. In these cases we did not record any cutaneous pain, sensory disturbances, or CSF leakage. The average diameter of the craniectomy was 18 mm. No patient reported major complications related to the intradural microsurgical maneuvers. In all cases the neurovascular conflict was found and solved with a good outcome in terms of pain disappearance. CONCLUSIONS Our minimally invasive approach was demonstrated to guarantee an optimal exposure of the cerebellopontine angle and minimize the rate of complications related to skin incision and muscular dissection, microsurgical steps, and closure.

Resting-state fMR evidence of network reorganization induced by navigated transcranial magnetic repetitive stimulation in phantom limb pain

Abstract Objectives Repetitive transcranial magnetic stimulation (rTMS) is a promising tool for treatment of chronic pain. We describe the use of navigated rTMS to treat a patient affected by phantom limb pain (PLP) and to modulate brain functional connectivity. We reviewed the literature on the use of rTMS as a tool for relieving central pain by promoting brain plasticity. Methods A 69-year-old patient came to our observation blaming severe pain (Visual Analog scale, VAS, score 9) to a phantom right lower limb. We mapped left primary motor area (PMA) by navigated TMS and assessed connectivity with resting-state functional MR (rsfMR). The patient underwent 30-days navigated rTMS treatment. We applied low-frequency stimulation (1 Hz) over the primary somatosensory area (PSA) and high-frequency stimulation (10 Hz) over PMA and dorsolateral prefrontal cortex (DLPFC) of the left hemisphere. Results This strategy allowed a pain relief with a reduction of 5 points of the VAS score after 1 month. Post-treatment rsfMR showed increased connectivity, mainly in the sensory-motor network and the unaffected hemisphere (P < 0.05). Discussion This report represents a proof-of-concept that navigated rTMS can be effectively used to stimulate selected brain areas in PLP patients in order to promote brain connectivity, and that rsfMR is a useful tool able to analyze functional results. In the literature, we found data supporting the assumption that, in patients affected by PLP, a reduced connectivity in interhemispherical and sensory-motor network plays a role in generating pain and that rTMS has the potential to restore impaired connectivity.

Neuropsychological Assessment in the Differential Diagnosis of Idiopathic Normal Pressure Hydrocephalus. An Important Tool for the Maintenance and Restoration of Neuronal and Neuropsychological Functions

Idiopathic normal pressure hydrocephalus (iNPH) is a progressive clinical syndrome that includes gait disturbances, urinary incontinence, and cognitive impairment. iNPH shows similarities to other neurodegenerative disorders, primarily Alzheimers Disease (AD). Definition of the neuropsychological profile of iNPH and the qualitative analysis of systematic mistakes made in cognitive tests could represent a valid method for systematizing possible specific markers of iNPH dementia and differentiating it from other dementias. To evaluate the role and the efficacy of a neuropsychological protocol, designed at our institution, based on psychometric analysis and qualitative assessment, in the differential diagnosis of iNPH from AD dementia, we prospectively enrolled 12 patients with suspected iNPH, 11 patients with AD, and 10 healthy controls (HC) who underwent neuropsychological assessment. The assessment was done with the Mini Mental State Examination (MMSE), Mental Deterioration Battery (MDB), Frontal Assessment Battery (FAB), and the Deux Barrage Test. Evaluation in the iNPH group was performed before extended lumbar drainage (ELD), 48 h after ELD, and 1 week and 3 months after the insertion of a ventriculoperitoneal shunt (VPS). Statistical analysis demonstrated the cognitive profile of iNPH, which was mainly characterized by executive function and immediate verbal memory impairment compared with AD. Additionally, the neuropsychological markers were different between the two groups. The qualitative analysis of systematic mistakes made on the tests demonstrated differences in cognitive performances between the iNPH, AD, and HC cohorts. Neuropsychological assessment and qualitative evaluation could represent a useful tool for achieving effective management and restoration of functions in patients with iNPH.

Silencing of telomere-binding protein adrenocortical dysplasia (ACD) homolog enhances radiosensitivity in glioblastoma cells

&NA; Adrenocortical dysplasia (ACD) is a shelterin protein involved in the maintenance of telomere length and in cancer radioresistance. This study investigated the expression profile of ACD in human gliomas and its role in radioresistance of glioma cells. The expression of ACD was analyzed in 62 different grades of glioma tissues and correlated with prognosis. A radioresistant cell line was generated from U87MG cells. For mechanistic studies, ACD was inhibited by small interfering RNA‐targeting ACD and the effect on cell radioresistance, telomerase activity, cyclinD1, caspase‐3, hTERT, and BIRC1 was evaluated. Clonogenic assay was performed after irradiation, to investigate the effect of ACD silencing on radiation sensitivity. ACD expression appeared strongly upregulated in higher grade gliomas, and its expression was significantly correlated to grading and poor prognosis. In glioma cell lines, ACD expression pattern was similar to those observed in glioma tissues. In irradiated cells, ACD expression was increased in an ionizing radiation dose‐dependent manner. A higher expression of ACD was observed in the radioresistant clones than parental cells. Silencing of ACD led to the enhanced radiation sensitivity, decreased telomerase activity and cyclin D1 expression, reduced expression of BIRC1, and finally to the upregulation of caspase‐3. This study represents the first report, which demonstrated the expression pattern of ACD in gliomas and its prognostic value. Our results suggested that ACD is involved in glioblastoma radioresistance, likely through the modulation of telomerase activity, proliferation, and apoptosis. ACD might represent a potential molecular biomarker and a novel therapeutic target in glioblastoma.

Aggiornamento sulla chirurgia ipofisaria per via endoscopica: indicazioni, vantaggi e limiti

SommarioLa chirurgia applicata alle patologie dell’ipofisi, e più in generale della regione sellare, si è raffinata sempre più nel corso degli anni. Oggi disponiamo di varie strategie e tecniche adattabili alle diverse caratteristiche della patologia da affrontare. Tra queste, la tecnica endoscopica trans-sfenoidale è, ad oggi, la metodica più utilizzata per la patologia adenomatosa, rappresentando, oramai, il gold standard per le patologie coinvolgenti questa regione del basicranio.

The Pioneering Contribution of Italian Surgeons to Skull Base Surgery

The origin of neurosurgery as a modern, successful, and separate branch of surgery could be dated back to the end of the 19th century. The most important development of surgery occurred in Europe, particularly in Italy, where there was a unique environment, allowing brilliant open-minded surgeons to perform, with success, neurosurgical operations. Neurosurgery began at the skull base. In everyday practice, we still pay tribute to early Italian neuroanatomists and pioneer neurosurgeons who represented a starting point in a new, obscure, and still challenging field of medicine and surgery during their times. In this paper, we report at a glance the contributions of Tito Vanzetti from Padua (1809-1888), for his operation on a destructive skull base cyst that had, indeed, an intracranial expansion; of Davide Giordano (1864-1954) from Venice, who described the first transnasal approach to the pituitary gland; and, most importantly, of Francesco Durante from Messina (1844-1934), who was the first surgeon in the history of neurosurgery to successfully remove a cranial base meningioma. They carried out the first detailed reported surgical excision of intracranial lesions at the skull base, diagnosed only through clinical signs; used many of the advances of the 19th century; and conceived and performed new operative strategies and approaches. Their operations were radical enough to allow the patient to survive the surgery and, in the case of Durante, for the first time, to obtain more than 12 years of good survival at a time when a tumor of this type would have been fatal.