Impact of augmented reality fiber tractography on the extent of resection and functional outcome of primary motor area tumors.

OBJECTIVE: This study aimed to evaluate the impact of augmented reality intraoperative fiber tractography (AR-iFT) on extent of resection (EOR), motor functional outcome, and survival of patients with primary motor area (M1) intra-axial malignant tumors. METHODS: Data obtained from patients who underwent AR-iFT for M1 primary tumors were retrospectively analyzed and compared with those from a control group who underwent unaugmented reality intraoperative fiber tractography (unAR-iFT). A full asleep procedure with electrical stimulation mapping and fluorescein guidance was performed in both groups. The Neurological Assessment in Neuro-Oncology (NANO), Medical Research Council (MRC), and House-Brackmann grading systems were used for neurological, motor, and facial nerve assessment, respectively. Three-month postoperative NANO and MRC scores were used as outcome measures of the safety of the technique, whereas EOR and survival curves were related to its cytoreductive efficacy. In this study, p < 0.05 indicated statistical significance. RESULTS: This study included 34 and 31 patients in the AR-iFT and unAR-iFT groups, respectively. The intraoperative seizure rate, 3-month postoperative NANO score, and 1-week and 1-month MRC scores were significantly (p < 0.05) different and in favor of the AR-iFT group. However, no difference was observed in the rate of complications. Glioma had incidence rates of 58.9% and 51.7% in the study and control groups, respectively, with no statistical difference. Metastasis had a slightly higher incidence rate in the control group, without statistical significance, and the gross-total resection and near-total resection rates and progression-free survival (PFS) rate were higher in the study group. Overall survival was not affected by the technique. CONCLUSIONS: AR-iFT proved to be feasible, effective, and safe during surgery for M1 tumors and positively affected the EOR, intraoperative seizure rate, motor outcome, and PFS. Integration with electrical stimulation mapping is critical to achieve constant anatomo-functional intraoperative feedback. The accuracy of AR-iFT is intrinsically limited by diffusion tensor-based techniques, parallax error, and fiber tract crowding. Further studies are warranted to definitively validate the benefits of augmented reality navigation in this surgical scenario.

A Dedicated Tool for Presurgical Mapping of Brain Tumors and Mixed-Reality Navigation During Neurosurgery.

Brain tumor surgery requires a delicate tradeoff between complete removal of neoplastic tissue while minimizing loss of brain function. Functional magnetic resonance imaging (fMRI) and diffusion tensor imaging (DTI) have emerged as valuable tools for non-invasive assessment of human brain function and are now used to determine brain regions that should be spared to prevent functional impairment after surgery. However, image analysis requires different software packages, mainly developed for research purposes and often difficult to use in a clinical setting, preventing large-scale diffusion of presurgical mapping. We developed a specialized software able to implement an automatic analysis of multimodal MRI presurgical mapping in a single application and to transfer the results to the neuronavigator. Moreover, the imaging results are integrated in a commercially available wearable device using an optimized mixed-reality approach, automatically anchoring 3-dimensional holograms obtained from MRI with the physical head of the patient. This will allow the surgeon to virtually explore deeper tissue layers highlighting critical brain structures that need to be preserved, while retaining the natural oculo-manual coordination. The enhanced ergonomics of this procedure will significantly improve accuracy and safety of the surgery, with large expected benefits for health care systems and related industrial investors.

Microneurosurgical Management of Posterior Inferior Cerebellar Artery Aneurysms: Results of a Consecutive Series.

Aneurysms of the posterior inferior cerebellar artery (PICA) are uncommon. The complex anatomy of PICA and its intimate relationships with medulla, lower cranial nerves, and jugular tubercle makes the surgical treatment of these aneurysms fascinating. The reported is study aimed at a critical review of the overall results of a personal series of PICA aneurysms, treated by the senior author, R. Galzio. Demographics, charts, videos, outcome, and follow-up of a cohort of PICA aneurysms managed in the last 10 years were retrospectively analyzed, focusing only upon those treated with microneurosurgery. Twenty-five patients, harboring a single aneurysm, were operated on. Fifteen aneurysms were ruptured. Nineteen were proximal, all of these being been treated through a far-lateral approach. Trans-condylar or trans-tubercular variants were rarely necessary and however reserved to peculiar cases. Twenty-three aneurysms underwent direct treatment consisting of clip ligation. At 6-month follow-up, 60% of patients had a modified Rankin Score (mRS) of 0-2. Given the high anatomical variability of both PICA and patients' bony anatomy, a case-by-case meticulous preoperative imaging evaluation is mandatory for the choice of the most suitable and tailored surgical corridor which, in turn, is pivotal to achieve the best outcome.

Posterior Circulation Aneurysms: A Critical Appraisal of a Surgical Series in Endovascular Era.

The advent of the endovascular era has apparently decreased the role of microneurosurgery for many of the posterior circulation aneurysms. This study consists of a critical appraisal of a retrospective surgical series regarding posterior circulation aneurysms, targeted to define whether microneurosurgery still has a role for some of these. In 28 years, 157 aneurysms were surgically treated, 98 of which ruptured. The Average patient age was 56.7 ± 14.2 years, while in hemorrhagic cases, the mean Hunt-Hess score was 2.17 ± 0.8. Basilar tip, vertebral artery and proximal posterior inferior cerebellar artery were the most frequently involved sites. The treatment consisted of 128 clippings, 19 trappings, 7 wrappings, and 3 bypasses. A total exclusion was achieved in 88.5% of the aneurysms. An average follow-up of 67.1 ± 61.3 months proved no recurrences. The best results were observed in patients <65 years old who harbored small-to-regular aneurysms of the basilar tip, distal cerebellar arteries, or vertebral artery.Clipping proved to be a definitive and durable treatment for a large part of posterior circulation aneurysms, whereas bypass allows for treating aneurysms not amenable for coiling, stenting, or clipping. The present study confirms that microneurosurgery continues to have a paramount role within neurovascular pathology.

Microneurosurgery for Paraclinoid Aneurysms in the Context of Flow Diverters.

The advent of flow diverter (FD) stents has apparently reduced the role of microneurosurgery for paraclinoid aneurysms despite sparse high-quality evidence about their long-term effects.The present study critically reviews the overall results of a microneurosurgical series of 57 paraclinoid aneurysms.Of these aneurysms, 47.4% were regular in size while 19.3 were giant. Barami type I was predominant. In 21 aneurysms a hemorrhagic onset occurred. Pterional approach with intradural anterior clinoidectomy was preferred by far. Clipping was possible in 91.2% of aneurysms and a high-flow bypass was the choice in five cases. An mRS of 0-2 was achieved in 77.3% of patients, typically <50 years old.Visual field appeared improved or unchanged in 36.3% and 63.6% of the symptomatic patients, respectively. In 76.1% of incidental aneurysms, campimetry was unaffected by surgery.A complete aneurysm exclusion was achieved in 93% of cases using a single procedure. No recurrences were documented on an average follow-up of 54.1 ± 34 months.Microneurosurgery is still a valuable, definitive, and durable option for Barami type Ia, Ib, or II paraclinoid aneurysm, especially in patients <50 years old and visually symptomatic. Conditions other than these are ideal candidates for FD stents.

The Preoperative Functional Downgrading of Brain AVMs.

The actual role of preoperative embolization of brain arteriovenous malformations (AVMs) is undervalued.The present study aims to describe the effectiveness, safety, technics, and results of the endovascular-based functional downgrading of brain AVMs.Data regarding 31 Spetzler-Martin (SM) grade III AVMs that consecutively underwent a combined endovascular-surgical treatment were reviewed. Clinical and radiological outcomes were evaluated according to modified Ranking Scale score (mRS) and postoperative angiography, respectively.Low-density Onyx was used in all cases, and the timeframe between the embolizations was 10-15 days. Procedures were 1.6 (±0.6) on average. Superselective nidal catheterization was essential to reach the deepest parts of the AVMs, which were the targets. Onyx made the nidus compact and easier to dissect. The Average obliteration rate was 29.6%, with negligible morbidity. Surgery was performed after 3.7 days on average and the AVM exclusion was complete in 83.4% of cases. An mRS score between 0 and 2 was reported in 77.5% of patients, while the best outcome was achieved in small and medium-deep malformations.An effective and safe functional downgrading of brain AVMs must be based upon specific technical key aspects, which make surgery easier and, ultimately, allow for the achievement of the best outcome.

Supratentorial high-grade gliomas: maximal safe anatomical resection guided by augmented reality high-definition fiber tractography and fluorescein.

OBJECTIVE: The theoretical advantages of augmented reality (AR) with diffusion tensor imaging (DTI)-based high-definition fiber tractography (HDFT) and sodium fluorescein (F) in high-grade glioma (HGG) surgery have not been investigated in detail. In this study, the authors aimed to evaluate the safety and efficacy profiles of HDFT-F microscope-based AR cytoreductive surgery for newly diagnosed supratentorial HGGs. METHODS: Data of patients with newly diagnosed supratentorial HGGs who underwent surgery using the AR HDFT-F technique were reviewed and compared with those of a cohort of patients who underwent conventional white-light surgery assisted by infrared neuronavigation. The safety and efficacy of the techniques were reported based on the postoperative Neurological Assessment in Neuro-Oncology (NANO) scores, extent of resection (EOR), and Kaplan-Meier curves, respectively. The chi-square test was conducted for categorical variables. A p value < 0.05 was considered statistically significant. RESULTS: A total of 54 patients underwent surgery using the AR HDFT-F technique, and 63 underwent conventional white-light surgery assisted by infrared neuronavigation. The mean postoperative NANO scores were 3.8 ± 2 and 5.2 ± 4 in the AR HDFT-F group and control group, respectively (p < 0.05). The EOR was higher in the AR HDFT-F group (p < 0.05) than in the control group. With a mean follow-up of 12.2 months, the rate of progression-free survival (PFS) was longer in the study group (log-rank test, p = 0.006) than in the control group. Moreover, the complication rates were 9.2% and 9.5% in the study and control groups, respectively. CONCLUSIONS: Overall, AR HDFT-F-assisted surgery is safe and effective in maximizing the EOR and PFS rate for patients with newly diagnosed supratentorial HGGs, and in optimizing patient functional outcomes.

Shedding the Light on the Natural History of Intracranial Aneurysms: An Updated Overview.

The exact molecular pathways underlying the multifactorial natural history of intracranial aneurysms (IAs) are still largely unknown, to the point that their understanding represents an imperative challenge in neurovascular research. Wall shear stress (WSS) promotes the genesis of IAs through an endothelial dysfunction causing an inflammatory cascade, vessel remodeling, phenotypic switching of the smooth muscle cells, and myointimal hyperplasia. Aneurysm growth is supported by endothelial oxidative stress and inflammatory mediators, whereas low and high WSS determine the rupture in sidewall and endwall IAs, respectively. Angioarchitecture, age older than 60 years, female gender, hypertension, cigarette smoking, alcohol abuse, and hypercholesterolemia also contribute to growth and rupture. The improvements of aneurysm wall imaging techniques and the implementation of target therapies targeted against inflammatory cascade may contribute to significantly modify the natural history of IAs. This narrative review strives to summarize the recent advances in the comprehension of the mechanisms underlying the genesis, growth, and rupture of IAs.

Targeted therapy of human glioblastoma via delivery of a toxin through a peptide directed to cell surface nucleolin.

Targeted anticancer therapies demand discovery of new cellular targets to be exploited for the delivery of toxic molecules and drugs. In this perspective, in the last few years, nucleolin has been identified as an interesting surface marker to be used for the therapy of glioblastoma. In this study, we investigated whether a synthetic antagonist of cell-surface nucleolin known as N6L, previously reported to decrease both tumor growth and tumor angiogenesis in several cancer cell lines, including glioblastoma cells, as well as endothelial cells proliferation, could be exploited to deliver a protein toxin (saporin) to glioblastoma cells. The pseudopeptide N6L cross-linked to saporin-S6 induced internalization of the toxin inside glioblastoma cancer cells. Our results in vitro demonstrated the effectiveness of this conjugate in inducing cell death, with an ID50 four orders of magnitude lower than that observed for free N6L. Furthermore, the preliminary in vivo study demonstrated efficiency in reducing the tumor mass in an orthotopic mouse model of glioblastoma.

Endoscope-Assisted Microneurosurgery for Intracranial Aneurysms: Operative Technique, Reliability, and Feasibility Based on 14 Years of Personal Experience.

Endoscope-assisted microneurosurgery (EAM) combines endoscopic and microsurgical techniques for the treatment of deeply located intracranial lesions. During aneurysm surgery, endoscopic assistance may aid in the visualization of perforating arteries, especially when minimally invasive approaches are used. Between 2002 and 2015, a total of 183 patients with 208 intracranial aneurysms were surgically treated in our department. EAM was performed in 191 procedures. In all, 159 aneurysms were located in the anterior circulation and 49 in the posterior circulation. Of these, 135 aneurysms were ruptured. Lesions were exposed through standard skull base microsurgical approaches. The endoscope was employed during three steps: initial inspection, true operative time, and final inspection. Complications directly related to endoscopic procedures were rare; no surgical mortality was observed in this series. A retrospective analysis of each procedure showed that the usefulness of EAM depended on the anatomical location and size of the lesions. Its advantages were especially evident when dedicated scopes and holders were used.

Giant and Very Large Intracranial Aneurysms: Surgical Strategies and Special Issues.

Giant intracranial aneurysms (GIAs) and very large intracranial aneurysms (VLAs) have a poor natural history because of a high incidence of bleeding and strokes. These lesions always represent a great challenge for neurosurgeons and interventional neuroradiologists because of some peculiar intrinsic features such as size, angioarchitecture, wide neck, mass effect, intraluminal thrombosis, atherosclerotic changes, involvement of branches and perforators, and a frequent need to perform revascularization procedures. The results of a cumulative surgical series of 75 VLAs and GIAs are reported. Thirty-three aneurysms were unruptured. Sixty aneurysms underwent direct surgical treatment consisting of 56 direct clippings, 3 trappings w/o revascularization, and 1 wrapping. Fifteen aneurysms were treated by means of extracranial to intracranial (EC-IC) high-flow bypass. An mRS score ranging between 0 and 2 was observed in 54 patients, whereas an mRS of 3 was seen in 5 patients. Four patients had a severe disability (mRS 4-5) and six patients died. Aneurysm's fragmentation, with stacking and seating clips, thrombectomy, and aneurysmorrhaphy were the techniques most frequently employed. Revascularization options involving EC-IC high-flow bypass were used in cases not amenable for direct treatment. Some technical tips and special issues related to the surgical management of these complex lesions are discussed.

Surgical Treatment of Arteriovenous Malformations: Role of Preoperative Staged Embolization.

Preoperative embolization is complementary to surgery for large brain arteriovenous malformations (AVMs). From January 2005 to December 2015, 69 patients harboring an AVM were managed in our department by the same surgeon (RG). Forty one were ruptured and 65 were supratentorial. Thirty nine smaller AVMs were treated with surgery stand-alone, whereas, for 30 larger malformations, surgery was combined with adjuvant treatment involving preoperative staged embolization and/or, less frequently, radiosurgery. In all patients treated with surgery alone, complete resection of AVM was achieved. A successful preoperative partial endovascular obliteration of AVM was obtained in 24 out of 27 more complex cases, with a zero mortality rate and a very low morbidity. Here, embolization was of a certain utility in the handling of deeper feeders and nidus excision, also facilitating intraoperative hemostasis. In three cases of residuals, radiosurgery was performed. In those patient treated with a combined approach, a good overall outcome, 0-2 modified Rankin Scale (mRS), was achieved in 25 cases. Preoperative embolization proved to be a reasonable option complementary to high-grade AVMs surgery, reducing the frequency of breakthrough hemorrhages, aiding the elimination of deep feeders, and making the nidus dissection easier.

PPARα Antagonist AA452 Triggers Metabolic Reprogramming and Increases Sensitivity to Radiation Therapy in Human Glioblastoma Primary Cells.

Glioblastoma (GB) is the most common cancer in the brain and with an increasing incidence. Despite major advances in the field, there is no curative therapy for GB to date. Many solid tumors, including GB, experienced metabolic reprogramming in order to sustain uncontrolled proliferation, hypoxic conditions, and angiogenesis. PPARs, member of the steroid hormone receptor superfamily, are particularly involved in the control of energetic metabolism, particularly lipid metabolism, which has been reported deregulated in gliomas. PPARα was previously indicated by us as a potential therapeutic target for this neoplasm, due to the malignancy grade dependency of its expression, being particularly abundant in GB. In this work, we used a new PPARα antagonist on patient-derived GB primary cells, with particular focus on the effects on lipid metabolism and response to radiotherapy. The results obtained demonstrated that blocking PPARα results in cell death induction, increase of radiosensitivity, and decrease of migration. Therefore, AA452 is proposed as a new adjuvant for the gold standard therapies for GB, opening the possibility for preclinical and clinical trials for this class of compounds. J. Cell. Physiol. 232: 1458-1466, 2017. © 2016 Wiley Periodicals, Inc.

Patient outcomes following second surgery for recurrent glioblastoma.

BACKGROUND: The most appropriate management of recurrent glioblastoma is still controversial. In particular, the role of surgery at recurrence remains uncertain. PATIENTS & METHODS: From our Institutional data warehouse we analyzed 270 consecutive patients who received second surgery for recurrent glioblastoma, to assess survival after second surgery, and to evaluate prognostic factors. RESULTS: Complete resection was found in 128 (47.4%) and partial resection in 142 patients (52.6%). Median survival from second surgery was 11.4 months (95% CI: 10.0-12.7). Multivariate analysis showed that age (p = 0.001), MGMT methylation (p = 0.021) and extent of surgery (p < 0.001) are associated with better survival. CONCLUSION: A complete resection should be the goal for second resection and younger age and MGMT methylation status might be considered in the selection of patients.

Intraforaminal ozone therapy and particular side effects: preliminary results and early warning.

BACKGROUND: The term "low back pain syndrome" represents a complex nosological entity. The therapeutic approach is often only symptomatic and not etiologic. METHODS: Since 2013, 186 patients (97 males and 89 females, mean age 59.8 years) have undergone microsurgery for lumbar disc hernia or lumbar segmental stenosis. Among these patients, 23 had been previously treated with ozone therapy by the intraforaminal approach and 28 by intraforaminal steroid injections in other hospitals between 12 and 24 months before our clinical evaluation. These patients received 16 applications in an 8-week period (standard therapy). RESULTS: During the surgery, many hard adhesions between the soft tissues and bony structures were unexpectedly discovered. In particular, it was noted that the root contracted and had firm adhesions to the dural sac and/or fragmented disc, which were difficult to resolve. These specific pathological patterns were observed only in the patients who received ozone injections by the intraforaminal approach. We did not find any pathological abnormalities in the patients who did not receive any injections or who received intraforaminal steroid injections. Thus, we could exclude that the tissue damage was due to the mechanical action of the needle. CONCLUSION: It is important to assert that ozone therapy procedures can be associated with several major complications. Therefore, performing a revision of the guidelines and protocols for ozone therapy application is indispensable.

Immunophenotypic characterization of human glioblastoma stem cells: correlation with clinical outcome.

Recently, glioma stem cells have been identified as the main cause of glioma propagation and recurrence and a number of several cell markers have been indicated as putative GSC markers. In the present work, a retrospective study to evaluate the prognostic potential of ability to generate GSCs in our series of 15 glioblastoma patients is described. ß-tubulin III, nestin, CD133, GFAP, and SOX-2 marker expression, both in primary GBM cultures and in respective glioblastoma stem cells (GSCs), was evaluated by flow cytometric analysis. Our results demonstrated various expression levels of these markers in both cell cultures; of note, only those cells expressing SOX-2 at greater than 30% levels were able to produce in vitro neurospheres. Moreover, statistical analysis revealed that the GSCs generation negatively affected overall survival (OS) (P = 0.000) and progression-free survival (PFS) (P = 0.001). In addition, a very poor OS (P = 0.000) and PFS (P = 0.000) were observed among patients whose tumors expressed Ki67, evaluated by immunohistochemistry, and showed the ability to generate in vitro GSCs. Overall, the results suggest that in vitro GSCs generation associated to the expression of Ki67 and SOX-2 may be useful to identify patients at risk of disease progression.

Syringobulbia associated with posterior fossa meningioma: a review of the literature.

PURPOSE: Syringomyelia can be defined as a degenerative, progressive and chronic spinal cord disease. Its association with tumors of the posterior cranial fossa (PCF) is a rare condition. METHODS: The authors report a rare case of syringobulbia consequent to a meningioma originating from PCF in a 17-year-old female, discussing the pathogenetic mechanism of development and the resolution of the syrinx cavity after surgical procedure. RESULTS: The postoperative period was uneventful without complications. At 6-month follow-up, MRI revealed complete tumor removal with resolution of the syrinx cavity. CONCLUSIONS: In cases of syringomyelia and tonsillar herniation associated with PCF meningioma, the tumor resection allows to eliminate the mass effect and increases the size of the posterior fossa with the progressive ascent of the cerebellar tonsils and the consequent reduction of their downward movement with systolic pulsation. The re-establishment of a normal anatomical condition led to the gradual disappearance of syrinx and hydrocephalus.

Intraoperative Augmented Reality Fiber Tractography for Primary Motor Area Glioma Resection.

The implementation of intraoperative augmented reality fiber tractography (iAR-FT) into the surgical workflow for high-grade supratentorial gliomas has been shown to be effective and safe in maximizing the extent of resection and progression-free survival through the surgeon's enhanced 3-dimensional awareness of the spatial localization of fiber tracts.1-3 Primary motor area tumors present special challenges due to the high eloquence of the precentral gyrus and risk of postoperative onset or worsening of motor deficits, as well as limited postoperative plasticity.4 Although essential, electrical stimulation mapping (ESM) techniques have a number of limitations with respect to primary motor pathways, including a higher risk of intraoperative stimulation-evoked seizures, a risk of false negatives in the presence of preoperative deficits, a nonnegligible risk of permanent deterioration even in the presence of negative stimulation maps, and, most importantly, limited spatial resolution.4-8 The rationale for integrating ESM and iAR-FT is to compensate for the limitations of the former in terms of morphologic and spatial representation of fiber tracts. The benefits of coupling iAR-FT with ESM techniques allow for continuous integrated anatomical-functional feedback during surgery. In Video 1 we describe the key technical aspects and benefits of iAR-FT-assisted surgery for maximal safe gross total resection of a primary motor area grade IV astrocytoma.