The "STARS" study: advanced preoperative rehearsal and intraoperative navigation in neurosurgical oncology.

BACKGROUND: Neurosurgical 3D visualizers and simulators are innovative devices capable of defining a surgical strategy in advance and possibly making neurosurgery safer by rehearsing the phases of the operation beforehand. The aim of this study is to evaluate Surgical Theater™ (Surgical Theater LLC, Mayfield, OH, USA), a new 3D neurosurgical planning, simulation, and navigation system, and qualitatively assess its use in the operating room. METHODS: Clinical data were collected from 30 patients harboring various types of brain tumors; Surgical Theater™ was used for the preoperative planning and intraoperative 3D navigation. Preoperative and postoperative questionnaires were completed by first and second operators to get qualitative feedback on the system's functionality. Furthermore, we measured and compared the impact of this technology on surgery duration. RESULTS: Neurosurgeons were overall satisfied when using this rehearsal and navigation tool and found it efficient and easy to use; interestingly, residents considered this device more useful as compared to their more senior colleagues (with significantly higher scores, P<0.05), possibly because of their limited anatomical experience and spatial/surgical rehearsal ability. The length of the surgical procedure was not affected by this technology (P>0.05). CONCLUSIONS: Surgical Theater™ system was found to be clinically useful in improving anatomical understanding, surgical planning, and intraoperative navigation, especially for younger and less experienced neurosurgeons.

Informed consent through 3D virtual reality: a randomized clinical trial.

BACKGROUND: The informed consent is a defining moment that should allow patients to understand their condition, what procedure they are undergoing, and what consequences may follow. This process should foster trust and promote confidence, without increasing patients' anxiety. New immersive 3D imaging technologies may serve as a tool to facilitate this endeavor. METHODS: In a prospective, single-center, randomized controlled clinical trial (SPLICE Study: Surgical Planning and Informed Consent Study; ClinicalTrials.gov NCT03503487), 40 patients undergoing surgery for intracranial tumors were enrolled. After undergoing a traditional surgical informed consent acquisition, 33 patients were randomized 1:1:1 to 3 groups: in 2 experimental groups, patients underwent a 3D, immersive informed consent with two different surgical planners (group 1 and group 2); in the control group, patients underwent an informed consent supported by traditional 2D radiological images. RESULTS: Patients in the experimental groups appreciated this communication experience, while their objective comprehension was higher ((score mean (SD)): group 1 82.65 (6.83); group 2 77.76 (10.19)), as compared with the control group (57.70 (12.49); P < 0.001). Subjective comprehension and anxiety levels did not differ between experimental groups and control group. CONCLUSIONS: 3D virtual reality can help surgeons and patients in building a better relationship before surgery; immersive 3D-supported informed consent improves patients' comprehension of their condition without increasing anxiety. This new paradigm may foster trust between surgeons and patients, possibly restraining medical-legal acts. TRAIL REGISTRATION: ClinicalTrials.gov NCT03503487.

Frameless Stereotactic Biopsy with DTI-Based Tractography Integration: How to Adjust the Trajectory-A Case Series.

BACKGROUND: Frameless stereotactic biopsy represents a minimally invasive procedure used for the histopathological diagnosis of brain tumors or to safely approach deep-seated lesions near eloquent areas not amenable for classical neurosurgical procedures. Traditionally, biopsy is performed relying on anatomical landmarks, but it can lead itself to intra- and postoperative complications, such as hemorrhage and fiber disruption. Diffusion tensor imaging (DTI) tractography represents a useful tool that can analyze the individual fiber tract conformation in cases of brain tumor and consequently identify the best biopsy trajectory, preserving white matter pathways. In our study, we present a novel technique that is based on the use of preoperative DTI for biopsy. METHODS: Between January 2018 and January 2020, data about patients who underwent frameless biopsy using DTI tractography were retrospectively reviewed. The inclusion criterion was adult patients eligible for elective surgery for a single or multiple deep-seated lesions with contraindications to complete surgical resection. RESULTS: We included 12 patients (mean age of 67.9 [±9.6] years). A single cranial lesion was detected in 7 cases, and multiple lesions in 5 cases. The use of DTI enabled the identification of white matter pathways in all cases and adjustment of the biopsy trajectory based on anatomical landmarks in 7 cases. Postoperative hematoma was reported in 1 case, and histological diagnosis was obtained in 11 cases. CONCLUSION: According to our results, tractography is a useful tool that can enhance the safety of cerebral lesions biopsy sparing any fiber tract damages.

Local alkylating chemotherapy applied immediately after 5-ALA guided resection of glioblastoma does not provide additional benefit.

Grade IV glioma is the most common and aggressive primary brain tumour. Gross total resection with 5-aminolevulinic acid (5-ALA) guided surgery combined with local chemotherapy (carmustine wafers) is an attractive treatment strategy in these patients. No previous studies have examined the benefit carmustine wafers in a treatment programme of 5-ALA guided resection followed by a temozolomide-based chemoradiotherapy protocol. The objective of this study was to examine the benefit of carmustine wafers on survival in patients undergoing 5-ALA guided resection. A retrospective cohort study of 260 patients who underwent 5-ALA resection of confirmed WHO 2007 Grade IV glioma between July 2009 and December 2014. Survival curves were calculated using the Kaplan-Meier method from surgery. The log-rank test was used to compare survival curves between groups. Cox regression was performed to identify variables predicting survival. A propensity score matched analysis was used to compare survival between patients who did and did not receive carmustine wafers while controlling for baseline characteristics. Propensity matched analysis showed no significant survival benefit of insertion of carmustine wafers over 5-ALA resection alone (HR 0.97 [0.68-1.26], p = 0.836). There was a trend to higher incidence of wound infection in those who received carmustine wafers (15.4 vs. 7.1%, p = 0.064). The Cox regression analysis showed that intraoperative residual fluorescent tumour and residual enhancing tumour on post-operative MRI were significantly predictive of reduced survival. Carmustine wafers have no added benefit following 5-ALA guided resection. Residual fluorescence and residual enhancing disease following resection have a negative impact on survival.

Radioguided Occult Lesion Localization in Deep Schwannomas of the Peripheral Nerves: Results of a Preliminary Case Series.

BACKGROUND: The detection of small deep schwannomas of the peripheral nerves has been increasing since the the use of precise neuroimaging techniques has become more widespread; however, although nonpalpable lesions can be well defined by images, it is often difficult to identify them during the surgical procedure. The authors report seven cases of nonpalpable small deep schwannomas surgically treated after their identification using the radioguided occult lesion localization (ROLL) technique. METHODS: Seven men, whose ages ranged from 34 to 70 years (mean 52 years), presented with symptomatic nonpalpable peripheral nerve lesions; two cases involved the sciatic nerve, two the femoral nerve, two the radial nerve, and one the tibial nerve. Before the operation, all the patients were studied by ultrasonography and magnetic resonance imaging (MRI); 1 h before the surgery 3-5 MBq of 99mTc labeled with human albumin macroaggregates was injected into the lesion. A gamma detection probe permitted the preoperative and intraoperative detection of the nonpalpable schwannomas. CONCLUSIONS: The ROLL technique provides good support for identifying small lesions of the peripheral nerves both preoperatively and intraoperatively. This technique permits the use of minimally invasive approaches performed with local anesthesia, with good cosmetic results and acceptance by the patients.

Conus medullaris-cauda arteriovenous malformation and Klippel-Trenaunay syndrome: what is the treatment goal?

A 29-year-old man with Klippel-Trenaunay syndrome (KTS) presented with a symptomatic conus medullaris-cauda arteriovenous malformation (AVM) manifesting as back and right limb pain, which abruptly worsened with the onset of right limb weakness and urinary retention. He was treated by multisession endovascular embolization resulting in improved neurological status. KTS is a sporadic disease with unknown etiology, but genetic susceptibility may lead to the over-expression of angiogenic factors and increased angiogenesis. KTS may be exceptionally associated with slow-flow spinal AVM, but there is no consensus about the optimal treatment for these symptomatic lesions. Embolization treatment may represent a safe option to minimize complications and possibly improve the neurological status in patients with spinal AVM associated with KTS, if one or both legs are already impaired by hypertrophy or other vascular malformations. Genetic analysis may reveal an underlying angiogenesis change, so closer follow up might be indicated in selected patients.

Oncolytic herpes simplex virus counteracts the hypoxia-induced modulation of glioblastoma stem-like cells.

Glioblastoma (GBM), a fatal malignant brain tumor, contains abundant hypoxic regions that provide a "niche" to promote both the maintenance and enrichment of glioblastoma stem-like cells (GSCs) and confer resistance to chemo- and radiotherapy. Since GSCs, with an ability to resist conventional therapies, may be responsible for tumor recurrence, targeting GSCs located in such a hypoxic environment may be critical to improving the therapeutic outcome for GBM patients. Oncolytic viral therapies have been tested in the clinic as a promising therapeutic approach for GBM. In this study, we analyzed and compared the therapeutic effects of oncolytic herpes simplex virus (oHSV) type 1 G47Δ (γ34.5(-)ICP6(-)LacZ(+)α47(-)) in patient-derived GSCs under normoxia (21% oxygen) and hypoxia (1% oxygen). GSCs cultured in hypoxia showed an increased ability to form neurospheres and expressed higher levels of the putative stem cell marker CD133 compared with GSCs cultured in normoxia. G47Δ exhibited a comparable ability to infect, replicate, and kill GSCs in normoxia and hypoxia in vitro. Importantly, G47Δ could counteract hypoxia-mediated enhancement of the stem-like properties of GSCs, inhibiting their self-renewal and stem cell marker expression. Using orthotopic human GSC xenografts in mice, we demonstrated that intratumoral injection of G47ΔUs11fluc, a newly developed G47Δ derivative that expresses firefly luciferase driven by a true late viral promoter, led to an equivalent frequency of viral infection and replication in hypoxic and nonhypoxic tumor areas. These findings suggest that oHSV G47Δ represents a promising therapeutic strategy to target and kill GSCs, not only in normoxic areas of GBM but also within the hypoxic niche.

Effect of γ34.5 deletions on oncolytic herpes simplex virus activity in brain tumors.

The ICP34.5 protein of herpes simplex virus (HSV) is involved in many aspects of viral pathogenesis; promoting neurovirulence, inhibiting interferon-induced shutoff of protein synthesis, interacting with PCNA and TBK1, inhibiting dendritic cell (DC) maturation, and binding to Beclin 1 to interfere with autophagy. Because of its key role in neuropathogenicity, the γ34.5 gene is deleted in all oncolytic HSVs (oHSVs) currently in clinical trial for treating malignant gliomas. Unfortunately, deletion of γ34.5 attenuates virus replication in cancer cells, especially human glioblastoma stem cells (GSCs). To develop new oHSVs for use in the brain and that replicate in GSCs, we explored the effect of deleting the γ34.5 Beclin 1 binding domain (BBD). To ensure cancer selectivity and safety, we inactivated the ICP6 gene (UL39, large subunit of ribonucleotide reductase), constructing ICP6 mutants with different γ34.5 genotypes: Δ68HR-6, intact γ34.5; Δ68H-6, γ34.5 BBD deleted; and 1716-6, γ34.5 deleted. Multimutated Δ68H-6 exhibited minimal neuropathogenicity in HSV-1-susceptible mice, as opposed to Δ68H and Δ68HR-6. It replicated well in human glioma cell lines and GSCs, effectively killing cells in vitro and prolonging survival of mice bearing orthotopic brain tumors. In contrast, 1716 and 1716-6 barely replicated in GSCs. Infection of glioma cells with Δ68H-6 and 1716-6 induced autophagy and increased phosphorylation of eIF2α, while inhibition of autophagy, by Beclin 1 short hairpin RNA (shRNA) knockdown or pharmacological inhibition, had no effect on virus replication or phosphorylated eIF2α (p-eIF2α) levels. Thus, Δ68H-6 represents a new oHSV vector that is safe and effective against a variety of brain tumor models.

Oncolytic virus-mediated manipulation of DNA damage responses: synergy with chemotherapy in killing glioblastoma stem cells.

BACKGROUND: Although both the alkylating agent temozolomide (TMZ) and oncolytic viruses hold promise for treating glioblastoma, which remains uniformly lethal, the effectiveness of combining the two treatments and the mechanism of their interaction on cancer stem cells are unknown. METHODS: We investigated the efficacy of combining TMZ and the oncolytic herpes simplex virus (oHSV) G47Δ in killing glioblastoma stem cells (GSCs), using Chou-Talalay combination index analysis, immunocytochemistry and fluorescence microscopy, and neutral comet assay. The role of treatment-induced DNA double-strand breaks, activation of DNA damage responses, and virus replication in the cytotoxic interaction between G47Δ and TMZ was examined with a panel of pharmacological inhibitors and short-hairpin RNA (shRNA)-mediated knockdown of DNA repair pathways. Comparisons of cell survival and virus replication were performed using a two-sided t test (unpaired). The survival of athymic mice (n = 6-8 mice per group) bearing GSC-derived glioblastoma tumors treated with the combination of G47Δ and TMZ was analyzed by the Kaplan-Meier method and evaluated with a two-sided log-rank test. RESULTS: The combination of G47Δ and TMZ acted synergistically in killing GSCs but not neurons, with associated robust induction of DNA damage. Pharmacological and shRNA-mediated knockdown studies suggested that activated ataxia telangiectasia mutated (ATM) is a crucial mediator of synergy. Activated ATM relocalized to HSV DNA replication compartments where it likely enhanced oHSV replication and could not participate in repairing TMZ-induced DNA damage. Sensitivity to TMZ and synergy with G47Δ decreased with O(6)-methylguanine-DNA-methyltransferase (MGMT) expression and MSH6 knockdown. Combined G47Δ and TMZ treatment extended survival of mice bearing GSC-derived intracranial tumors, achieving long-term remission in four of eight mice (median survival = 228 days; G47Δ alone vs G47Δ + TMZ, hazard ratio of survival = 7.1, 95% confidence interval = 1.9 to 26.1, P = .003) at TMZ doses attainable in patients. CONCLUSIONS: The combination of G47Δ and TMZ acts synergistically in killing GSCs through oHSV-mediated manipulation of DNA damage responses. This strategy is highly efficacious in representative preclinical models and warrants clinical translation.

Bleeding spinal artery aneurysms.

The authors report a case of acute subarachnoid hemorrhage due to the rupture of multiple anterior spinal artery aneurysms. In view of the clinical and radiological findings, surgery was excluded and a wait-and-see policy was followed. A magnetic resonance imaging study performed 3 months after presentation and an angiographic study performed 6 months after presentation confirmed spontaneous regression of the aneurysms and preservation of blood flow through the anterior spinal artery.