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The major shortcoming of image-guided navigation systems is the use of presurgically acquired image data, which does not account for intra-operative changes such as brain shift, tissue deformation and tissue removal occurring during the surgical procedure. Intra-operative ultrasound (iUS) is becoming widely used in neurosurgery but they lack orientation and panoramic view. In this article, we describe our procedure for US-based real-time neuro-navigation during surgery. We used fusion imaging between preoperative magnetic resonance imaging (MRI) and iUS for brain lesion removal in 67 patients so far. Surgical planning is based on preoperative MRI only. iUS images obtained during surgery are fused with the preoperative MRI. Surgery is performed under intra-operative US control. Relying on US imaging, it is possible to recalibrate navigated MRI imaging, adjusting distortion due to brain shift and tissue resection, continuously updating the two modalities. Ultrasound imaging provides excellent visualization of targets, their margins and surrounding structures. The use of navigated MRI is helpful in better understanding cerebral ultrasound images, providing orientation and panoramic view. Intraoperative US-guided neuro-navigation adjustments are very accurate and helpful in the event of brain shift. The use of this integrated system allows for a true real-time feedback during surgery.

BackgroundGlioblastoma multiforme (GBM) is an incurable glial tumor affecting the central nervous system. The reported median survival and the percentage of patient surviving up to 2-years in the unfavorable patients’ subgroup with unmethylated (u)MGMT promoter is 12.7 months and less than then 15% (Stupp et al., 2009), respectively. Despite immunotherapies being able to slow or eradicate numerous tumors, even those metastasized to the brain, none so far have extended survival in GBM.MethodsWe have developed a personalized hematopoietic stem cell-based immunotherapy platform delivering immunotherapeutic payloads into the TME through a subset of tumor infiltrating macrophages. Specifically, Temferon has been designed to deliver IFN-α2 within the TME by Tie-2 expressing macrophages (TEMs). Temferon is currently under testing in an open-label, Phase 1/2a dose-escalation study (NCT03866109) evaluating its safety, and biological activity in up to 27 newly diagnosed GBM patients with uMGMT. Temferon is administered by ASCT after the RTx treatment without the concurrent administration of Temozolomide, whose survival benefit is known to be marginal in the uMGMT population.ResultsAs of June 2023, 4 incremental doses of Temferon (0.5–3.0 x106 cells/kg) have been tested across 21 patients (median age at enrolment 57) assigned to seven cohorts. Median Overall Survival (OS)) after 1st surgery is 15 months (5–40 months). The haematological recovery occurred in all the patients irrespective of dose administered. The percentage of transduced cells found in the BM, reached for the highest dose tested up to the 50% at 1 month and persisted at detectable level in the long-term. Very low median concentrations of IFNα were detected in the plasma, indicating tight regulation of vector expression. Notably, as predicted by TEMs biological behaviour, in the CSF the concentration of IFNa increased concomitantly to evidence of disease progression suggesting increase tumor recruitment of TEMs and subsequent release of IFNa . The 57% of the treated patients underwent a 2nd-line treatment (either pharmacological or surgical) with an interim survival rate at 2-years of 28% (5 of 18 patients; 3 patients excluded as follow-up is below 12 months), which is higher than that reported in literature (15%). One out of the surviving patients was enrolled in a long-term follow-up study and survived up to 3 years after surgery without any 2nd-line therapy added for 2 years.ConclusionsThese data provide initial evidence on Temferon potential to counteract disease progression and improve the survival of uMGMT GBM patients.

Background Spinal cord herniation is a rare entity that has been recognized and described with increasing frequency in the past few years. It is characterized by herniation of the spinal cord through an anterior dural defect. In their study of 12 cases, the authors attempt to develop management and treatment guidelines for patients suffering from this condition. Methods A retrospective analysis of the medical files was carried out in a series of 12 consecutive patients treated at our Institution between 1998 and 2011 for spinal cord herniation. The clinical, radiological and surgical findings, management and outcome were reviewed. Results The male:female ratio was 5:7, with a mean age of 47 years (range 26–71 years). All patients presented a progressively worsening symptomatology. Symptoms at presentation included progressive myelopathy, corticospinal tract sign, algoparesthesia and sphincter dysfunction. The radiological appearance was uniform. All the lesions were located between the T2 and T8 vertebrae. One patient was initially managed conservatively. All patients underwent surgical correction via a posterior approach, with reduction of the herniated spinal cord, the positioning of a muscular autograft to fill the anterior cavity and closure of the dural defect with an artificial dural patch. Six patients showed improvement of preoperative symptomatology at follow-up, while the others remained free from symptom progression. Conclusions The authors present one of the largest studies to date regarding patients with spinal cord herniation and emphasize that the possibility of this condition must be kept in mind when addressing all patients with progressive myelopathy.

Abstract BACKGROUND: Contrast-enhanced ultrasound (CEUS) is a dynamic and continuous modality that offers a real-time, direct view of vascularization patterns and tissue resistance for many organs. Thanks to newer ultrasound contrast agents, CEUS has become a well-established, live-imaging technique in many contexts, but it has never been used extensively for brain imaging. The use of intraoperative CEUS (iCEUS) imaging in neurosurgery is limited. OBJECTIVE: To provide the first dynamic and continuous iCEUS evaluation of a variety of brain lesions. METHODS: We evaluated 71 patients undergoing iCEUS imaging in an off-label setting while being operated on for different brain lesions; iCEUS imaging was obtained before resecting each lesion, after intravenous injection of ultrasound contrast agent. A semiquantitative, offline interobserver analysis was performed to visualize each brain lesion and to characterize its perfusion features, correlated with histopathology. RESULTS: In all cases, the brain lesion was visualized intraoperatively with iCEUS. The afferent and efferent blood vessels were identified, allowing evaluation of the time and features of the arterial and venous phases and facilitating the surgical strategy. iCEUS also proved to be useful in highlighting the lesion compared with standard B-mode imaging and showing its perfusion patterns. No adverse effects were observed. CONCLUSION: Our study is the first large-scale implementation of iCEUS in neurosurgery as a dynamic and continuous real-time imaging tool for brain surgery and provides the first iCEUS characterization of different brain neoplasms. The ability of CEUS to highlight and characterize brain tumor will possibly provide the neurosurgeon with important information anytime during a surgical procedure.

BACKGROUND:Concern about radiation-induced optic neuropathy (RION) has governed recent thinking about the role of radiation therapy in the treatment of meningiomas involving the anterior optic pathways. Despite this concern, during the last few years, the use of radiosurgery for such lesions has increased steadily. OBJECTIVE:To define both the tumor control rate and the risk of RION over a long-term follow-up period in a large cohort of patients treated with multisession radiosurgery. METHODS:The local control and visual outcome of 143 patients who underwent multisession radiosurgery (mRS) were evaluated. Neurological outcome was also analyzed. The data for the present study were obtained from a prospectively maintained database. RESULTS:The mean follow-up was 44 months (range, 12-113 months). All patients underwent mRS. The median prescription dose was 25 Gy delivered in 3 to 5 fractions. The prescription isodose, which typically encompassed at least 95% of the tumor, ranged from 65% to 86% (median, 80%). The mean tumor volume was 11.0 cm (range, 0.1-126.3 cm; median, 8 cm). The progression-free survival at 3, 5, and 8 years was 100%, 93%, and 90%, respectively. Compared with baseline, visual function improved in 36% of patients, whereas 7.4% experienced a worsening in visual function (5.1% excluding the patients with progressive disease). CONCLUSION:Good local control rate and a low risk of RION indicate that mRS is a safe and effective treatment option in cases of large meningiomas. ABBREVIATIONS:AOP, anterior optic pathwayAVP, anterior visual pathwaymRS, multisession radiosurgeryPD, progressive diseaseRION, radiation-induced optic neuropathysRS, stereotactic radiosurgery

Background Intraoperative vessel visualization is highly desirable, especially when the target is related to or close to main vessels, such as in the skull base and vascular surgery. Contrast-enhanced ultrasound (CEUS) is an imaging technique that allows visualization of tissue perfusion and vascularization through the infusion of purely intravascular ultrasound contrast agents (UCA). Methods After cerebral scanning with B-mode ultrasound (US) CEUS is performed, UCA are injected and insonated with low mechanical index US. A UCA-specific harmonic signal is transduced using a contrast-specific algorithm to obtain real-time angiosonography (ASG). Conclusions Real-time intraoperative ASG is a rapid, reliable, repeatable method for vessel visualization and evaluation of tissue perfusion. Key points • ASG permits to assess vessel position, dimension, and relationships; it also allows a qualitative evaluation of flow entity and direction. • ASG shows vessels in depth without the need of their direct exposure, as for fluorescence-guided surgery. • ASG permits to study the entire vascular tree without the necessity to set gain or pulse repetition frequency as in Doppler imaging. • Vessels of interest can be visualized following their entire length across the surgical field, along the arterial, capillary, and venous districts. • ASG scan is repeatable multiple times throughout the operation, and each exam could be recorded as a clip to be visualized at a later stage. • In case of neoplastic lesion, ASG characterizes the perfusion pattern in three phases: arterial, venous, and parenchymal, permitting to visualize afferent and efferent vessels, facilitating the surgical strategy. • During tumor debulking, ASG shows the remaining distance to major vessels, providing information to avoid direct vessel damage. • In tumor and AVM surgery, ASG shows nidus or tumoral remnants that might be covered by healthy tissue, thus not visible on the surface. • In case of aneurysm surgery, post-clipping angiosonographic control confirms proper aneurysm exclusion and distal vessels flow.

Background. Contrast enhanced ultrasound (CEUS) is a dynamic and continuous modality providing real-time view of vascularization and flow distribution patterns of different organs and tumors. Nevertheless its intraoperative use for brain tumors visualization has been performed few times, and a thorough characterization of cerebral glioma had never been performed before. Aim. To perform the first characterization of cerebral glioma using CEUS and to possibly achieve an intraoperative differentiation of different gliomas. Methods. We performed CEUS in an off-label setting in 69 patients undergoing surgery for cerebral glioma. An intraoperative qualitative analysis was performed comparing iCEUS with B-mode imaging. A postprocedural semiquantitative analysis was then performed for each case, according to EFSUMB criteria. Results were related to histopathology. Results. We observed different CE patterns: LGG show a mild, dotted CE with diffuse appearance and slower, delayed arterial and venous phase. HGG have a high CE with a more nodular, nonhomogeneous appearance and fast perfusion patterns. Conclusion. Our study characterizes for the first time human brain glioma with CEUS, providing further insight regarding these tumors’ biology. CEUS is a fast, safe, dynamic, real-time, and economic tool that might be helpful during surgery in differentiating malignant and benign gliomas and refining surgical strategy.

Abstract BACKGROUND Sonoelastography is an ultrasound imaging technique able to assess mechanical properties of tissues. Strain elastography (SE) is a qualitative sonoelastographic modality with a wide range of clinical applications, but its use in brain tumor surgery has been so far very limited. OBJECTIVE To describe the first large-scale implementation of SE in oncological neurosurgery for lesions discrimination and characterization. METHODS We analyzed retrospective data from 64 patients aiming at (i) evaluating the stiffness of the lesion and of the surrounding brain, (ii) assessing the correspondence between B-mode and SE, and (iii) performing subgroup analysis for gliomas characterization RESULTS (i) In all cases, we visualized the lesion and the surrounding brain with SE, permitting a qualitative stiffness assessment. (ii) In 90% of cases, lesion representations in B-mode and SE were superimposable with identical morphology and margins. In 64% of cases, lesion margins were sharper in SE than in B-mode. (iii) In 76% of cases, glioma margins were sharper in SE than in B-mode. Lesions morphology/dimensions in SE and in B-mode were superimposable in 89%. Low-grade (LGG) and high-grade (HGG) gliomas were significantly different in terms of stiffness and stiffness contrast between tumors and brain, LGG appearing stiffer while HGG softer than brain (all P < ·001). A threshold of 2.5 SE score had 85.7% sensitivity and 94.7% specificity in differentiating LGG from HGG. CONCLUSION SE allows to understand mechanical properties of the brain and lesions in examination and permits a better discrimination between different tissues compared to B-mode. Additionally, SE can differentiate between LGG and HGG.

Abstract BACKGROUND Maximizing extent of resection (EOR) and reducing residual tumor volume (RTV) while preserving neurological functions is the main goal in the surgical treatment of gliomas. Navigated intraoperative ultrasound (N-ioUS) combining the advantages of ultrasound and conventional neuronavigation (NN) allows for overcoming the limitations of the latter. OBJECTIVE To evaluate the impact of real-time NN combining ioUS and preoperative magnetic resonance imaging (MRI) on maximizing EOR in glioma surgery compared to standard NN. METHODS We retrospectively reviewed a series of 60 cases operated on for supratentorial gliomas: 31 operated under the guidance of N-ioUS and 29 resected with standard NN. Age, location of the tumor, pre- and postoperative Karnofsky Performance Status (KPS), EOR, RTV, and, if any, postoperative complications were evaluated. RESULTS The rate of gross total resection (GTR) in NN group was 44.8% vs 61.2% in N-ioUS group. The rate of RTV > 1 cm3 for glioblastomas was significantly lower for the N-ioUS group (P < .01). In 13/31 (42%), RTV was detected at the end of surgery with N-ioUS. In 8 of 13 cases, (25.8% of the cohort) surgeons continued with the operation until complete resection. Specificity was greater in N-ioUS (42% vs 31%) and negative predictive value (73% vs 54%). At discharge, the difference between pre- and postoperative KPS was significantly higher for the N-ioUS (P < .01). CONCLUSION The use of an N-ioUS-based real-time has been beneficial for resection in noneloquent high-grade glioma in terms of both EOR and neurological outcome, compared to standard NN. N-ioUS has proven usefulness in detecting RTV > 1 cm3.

The main goal in meningioma surgery is to achieve complete tumor removal, when possible, while improving or preserving patient neurological functions. Intraoperative imaging guidance is one fundamental tool for such achievement. In this regard, intra-operative ultrasound (ioUS) is a reliable solution to obtain real-time information during surgery and it has been applied in many different aspect of neurosurgery. In the last years, different ioUS modalities have been described: B-mode, Fusion Imaging with pre-operative acquired MRI, Doppler, contrast enhanced ultrasound (CEUS), and elastosonography. In this paper, we present our US based multimodal approach in meningioma surgery. We describe all the most relevant ioUS modalities and their intraoperative application to obtain precise and specific information regarding the lesion for a tailored approach in meningioma surgery. For each modality, we perform a review of the literature accompanied by a pictorial essay based on our routinely use of ioUS for meningioma resection.