Improvement of diffusion tensor imaging-based tractography by free-water correction in nonedematous gliomas: assessment with brain mapping.

OBJECTIVE: The free-water correction algorithm (Freewater Estimator Using Interpolated Initialization [FERNET]) can be applied to standard diffusion tensor imaging (DTI) tractography to improve visualization of subcortical bundles in the peritumoral area of highly edematous brain tumors. Interest in its use for presurgical planning in purely infiltrative gliomas without peritumoral edema has never been evaluated. Using subcortical maps obtained with direct electrostimulation (DES) in awake surgery as a reference standard, the authors sought to 1) assess the accuracy of preoperative DTI-based tractography with FERNET in a series of nonedematous glioma patients, and 2) determine its potential usefulness in presurgical planning. METHODS: Based on DES-induced functional disturbances and tumor topography, the authors retrospectively reconstructed the putatively stimulated bundles and the peritumoral tracts of interest (various associative and projection pathways) of 12 patients. The tractography data obtained with and without FERNET were compared. RESULTS: The authors identified 21 putative tracts from 24 stimulation sites and reconstituted 49 tracts of interest. The number of streamlines of the putative tracts crossing the DES area was 26.8% higher (96.04 vs 75.75, p = 0.016) and their volume 20.4% higher (13.99 cm3 vs 11.62 cm3, p < 0.0001) with FERNET than with standard DTI. Additionally, the volume of the tracts of interest was 22.1% higher (9.69 cm3 vs 7.93 cm3, p < 0.0001). CONCLUSIONS: Free-water correction significantly increased the anatomical plausibility of the stimulated fascicles and the volume of tracts of interest in the peritumoral area of purely infiltrative nonedematous gliomas. Because of the functional importance of the peritumoral zone, applying FERNET to DTI could have potential implications on surgical planning and the safety of glioma resection.

Application accuracy of Neuromate robot-guided deep brain stimulation procedures using the non-invasive frameless Neurolocate registration system.

OBJECTIVE: to measure the in vivo application accuracy of Neuromate robot-assisted deep brain stimulation procedures (DBS) using the new, non-invasive, frameless Neurolocate registration method. METHODS: Neurolocate accuracy was measured in 17 patients undergoing DBS (32 leads). The registration was obtained by automatic recognition of the spatial location of the Neurolocate fiducials, fixed on the robot arm, on 3D intraoperative computerized tomography (CT) images relative to the patient's skull contours. Application accuracy was measured as the Euclidian distance between the points theoretically targeted on preoperative magnetic resonance imagingand the tip of the guiding tube visible on intraoperative CT images after merging images. RESULTS: Mean robot inaccuracy was 0.72 mm (SD 0.40; range 0.2-1.7 mm). Inaccuracies ≥1.5 mm were observed in 2/32 cases. CONCLUSION: Our study confirms in vivo that the accuracy of the Neurolocate registration is compatible with the accuracy required for DBS procedures.

CELF2 Sustains a Proliferating/OLIG2+ Glioblastoma Cell Phenotype via the Epigenetic Repression of SOX3.

Glioblastomas (GBs) are incurable brain tumors. The persistence of aggressive stem-like tumor cells after cytotoxic treatments compromises therapeutic efficacy, leading to GBM recurrence. Forcing the GBM cells to irreversibly abandon their aggressive stem-like phenotype may offer an alternative to conventional cytotoxic treatments. Here, we show that the RNA binding protein CELF2 is strongly expressed in mitotic and OLIG2-positive GBM cells, while it is downregulated in differentiated and non-mitotic cells by miR-199a-3p, exemplifying GBM intra-tumor heterogeneity. Using patient-derived cells and human GBM samples, we demonstrate that CELF2 plays a key role in maintaining the proliferative/OLIG2 cell phenotype with clonal and tumorigenic properties. Indeed, we show that CELF2 deficiency in patient-derived GSCs drastically reduced tumor growth in the brains of nude mice. We further show that CELF2 promotes TRIM28 and G9a expression, which drive a H3K9me3 epigenetic profile responsible for the silencing of the SOX3 gene. Thus, CELF2, which is positively correlated with OLIG2 and Ki67 expression in human GBM samples, is inversely correlated with SOX3 and miR-199a-3p. Accordingly, the invalidation of SOX3 in CELF2-deficient patient-derived cells rescued proliferation and OLIG2 expression. Finally, patients expressing SOX3 above the median level of expression tend to have a longer life expectancy. CELF2 is therefore a crucial target for the malignant potential of GBM and warrants attention when developing novel anticancer strategies.

Free-water correction DTI-based tractography in brain tumor surgery: assessment with functional and electrophysiological mapping of the white matter.

Peritumoral edema prevents fiber tracking from diffusion tensor imaging (DTI). A free-water correction may overcome this drawback, as illustrated in the case of a patient undergoing awake surgery for brain metastasis. The anatomical plausibility and accuracy of tractography with and without free-water correction were assessed with functional mapping and axono-cortical evoked-potentials (ACEPs) as reference methods. The results suggest a potential synergy between corrected DTI-based tractography and ACEPs to reliably identify and preserve white matter tracts during brain tumor surgery.

CrOssing fiber Modeling in the Peritumoral Area using dMRI (COMPARI).

Visualization of fiber tracts around the tumor is critical for neurosurgical planning and preservation of crucial structural connectivity during tumor resection. Biophysical modeling approaches estimate fiber tract orientations from differential water diffusivity information of diffusion MRI. However, the presence of edema and tumor infiltration presents a challenge to visualize crossing fiber tracts in the peritumoral region. Previous approaches proposed free water modeling to compensate for the effect of water diffusivity in edema, but those methods were limited in estimating complex crossing fiber tracts. We propose a new cascaded multi-compartment model to estimate tissue microstructure in the presence of edema and pathological contaminants in the area surrounding brain tumors. In our model (COMPARI), the isotropic components of diffusion signal, including free water and hindered water, were eliminated, and the fiber orientation distribution (FOD) of the remaining signal was estimated. In simulated data, COMPARI accurately recovered fiber orientations in the presence of extracellular water. In a dataset of 23 patients with highly edematous brain tumors, the amplitudes of FOD and anisotropic index distribution within the peritumoral region were higher with COMPARI than with a recently proposed multi-compartment constrained deconvolution model. In a selected patient with metastatic brain tumor, we demonstrated COMPARI's ability to effectively model and eliminate water from the peritumoral region. The white matter bundles reconstructed with our model were qualitatively improved compared to those of other models, and allowed the identification of crossing fibers. In conclusion, the removal of isotropic components as proposed with COMPARI improved the bio-physical modeling of dMRI in edema, thus providing information on crossing fibers, thereby enabling improved tractography in a highly edematous brain tumor. This model may improve surgical planning tools to help achieve maximal safe resection of brain tumors.

Added value of [18F]FDOPA PET to the management of high-grade glioma patients after their initial treatment: a prospective multicentre study.

BACKGROUND: Diagnostic value of 3,4-dihydroxy-6-[18F]fluoro-L-phenylalanine ([18F]FDOPA) PET in patients with suspected recurrent gliomas is recognised. We conducted a multicentre prospective study to assess its added value in the practical management of patients suspected of recurrence of high grade gliomas (HGG). METHODS: Patients with a proven HGG (WHO grade III and IV) were referred to the multidisciplinary neuro-oncology board (MNOB) during their follow-up after initial standard of care treatment and when MRI findings were not fully conclusive. Each case was discussed in 2 steps. For step 1, a diagnosis and a management proposal were made only based on the clinical and the MRI data. For step 2, the same process was repeated taking the [18F]FDOPA PET results into consideration. A level of confidence for the decisions was assigned to each step. Changes in diagnosis and management induced by [18F]FDOPA PET information were measured. When unchanged, the difference in the confidence of the decisions were assessed. The diagnostic performances of each step were measured. RESULTS: 107 patients underwent a total of 138 MNOB assessments. The proposed diagnosis changed between step 1 and step 2 in 37 cases (26.8%) and the proposed management changed in 31 cases (22.5%). When the management did not change, the confidence in the MNOB final decision was increased in 87 cases (81.3%). Step 1 had a sensitivity, specificity and accuracy of 83%, 58% and 66% and step 2, 86%, 64% and 71% respectively. CONCLUSION: [18F]FDOPA PET adds significant information for the follow-up of HGG patients in clinical practice. When MRI findings are not straightforward, it can change the management for more than 20% of the patients and increases the confidence level of the multidisciplinary board decisions.

Identifying subcortical connectivity during brain tumor surgery: a multimodal study.

Bipolar direct electrical stimulation (DES) of an awake patient is the reference technique for identifying brain structures to achieve maximal safe tumor resection. Unfortunately, DES cannot be performed in all cases. Alternative surgical tools are, therefore, needed to aid identification of subcortical connectivity during brain tumor removal. In this pilot study, we sought to (i) evaluate the combined use of evoked potential (EP) and tractography for identification of white matter (WM) tracts under the functional control of DES, and (ii) provide clues to the electrophysiological effects of bipolar stimulation on neural pathways. We included 12 patients (mean age of 38.4 years) who had had a dMRI-based tractography and a functional brain mapping under awake craniotomy for brain tumor removal. Electrophysiological recordings of subcortical evoked potentials (SCEPs) were acquired during bipolar low frequency (2 Hz) stimulation of the WM functional sites identified during brain mapping. SCEPs were successfully triggered in 11 out of 12 patients. The median length of the stimulated fibers was 43.24 ± 19.55 mm, belonging to tracts of median lengths of 89.84 ± 24.65 mm. The electrophysiological (delay, amplitude, and speed of propagation) and structural (number and lengths of streamlines, and mean fractional anisotropy) measures were correlated. In our experimental conditions, SCEPs were essentially limited to a subpart of the bundles, suggesting a selectivity of action of the DES on the brain networks. Correlations between functional, structural, and electrophysiological measures portend the combined use of EPs and tractography as a potential intraoperative tool to achieve maximum safe resection in brain tumor surgery.

A New Noninvasive Frameless Registration System for Stereotactic Cranial Biopsy: A Technical Note.

BACKGROUND: Although frame-based stereotactic biopsy is still considered the gold standard for brain biopsies, frameless robot-assisted stereotactic systems are now able to provide an equal level of safety and accuracy. However, both systems suffer from a lack of efficiency of the operative workflow. OBJECTIVE: To describe the technique of a new frameless and noninvasive registration tool Neurolocate (Renishaw). This tool, combined with an intraoperative cone-beam computed tomography imaging system like O-ARM (Medtronic), might facilitate the achievement and workflow of robot-assisted stereotactic intracranial biopsies. METHODS: Neurolocate is a 3-dimensional fiducial tool fixed directly on the Neuromate (Renishaw) robot arm. It consists of 5 radio-opaque spherical fiducials, whose geometry is constant. This tool made it possible to carry out the coregistration then the biopsy in the same operating time, following a five-step procedure described here. We retrospectively extracted selected preliminary results from our initial experience. RESULTS: Over 1 year, 23 consecutive adult patients were biopsied with Neurolocate in our center. The mean overall operative time, from patient's installation to skin closure, was 97 minutes ± 27 (SD). The entire procedure took place in a single location unit (operating room), which facilitated workflow and surgical planning. No invasive gesture was performed outside of the operating time. CONCLUSION: Neurolocate is a new frameless and noninvasive registration tool that could improve workflow and flexibility for operating room management and surgical planning. It may also increase the comfort of patients undergoing robot-assisted intracranial stereotactic biopsies. The accuracy and safety profile should be addressed in specific studies.

Glioblastoma cell motility depends on enhanced oxidative stress coupled with mobilization of a sulfurtransferase.

Cell motility is critical for tumor malignancy. Metabolism being an obligatory step in shaping cell behavior, we looked for metabolic weaknesses shared by motile cells across the diverse genetic contexts of patients' glioblastoma. Computational analyses of single-cell transcriptomes from thirty patients' tumors isolated cells with high motile potential and highlighted their metabolic specificities. These cells were characterized by enhanced mitochondrial load and oxidative stress coupled with mobilization of the cysteine metabolism enzyme 3-Mercaptopyruvate sulfurtransferase (MPST). Functional assays with patients' tumor-derived cells and -tissue organoids, and genetic and pharmacological manipulations confirmed that the cells depend on enhanced ROS production and MPST activity for their motility. MPST action involved protection of protein cysteine residues from damaging hyperoxidation. Its knockdown translated in reduced tumor burden, and a robust increase in mice survival. Starting from cell-by-cell analyses of the patients' tumors, our work unravels metabolic dependencies of cell malignancy maintained across heterogeneous genomic landscapes.

Phantom vision after eye removal: prevalence, features and related risk factors.

AIM: Phantom eye syndrome is a poorly understood and underestimated complication of eye removal (ER). Seeing with the amputated eye, referred to as phantom vision (PV), is undoubtedly the most intriguing and confusing complication experienced by anophthalmic patients. The aim of the study was to assess PV prevalence, clinical features and risk factors after ER. METHODS: A multicentric questionnaire-based study was conducted between April 2016 and July 2017. Patients >18 years who underwent ER >3 months ago had a socket examination before inclusion. Data recorded included patients' demographics, and preoperative, surgical and postoperative features. RESULTS: One hundred patients (53 men) with a mean age of 65.1 years (29-92; SD=13.0) were included. ER indications were: uveal melanoma (n=24, 24%), trauma (n=20, 20%), retinal detachment (n=20, 20%), glaucoma (n=14, 14%) and endophthalmitis (n=12, 12%). Thirty (30%) patients experienced PV. Elementary and complex visual hallucinations were experienced by 80% and 20% of patients, respectively. PV usually appeared within the first postoperative month and tended to decrease over time. Risk factors for PV were the preoperative use of proton beam therapy (p=0.006), uveal melanoma (p=0.014), enucleation (p=0.015), anxiety with a Hospital and Anxiety Depression (HAD) score ≥8 (p=0.042), depression with a HAD score ≥8 (p=0.030), phantom eye pain (p=0.044) and phantom eye sensations (p=0.002). CONCLUSION: PV was reported by one-third of our patients. Despite being widely misunderstood, ophthalmologists and neurologists should be aware of this complication to adequately reassure patients.

Transfacet screws using spinal navigation in addition to anterior or oblique lumbar interbody fusion: technical note and preliminary results.

Transfacet screws (TFS) are an alternative to the classic bilateral pedicular screws (BPS) in addition to anterior (ALIF) or oblique (OLIF) lumbar interbody fusion. Spinal navigation could help the surgeon in technically demanding procedures in order to avoid screw malposition. Although spinal navigation is commonly used in BPS, its contribution in TFS remains unclear. Our aim here was to assess the feasibility of TFS using spinal navigation in addition to anterior lumbar fusion. Five patients suffering from lumbar degenerative disc disease were included. During the same general anaesthesia, we performed successively an ALIF or OLIF and then a TFS according to Boucher technique using spinal navigation (O-arm). No peri-operative complication occurred, and all the screws were successfully positioned (n = 10). All clinical scores (ODI, VAS L and VAS R) improved at 6-month follow-up. Segmental lordosis increased from 6° [2.4°-12°] to 13.6° [8°-17°]. Fusion was achieved for the five patients. TFS using O-arm in addition to ALIF/OLIF is feasible. To confirm our early favourable outcomes on clinical and radiological data, this technique must be evaluated on larger samples of patients.

Homotopic redistribution of functional connectivity in insula-centered diffuse low-grade glioma.

OBJECTIVE: In the event of neural injury, the homologous contralateral brain areas may play a compensatory role to avoid or limit the functional loss. However, this dynamic strategy of functional redistribution is not clearly established, especially in the pathophysiological context of diffuse low-grade glioma. Our aim here was to assess the extent to which unilateral tumor infiltration of the insula dynamically modulates the functional connectivity of the contralesional one. METHODS: Using resting-state functional connectivity MRI, a seed-to-ROI approach was employed in 52 insula-centered glioma patients (n = 30 left and 22 right) compared with 19 age-matched healthy controls. RESULTS: Unsurprisingly, a significant decrease of the inter-insular connectivity was observed in both patient groups. More importantly, the analyses revealed a significant increase of the contralesional insular connectivity towards both cerebral hemispheres, especially in cortical areas forming the visual and the sensorimotor networks. This functional redistribution was not identified when the analyses were performed on three control regions for which the homologous area was not impaired by the tumor. This overall pattern of results indicates that massive infiltration of the insular cortex causes a significant redeployment of the contralesional functional connectivity. CONCLUSION: This general finding suggests that the undamaged insula plays a role in the functional compensation usually observed in this patient population, and thus provides compelling support for the concept of homotopic functional plasticity in brain-damaged patients.

Post-traumatic orbitorrhea: An underestimated life-threatening complication following anterior skull base fractures.

Orbitorrhea is defined as a leak of cerebrospinal fluid from a cranio-orbital fistula. It is usually related to anterior skull base trauma. Orbitorrhea is an exceptional and life-threatening condition which should be promptly managed. We herein report the case of a right post-traumatic orbitorrhea following anterior skull base trauma. Conservative treatment was initially attempted. At 6 weeks, recurrence was noted, and the patient underwent neurosurgical management. A few months later, a secondary upper lid retraction was diagnosed and treated by full-thickness skin graft with favourable outcome. To our knowledge, fewer than 30 cases have been previously reported. Ophthalmologists should be aware of this life-threatening condition which could be underestimated.

Phantom eye pain: a multicentric study in 100 patients.

PURPOSE: Phantom eye syndrome (PES) is an underestimated complication of eye amputation (EA) characterized by phantom eye pain (PEP), phantom visions and/or phantom sensations. The aim of this study was to assess PEP prevalence, features, risk factors, social and psychological consequences and associated quality of life. METHODS: A questionnaire study was conducted in three oculoplastic departments between April 2016 and July 2017. Patients >18 years who had undergone EA ≥3 months earlier were included and asked to complete a prestamped questionnaire. Patient's characteristics, preoperative, surgical and postoperative data were collected. RESULTS: Of the 185 questionnaires given, 115 (62%) were returned for analysis. Hundred patients with a mean age of 65.1 years (29-92; SD = 13.0) were included. Eye amputation (EA) indications were uveal melanoma (n = 24, 24%), trauma (n = 20, 20%), retinal detachment (n = 20, 20%), glaucoma (n = 14, 14%) and endophthalmitis (n = 12, 12%). Forty-seven (47%), 30 (30%) and 38 (38%) patients experienced PEP, phantom visions and phantom sensations, respectively. Anxiety and depression [Hospital Anxiety Depression scale (HADS) score ≥8 for both] were diagnosed in 34 (34%) and 42 (42%) patients, respectively. The mean EQ-5D-3L and EQ-5D visual analogue scale scores were 0.8 (0.06-1; SD = 0.2) and 68 (0-100; SD = 22), respectively. Preoperative eye pain (p = 0.031), glaucoma (p = 0.027), postoperative anxiety with HADS score ≥8 (p = 0.012) and ≥11 (p = 0.014), aesthetic discomfort (p = 0.002) and EQ-5D-3L score <0.8 (p < 0.001) were significantly associated with PEP in the univariate analysis. In the multivariate analysis, only anxiety (HADS score ≥8) was significantly associated with PEP (p = 0.009). CONCLUSION: Phantom eye pain (PEP) is a common complication of EA strongly associated with postoperative anxiety.

Autologous dermis graft versus conchal cartilage graft for managing lower eyelid retraction: A comparative study.

PURPOSE: Lower eyelid management is challenging. The conchal cartilage is often considered a spacer of choice for treating lower eyelid retraction. However, dermis graft has also recently been shown to be a viable spacer. The aim of this study was to compare the efficacy of dermis graft to that of conchal cartilage graft in this indication. METHODS: A retrospective comparative study was conducted in patients who underwent lower eyelid lengthening with autologous dermis graft (group 1) or autologous conchal cartilage graft (group 2). The main outcome measure was the reduction in inferior scleral show (ISS) assessed by three independent masked surgeons. Secondary outcome measures was the assessment of lagophthalmos and corneal keratitis. Complications were also recorded. RESULTS: Twenty-five eyelids of 23 patients were included: 11 and 14 eyelids, respectively in group 1 (dermis graft) and group 2 (conchal cartilage graft). Patient mean follow-up was 12.3 (±12.5) and 7.1 (±7.7) months, respectively. No statistical differences in postoperative ISS reduction, lagophthalmos and exposure keratitis was observed (p = 0.540, p = 0.946, p = 0.934, respectively). Three patients experienced a grade I Clavien-Dindo complication in group 1 and one patient experienced a grade II complication in group 2 (p = 0.540). CONCLUSION: Autologous dermis grafts and conchal cartilage grafts provide favorable outcomes without major complications.

Towards linking diffusion MRI based macro- and microstructure measures with cortico-cortical transmission in brain tumor patients.

We aimed to link macro- and microstructure measures of brain white matter obtained from diffusion MRI with effective connectivity measures based on a propagation of cortico-cortical evoked potentials induced with intrasurgical direct electrical stimulation. For this, we compared streamline lengths and log-transformed ratios of streamlines computed from presurgical diffusion-weighted images, and the delays and amplitudes of N1 peaks recorded intrasurgically with electrocorticography electrodes in a pilot study of 9 brain tumor patients. Our results showed positive correlation between these two modalities in the vicinity of the stimulation sites (Pearson coefficient 0.54±0.13 for N1 delays, and 0.47±0.23 for N1 amplitudes), which could correspond to the neural propagation via U-fibers. In addition, we reached high sensitivities (0.78±0.07) and very high specificities (0.93±0.03) in a binary variant of our comparison. Finally, we used the structural connectivity measures to predict the effective connectivity using a multiple linear regression model, and showed a significant role of brain microstructure-related indices in this relation.

ERK-Mediated Loss of miR-199a-3p and Induction of EGR1 Act as a "Toggle Switch" of GBM Cell Dedifferentiation into NANOG- and OCT4-Positive Cells.

There is great interest in understanding how the cancer stem cell population may be maintained in solid tumors. Here, we show that tumor cells exhibiting stem-like properties and expression of pluripotency markers NANOG and OCT4 can arise from original differentiated tumor cells freshly isolated from human glioblastomas (GBM) and that have never known any serum culture conditions. Induction of EGR1 by EGFR/ERK signaling promoted cell conversion from a less aggressive, more differentiated cellular state to a self-renewing and strongly tumorigenic state, expressing NANOG and OCT4. Expression of these pluripotency markers occurred before the cells re-entered the cell cycle, demonstrating their capacity to change and dedifferentiate without any cell divisions. In differentiated GBM cells, ERK-mediated repression of miR-199a-3p induced EGR1 protein expression and triggered dedifferentiation. Overall, this signaling pathway constitutes an ERK-mediated "toggle switch" that promotes pluripotency marker expression and stem-like features in GBM cells. SIGNIFICANCE: This study defines an ERK-mediated molecular mechanism of dedifferentiation of GBM cells into a stem-like state, expressing markers of pluripotency.See related commentary by Koncar and Agnihotri, p. 3195.

Anesthesia management for low-grade glioma awake surgery: a European Low-Grade Glioma Network survey.

BACKGROUND: Awake surgery has become a key treatment of diffuse low-grade gliomas (DLGG) and is divided in three main phases: opening, tumor resection - during which the patient needs to be fully awake - and closure. The anesthetic management of awake neurosurgery is a challenge, and there are currently no guidelines. OBJECTIVE: The objective of the survey was to explore differences and commonalities regarding the anesthetic management of awake DLGG surgery within the European Low-Grade Glioma Network (ELGGN) centers. METHODS: A form that contained 14 questions about the anesthetic management was sent to 28 centers in May 2015. RESULTS: Twenty centers responded. During the opening and closing non-awake periods, 56% of teams chose general anesthesia with mechanical ventilation for at least one period (asleep-awake-asleep, SAS protocol), and 44% monitored anesthesia care including sedation without mechanical ventilation (MAC protocol). In case of SAS, all the teams chose intravenous anesthesia, 82% used laryngeal mask instead of endotracheal intubation during the opening sequence, and 71% during closure. Local and regional anesthesia was practiced by all the teams. The most frequently reported cause of pain was dural and cerebral vessels manipulation (77%). Pain management was mostly based on paracetamol (70%) and remifentanil (55%). CONCLUSION: Our survey showed that there was an equivalent proportion of centers using SAS or MAC protocols in the anesthetic management of awake surgery in ELGGN centers. The advantages and disadvantages of each anesthesia protocol were reviewed.

Early Toxicities After High Dose Rate Proton Therapy in Cancer Treatments.

BACKGROUND: The conventional dose rate of radiation therapy is 0.01-0.05 Gy per second. According to preclinical studies, an increased dose rate may offer similar anti-tumoral effect while dramatically improving normal tissue protection. This study aims at evaluating the early toxicities for patients irradiated with high dose rate pulsed proton therapy (PT). MATERIALS AND METHODS: A single institution retrospective chart review was performed for patients treated with high dose rate (10 Gy per second) pulsed proton therapy, from September 2016 to April 2020. This included both benign and malignant tumors with ≥3 months follow-up, evaluated for acute (≤2 months) and subacute (>2 months) toxicity after the completion of PT. RESULTS: There were 127 patients identified, with a median follow up of 14.8 months (3-42.9 months). The median age was 55 years (1.6-89). The cohort most commonly consisted of benign disease (55.1%), cranial targets (95.1%), and were treated with surgery prior to PT (56.7%). There was a median total PT dose of 56 Gy (30-74 Gy), dose per fraction of 2 Gy (1-3 Gy), and CTV size of 47.6 ml (5.6-2,106.1 ml). Maximum acute grade ≥2 toxicity were observed in 49 (38.6%) patients, of which 8 (6.3%) experienced grade 3 toxicity. No acute grade 4 or 5 toxicity was observed. Maximum subacute grade 2, 3, and 4 toxicity were discovered in 25 (19.7%), 12 (9.4%), and 1 (0.8%) patient(s), respectively. CONCLUSION: In this cohort, utilizing high dose rate proton therapy (10 Gy per second) did not result in a major decrease in acute and subacute toxicity. Longer follow-up and comparative studies with conventional dose rate are required to evaluate whether this approach offers a toxicity benefit.