Supplemental Figure 2. Pre- and post-LITT images of patient gliomas

Supplemental Figure 1. Surgical workflow for tumor biopsy and placement of minibolt

PURPOSE:Laser interstitial thermal therapy (LITT) is a minimally invasive surgical intervention permitting thermal ablation of intracranial targets such as tumors, radiation necrosis, or epileptogenic brain, including lesions that are deep, difficult to access, or recurrent that would otherwise have few viable surgical options. Despite its advantages, LITT has several limitations, including a restricted effective treatment zone (approximately 3 cm) and a limited ability to distinguish tumor margins from healthy brain tissue. Few viable animal models of appropriate size exist for studying LITT's impact on these disorders or for optimizing the technology and obviating its current limitations. Pet dogs develop these same disorders at similar rates to humans. We hypothesized that LITT could be made feasible in dogs, creating a unique model for in vivo LITT research and development. EXPERIMENTAL DESIGN:Canine cadaveric specimens and live dogs, including canine patients with spontaneously occurring intracranial gliomas, were used in this study. Commercially available equipment was used for neuronavigation (Curve, Brainlab) and to perform LITT (NeuroBlate, Monteris Medical). RESULTS:Canine cadavers and two end-of-life laboratory dogs allowed adaptation of the neuronavigation and LITT systems to dogs, with successful targeting and ablation of intracranial targets. Four canine patients with intracranial gliomas were subsequently successfully treated with these same technologies. CONCLUSIONS:This work establishes a unique canine model for in vivo LITT research and development using commercially available systems, as well as creating a viable cutting-edge therapeutic intervention for pet dogs with intracranial lesions.

BackgroundPeritumoral edema alters diffusion anisotropy, resulting in false negatives in tractography reconstructions negatively impacting surgical decision-making. With supratotal resections tied to survival benefit in glioma patients, advanced diffusion modeling is critical to visualize fibers within the peritumoral zone to prevent eloquent fiber transection thereafter. A preoperative assessment paradigm is therefore warranted to systematically evaluate multi-subject tractograms along clinically meaningful parameters. We propose a novel noninvasive surgically-focused survey to evaluate the benefits of a tractography algorithm for preoperative planning, subsequently applied to Synaptive Medical’s free-water correction algorithm developed for clinically feasible single-shell DTI data.MethodsTen neurosurgeons participated in the study and were presented with patient datasets containing histological lesions of varying degrees of edema. They were asked to compare standard (uncorrected) tractography reconstructions overlaid onto anatomical images with enhanced (corrected) reconstructions. The raters assessed the datasets in terms of overall data quality, tract alteration patterns, and the impact of the correction on lesion definition, brain-tumor interface, and optimal surgical pathway. Inter-rater reliability coefficients were calculated, and statistical comparisons were made.ResultsStandard tractography was perceived as problematic in areas proximal to the lesion, presenting with significant tract reduction that challenged assessment of the brain-tumor interface and of tract infiltration. With correction applied, significant reduction in false negatives were reported along with additional insight into tract infiltration. Significant positive correlations were shown between favorable responses to the correction algorithm and the lesion-to-edema ratio, such that the correction offered further clarification in increasingly edematous and malignant lesions. Lastly, the correction was perceived to introduce false tracts in CSF spaces and - to a lesser degree - the grey-white matter interface, highlighting the need for noise mitigation. As a result, the algorithm was modified by free-water-parameterizing the tractography dataset and introducing a novel adaptive thresholding tool for customizable correction guided by the surgeon’s discretion.ConclusionHere we translate surgeon insights into a clinically deployable software implementation capable of recovering peritumoral tracts in edematous zones while mitigating artifacts through the introduction of a novel and adaptive case-specific correction tool. Together, these advances maximize tractography’s clinical potential to personalize surgical decisions when faced with complex pathologies.

Due to improvements in population health, systemic cancer therapies and screening tools, the incidence of brain cancer metastases has continued to rise. The constituent cells possess unique characteristics that allow them to penetrate the blood–brain barrier, colonize the central nervous system, and co-opt their surroundings to thrive while evading surveillance by the immune system. This presents a unique challenge both to the multidisciplinary teams that care for these patients and the investigators striving to leverage these tumors' distinctive attributes into novel treatments. In this chapter, we outline the pathways and mechanisms underlying the development and survival of brain metastases, and how they inform current and emerging treatment strategies.

Abstract Malignant gliomas are devastating intracranial tumors with dismal prognoses that impose unique therapeutic challenges. Treatment options include surgical resection, radiation, and chemotherapy, but efficacy is limited and carries associated morbidity. Promise persists for newer modalities, such as immune-based platforms, but the blood-brain barrier (BBB) restricts intracranial therapeutic access, limiting success. Laser interstitial thermal therapy (LITT) is a minimally invasive surgical intervention permitting thermal ablation of brain tumors and other intracranial lesions. During LITT, a laser probe is stereotactically introduced through a small skull burr hole into the lesion. Continuous MRI is used to conduct real-time temperature monitoring via software-based calculation of cumulative thermal dosage zones. LITT is not only capable of ablating neoplastic tissue, but can also open the BBB in peritumoral regions, and thus may synergize with other emerging therapies. We adapted a commercially available LITT system (Monteris Medical) for use in dogs with intracranial lesions. Canine cadavers were used to optimize LITT procedures before employing this platform in live dogs. Our approach consists of 1. obtaining volumetric, T1-weighted, MRI studies to plan trajectories to intracranial targets, 2. fixing canine patients to a surgical bed and registering them for surface matching to a volume rendered image, 3. using an integrated instrument holder (Varioguide, Brainlab) to guide drilling of 4.5 mm skull burr holes for placement of self-tapping titanium “mini-bolts” (Monteris Medical), and 4. introducing the laser catheter probe through the mini-bolts for lesion ablation in the MRI suite. This method allows for rigid stereotaxy, successful neuronavigation, and a minimally invasive approach. We have successfully performed LITT on four canine patients with spontaneously occurring intracranial gliomas and plan to treat additional canine patients with intracranial lesions. Future studies will explore combination therapeutic platforms, including immunotherapy and gold nanoparticles to improve the efficiency and specificity of tumor ablation.

Malignant gliomas are devastating intracranial tumors with dismal prognoses that impose unique therapeutic challenges. Treatment options include surgical resection, radiation, and chemotherapy, but efficacy is limited and carries associated morbidity. Promise persists for newer modalities, such as immune-based platforms, but obstacles include limited therapeutic access due to the blood-brain barrier (BBB) and the highly immunosuppressive tumor microenvironment. Laser interstitial thermal therapy (LITT) is a minimally invasive surgical intervention permitting thermal ablation of intracranial tumors. During LITT, a laser probe is stereotactically placed in the lesion through a skull burr hole. Real-time MRI is used to calculate thermal dosage zones to monitor ablation progress. LITT is not only cytoreductive but also opens the BBB and induces a powerful hyperthermia-driven anti-tumor immune response; it thus may synergize with other emerging therapies. Spontaneous canine glioma offers a matchless, optimally recapitulative appropriately sized tumor model, providing a unique opportunity to investigate and optimize the LITT platform. We adapted a commercially available LITT system (Monteris Medical) for application in canines with intracranial lesions. Initially, canine cadavers were used to optimize LITT procedures; we then performed LITT in live dogs. Our approach consists of 1. obtaining volumetric MRI studies for trajectory planning, 2. fixing canine patients to the surgical bed, 3. registering anatomic landmarks (Brainlab) to a volume rendered image, 4. using an integrated instrument holder (Varioguide, Brainlab) to guide drilling of 4.5 mm skull burr holes for placement of self-tapping titanium “mini-bolts” (Monteris Medical), and 5. introducing the laser through the mini-bolts for ablation in the MRI suite. This method allows for rigid stereotaxy, successful neuronavigation, and a minimally invasive approach. We have successfully performed LITT on four canine patients with intracranial gliomas. Future studies will explore immunologic mechanisms underlying the post-LITT anti-tumor response as well as combination therapeutic platforms, including nanoparticles and stereotactic radiotherapy.

BACKGROUND: Radiation necrosis (RN) after stereotactic radiosurgery (SRS) for brain metastases (BM) can result in significant morbidity, compounded by the effects of extended steroid therapy. Laser interstitial thermal therapy (LITT) is a minimally invasive procedure that can offer definitive treatment for RN while potentially obviating the need for prolonged steroid use. OBJECTIVE: To compare LITT vs medical management (MM) in the treatment of RN. METHODS: A multicenter, retrospective study was performed of SRS-treated patients with BM who developed biopsy-proven RN and were treated with LITT or MM. Clinical outcome data were compared by treatment modality. RESULTS: Seventy-two patients met criteria with a median follow-up of 10.0 months (4.2-25.1), and 57 patients (79%) underwent LITT. Four MM (27%) and 3 LITT patients (5%) demonstrated radiographic progression ( P = .031) at a median of 5.3 and 4.0 months ( P = .40). There was no significant difference in overall survival (LITT median of 15.2 vs 11.6 months, P = .60) or freedom from local progression (13.6 vs 7.06 months, P = .40). Patients stopped steroid therapy earlier in the LITT cohort at a median of 37 days compared with 245 days ( P < .001). When controlled for follow-up duration, patients treated with LITT were 3 times more likely to be weaned off steroids before the study end point ( P = .003). CONCLUSION: These data suggest that LITT for treatment of biopsy-proven RN after SRS for BM significantly decreases time to steroid independence. Prospective trials should be designed to further validate the utility of LITT for RN and its impact on steroid-induced morbidity.

Abstract Introduction Laser interstitial thermal therapy (LITT) is a minimally-invasive treatment option often used for patients with deep-seated intracranial lesions. It has been implemented as a definitive treatment for radiation necrosis (RN), which occurs in 9–14% of patients after stereotactic radiosurgery (SRS) for brain metastases (BM). Medical management (MM) with steroids is a common first-line therapy, with variable response and numerous side effects, especially regarding immunotherapy. Methods Patients with biopsy-proven RN after SRS for BM who received LITT or MM at two academic centers were retrospectively reviewed. Treatment failure was defined as radiographic progression that necessitated a change in management. Measurements of total (TLV) and contrast-enhancing lesion volume (ceLV) were obtained from MRI by semi-automated analysis using the BrainLab iPlan Cranial 3.0 software. Results Seventy-two patients were followed for 10.0 (4.2–25.1) months and 57 (79%) received LITT. Steroid cessation occurred at a median of 37 days post-LITT compared to 245 days after MM (p<0.01). On Kaplan-Meier analyses, there was no significant difference between the two groups in overall survival (LITT median of 15.2 months vs 11.6 months, p = 0.60) or freedom from local progression (13.6 months vs. 7.06 months), though LITT trended to show a benefit in both metrics. When controlled for follow-up duration, patients treated with LITT were three times more likely to be weaned off steroids prior to the study endpoint compared to those who were medically managed (p=0.003). The LITT cohort demonstrated a general radiographic trend of initially increased CeLV followed by contraction, with significant decreases from pre-operative at 10–12 months (p<0.01). The MM group did not demonstrate any statistically significant radiographic trends. Conclusion These results suggest that LITT for RN significantly reduces the time to steroid cessation and characterize a stereotyped radiographic response to LITT. Future prospective studies will be important to their validation.

BACKGROUND:An impermeable blood-brain barrier and drug efflux via ATP-binding cassette (ABC) transporters such as p-glycoprotein may contribute to underwhelming efficacy of peripherally delivered agents to treat diffuse intrinsic pontine glioma (DIPG). OBJECTIVE:To explore the pharmacological augmentation of convection-enhanced delivery (CED) infusate for DIPG. METHODS:The efficacy of CED dasatinib, a tyrosine kinase inhibitor, in a transgenic H3.3K27M mutant murine model was assessed. mRNA expression of ABCB1 (p-glycoprotein) was analyzed in 14 tumor types in 274 children. In Vitro viability studies of dasatinib, the p-glycoprotein inhibitor, tariquidar, and dexamethasone were performed in 2 H3.3K27M mutant cell lines. Magnetic resonance imaging (MRI) was used to evaluate CED infusate (gadolinium/dasatinib) distribution in animals pretreated with tariquidar and dexamethasone. Histological assessment of apoptosis was performed. RESULTS:Continuous delivery CED dasatinib improved median overall survival (OS) of animals harboring DIPG in comparison to vehicle (39.5 and 28.5 d, respectively; P = .0139). Mean ABCB1 expression was highest in K27M gliomas. In Vitro, the addition of tariquidar and dexamethasone further enhanced the efficacy of dasatinib (P < .001). In Vivo, MRI demonstrated no difference in infusion dispersion between animals pretreated with dexamethasone plus tariquidar prior to CED dasatinib compared to the CED dasatinib. However, tumor apoptosis was the highest in the pretreatment group (P < .001). Correspondingly, median OS was longer in the pretreatment group (49 d) than the dasatinib alone group (39 d) and no treatment controls (31.5 d, P = .0305). CONCLUSION:ABC transporter inhibition plus dexamethasone enhances the efficacy of CED dasatinib, resulting in enhanced tumor cellular apoptosis and improved survival in H3.3K27M mutant DIPG.

Radiation necrosis (RN) occurs in 9–14% of patients after stereotactic radiosurgery (SRS) for brain metastases (BM). Medical management (MM) with steroids is a common first-line therapy, with variable response and numerous side effects, especially regarding immunotherapy. Laser interstitial thermal therapy (LITT) has been introduced as an efficacious, steroid-reducing alternative, however limited data exists comparing LITT to MM. Patients with biopsy-proven RN after SRS for BM who received LITT or MM at two academic centers were retrospectively reviewed. Treatment failure was defined as radiographic progression that necessitated a change in management. Measurements of total (TLV) and contrast-enhancing lesion volume (ceLV) were obtained from MRI by semi-automated analysis using the BrainLab iPlan Cranial 3.0 software. Eighty-one patients were followed for 11.7 (4.3–27.0) months and 57 (70%) received LITT. Steroid cessation occurred at a median of 37 days post-LITT compared to 162 days after MM (p< 0.01). Treatment failure occurred in 5% of LITT patients at 4.0 (3.2–4.8) months and 13% of MM patients at 4.4 (4.1–5.3) months (p >0.05). Patients were 3.2 times more likely to be weaned off steroids when treated with LITT compared to MM (p< 0.01), when controlled for age, pre-operative ceLV, and post-operative seizure on multivariate analysis. Both groups demonstrated decreasing TLV and ceLV between baseline and last follow-up MRI. At 6–9 months, the LITT cohort demonstrated a -59% change in ceLV compared to -7% with MM (p >0.05). The LITT cohort demonstrated a significant decrease in ceLV between scans at 0–2 and 6–9 months (p< 0.01). The MM group did not demonstrate a statistically significant decrease in ceLV until 12 months. This study suggests that LITT for RN significantly reduces the time to steroid cessation, and earlier radiographic response to treatment by LITT. Large, prospective trials are needed to validate these findings.

Sankey, Eric W MD; Grabowski, Matthew M MD; Srinavasan, Ethan; Griffin, Andrew; Howell, Elizabeth P BS; Otvos, Balint MD, PhD; Tsvankin, Vadim MD; Atik, Ahmet; Johsi, Krishna; Barnett, Gene H MD; Fecci, Peter E MD, PhD; Mohammadi, Alireza M MD Author Information

Purpose: Although pituitary adenoma is classified as benign, Cushing disease is associated with significant morbidity due to the numerous sequelae of elevated cortisol levels. Successful therapy for Cushing disease remains elusive due to high rates of treatment-refractory recurrence. The frequent emergence of lymphocytic hypophysitis following checkpoint blockade for other cancers, as well as the expression of PD-L1 on pituitary adenomas, suggest a role for immunotherapy. Experimental Design: This study confirms PD-L1 expression on functioning pituitary adenomas and is the first to evaluate the efficacy of checkpoint blockade (anti–PD-L1) therapy in a preclinical model of Cushing disease. Results: Herein, treatment with anti–PD-L1 was successful in reducing adrenocorticotropic hormone plasma levels, decreasing tumor growth, and increasing survival in our model. Furthermore, tumor-infiltrating T cells demonstrated a pattern of checkpoint expression similar to other checkpoint blockade–susceptible tumors. Conclusions: This suggests that immunotherapy, particularly blockade of the PD1/PD-L1 axis, may be a novel therapeutic option for refractory Cushing disease. Clinical investigation is encouraged.

The number of patients who develop metastatic brain lesions is increasing as the diagnosis and treatment of systemic cancers continues to improve, resulting in longer patient survival. The role of surgery in the management of brain metastasis (BM), particularly multiple and recurrent metastases, remains controversial and continues to evolve. However, with appropriate patient selection, outcomes after surgery are typically favorable. In addition, surgery is the only means to obtain a tissue diagnosis and is the only effective treatment modality to quickly relieve neurological complications or life-threatening symptoms related to significant mass effect, CSF obstruction, and peritumoral edema. As such, a thorough understanding of the role of surgery in patients with metastatic brain lesions, as well as the factors associated with surgical outcomes, is essential for the effective management of this unique and growing patient population.

Study Design: This is a meta-analysis. Objective: Perform a systematic review and quantitative meta-analysis of neurological outcomes from all available spinal epidural abscess (SEA) literature published between 1980 and 2016. Summary of Background Data: Current literature on SEAs lacks large-scale data characterizing prognostic factors and surgical indications. Materials and Methods: PubMed was queried for studies reporting neurological outcomes from patients undergoing conservative or surgical management for spontaneous SEA. Inclusion criteria included outcomes data measured >= 6 months after presentation, >= 10 human subjects, and diagnosis by magnetic resonance imaging or Computed tomography-myelogram. Where available, demographic data, abscess location, comorbidities, pretreatment neurological deficits, treatment methods, bacterial speciation, and complications were extracted from each study. Potential outcome predictors represented by continuous variables were compared using student t test and categorical variables were compared using the Pearson chi(2) test. Variables identified as potentially associated with outcome (P <= 0.05) were subjected to meta-analysis using Cochran-Mantel-Haenszel testing to calculate odds ratios (ORs) and 95% confidence intervals (CIs). Results: In total, 808 patients were analyzed from 20 studies that met inclusion criteria. 456 (56.3%) patients were treated with surgery and antibiotics, and 353 (43.7%) patients were managed with antibiotics alone. Neither surgical intervention (OR=1.01, 95% CI=0.40-2.59), lumbosacral location (OR=1.51, 95% CI=0.23-9.79), nor neurological deficit on presentation (OR=0.88, 95% CI=0.40-1.92) were significantly associated with good (stable or improved) or bad (worsened) neurological outcome, whereas delayed surgery was significantly associated with bad outcome (OR=0.01, 95% CI=0.02-0.62) and cervicothoracic location approached significance for predicting bad outcome (OR=0.41, 95% CI=0.15-1.09). Conclusions: Current literature does not definitively support or oppose surgical intervention in all SEA cases. Therefore, until better evidence exists, the decision to operate must be made on an individual case-by-case basis with the goals of preventing neurological decline, obtaining source control after failed conservative treatment, or restoring spinal stability.

Purpose: This work investigates a new approach to enhance radiotherapy through a photo therapeutic agent activated by Cherenkov light produced from the megavoltage photon beam. The process is termed Radiotherapy Enhanced with Cherenkov photo-Activation (RECA). RECA is compatible with various photo-therapeutics, but here we focus on use with psoralen, an ultraviolet activated therapeutic with extensive history of application in superficial and extracorporeal settings. RECA has potential to extend the scope of psoralen treatments beyond superficial to deep seated lesions. Methods and Materials: In vitro studies in B16 melanoma and 4T1 murine breast cancer cells were performed to investigate the potential of RT plus RECA versus RT alone for increasing cytotoxicity (local control) and increasing surface expression of major histocompatibility complex I (MHC I). The latter represents potential for immune response amplification (increased antigen presentation), which has been observed in other psoralen therapies. Cytotoxicity assays included luminescence and clonogenics. The MHC I assays were performed using flow cytometry. In addition, Cherenkov light intensity measurements were performed to investigate the possibility of increasing the Cherenkov light intensity per unit dose from clinical megavoltage beams, to maximize psoralen activation. Results: Luminescence assays showed that RECA treatment (2 Gy at 6 MV) increased cytotoxicity by up to 20% and 9.5% for 4T1 and B16 cells, respectively, compared with radiation and psoralen alone (ie, Cherenkov light was blocked). Similarly, flow cytometry revealed median MHC I expression was significantly higher in RECA-treated cells, compared with those receiving radiation and psoralen alone (approximately 450% and 250% at 3 Gy and 6 Gy, respectively, P << .0001). Clonogenic assays of B16 cells at doses of 6 Gy and 12 Gy showed decreases in tumor cell viability of 7% (P = .017) and 36% (P = .006), respectively, when Cherenkov was present. Conclusion: This work demonstrates for the first time the potential for photo-activation of psoralen directly in situ, from Cherenkov light generated by a clinical megavoltage treatment beam. (C) 2017 Elsevier Inc. All rights reserved.

Diffuse intrinsic pontine glioma (DIPG) is the leading cause of brain tumor-related death in children, with a median survival of nine months. The efficacy of in vitro preclinical models contrasted to poor outcomes in clinical trials suggests the possibility of inadequate drug delivery to the tumor; this has been attributed to a combination of poor penetration beyond the blood-brain barrier (BBB) and rapid drug efflux via ATP-binding cassette (ABC) transporters. Convection-enhanced delivery (CED) mechanically circumvents the BBB; however, the mechanism underlying infusate clearance is poorly understood, and may include passive diffusion through a leaky BBB or active efflux via ABC transporters. The multi-kinase inhibitor dasatinib was administered systemically or via CED in transgenic mice harboring histone H3.3K27M mutant DIPG. Concurrently, infusate retention behind the BBB was augmented by blocking ABC transporters with tariquidar and reducing BBB permeability with dexamethasone. Real-time MRI was used to evaluate the rate of CED infusate clearance and distribution volume. Systemic and CED administration routes both extended survival over vehicle (median 37.5 and 36 days, respectively, compared to 28.5 days; P=0.01) Notably, no survival benefit was found in CED-treated animals (5µL at 2µM) over intraperitoneal injection (25mg/kg; p=0.36). Systemic pretreatment with dexamethasone (0.5mg/kg) and tariquidar (5µg/kg) in CED-treated animals did not result in increased survival (p=0.66). Real-time MRI of animals infused with dasatinib-gadolinium did not reveal significant differences in distribution volume or clearance rate in animals pretreated with tariquidar and dexamethasone (p>0.05). Dasatinib delivered either systemically or via CED significantly improves survival in histone H3.3K27M mutant DIPG. Histologic mechanistic data regarding cellular apoptosis and proliferation are forthcoming. ABC transporter inhibition and BBB permeability reduction do not appear to improve the efficacy of dasatinib delivered by CED; it is therefore unlikely that these are significant mechanisms of CED infusate clearance.

Brain metastases represent the most common type of brain tumor. These tumors offer a dismal prognosis and significantly impact quality of life for patients. Their capacity for central nervous system (CNS) invasion is dependent upon induced disruptions to the blood-brain barrier (BBB), alterations to the brain microenvironment, and mechanisms for escaping CNS immunosurveillance. In the emerging era of immunotherapy, understanding how metastases are influenced by the immunologic peculiarities of the CNS will be crucial to forging therapeutic advances. In this review, the immunology of brain metastasis is explored.