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The Lightning software, was added to the Gamma Knife's Leksell GammaPlan as a fully automated inverse planner, differently from the prior software, Wizard . In this paper we compare their treatment planning capacity and quality. Thirty-eight cases were compared under four different planning techniques. First, manual forward planning aided by the Wizard optimization tool. Second, inverse planning with Wizard . The third and fourth plans used Lightning with and without consideration for organs at risk (OAR). They were analysed for: planning time, number of shots, coverage, selectivity, gradient index, bean-on time, and OAR dose. Comparison based on pathology was added due to their idiosyncrasies. For quality comparison, dose-volume histograms (DVH) were compared to plans developed under our treatment standards. Tumor's volume and time to plan were correlated with Pearson's coefficient. Lightning had better coverage (8%) and gradient index (15%) but had 12% decrease in selectivity. Planning and delivery times had a reduction of 57% and 5% respectively, despite having three times the number of shots. Only Lightning with protection of OAR met the dose constrains in all plans. DVH showed similar plan qualities. Lightning allowed the planner to explore different optimization parameters to achieve a plan that suits the clinical problem at hand. It took less time to calculate shots placement, OAR protection and the ideal isodose line than the Wizard . This can be useful to plan multiple and complex targets at a faster time, increase the patient's tolerance and, may have a radiobiological advantage by impacting intra-fraction repair.

Purpose Atypical meningiomas have histologic and clinical features that fall between those for benign and malignant meningiomas. The incidence of atypical meningiomas has not been well studied with respect to changes in the World Health Organization (WHO) classification scheme over time. Methods The National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) database was queried to obtain data from 2004 to 2018 for patients with all meningiomas, including atypical. Age-adjusted incidence rates were generated and annual percent change (APC) in the incidence rates was calculated with joinpoint regression. Survival was analyzed using the Kaplan–Meier method and Cox proportional hazards models. Results A total of 4476 patients diagnosed with meningioma were identified from the SEER 18 registries. The incidence of atypical meningioma increased at an APC of 5.6% [95% confidence interval [CI], 3.4–7.8]; significantly faster than all meningiomas, which rose at an APC of 2.5% (95%CI 1.8–3.1;p = 0.008). For atypical meningiomas, the 1, 3, 5, and 10-year survival rates were 91.9%, 81.3%, 68.8%, and 34.3%, respectively. Male sex, older age (≥ 60 years), and large tumor size (> 5 cm) were independent risk factors for an unfavorable prognosis. Conclusions The incidence of atypical meningioma was observed to be increasing relative to all meningiomas. It is important to diligently monitor atypical meningioma incidence and mortality rates over time to see whether observed uptrends persist. Continued effort toward improving outcomes in patients with atypical meningiomas is warranted, especially in light of an apparent rise in incidence.

PurposeStandard-of-care for glioblastoma remains surgical debulking followed by temozolomide and radiation. However, many tumors become radio-resistant while radiation damages surrounding brain tissue. Novel therapies are needed to increase the effectiveness of radiation and reduce the required radiation dose. Drug candidate CBL0137 is efficacious against glioblastoma by inhibiting histone chaperone FACT, known to be involved in DNA damage repair. We investigated the combination of CBL0137 and radiation on glioblastoma.MethodsIn vitro, we combined CBL0137 with radiation on U87MG and A1207 glioblastoma cells using the clonogenic assay to evaluate the response to several treatment regimens, and the Fast Halo Assay to examine DNA repair. In vivo, we used the optimum combination treatment regimen to evaluate the response of orthotopic tumors in nude mice.ResultsIn vitro, the combination of CBL0137 and radiation is superior to either alone and administering CBL0137 two hours prior to radiation, having the drug present during and for a prolonged period post-radiation, is an optimal schedule. CBL0137 inhibits DNA damage repair following radiation and affects the subcellular distribution of histone chaperone ATRX, a molecule involved in DNA repair. In vivo, one dose of CBL0137 is efficacious and the combination of CBL0137 with radiation increases median survival over either monotherapy.ConclusionsCBL0137 is most effective with radiation for glioblastoma when present at the time of radiation, immediately after and for a prolonged period post-radiation, by inhibiting DNA repair caused by radiation. The combination leads to increased survival making it attractive as a dual therapy.

This paper discusses recent results and near-term prospects of the long-baseline neutrino experiments MINOS, MINOS+, T2K and NOvA. The non-zero value of the third neutrino mixing angle θ13 allows experimental analysis in a manner which explicitly exhibits appearance and disappearance dependencies on additional parameters associated with mass-hierarchy, CP violation, and any non-maximal θ23. These current and near-future experiments begin the era of precision accelerator long-baseline measurements and lay the framework within which future experimental results will be interpreted.

Thermoplastic mask immobilization is used to perform hypo-fractionated treatments with the Gamma Knife ICON®. We evaluated the curing characteristics of the ICON® Nanor mask using force sensing resistors coupled with a data logging tool designed by us. For patients being treated with masks made the same day as the treatment, often in the same sitting with no removal and replacement of the patient from the treatment cradle, based on the curves 80% of the force of fixation is reached at 30 minutes. Allowing for curing over 10-15 minutes and the subsequent localizing and delivery Cone beam CT (CBCT)s as well as the plan evaluation this is a reasonable time to start of therapy. For more exacting targets that are still requiring hypo-fractionation a cure period of 15 hours or greater will ensure that maximum rigidity of fixation is achieved.

Despite the male preponderance for developing glial tumors and a body of published literature that suggests a female gender advantage for long term survival in both human and animal studies, there have been relatively few rigorous investigations into the hormonal effects on glial tumor growth. In a previous study, we concluded that estrogen played a major role in the female survival bias seen in an intracerebral nude rat model of glioblastoma multiforme. Here we explore the potential therapeutic effect of exogenous estradiol delivery in nude rats with orthotopic glioblastoma tumors and examine the mechanism of action of estradiol on reducing tumor growth in this animal model. We administered estradiol, in several dosing regimens, to male, female and ovariectomized nude rats in a survival study. Brain sections, taken at various time points in tumor progression, were analyzed for estrogen receptor protein, proliferative index and apoptotic index. Estradiol increased survival of male, female and ovariectomized nude rats with intracerebral U87MG tumors, in a gender specific manner. The estradiol mediated effect occurred early in tumor progression, and appeared to be caused in-part by an increase in apoptotic activity. It remains unclear if estradiol’s effect is direct or indirect and if it is estrogen receptor mediated. Estradiol-based or adjunctive therapy may be beneficial in treating GBM and further study is clearly warranted.

Historically, intra-arterial (IA) drug administration for malignant brain tumors including glioblastoma multiforme (GBM) was performed as an attempt to improve drug delivery. With the advent of percutaneous neuorovascular techniques and modern microcatheters, intracranial drug delivery is readily feasible; however, the question remains whether IA administration is safe and more effective compared to other delivery modalities such as intravenous (IV) or oral administrations. Preclinical large animal models allow for comparisons between treatment routes and to test novel agents, but can be expensive and difficult to generate large numbers and rapid results. Accordingly, we developed a murine model of IA drug delivery for GBM that is reproducible with clear readouts of tumor response and neurotoxicities. Herein, we describe a novel mouse model of IA drug delivery accessing the internal carotid artery to treat ipsilateral implanted GBM tumors that is consistent and reproducible with minimal experience. The intent of establishing this unique platform is to efficiently interrogate targeted anti-tumor agents that may be designed to take advantage of a directed, regional therapy approach for brain tumors.

PurposeThe differentiation between adverse radiation effects (ARE) and tumor recurrence or progression (TRP) is a major decision-making point in the follow-up of patients with brain tumors. The advent of immunotherapy, targeted therapy and radiosurgery has made this distinction difficult to achieve in several clinical situations. Contrast clearance analysis (CCA) is a useful technique that can inform clinical decisions but has so far only been histologically validated in the context of high-grade gliomas.MethodsThis is a series of 7 patients, treated between 2018 and 2023, for various brain pathologies including brain metastasis, atypical meningioma, and high-grade glioma. MRI with contrast clearance analysis was used to inform clinical decisions and patients underwent surgical resection as indicated. The histopathology findings were compared with the CCA findings in all cases.ResultsAll seven patients had been treated with gamma knife radiosurgery and were followed up with periodic MR imaging. All patients underwent CCA when the necessity to distinguish tumor recurrence from radiation necrosis arose, and subsequently underwent surgery as indicated. Concordance of CCA findings with histological findings was found in all cases (100%).ConclusionsBased on prior studies on GBM and the surgical findings in our series, delayed contrast extravasation MRI findings correlate well with histopathology across a wide spectrum of brain tumor pathologies. CCA can provide a quick diagnosis and have a direct impact on patients’ treatment and outcomes.

Purpose To challenge the prevalent pessimism regarding the outcome of patients with metastases in the brainstem resulting in the use of whole brain radiation for palliation rather than stereotactic radiosurgery for definitive control and preservation of quality of life. We present our single institution review of the efficacy and safety of treating brainstem metastases aggressively with GKRS. Methods Forty-one patients with 45 total lesions treated with GKRS were included. Mean age was 58.7 years, ranging from 22 to 82. Tumor volumes were objectively calculated, treatment effects assessed on imaging and clinical data collected and correlated to the radiosurgical response. Results Mean survival after diagnosis of BSM was 11.6 months, ranging from 1.4 to 58.8 months. Margin dose ranged from 12 to 20 Gy. At first follow up, 11 (27%) patients had complete resolution of the treated lesion. At the second follow up 15 (37%) and third follow up 19 (46%) patients had a complete response. On average, there was a 64% decrease in tumor size at first follow up after treatment. 25 (61%) patients received WBRT in addition to radiosurgery; 16 (39%) received radiosurgery alone. There was no difference in overall survival between the two groups (p = 0.1324). ARE was seen in one patient who received  16 Gy to the margin of a 2.06 cm 3 pontine tumor, but without correlative symptoms. One patient was treated with Bevacizumab ® for progressive, but asymptomatic, edema following treatment that was not controlled by corticosteroids. Conclusions Location in brainstem should not be a deterrent to the use of radiosurgery for these patients. The addition or exclusion of WBRT should be based on the clinical progression of the patient and within the limits of this study does not seem to impact overall survival. With improved survival as a result of better systemic therapy, these patients can benefit from better preservation of cognitive function by this strategy.

Osteopontin (OPN) is a pleotrophic molecule that has been associated with multiple disorders of the central nervous system (CNS). Its roles in CNS malignancy are unclear but suggest that higher levels of OPN expression correlate with increased tumor grade and increased migratory capacity of tumor cells. In this study OPN cDNA was cloned into a retroviral vector and used to infect F98 Fischer rat-derived glioma cells and U87 human-derived glioblastoma multiforme (GBM) cells in vitro. Cells expressing high levels of OPN migrated less distance than control cells in vitro. This effect was not RGD mediated, but was reversed in the presence of c-Jun N-terminal kinase (JNK) inhibitor suggesting that JNK1 is an essential component of a negative feedback loop affecting OPN activated signaling cascades. Implantation of tumor cells expressing high levels of OPN into adult Fischer rats and nude rats resulted in morphologically distinct tumors and prolonged host survival relative to controls. We propose that local produced, high level OPN expression limits the malignant character of glioma cells and that the downstream mechanisms involved represent pathways that may have therapeutic value in the treatment of human CNS malignancy.