Or Cohen-Inbar

Stereotactic radiosurgery for deep intracranial arteriovenous malformations, part 2: Basal ganglia and thalamus arteriovenous malformations

The aim of this review is to critically analyze the outcomes following stereotactic radiosurgery (SRS) for arteriovenous malformations (AVM) of the basal ganglia and thalamus. The management of these deep-seated lesions continues to challenge neurosurgeons. Basal ganglia and thalamic AVM show a higher risk of hemorrhage, and an associated devastating morbidity and mortality, as compared to AVM in more superficial locations. Any of the currently available treatment modalities may fail or result in iatrogenic neurologic deterioration. Recent evidence from A Randomized Trial of Unruptured Brain AVM (ARUBA) further deters aggressive approaches that carry a significant risk of treatment-related adverse events. Microsurgical resection, endovascular embolization and SRS all play a role in the treatment of AVM. SRS is an effective therapeutic option for AVM of the thalamus and basal ganglia that are deemed high risk for resection. SRS offers acceptable obliteration rates, with generally lower risks of hemorrhage occurring during the latency period compared to the AVM natural history. Considering that incompletely obliterated lesions still harbor the potential for rupture, additional treatments such as repeat SRS and microsurgical resection should be considered when complete obliteration is not achieved by an initial SRS procedure. Patients with AVM of the basal ganglia and thalamus require continued clinical and radiologic observation and follow-up after SRS, even after angiographic obliteration has been confirmed.

A quantitative analysis of adverse radiation effects following Gamma Knife radiosurgery for arteriovenous malformations

OBJECT The authors review outcomes following Gamma Knife radiosurgery (GKRS) of cerebral arteriovenous malformations (AVMs) and their correlation to postradiosurgery adverse radiation effects (AREs). METHODS From a prospective institutional review board-approved database, the authors identified patients with a minimum of 2 years of follow-up and thin-slice T2-weighted MRI sequences for volumetric analysis. A total of 105 AVM patients were included. The authors analyzed the incidence and quantitative changes in AREs as a function of time after GKRS. Statistical analysis was performed to identify factors related to ARE development and changes in the ARE index. RESULTS The median clinical follow-up was 53.8 months (range 24-212.4 months), and the median MRI follow-up was 36.8 months (range 24-212.4 months). 47.6% of patients had an AVM with a Spetzler-Martin grade ≥ III. The median administered margin and maximum doses were 22 and 40 Gy, respectively. The overall obliteration rate was 70.5%. Of patients who showed complete obliteration, 74.4% developed AREs within 4-6 months after GKRS. Late-onset AREs (i.e., > 12 months) correlated to a failure to obliterate the nidus. 58.1% of patients who developed appreciable AREs (defined as ARE index > 8) proceeded to have a complete nidus obliteration. Appreciable AREs were found to be influenced by AVM nidus volume > 3 ml, lobar location, number of draining veins and feeding arteries, prior embolization, and higher margin dose. On the other hand, a minimum ARE index > 8 predicted obliteration (p = 0.043). CONCLUSIONS ARE development after radiosurgery follows a temporal pattern peaking at 7-12 months after stereotactic radiosurgery. The ARE index serves as an important adjunct tool in patient follow-up and outcome prediction.

The effect of timing of stereotactic radiosurgery treatment of melanoma brain metastases treated with ipilimumab

OBJECTIVE Melanoma represents the third most common cause of CNS metastases. Immunotherapy has evolved as a treatment option for patients with Stage IV melanoma. Stereotactic radiosurgery (SRS) also elicits an immune response within the brain and may interact with immunotherapy. The authors report on a cohort of patients treated for brain metastases with immunotherapy and evaluate the effect of SRS timing on the intracranial response. METHODS All consecutively treated melanoma patients receiving ipilimumab and SRS for treatment of brain metastases at the University of Virginia between 2009 and 2014 were included in this retrospective analysis; data from 46 patients harboring 232 brain metastases were reviewed. The median duration of clinical follow-up was 7.9 months (range 3-42.6 months). The median age of the patients was 63 years (range 24.3-83.6 years). Thirty-two patients received SRS before or during ipilimumab cycles (Group A), whereas 14 patients received SRS after ipilimumab treatment (Group B). Radiographic and clinical responses were assessed at approximately 3-month intervals after SRS. RESULTS The 2 cohorts were comparable in pertinent baseline characteristics with the exception of SRS timing relative to ipilimumab. Local recurrence-free duration (LRFD) was significantly longer in Group A (median 19.6 months, range 1.1-34.7 months) than in Group B patients (median 3 months, range 0.4-20.4 months) (p = 0.002). Post-SRS perilesional edema was more significant in Group A. CONCLUSIONS The effect of SRS and ipilimumab on LRFD seems greater when SRS is performed before or during ipilimumab treatments. The timing of immunotherapy and SRS may affect LRFD and postradiosurgical edema. The interactions between immunotherapy and SRS warrant further investigation so as to optimize the therapeutic benefits and mitigate the risks associated with multimodality, targeted therapy.

Gamma knife radiosurgery in patients with persistent acromegaly or Cushing's disease: long-term risk of hypopituitarism

For patient with a recurrent or residual acromegaly or Cushings disease (CD) after resection, gamma knife radiosurgery (GKRS) is often used. Hypopituitarism is the most common adverse effect after GKRS treatment. The paucity of studies with long‐term follow‐up has hampered understanding of the latent risks of hypopituitarism in patients with acromegaly or CD. We report the long‐term risks of hypopituitarism for patients treated with GKRS for acromegaly or CD.

BRAF V600E mutation and BRAF kinase inhibitors in conjunction with stereotactic radiosurgery for intracranial melanoma metastases

OBJECTIVE Recent advancements in molecular biology have identified the BRAF mutation as a common mutation in melanoma. The wide use of BRAF kinase inhibitor ( BRAFi) in patients with metastatic melanoma has been established. The objective of this study was to examine the impact of BRAF mutation status and use of BRAFi in conjunction with stereotactic radiosurgery (SRS). METHODS This was a single-center retrospective study. Patients charts and electronic records were reviewed for date of diagnosis of primary malignancy, BRAF mutation status, chemotherapies used, date of the diagnosis of CNS metastases, date of SRS, survival, local tumor control after SRS, and adverse events. Patients were divided into 3 groups: Group A, those with mutant BRAF without BRAFi treatment (13 patients); Group B, those with mutant BRAF with BRAFi treatment (17 patients); and Group C, those with wild-type BRAF (35 patients). Within a cohort of 65 patients with the known BRAF mutation status and treated with SRS between 2010 and 2014, 436 individual brain metastases (BMs) were identified. Kaplan-Meier methodology was then used to compare survival based on each binary parameter. RESULTS Median survival times after the diagnosis of melanoma BM and after SRS were favorable in patients with a BRAF mutation and treated with SRS in conjunction with BRAFi (Group B) compared with the patients with wild-type BRAF (Group C, 23 vs 8 months and 13 vs 5 months, respectively; p < 0.01, log-rank test). SRS provided a local tumor control rate of 89.4% in the entire cohort of patients. Furthermore, the local control rate was improved in the patients treated with SRS in conjunction with BRAFi (Group B) compared with patients with wild-type (Group C) or with BRAF mutation but no BRAFi (Group A) as an adjunct treatment for BMs. CONCLUSIONS BRAF mutation status appears to play an important role as a potent prognostic factor in patients harboring melanoma BM. BRAFi in conjunction with SRS may benefit this group of patients in terms of BM survival and SRS with an acceptable safety profile.

Focused ultrasound-aided immunomodulation in glioblastoma multiforme: a therapeutic concept

Patients with glioblastoma multiforme (GBM) exhibit a deficient anti-tumor immune response. Both arms of the immune system were shown to be hampered in GBM, namely the local cellular immunity mediated by the Th1 subset of helper T cells and the systemic humoral immunity mediated by the Th2 subset of helper T cells. Immunotherapy is rapidly becoming one of the pillars of anti-cancer therapy. GBM has not received similar clinical successes as of yet, which may be attributed to its relative inaccessibility (the blood-brain barrier (BBB)), its poor immunogenicity, few characterized cancer antigens, or any of the many other immune mechanisms known to be hampered. Focused ultrasound (FUS) is emerging as a promising treatment approach. The effects of FUS on the tissue are not merely thermal. Mounting evidence suggests that in addition to thermal ablation, FUS induces mechanical acoustic cavitation and immunomodulation plays a key role in boosting the host anti-tumor immune responses. We separately discuss the different pertinent immunosuppressive mechanisms harnessed by GBM and the immunomodulatory effects of FUS. The effect of FUS and microbubbles in disrupting the BBB and introducing antigens and drugs to the tumor milieu is discussed. The FUS-induced pro-inflammatory cytokines secretion and stress response, the FUS-induced change in the intra-tumoral immune-cells populations, the FUS-induced augmentation of dendritic cells activity, and the FUS-induced increased cytotoxic cells potency are all discussed. We next attempt at offering a conceptual synopsis of the synergistic treatment of GBM utilizing FUS and immunotherapy. In conclusion, it is increasingly apparent that no single treatment modality will triumph on GBM. The reviewed FUS-induced immunomodulation effects can be harnessed to current and developing immunotherapy approaches. Together, these may overcome GBM-induced immune-evasion and generate a clinically relevant anti-tumor immune response.

Long-Term Results of Stereotactic Radiosurgery for Skull Base Meningiomas.

BACKGROUND Gamma knife radiosurgery (GKRS) is well established in the management of inaccessible, recurrent, or residual benign skull base meningiomas. Most series report clinical outcome parameters and complications in the short intermediate period after radiosurgery. Reports of long-term tumor control and neurological status are still lacking. OBJECTIVE To report the presentation, treatment, and long-term outcome of skull base meningiomas after GKRS. METHODS From a prospectively collected institutional review board-approved database, we selected patients with a World Health Organization grade I skull base meningioma treated with a single-session GKRS and a minimum of 60 months follow-up. One hundred thirty-five patients, 54.1% males (n = 73), form the cohort. Median age was 54 years (19-80). Median tumor volume was 4.7 cm (0.5-23). Median margin dose was 15 Gy (7.5-36). Median follow-up was 102.5 months (60.1-235.4). Patient and tumor characteristics were assessed to determine the predictors of neurological function and tumor progression. RESULTS At last follow-up, tumor volume control was achieved in 88.1% (n = 119). Post-GKRS clinical improvement or stability was reported in 61.5%. The 5-, 10-, and 15-year actuarial progression-free survival rates were 100%, 95.4%, and 68.8%, respectively. Favorable outcome (both tumor control and clinical preservation/improvement) was attained in 60.8% (n = 79). Pre-GKRS performance status (Karnofsky Performance Scale) was shown to influence tumor progression (P = .001) and post-GKRS clinical improvement/preservation (P = .003). CONCLUSION GKRS offers a highly durable rate of tumor control for World Health Organization grade I skull base meningiomas, with an acceptably low incidence of neurological deficits. The Karnofsky Performance Scale at the time of radiosurgery serves as a reliable long-term predictor of overall outcome. ABBREVIATIONS ARE, adverse radiation effectGKRS, Gamma knife radiosurgeryKPS, Karnofsky Performance ScaleWHO, World Health Organization.

Glioblastoma multiforme targeted therapy: The Chlorotoxin story

Glioblastoma multiforme (GBM) is the most common malignant primary brain neoplasm having a mean survival of <24months. Scorpion toxins are considered promising cancer drug candidates, primarily due to the discovery of hlorotoxin, derived from the venom of the Israeli yellow scorpion. This intriguing short peptide of only 36 amino-acids length and tight configuration, possess the ability to bind to GBM cells in a grade-related manner with ∼100% of GBM cells staining positive and no cross reactivity to normal brain. Chlorotoxin has an anti-angiogenic effect as well. Molecular targets for Chlorotoxin include voltage gated chloride channels (GCC), calcium-dependent phospholipid-binding protein Annexin-2, and the inducible extracellular enzyme Matrix Metalloproteinase-2 (MMP-2). Of all its targets, MMP-2 seems to bear the most anti-neoplastic potential. Chlorotoxin is a promising tumortargeting peptide. Its small size and compact shape are convenient for intracranial delivery. We present a short discussion on Chlorotoxin. The structure, biological activity, molecular targets and possible clinical role of Chlorotoxin are discussed. Chlorotoxin can be utilized as a targeting domain as well, attaching different effector functions to it. Clinical applications in GBM therapy, intraoperative imaging, nano-probes and nano-vectors based technology; targeted chemotherapy and immunotherapy are discussed as well. Chlorotoxin is likely to play a significant role in effective GBM immunotherapy in the future.

Volume-staged versus dose-staged stereotactic radiosurgery outcomes for large brain arteriovenous malformations: a systematic review

OBJECTIVE Several recent studies have improved our understanding of the outcomes of volume-staged (VS) and dose-staged (DS) stereotactic radiosurgery (SRS) for the treatment of large (volume > 10 cm3) brain arteriovenous malformations (AVMs). In light of these recent additions to the literature, the aim of this systematic review is to provide an updated comparison of VS-SRS and DS-SRS for large AVMs. METHODS A systematic review of the literature was performed using PubMed to identify cohorts of 5 or more patients with large AVMs who had been treated with VS-SRS or DS-SRS. Baseline data and post-SRS outcomes were extracted for analysis. RESULTS A total of 11 VS-SRS and 10 DS-SRS studies comprising 299 and 219 eligible patients, respectively, were included for analysis. The mean obliteration rates for VS-SRS and DS-SRS were 41.2% (95% CI 31.4%-50.9%) and 32.3% (95% CI 15.9%-48.8%), respectively. Based on pooled individual patient data, the outcomes for patients treated with VS-SRS were obliteration in 40.3% (110/273), symptomatic radiation-induced changes (RICs) in 13.7% (44/322), post-SRS hemorrhage in 19.5% (50/256), and death in 7.4% (24/323); whereas the outcomes for patients treated with DS-SRS were obliteration in 32.7% (72/220), symptomatic RICs in 12.2% (31/254), post-SRS hemorrhage in 10.6% (30/282), and death in 4.6% (13/281). CONCLUSIONS Volume-staged SRS appears to afford higher obliteration rates than those achieved with DS-SRS, although with a less favorable complication profile. Therefore, VS-SRS or DS-SRS may be a reasonable treatment approach for large AVMs, either as stand-alone therapy or as a component of a multimodality management strategy.

Stereotactic radiosurgery and immunotherapy for metastatic spinal melanoma

The management of metastatic spinal melanoma involves maximizing local control, preventing recurrence, and minimizing treatment-associated toxicity and spinal cord damage. Additionally, therapeutic measures should promote mechanical stability, facilitate rehabilitation, and promote quality of life. These objectives prove difficult to achieve given melanomas elusive nature, radioresistant and chemoresistant histology, vascular character, and tendency for rapid and early metastasis. Different therapeutic modalities exist for metastatic spinal melanoma treatment, including resection (definitive, debulking, or stabilization procedures), stereotactic radiosurgery, and immunotherapeutic techniques, but no single treatment modality has proven fully effective. The authors present a conceptual overview and critique of these techniques, assessing their effectiveness, separately and combined, in the treatment of metastatic spinal melanoma. They provide an up-to-date guide for multidisciplinary treatment strategies. Protocols that incorporate specific, goal-defined surgery, immunotherapy, and stereotactic radiosurgery would be beneficial in efforts to maximize local control and minimize toxicity.