Christopher P. Cifarelli

Cranial nerve dysfunction following Gamma Knife surgery for pituitary adenomas: long-term incidence and risk factors.

OBJECT Gamma Knife surgery (GKS) has become a significant component of neurosurgical treatment for recurrent secretory and nonsecretory pituitary adenomas. Although the long-term risks of visual dysfunction following microsurgical resection of pituitary adenomas has been well studied, the comparable risk following radiosurgery is not well defined. This study evaluates the long-term risks of ophthalmological dysfunction following GKS for recurrent pituitary adenomas. METHODS An analysis of 217 patients with recurrent secretory (n = 131) and nonsecretory (n = 86) pituitary adenomas was performed to determine the incidence of and risk factors for subsequent development of visual dysfunction. Patients underwent ophthalmological evaluation as part of post-GKS follow-up to assess for new or worsened cranial nerve II, III, IV, or VI palsies. The median follow-up duration was 32 months. The median maximal dose was 50 Gy, and the median peripheral dose was 23 Gy. A univariate analysis was performed to assess for risk factors of visual dysfunction post-GKS. RESULTS Nine patients (4%) developed new visual dysfunctions, and these occurred within 6 hours to 34 months following radiosurgery. None of these 9 patients had tumor growth on post-GKS neuroimaging studies. Three of these patients had permanent deficits whereas in 6 the deficits resolved. Five of the 9 patients had prior GKS or radiotherapy, which resulted in a significant increase in the incidence of cranial nerve dysfunction (p = 0.0008). An increased number of isocenters (7.1 vs 5.0, p = 0.048) was statistically related to the development of visual dysfunction. Maximal dose, margin dose, optic apparatus dose, tumor volume, cavernous sinus involvement, and suprasellar extension were not significantly related to visual dysfunction (p >0.05). CONCLUSIONS Neurological and ophthalmological assessment in addition to routine neuroimaging and endocrinological follow-up are important to perform following GKS. Patients with a history of radiosurgery or radiation therapy are at higher risk of cranial nerve deficits. Also, a reduction in the number of isocenters delivered, along with volume treated, particularly in the patients with secretory tumors, appears to be the most reasonable strategy to minimize the risk to the visual system when treating recurrent pituitary adenomas with stereotactic radiosurgery.

Effect of trans sodium crocetinate on brain tumor oxgenation: Laboratory investigation

OBJECT Glioblastoma multiforme tumors typically exhibit regions of hypoxia. Hypoxic regions within the tumor make cells less sensitive to radiosurgery and radiation therapy. Trans sodium crocetinate (TSC) has been shown to be a radiosensitizer. The goal of this research was to elucidate the underlying mechanism of TSCs radiosensitizing effect. METHODS A rat C6 glioma model was used. The C6 glioma cells were stereotactically injected into the rat brain to create a tumor. Two weeks later, MR imaging was used to confirm the presence of a glioma. Following demonstration on MR imaging of a brain tumor, animals were randomized into 1 of 2 groups: 1) TSC alone (100 microg/kg), or 2) saline control. Licox probes were inserted into the brain tumor and contralateral cerebral hemisphere. Tissue oxygenation measurements were recorded before and after intravenous infusion of either TSC or saline. RESULTS Not surprisingly, tissue oxygenation measurements revealed that the brain tumor was hypoxic relative to the contralateral cerebral hemisphere brain tissue. Two to 8 minutes after TSC was infused, tissue oxygenation measurements in the brain tumor increased above baseline by as much as 60%. After this temporary elevation following TSC infusion, tumor oxygenation measurements returned to baseline. No significant elevations in tissue oxygenation were seen on the contralateral side. Similarly, the saline vehicle was not observed to increase tissue oxygenation in either the brain tumor or the contralateral brain tissue. CONCLUSIONS Administration of TSC transiently improves tissue oxygenation in hypoxic gliomas. Such an effect is one potential mechanism for the radiosensitization previously observed after addition of TSC.

Trans-sodium crocetinate enhancing survival and glioma response on magnetic resonance imaging to radiation and temozolomide

OBJECT Glioblastoma (GB) tumors typically exhibit regions of hypoxia. Hypoxic areas within the tumor can make tumor cells less sensitive to chemotherapy and radiation therapy. Trans-sodium crocetinate (TSC) has been shown to transiently increase oxygen to hypoxic brain tumors. The authors examined whether this improvement in intratumor oxygenation translates to a therapeutic advantage when delivering standard adjuvant treatment to GBs. METHODS The authors used C6 glioma cells to create a hypoxic GB model. The C6 glioma cells were stereotactically injected into the rat brain to create a tumor. Fifteen days later, MR imaging was used to confirm the presence of a glioma. The animals were randomly assigned to 1 of 3 groups: 1) temozolomide alone (350 mg/m(2)/day for 5 days); 2) temozolomide and radiation therapy (8 Gy); or 3) TSC (100 microg/kg for 5 days), temozolomide, and radiation therapy. Animals were followed through survival studies, and tumor response was assessed on serial MR images obtained at 15-day intervals during a 2-month period. RESULTS Mean survival (+/- SEM) of the temozolomide-alone and the temozolomide/radiotherapy groups was 23.2 +/- 0.9 and 29.4 +/- 4.4 days, respectively. Mean survival in the TSC/temozolomide/radiotherapy group was 39.8 +/- 6 days, a statistically significant improvement compared with either of the other groups (p < 0.05). Although tumor size was statistically equivalent in all groups at the time of treatment initiation, the addition of TSC to temozolomide and radiotherapy resulted in a statistically significant reduction in the MR imaging-documented mean tumor size at 30 days after tumor implantation. The mean tumor size in the TSC/temozolomide/radiotherapy group was 18.9 +/- 6.6 mm(2) compared with 42.1 +/- 2.7 mm(2) in the temozolomide-alone group (p = 0.047) and 35.8 +/- 5.1 mm(2) in the temozolomide/radiation group (p = 0.004). CONCLUSIONS In a hypoxic GB model, TSC improves the radiological and clinical effectiveness of temozolomide and radiation therapy. Further investigation of this oxygen diffusion enhancer as a radiosensitizer for hypoxic brain tumors seems warranted.

Cadherin-dependent adhesion of human U373MG glioblastoma cells promotes neurite outgrowth and increases migratory capacity. Laboratory investigation.

OBJECT The current management of primary CNS tumors involves a multimodal approach, incorporating cytoreductive techniques including resection, radiotherapy, and antiproliferative chemotherapeutic agents. Despite these attempts, the majority of patients with a diagnosis of a high-grade glioma have a dismal prognosis, with the leading cause of treatment failure and tumor recurrence attributable to local invasion of adjacent brain parenchyma. The current study examines the capacity of glioma tumor cells to undergo neurite outgrowth and local migration, specifically focusing on the role of the cadherin cell adhesion system. METHODS Using a recombinant cadherin ectodomain protein, U373MG human glioblastoma cells were assessed for their ability to adhere and migrate in a cadherin-dependent manner in culture. Adhesion was evaluated via growth assessment and neurite length at 72 hours growth on an immobilized cadherin substrate and compared with other matrix adhesion proteins, such as Type IV collagen and vitronectin. Migratory capacity was measured via modified transwell assays, also using recombinant cadherin ectodomain in comparison with collagen and vitronectin. Results Cadherin adherent cells adopt a fasciculated morphology, with a significant increase in neurite extension, measuring 104 ± 13.3 μm in length, compared with background adhesion on bovine serum albumin and nonfunctional cadherin ectodomain controls measuring 55 ± 4.4 and 47 ± 3.84 μm, respectively (p = 0.029). Significant increases in neurite length compared with controls were also observed in the vitronectin (81 ± 4.69 μm) and Type IV collagen (91 ± 7.7 μm) groups (p = 0.017 and 0.025, respectively). With respect to migration, U373 cells demonstrate increased invasion in response to cadherin ectodomain exposure, whereas vitronectin and Type IV collagen were not potent initiators of migration through the transwell barrier. Both adhesion and migration outcomes were noted in the absence of any relative changes in cell proliferation, indicating a primary role for the cadherin-based adhesion system in tumor invasion. CONCLUSIONS Cadherin-based adhesion promotes increased adhesion, neurite outgrowth, and migration in human U373MG glioblastoma cells, providing a novel area of research for the development of therapeutic targets addressing local tumor invasion.

Stereotactic Radiosurgery for Acromegaly: An International Multicenter Retrospective Cohort Study

BACKGROUND Stereotactic radiosurgery (SRS) is a treatment option for persistent or recurrent acromegaly secondary to a growth hormone secreting pituitary adenoma, but its efficacy is inadequately defined. OBJECTIVE To assess, in a multicenter, retrospective cohort study, the outcomes of SRS for acromegaly and determine predictors. METHODS We pooled and analyzed data from 10 participating institutions of the International Gamma Knife Research Foundation for patients with acromegaly who underwent SRS with endocrine follow-up of ≥6 mo. RESULTS The study cohort comprised 371 patients with a mean endocrine follow-up of 79 mo. IGF-1 lowering medications were held in 56% of patients who were on pre-SRS medical therapy. The mean SRS treatment volume and margin dose were 3.0 cm3 and 24.2 Gy, respectively. The actuarial rates of initial and durable endocrine remission at 10 yr were 69% and 59%, respectively. The mean time to durable remission after SRS was 38 mo. Biochemical relapse after initial remission occurred in 9%, with a mean time to recurrence of 17 mo. Cessation of IGF-1 lowering medication prior to SRS was the only independent predictor of durable remission (P = .01). Adverse radiation effects included the development of ≥1 new endocrinopathy in 26% and ≥1 cranial neuropathy in 4%. CONCLUSION SRS is a definitive treatment option for patients with persistent or recurrent acromegaly after surgical resection. There appears to be a statistical association between the cessation of IGF-1 lowering medications prior to SRS and durable remission.

Gamma Knife Radiosurgery for Arteriovenous Malformations Using a Four-Dimensional Dynamic Volume Computed Tomography Angiography Planning System as an Alternative to Traditional Catheter Angiogram

Background Gamma knife radiosurgery (GKRS) remains a critical intervention in the long-term management of arteriovenous malformations (AVMs). For planning a treatment, identification of the nidus is essential, and it is dependent on high-resolution blood flow imaging, usually in the form of a traditional angiogram. The development of dynamic 320-slice computed tomography (CT) angiography has offered a noninvasive alternative to intra-arterial fluoroscopic imaging, and it is capable of providing equivalent temporal resolution. In this study, we describe the feasibility of using four-dimensional CT angiography (4D-CTA) in GKRS planning for AVM treatment and a comparative analysis with a traditional angiogram. Methods A retrospective review was performed on AVM patients treated via GKRS with a 4D-CTA prior to the day of treatment, on the day of treatment, or with a day-of-treatment angiogram. Treatment times, along with total times in the Leksell® coordinate frame G, were obtained from the medical records. The frame-on time was calculated by subtracting the treatment time from the total time starting from application to removal, and the statistical analysis was performed across groups using analysis of variance (ANOVA). All treatments were performed on the Perfexion™ model with a dynamic flow imaging procured via a 320-slice CT scanner or traditional angiography platform. Results Some 27 patients underwent a total of 29 GKRS procedures for AVM treatment at our institution between September 2011 and January 2017. Mean age at the time of treatment was 35.5 (6-65) years, and male:female ratio was 5:4. Some 12 patients had 4D-CTA performed prior to the day of treatment, eight patients had the same CTA completed after frame placement on the day of treatment, while seven patients underwent traditional angiography. The mean frame-on times of each group were 190, 336, and 426 minutes, respectively (p < 0.0001). No procedures were aborted based on the image quality. Conclusions 4D-CTA is an effective tool in identifying the AVM nidus for GKRS planning. These studies can be performed prior to the day of treatment, allowing for a significant reduction in frame-on time and eliminating the risk of angiogram complication on the day of GKRS.

Efficacy of Stereotactic Radiosurgery in Patients with Multiple Metastases: Importance of Volume Rather Than Number of Lesions

The role of stereotactic radiosurgery (SRS) in the treatment of multiple brain metastases is controversial. While whole brain radiation therapy (WBRT) has historically been the mainstay of treatment, its value is increasingly being questioned as emerging data supports that SRS alone can provide comparable therapeutic outcomes for limited (one to three) intracranial metastases with fewer adverse effects, including neurocognitive decline. Multiple recent studies have also demonstrated that patients with multiple (> 3) intracranial metastases with a low overall tumor volume have a favorable therapeutic response to SRS, with no significant difference compared to patients with limited metastases. Herein, we present a patient with previously controlled breast cancer who presented with multiple recurrences of intracranial metastases but low total intracranial tumor volume each time. This patient underwent SRS alone for a total of 40 metastatic lesions over three separate procedures with good local control and without any significant cognitive toxicity. The patient eventually opted for enrollment in the NRG-CC001 clinical trial after multiple cranial recurrences. She received conventional WBRT with six months of memantine and developed significant neurocognitive side effects. This case highlights the growing body of literature supporting the role of SRS alone in the management of multiple brain metastases and the importance of maximizing neurocognition as advances in systemic therapies prolong survival in Stage IV cancer.