Loss of LCMT1 and biased protein phosphatase 2A heterotrimerization drive prostate cancer progression and therapy resistance.

Loss of the tumor suppressive activity of the protein phosphatase 2A (PP2A) is associated with cancer, but the underlying molecular mechanisms are unclear. PP2A holoenzyme comprises a heterodimeric core, a scaffolding A subunit and a catalytic C subunit, and one of over 20 distinct substrate-directing regulatory B subunits. Methylation of the C subunit regulates PP2A heterotrimerization, affecting B subunit binding and substrate specificity. Here, we report that the leucine carboxy methyltransferase (LCMT1), which methylates the L309 residue of the C subunit, acts as a suppressor of androgen receptor (AR) addicted prostate cancer (PCa). Decreased methyl-PP2A-C levels in prostate tumors is associated with biochemical recurrence and metastasis. Silencing LCMT1 increases AR activity and promotes castration-resistant prostate cancer growth. LCMT1-dependent methyl-sensitive AB56αCme heterotrimers target AR and its critical coactivator MED1 for dephosphorylation, resulting in the eviction of the AR-MED1 complex from chromatin and loss of target gene expression. Mechanistically, LCMT1 is regulated by S6K1-mediated phosphorylation-induced degradation requiring the ß-TRCP, leading to acquired resistance to anti-androgens. Finally, feedforward stabilization of LCMT1 by small molecule activator of phosphatase (SMAP) results in attenuation of AR-signaling and tumor growth inhibition in anti-androgen refractory PCa. These findings highlight methyl-PP2A-C as a prognostic marker and that the loss of LCMT1 is a major determinant in AR-addicted PCa, suggesting therapeutic potential for AR degraders or PP2A modulators in prostate cancer treatment.

Effect of trans sodium crocetinate on brain tumor oxygenation. 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 TSC's 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.

Interstitial Pulmonary Edema Assessed by Lung Ultrasound on Ascent to High Altitude and Slight Association with Acute Mountain Sickness: A Prospective Observational Study.

Background: Acute mountain sickness (AMS) is a common disease that may have a pulmonary component, as suggested by interstitial pulmonary edema quantified by the B-line score (BLS) on ultrasound (US). This subclinical pulmonary edema has been shown to increase with ascent to high altitude and AMS severity, but has not been prospectively associated with AMS incidence in a large prospective study. Materials and Methods: This prospective observational study was part of a randomized controlled trial enrolling healthy adults over four weekends ascending White Mountain, California. Subjects were assessed by lung US and the Lake Louise Questionnaire at 4110 ft (1240 m), upon ascent to 12,500 ft (3810 m), and the next morning at 12,500 ft (3810 m). Results: Three hundred five USs in total were completed on 103 participants, with 73% total incidence of AMS. The mean (±standard deviation) BLS increased from baseline (1.15 ± 1.80) to high altitude (2.56 ± 2.86), a difference of 1.37 (±2.48) (p = 0.04). Overall BLS was found, on average, to be higher among those diagnosed with AMS than without (2.97 vs. 2.0, p = 0.04, 95% confidence interval [CI] -∞ to -0.04). The change in BLS (ΔBLS) from low altitude baseline was significantly associated with AMS (0.88 vs. 1.72, r2 = 0.023, 95% CI -∞ to -0.01, p = 0.048). Conclusions: Interstitial subclinical pulmonary edema by lung US was found to have a small but significant association with AMS.

Evaluation of the role of Gamma Knife surgery in the treatment of craniopharyngiomas.

The management of craniopharyngioma involves balancing adequate reduction in tumor volume and prevention of recurrence while minimizing damage to delicate surrounding structures. Because of the lesion's proximity to the optic chiasm and its relationship to the hypothalamic-pituitary axis, morbidity rates following treatment can be high. Gamma Knife surgery (GKS) is now being considered as a viable method of providing tumor control while ensuring minimal side effects. The authors conducted a literature review of 10 studies in which GKS was used to treat craniopharyngioma; some lesions had been previously treated and some had not. The mean marginal dose ranged from 5 to 16.4 Gy (mean 12.3 Gy). Tumor control was achieved in 75% of cases overall and varied with tumor subtype (cystic, solid, mixed). Control was seen in 90% of solid, 80% of cystic, and 59% of mixed tumors. The overall morbidity rate resulting from radiosurgery was 4% and the overall mortality rate was 0.5%. These results suggest that GKS may provide a favorable benefit-to-risk profile for many patients with craniopharyngiomas.

Temozolomide-induced inhibition of pituitary adenoma cells.

OBJECT: Aggressive pituitary adenomas frequently require multimodality treatment including pituitary-suppressive medications, microsurgery, and radiation therapy or radiosurgery. The effectiveness of temozolomide in terms of growth suppression and decreased hormonal production is evaluated. METHODS: Three pituitary adenoma cell lines--MMQ, GH3, and AtT20--were used. A dose escalation of temozolomide was performed for each cell line, and inhibition of cell proliferation was assessed using an MTT assay. Concentrations of temozolomide that produced statistically significant inhibition of cell proliferation for each cell type were identified. Extent of apoptosis for each selected temozolomide concentration was studied using TUNEL staining. The effect of temozolomide on prolactin secretion in MMQ and GH3 cells was also measured via ELISA. RESULTS: Significant inhibition of cell proliferation was noted for MMQ and GH3 cells at a concentration of 250 µM temozolomide. The AtT20 cells demonstrated statistically significant cell inhibition at a concentration of only 50 µM temozolomide (p < 0.05). Apoptosis significantly increased in all cell lines in as little as 24 hours of incubation at the respective temozolomide concentrations (p < 0.05). Prolactin secretion in the prolactin secreting MMQ and GH3 cell lines was inhibited by 250 µM temozolomide. CONCLUSIONS: Temozolomide inhibits cell proliferation and induces apoptotic cell death in aggressive pituitary adenoma cells. A reduction in hormonal secretion in prolactinoma cells was also afforded by temozolomide. Temozolomide may prove useful in the multimodality management of aggressive pituitary adenomas.

Gamma knife radiosurgery of tentorial meningiomas.

OBJECTIVE: Tentorial meningiomas are complex lesions that may not always be completely resected without significant morbidity or mortality. In this study, we evaluate the outcomes of tentorial meningiomas treated with Gamma Knife radiosurgery (GKRS). METHODS: We performed a retrospective review of a prospectively compiled database evaluating the outcomes of 35 patients with tentorial meningiomas treated at the University of Virginia from 1990 to 2006. There were 29 females and 6 males with a median age of 60 years (range 21-82). Twenty were treated with primary radiosurgery, and 15 patients were treated with adjuvant radiosurgery after surgical resection. Patients were assessed clinically and radiologically at routine intervals following GKRS. Kaplan-Meier analysis was used to assess tumor progression. RESULTS: The mean follow-up was 5 years (range 2-16 years). The mean pre-radiosurgery tumor volume was 5.1 cc (range 0.7-27.3cc). At last follow-up, 31 patients (89%) displayed either no growth or a decrease in tumor volume. Four (11%) patients displayed an increase in volume. Kaplan Meier analysis demonstrated radiographic progression free survival at 3, 5, and 10 years to be 96%, 91%, and 73% respectively. At the last clinical follow-up, 33 patients (94%) demonstrated no change or improvement in their neurological condition and 2 patients clinically declined (6%). CONCLUSION: GKRS offers an acceptable rate of tumor control for tentorial meningiomas, and accomplishes this with a low incidence of new or worsening neurological deficits.

Timing and risk factors for new brain metastasis formation in patients initially treated only with Gamma Knife surgery. Clinical article.

OBJECT: Stereotactic radiosurgery has been shown to afford a reasonable chance of local tumor control. However, new brain metastasis can arise following successful local tumor control from radiosurgery. This study evaluates the timing, number, and risk factors for development of subsequent new brain metastasis in a group of patients treated with stereotactic radiosurgery alone. METHODS: One hundred seventeen patients with histologically confirmed metastatic cancer underwent Gamma Knife surgery (GKS) to treat all brain metastases demonstrable on MR imaging. Patients were followed clinically and radiologically at approximately 3-month intervals for a median of 14.4 months (range 0.37-51.8 months). Follow-up MR images were evaluated for evidence of new brain metastasis formation. Statistical analyses were performed to determine the timing, number, and risk factors for development of new brain metastases. RESULTS: The median time to development of a new brain metastasis was 8.8 months. Patients with 3 or more metastases at the time of initial radiosurgery or those with cancer histologies other than non-small cell lung carcinoma were found to be at increased risk for early formation of new brain metastasis (p < 0.05). The mean number of new metastases per patient was 1.6 (range 0-11). Those with a higher Karnofsky Performance Scale score at the time of initial GKS were significantly more likely to develop a greater number of brain metastases by the last follow-up evaluation. CONCLUSIONS: The timing and number of new brain metastases developing in patients treated with GKS alone is not inconsequential. Those with 3 or more metastases at the time of radiosurgery and those with cancer histology other than non-small cell lung carcinoma were at greater risk of early formation of new brain metastasis. Frequent follow-up evaluations, such as at 3-month intervals, appears appropriate in this patient population, particularly in high-risk patients. When detected early, salvage treatments including repeat radiosurgery can be used to treat new brain metastasis.

Gamma Knife surgery for parasellar meningiomas: long-term results including complications, predictive factors, and progression-free survival.

OBJECT: Stereotactic radiosurgery serves as an important primary and adjuvant treatment option for patients with many types of intracranial meningiomas. This is particularly true for patients with parasellar meningiomas. In this study, the authors evaluated the outcomes of Gamma Knife surgery (GKS) used to treat parasellar meningiomas. METHODS: The study is a retrospective review of the outcomes in 138 patients with meningiomas treated at the University of Virginia from 1989 to 2006; all patients had a minimum follow-up of 24 months. There were 31 men and 107 women whose mean age was 54 years (range 19-85 years). Eighty-four patients had previously undergone resection. The mean pre-GKS tumor volume was 7.5 ml (range 0.2-54.8 ml). Clinical and radiographic evaluations were performed, and factors related to favorable outcomes in each case were assessed. RESULTS: The mean follow-up duration was 84 months (median 75.5 months, range 24-216 months). In 118 patients (86%), the tumor volume was unchanged or had decreased at last follow-up. Kaplan-Meier analysis demonstrated radiographic progression-free survival at 5 and 10 years to be 95.4% and 69%, respectively. Fourteen patients (10%) developed new cranial nerve palsies following GKS. Factors associated with tumor control included younger age, a higher isodose, and smaller tumor volume. A longer follow-up duration was associated with either a decrease or increase in tumor volume. Fourteen patients (10%) experienced new or worsening cranial nerve deficits after treatment. Factors associated with this occurrence were larger pretreatment tumor volume, lower peripheral radiation dose, lower maximum dose, tumor progression, and longer follow-up. CONCLUSIONS: Gamma Knife surgery offers an acceptable rate of tumor control for parasellar meningiomas and accomplishes this with a low incidence of neurological deficits. Radiological control after radiosurgery is more likely in those patients with a smaller tumor volume and a higher prescription dose.

Gamma Knife surgery of meningiomas located in the posterior fossa: factors predictive of outcome and remission.

OBJECT: Although numerous studies have analyzed the role of stereotactic radiosurgery for intracranial meningiomas, few studies have assessed outcomes of posterior fossa meningiomas after stereotactic radiosurgery. In this study, the authors evaluate the outcomes of posterior fossa meningiomas treated with Gamma Knife surgery (GKS). The authors also assess factors predictive of new postoperative neurological deficits and tumor progression. METHODS: A retrospective review was performed of a prospectively compiled database documenting the outcomes of 152 patients with posterior fossa meningiomas treated at the University of Virginia from 1990 to 2006. All patients had a minimum follow-up of 24 months. There were 30 males and 122 females, with a median age of 58 years (range 12-82 years). Seventy-five patients were treated with radiosurgery initially, and 77 patients were treated with GKS after resection. Patients were assessed clinically and radiographically at routine intervals following GKS. Factors predictive of new neurological deficit following GKS were assessed via univariate and multivariate analysis, and Kaplan-Meier analysis and Cox multivariate regression analysis were used to assess factors predictive of tumor progression. RESULTS: Patients had meningiomas centered over the tentorium (35 patients, 23%), cerebellopontine angle (43 patients, 28%), petroclival region (28 patients, 18%), petrous region (6 patients, 4%), and clivus (40 patients, 26%). The median follow-up was 7 years (range 2-16 years). The mean preradiosurgical tumor volume was 5.7 cm(3) (range 0.3-33 cm(3)), and mean postradiosurgical tumor volume was 4.9 cm(3) (range 0.1-33 cm(3)). At last follow-up, 55 patients (36%) displayed no change in tumor volume, 78 (51%) displayed a decrease in volume, and 19 (13%) displayed an increase in volume. Kaplan-Meier analysis demonstrated radiographic progression-free survival at 3, 5, and 10 years to be 98%, 96%, and 78%, respectively. In Cox multivariable analysis, pre-GKS covariates associated with tumor progression included age greater than 65 years (hazard ratio [HR] 3.24, 95% CI 1.12-9.37; p = 0.03) and a low dose to the tumor margin (HR 0.76, 95% CI 0.60-0.97; p = 0.03), and post-GKS covariates included shunt-dependent hydrocephalus (HR 25.0, 95% CI 3.72-100.0; p = 0.001). At last clinical follow-up, 139 patients (91%) demonstrated no change or improvement in their neurological condition, and 13 patients showed symptom deterioration (9%). In multivariate analysis, the only factors predictive of new or worsening symptoms were clival or petrous location (OR 4.0, 95% CI 1.1-13.7; p = 0.03). CONCLUSIONS: Gamma Knife surgery offers an acceptable rate of tumor control for posterior fossa meningiomas and accomplishes this with a low incidence of neurological deficits. In patients selected for GKS, tumor progression is associated with age greater than 65 years and decreasing dose to the tumor margin. Clival- or petrous-based locations are predictive of an increased risk of new or worsening neurological deficit following GKS.

Gamma Knife surgery for arteriovenous malformations in children.

OBJECT: The aim of this study was to evaluate the long-term imaging and clinical outcomes of intracranial arteriovenous malformations (AVMs) in children treated with Gamma Knife surgery (GKS). METHODS: Between 1989 and 2007, 200 patients with AVMs who were 18 years of age or younger were treated at the University of Virginia Health System. Excluding 14 patients who had not reached 2-year follow-up, 186 patients comprised this study. Hemorrhage was the most common presenting symptom leading to the diagnosis of AVMs (71.5%). The mean nidus volume was 3.2 cm(3) at the time of GKS, and a mean prescription dose of 21.9 Gy was used. RESULTS: After initial GKS, 49.5% of patients achieved total angiographic obliteration. Forty-one patients whose AVM nidi remained patent underwent additional GKS. The obliteration rate increased to 58.6% after a second or multiple GKS. Subtotal obliteration was achieved in 9 patients (4.8%). Forty-nine patients (26.3%) still had a patent residual nidus. In 19 patients (10.2%), obliteration was confirmed on MR imaging only. Ten patients had 17 hemorrhages during the follow-up period. The hemorrhage rate was 5.4% within 2 years after GKS and 0.8% between 2 and 5 years. Six patients developed neurological deficits along with the radiation-induced changes. Two patients developed asymptomatic meningiomas 10 and 12 years after GKS. After a mean clinical follow-up of 98 months, less than 4% of patients had difficulty attending school or developing a career. CONCLUSIONS: Gamma Knife surgery offers a reasonable chance of obliteration of an AVM in pediatric patients. The incidence of symptomatic radiation-induced changes is relatively low; however, long-term clinical and imaging follow-up is required to identify delayed cyst formation and secondary tumors.

Gamma knife radiosurgery of meningiomas involving the foramen magnum.

BACKGROUND: Foramen magnum meningiomas represent a challenging clinical entity. Although resection is performed for those with a mass effect, complete resection is not always feasible. For some patients, stereotactic radiosurgery may be used as the primary treatment modality. We evaluatedthe long-term outcome of Gamma Knife radiosurgery (GKRS) for the treatment of patientswith a foramen magnum meningioma. MATERIALS AND METHODS: Between 1991 and 2005, 222 patients with a meningioma in the posterior fossa were treated with GKRS at the University of Virginia. Of these patients, 5 had meningiomas involving the foramen magnum. At the time of GKRS, the median age of the patients was 60 years (range, 51-78). Three patients were treated with radiosurgery following an initial resection and 2 were treated with upfront radiosurgery. The patients were assessed clinically and radiologically at routine intervals following GKRS. RESULTS: The median tumor volume was 6.8 cc (range 1.9-17 cc). The GKRS tumor received a marginal dose of 12 Gy (range 10-15), and the median number of isocenters was 5 (range 3-19). The mean follow-up was 6 years (range 4-13). One lesion increased in size following GKRS requiring a second treatment, resulting in size stabilization. At the time of the last follow-up, all meningiomas had either demonstrated no growth (n = 4) or reduction in size (n = 1). No patients experienced post-radiotherapy complications. CONCLUSIONS: GKRS affords a high rate of tumor control and preservation of neurologic function for patients with foramen magnum meningiomas. Further study of its role in the neurosurgical management of such patients seems warranted.

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.