Longitudinal evaluation of neurocognitive function after treatment for central nervous system germ cell tumors in childhood.

BACKGROUND: Central nervous system germ cell tumors (CNS GCT) are typically localized to midline structures of the brain, including the pineal and suprasellar/pituitary regions. Management of these tumors depends on underlying histology (germinoma or nongerminomatous germ cell tumor). Knowledge about neurocognitive outcome in these patients is limited. Longitudinal neurocognitive outcome in CNS GCT patients seen for neuropsychological evaluation at a single institution was explored. METHODS: Thirty-five patients were seen for neurocognitive evaluation after diagnosis and treatment for a CNS GCT. Mean age at diagnosis was 11.66 years. Tumor location was suprasellar in 12 patients, pineal in 9, bifocal in 10, multifocal in 3, and thalamic in 1. Standardized cognitive tests of intelligence, receptive language, visual-motor ability, memory, and academic achievement were administered. Longitudinal and cross-sectional analyses were conducted. RESULTS: Intelligence, academic functioning, and receptive vocabulary were not significantly compromised in most patients treated for CNS GCT. Working memory, information processing speed, and visual memory declined significantly over time in all patients. Patients with pineal tumors showed early and stable deficits, whereas patients with suprasellar and bifocal tumors showed more protracted declines from initial average functioning. Patients treated with ventricular versus craniospinal radiation displayed better outcome. CONCLUSIONS: Although general cognitive abilities appeared stable and intact after treatment for most children with CNS GCT, a significant decline over time in working memory, processing speed, and visual memory was evident. Tumor location appeared to be important in understanding the trajectory of stability and decline in CNS GCT patients, as did radiation field.

Role of mTOR Inhibitors in Growth Hormone-Producing Pituitary Adenomas Harboring Different FGFR4 Genotypes.

Pituitary adenomas (PAs) are common intracranial lesions. Available medical therapies are limited in PAs, and therefore, it is essential to identify treatments that control PA growth when surgery is not an option. Fibroblast growth factor 4 is implicated in PA pathogenesis; therefore, in this study, we used an isogenic mammosomatotroph cell line (GH4C1) harboring different fibroblast growth factor receptor (FGFR)-4 genotypes to establish and characterize intracranial xenograft mouse models that can be used for preclinical drug testing. We show that proliferating GH4C1 tumors have an average latency of 3 weeks to form. Histological analysis revealed that prototypic FGFR4 (G388) tumors express increased prolactin and less GH, whereas tumors possessing the polymorphic variant of FGFR4 (R388) express increased GH relative to prolactin. All tumors show abundant mammalian target of rapamycin (mTOR) signaling as confirmed using phosphorylated (p)-S6 and p-4E-binding protein 1 as downstream regulators of this pathway. We subsequently demonstrate that the mTOR inhibitor RAD001 decreases tumor growth rate and reduces p-S6 but not p-4E-binding protein 1 activation, regardless of FGFR4 status. More importantly, GH activity was significantly reduced after mTOR inhibition in the R388 polymorphic variant tumors. This reduction was also associated with a concomitant reduction in serum IGF-1 levels in the R388 group. In summary, we demonstrate that the GH4C1 FGFR polymorphic xenograft is a useful model for examining PAs. Furthermore, we show that RAD001 can efficiently reduce tumor growth rate by a reduction in mTOR signaling and more importantly results in control of GH expression and IGF-1 secretion, providing further support for using mTOR inhibitors in PA patients, in particular GH-producing adenomas.

Null cell adenomas of the pituitary gland: an institutional review of their clinical imaging and behavioral characteristics.

The aim of the study was to establish if the null cell adenoma (NCA) forms a distinct subgroup with unique clinicopathological characteristics within the nonfunctioning pituitary adenoma group particularly in relation to the silent gonadotroph adenomas (SGAs). We identified 31 patients with the pathological diagnosis of NCA verified by routine histology and immunohistochemistry with distinct differentiation from SGAs by an established negative testing for SF-1 at the Toronto Western Hospital between December 2004 and August 2010. We reviewed their demographic data, clinical features, magnetic resonance imaging, and the histologic variables: MIB-1, FGFR4, and P27. We compared these to 63 SGAs identified within the same period. All the NCAs were macroadenomas with diameter ranging from 15-57 mm and tumor volumes between 1.95-53.5 mm(3). Preoperative cavernous sinus tumor growth was able to predict the presence of a residual after surgery (p = 0.023). Furthermore, preoperative cavernous sinus extension (p = 0.002) and negative P27 expression (p = 0.035) were able to independently predict the subsequent growth of the postoperative tumor residual. Comparing the NCA to SGA, we found that MIB-1 was higher in NCA (mean ± SD = 3.43 ± 2.76 %) compared to SGAs (mean ± SD = 2.49 ± 1.41 %) (p = 0.044). The preoperative and postoperative tumor volume doubling times (TVDTs) displayed a negative correlation in the SGA (r = -0.855, p = 0.002) while in the NCA, a positive correlation was evident (r = 0.718, p = 0.029). Our study suggests that the NCAs are a distinct group with differing behavioral characteristics from the SGAs. It also appears that the finding of cavernous sinus extension on preoperative imaging and a negative P27 expression on immunohistochemistry in NCAs may be valuable tools in predicting residual tumor growth which may impact on postoperative care.

The PI3K/AKT/mTOR pathway in the pathophysiology and treatment of pituitary adenomas.

Pituitary adenomas are common intracranial neoplasms. Patients with these tumors exhibit a wide range of clinically challenging problems, stemming either from results of sellar mass effect in pituitary macroadenoma or the diverse effects of aberrant hormone production by adenoma cells. While some patients are cured/controlled by surgical resection and/or medical therapy, a proportion of patients exhibit tumors that are refractory to current modalities. New therapeutic approaches are needed for these patients. Activation of the AKT/phophotidylinositide-3-kinase pathway, including mTOR activation, is common in human neoplasia, and a number of therapeutic approaches are being employed to neutralize activation of this pathway in human cancer. This review examines the role of this pathway in pituitary tumors with respect to tumor biology and its potential role as a therapeutic target.

Identifying predictors of early growth response and adverse radiation effects of vestibular schwannomas to radiosurgery.

PURPOSE: To determine whether pre-treatment growth rate of vestibular schwannomas (VS) predict response to radiosurgery. METHODS: A retrospective review of a prospectively maintained database of all VS patients treated with 12Gy prescription dose between September 2005 and June 2011 at our institution using the Leksell Model 4C Gamma Knife Unit was conducted. Patients who had a minimum of 12-months clinical and radiological assessment before and after radiosurgery were included in this study. Tumor growth rates were calculated using specific growth rate (SGR). Tumor volumes were measured on FIESTA-MRI scans using ITK-SNAP v2.2. RESULTS: Following radiosurgery, twenty-seven (42.9%) patients showed a significant decrease in volume after one year, twenty-nine (46.0%) stabilized, and seven (11.1%) continued to grow. There was no correlation between VS pre-treatment SGRs with post-treatment SGRs (p = 0.34), and incidence of adverse radiation effects (ARE). The reduction in tumors' SGRs after radiosurgery was proportional to pre-treatment SGRs, although this correlation was not statistically significant (p = 0.19). Analysis of risk factors revealed a positive correlation between post-treatment SGRs and incidence of non-auditory complications, most of which were attributed to ARE (p = 0.047). CONCLUSION: Pre-treatment growth rate of VS does not predict tumor response to radiosurgery or incidence of ARE. VS with higher SGRs post-radiosurgery are more likely to experience ARE.

Growth patterns of pituitary adenomas and histopathological correlates.

CONTEXT: The factors associated with pituitary adenoma (PA) growth rate remain unclear. OBJECTIVE: The objective of the study was to establish whether the preoperative growth and extension pattern of PA can predict postoperative growth rate and recurrence in addition to whether the PA growth rate correlates with proliferation and growth factor expression. PATIENTS: One hundred fifty-three consecutive patients who underwent surgery for pituitary adenoma from 1999 to 2011 at Toronto Western Hospital were identified. MAIN OUTCOME MEASURES: The PA growth rate was measured both pre- and postoperatively, and its association with patient demographics, magnetic resonance imaging, and histolopathological parameters was determined. RESULTS: The preoperative growth rate was associated with age (P = .0001), suprasellar growth (P = .003), the presence of a cyst/hemorrhage (P = .004), the mindbomb homolog-1 (P = .005), fibroblast growth factor receptor-4 positivity (P = .047), and p27 negativity (P = .007). After surgery, there were 34.6% residual volumes, which were associated with older age (P = .038) and also with growth patterns including anterior, posterior, suprasellar, and cavernous sinus extension (P = .001); 43.3% of these residuals grew and postoperative growth rate was calculated. Pre- and postoperative growth rates were correlated (r = 0.497, P = .026). Postoperative growth rate was associated with age (P = .015) and gender (P = .017). CONCLUSIONS: Our data suggest that the growth rate of PAs are influenced by various patient- and tumor-specific characteristics including the age and sex of the patient, the specific subtype of PA, its hormonal activity, its immunohistochemical profile including the mindbomb homolog 1 labeling index status, and its preponderance for different growth directions relative to the pituitary fossa. Furthermore, the pre- and postoperative PA growth rates were correlated, suggesting that postoperative PA growth rates can be predicted, in part, by preoperative growth rates, thus better informing postoperative outcome.

Endoscopic endonasal transsphenoidal approach to large and giant pituitary adenomas: institutional experience and predictors of extent of resection.

UNLABELLED: OBJECT.: While the use of endoscopic approaches has become increasingly accepted in the resection of pituitary adenomas, limited evidence exists regarding the success of this technique for patients with large and giant pituitary adenomas. This study reviews the outcomes of a large cohort of patients with large and giant pituitary adenomas who underwent endoscopic endonasal transsphenoidal surgery at the authors' institution and focuses on identifying factors that can predict extent of resection and hence aid in developing guidelines and indications for the use of endoscopic endonasal transsphenoidal surgery versus open craniotomy approaches to large and giant pituitary adenomas. METHODS: The authors reviewed 487 patients who underwent endoscopic endonasal transsphenoidal resection of sellar masses. From this group, 73 consecutive patients with large and giant pituitary adenomas (defined as maximum diameter ≥ 3 cm and tumor volume ≥ 10 cm(3)) who underwent endoscopic endonasal transsphenoidal surgery between January 1, 2006, and June 6, 2012, were included in the study. Clinical presentation, radiological studies, laboratory investigations, tumor pathology data, clinical outcomes, extent of resection measured by volumetric analysis, and complications were analyzed. RESULTS: The mean preoperative tumor diameter in this series was 4.1 cm and the volume was 18 cm(3). The average resection rate was 82.9%, corresponding with a mean residual volume of 3 cm(3). Gross-total resection was achieved in 16 patients (24%), near-total in 11 (17%), subtotal in 24 (36%), and partial in 15 (23%). Seventy-three percent of patients experienced improvement in visual acuity, while 24% were unchanged. Visual fields were improved in 61.8% and unchanged in 5.5%. Overall, 27 patients (37%) experienced a total of 32 complications. The most common complications were sinusitis (14%) and CSF leak (10%). Six patients underwent subsequent radiation therapy because of aggressive tumor histopathology. No deaths occurred in this cohort of patients. Statistically significant predictors of extent of resection included highest Knosp grade (p = 0.001), preoperative tumor volume (p = 0.025), preoperative maximum tumor diameter (p = 0.002), hemorrhagic component (p = 0.027), posterior extension (p = 0.001), and sphenoid sinus invasion (p = 0.005). CONCLUSIONS: Endoscopic endonasal transsphenoidal surgery is an effective treatment method for patients with large and giant pituitary adenomas, which results in high (> 80%) rates of resection and improvement in visual function. It is not associated with high rates of major complications and is safe when performed by experienced surgeons. The preoperative Knosp grade, tumor volume, tumor diameter, hemorrhagic components on MRI, posterior extension, and sphenoid sinus invasion may allow a prediction of extent of resection and in these patients a staged operation may be required to maximize extent of resection.

Gamma knife radiosurgery for the treatment of cystic cerebral metastases.

PURPOSE: To assess the role of Gamma Knife radiosurgery (GKRS) in the treatment of nonsurgical cystic brain metastasis, and to determine predictors of response to GKRS. METHODS: We reviewed a prospectively maintained database of brain metastases patients treated at our institution between 2006 and 2010. All lesions with a cystic component were identified, and volumetric analysis was done to measure percentage of cystic volume on day of treatment and consecutive follow-up MRI scans. Clinical, radiologic, and dosimetry parameters were reviewed to establish the overall response of cystic metastases to GKRS as well as identify potential predictive factors of response. RESULTS: A total of 111 lesions in 73 patients were analyzed; 57% of lesions received prior whole-brain radiation therapy (WBRT). Lung carcinoma was the primary cancer in 51% of patients, 10% breast, 10% colorectal, 4% melanoma, and 26% other. Fifty-seven percent of the patients were recursive partitioning analysis class 1, the remainder class 2. Mean target volume was 3.3 mL (range, 0.1-23 mL). Median prescription dose was 21 Gy (range, 15-24 Gy). Local control rates were 91%, 63%, and 37% at 6, 12, and 18 months, respectively. Local control was improved in lung primary and worse in patients with prior WBRT (univariate). Only lung primary predicted local control in multivariate analysis, whereas age and tumor volume did not. Lesions with a large cystic component did not show a poorer response compared with those with a small cystic component. CONCLUSIONS: This study supports the use of GKRS in the management of nonsurgical cystic metastases, despite a traditionally perceived poorer response. Our local control rates are comparable to a matched cohort of noncystic brain metastases, and therefore the presence of a large cystic component should not deter the use of GKRS. Predictors of response included tumor subtype. Prior WBRT decreased effectiveness of SRS for local control rates.

The role of mediators of cell invasiveness, motility, and migration in the pathogenesis of silent corticotroph adenomas.

Silent corticotroph adenomas (SCAs) represent a distinct subset of clinically non-functioning pituitary adenomas. There are two variants of SCA; type I are densely granulated basophilic tumors and type II are sparsely granulated and chromophobic tumors. SCAs are known to be aggressive than the more common non-functioning gonadotroph adenomas (NFGAs). Cell-matrix interactions play an important role in the pathogenesis of pituitary adenomas. In this study, we compared 19 SCAs and 50 NFGAs with known fibroblast growth factor receptor-4 (FGFR4) status using semi-quantitative immunohistochemistry to localize ß1-integrin, osteopontin, and matrix metalloproteinase-1 (MMP-1) as cytoplasmic, membranous, or mixed cytoplasmic-membranous staining to achieve scores of 1-4. Staining for ß1-integrin was significantly higher in SCAs (100 %, score 3.3) than in NFGAs (96 %; score 2.6) (p = 0.0482); there was no statistical difference within subgroups of SCA (type II score 3.4; type I score 2.8) (p = 0.2663). Osteopontin immunoreactivity was also higher in SCAs (100 %, score 3.7) than in NFGAs (42 %, score 0.8) (p = 0.0001); there was no statistical difference within subgroups of SCA (type II score 3.6; type I score 3.9) (p = 0.2787). In contrast, MMP-1 immunoreactivity was lower in SCAs (89 %; score 2.5) than in NFGAs (98 %; score 3.6) (p = 0.0005); there was no statistical difference within subgroups of SCA (type II score 2.7; type I score 2.0) (p = 0.30704). The MMP-1 results correlated with FGFR4 expression (NFGA 96 %, type II SCA 71 %, type I SCA 40 %). Our data indicate that the biological aggressivity of SCAs compared with NFGA may be due to high osteopontin expression; in contrast, high MMP-1 is characteristic of NFGAs that also express more FGFR4. Further investigations are warranted to clarify the underlying regulatory mechanisms of these markers. The high osteopontin or FGFR4/MMP-1 expression levels in SCAs and NFGAs, respectively, indicate the potential for therapeutic strategies targeting osteopontin or FGFR4/MMP-1 for inoperable tumors of these types.

Stereotactic radiosurgery for the treatment of melanoma and renal cell carcinoma brain metastases.

Renal cell carcinoma (RCC) and melanoma brain metastases have traditionally been considered radioresistant lesions when treated with conventional radiotherapeutic modalities. Radiosurgery provides high-dose radiation to a defined target volume with steep fall off in dose at lesion margins. Recent evidence suggests that stereotactic radiosurgery (SRS) is effective in improving local control and overall survival for a number of tumor subtypes including RCC and melanoma brain metastases. The purpose of this study was to compare the response rate to SRS between RCC and melanoma patients and to identify predictors of response to SRS for these 2 specific subtypes of brain metastases. We retrospectively reviewed a prospectively maintained database of all brain metastases treated with Gamma Knife SRS at the University Health Network (Toronto, Ontario) between October 2007 and June 2010, studying RCC and melanoma patients. Demographics, treatment history and dosimetry data were collected; and MRIs were reviewed for treatment response. Log rank, Cox proportional hazard ratio and Kaplan-Meier survival analysis using SPSS were performed. A total of 103 brain metastases patients (41 RCC; 62 melanoma) were included in the study. The median age, Karnofsky performance status score and Eastern Cooperative Oncology Group performance score was 52 years (range 27-81), 90 (range 70-100) and 1 (range 0-2), respectively. Thirty-four lesions received adjuvant chemotherapy and 56 received pre-SRS whole brain radiation therapy. The median follow-up, prescription dose, Radiation Therapy Oncology Group conformity index, target volume and number of shots was 6 months (range 1-41 months), 21 Gy (range 15-25 Gy), 1.93 (range 1.04-9.76), 0.4 cm3 (range 0.005-13.36 cm3) and 2 (range 1-22), respectively. Smaller tumor volume (P=0.007) and RCC pathology (P=0.04) were found to be positive predictors of response. Actuarial local control rate for RCC and melanoma combined was 89% at 6 months, 84% at 12 months, 76% at 18 months and 61% at 24 months. Local control at 12 months was 91 and 75% for RCC and melanoma, respectively. SRS is a valuable treatment option for local control of RCC and melanoma brain metastases. Smaller tumor volume and RCC pathology, predictors of response, suggest distinct differences in tumor biology and the extent of radioresponse between RCC and melanoma.

Pretreatment predictors of adverse radiation effects after radiosurgery for arteriovenous malformation.

PURPOSE: To identify vascular and dosimetric predictors of symptomatic T2 signal change and adverse radiation effects after radiosurgery for arteriovenous malformation, in order to define and validate preexisting risk models. METHODS AND MATERIALS: A total of 125 patients with arteriovenous malformations (AVM) were treated at our institution between 2005 and 2009. Eighty-five patients have at least 12 months of clinical and radiological follow-up. Any new-onset headaches, new or worsening seizures, or neurological deficit were considered adverse events. Follow-up magnetic resonance images were assessed for new onset T2 signal change and the volume calculated. Pretreatment characteristics and dosimetric variables were analyzed to identify predictors of adverse radiation effects. RESULTS: There were 19 children and 66 adults in the study cohort, with a mean age of 34 (range 6-74). Twenty-three (27%) patients suffered adverse radiation effects (ARE), 9 patients with permanent neurological deficit (10.6%). Of these, 5 developed fixed visual field deficits. Target volume and 12 Gy volume were the most significant predictors of adverse radiation effects on univariate analysis (p < 0.001). Location and cortical eloquence were not significantly associated with the development of adverse events (p = 0.12). No additional vascular parameters were identified as predictive of ARE. There was a significant target volume threshold of 4 cm(3), above which the rate of ARE increased dramatically. Multivariate analysis target volume and the absence of prior hemorrhage are the only significant predictors of ARE. The volume of T2 signal change correlates to ARE, but only target volume is predictive of a higher volume of T2 signal change. CONCLUSIONS: Target volume and the absence of prior hemorrhage is the most accurate predictor of adverse radiation effects and complications after radiosurgery for AVMs. A high percentage of permanent visual field defects in this series suggest the optic radiation is a critical radiosensitive structure.

Predicting nonauditory adverse radiation effects following radiosurgery for vestibular schwannoma: a volume and dosimetric analysis.

PURPOSE: To define clinical and dosimetric predictors of nonauditory adverse radiation effects after radiosurgery for vestibular schwannoma treated with a 12 Gy prescription dose. METHODS: We retrospectively reviewed our experience of vestibular schwannoma patients treated between September 2005 and December 2009. Two hundred patients were treated at a 12 Gy prescription dose; 80 had complete clinical and radiological follow-up for at least 24 months (median, 28.5 months). All treatment plans were reviewed for target volume and dosimetry characteristics; gradient index; homogeneity index, defined as the maximum dose in the treatment volume divided by the prescription dose; conformity index; brainstem; and trigeminal nerve dose. All adverse radiation effects (ARE) were recorded. Because the intent of our study was to focus on the nonauditory adverse effects, hearing outcome was not evaluated in this study. RESULTS: Twenty-seven (33.8%) patients developed ARE, 5 (6%) developed hydrocephalus, 10 (12.5%) reported new ataxia, 17 (21%) developed trigeminal dysfunction, 3 (3.75%) had facial weakness, and 1 patient developed hemifacial spasm. The development of edema within the pons was significantly associated with ARE (p = 0.001). On multivariate analysis, only target volume is a significant predictor of ARE (p = 0.001). There is a target volume threshold of 5 cm3, above which ARE are more likely. The treatment plan dosimetric characteristics are not associated with ARE, although the maximum dose to the 5th nerve is a significant predictor of trigeminal dysfunction, with a threshold of 9 Gy. The overall 2-year tumor control rate was 96%. CONCLUSIONS: Target volume is the most important predictor of adverse radiation effects, and we identified the significant treatment volume threshold to be 5 cm3. We also established through our series that the maximum tolerable dose to the 5th nerve is 9 Gy.