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Objective: To describe best practices and guidelines in symptom management at the end of life for adults with malignant glioma., Data Sources: Journal articles, evidence-based reviews, textbooks, and clinical guidelines., Conclusion: Symptom management is an essential element of end-of-life care that aims to preserve dignity and quality of life for patients with glioma and their family caregivers., Implications for Nursing Practice: Advance care planning using a holistic approach to the patient's symptoms experience and goals of care are necessary to develop, implement, and evaluate outcomes of an evidence-based plan of care tailored for each patient and family., (Copyright © 2018. Published by Elsevier Inc.)

Purpose: AZD1775, a first-in-class, small-molecule inhibitor of the Wee1 tyrosine kinase, is under evaluation as a potential chemo- and radiosensitizer for treating glioblastoma. This study was to prospectively, quantitatively, and mechanistically investigate the penetration of AZD1775 across the human blood-brain barrier (BBB). Experimental Design: AZD1775 plasma and tumor pharmacokinetics were evaluated in 20 patients with glioblastoma. The drug metabolism, transcellular passive permeability, and interactions with efflux and uptake transporters were determined using human derived in vitro systems. A whole-body physiologically based pharmacokinetic (PBPK) model integrated with a four-compartment permeability-limited brain model was developed for predicting the kinetics of AZD1775 BBB penetration and assessing the factors modulating this process. Results: AZD1775 exhibited good tumor penetration in patients with glioblastoma, with the unbound tumor-to-plasma concentration ratio ranging from 1.3 to 24.4 (median, 3.2). It was a substrate for ABCB1, ABCG2, and OATP1A2, but not for OATP2B1 or OAT3. AZD1775 transcellular passive permeability and active efflux clearance across MDCKII-ABCB1 or MDCKII-ABCG2 cell monolayers were dependent on the basolateral pH. The PBPK model well predicted observed drug plasma and tumor concentrations in patients. The extent and rate of drug BBB penetration were influenced by BBB integrity, efflux and uptake active transporter activity, and drug binding to brain tissue. Conclusions: In the relatively acidic tumor microenvironment where ABCB1/ABCG2 transporter-mediated efflux clearance is reduced, OATP1A2-mediated active uptake becomes dominant, driving AZD1775 penetration into brain tumor. Variations in the brain tumor regional pH, transporter expression/activity, and BBB integrity collectively contribute to the heterogeneity of AZD1775 penetration into brain tumors. Clin Cancer Res; 23(24); 7454-66. ©2017 AACR See related commentary by Peer et al., p. 7437 ., (©2017 American Association for Cancer Research.)

OBJECTIVE Hemangiopericytomas (HPCs) are rare tumors widely recognized for their aggressive clinical behavior, high recurrence rates, and distant and extracranial metastases even after a gross-total resection. The authors report a large multicenter study, through the International Gamma Knife Research Foundation (IGKRF), reviewing management and outcome following stereotactic radiosurgery (SRS) for recurrent or newly discovered HPCs. METHODS Eight centers participating in the IGKRF participated in this study. A total of 90 patients harboring 133 tumors were identified. Patients were included if they had a histologically diagnosed HPC managed with SRS during the period 1988-2014 and had a minimum of 6 months' clinical and radiological follow-up. A de-identified database was created. The patients' median age was 48.5 years (range 13-80 years). Prior treatments included embolization (n = 8), chemotherapy (n = 2), and fractionated radiotherapy (n = 34). The median tumor volume at the time of SRS was 4.9 cm 3 (range 0.2-42.4 cm 3 ). WHO Grade II (typical) HPCs formed 78.9% of the cohort (n = 71). The median margin and maximum doses delivered were 15 Gy (range 2.8-24 Gy) and 32 Gy (range 8-51 Gy), respectively. The median clinical and radiographic follow-up periods were 59 months (range 6-190 months) and 59 months (range 6-183 months), respectively. Prognostic variables associated with local tumor control and post-SRS survival were evaluated using Cox univariate and multivariate analysis. Actuarial survival after SRS was analyzed using the Kaplan-Meier method. RESULTS Imaging studies performed at last follow-up demonstrated local tumor control in 55% of tumors and 62.2% of patients. New remote intracranial tumors were found in 27.8% of patients, and 24.4% of patients developed extracranial metastases. Adverse radiation effects were noted in 6.7% of patients. During the study period, 32.2% of the patients (n = 29) died. The actuarial overall survival was 91.5%, 82.1%, 73.9%, 56.7%, and 53.7% at 2, 4, 6, 8, and 10 years, respectively, after initial SRS. Local progression-free survival (PFS) was 81.7%, 66.3%, 54.5%, 37.2%, and 25.5% at 2, 4, 6, 8, and 10 years, respectively, after initial SRS. In our cohort, 32 patients underwent 48 repeat SRS procedures for 76 lesions. Review of these 76 treated tumors showed that 17 presented as an in-field recurrence and 59 were defined as an out-of-field recurrence. Margin dose greater than 16 Gy (p = 0.037) and tumor grade (p = 0.006) were shown to influence PFS. The development of extracranial metastases was shown to influence overall survival (p = 0.029) in terms of PFS; repeat (multiple) SRS showed additional benefit. CONCLUSIONS SRS provides a reasonable rate of local tumor control and a low risk of adverse effects. It also leads to neurological stability or improvement in the majority of patients. Long-term close clinical and imaging follow-up is necessary due to the high probability of local recurrence and distant metastases. Repeat SRS is often effective for treating new or recurrent HPCs.

Object: Posterior fossa meningiomas represent a common yet challenging clinical entity. They are often associated with neurovascular structures and adjacent to the brainstem. Resection can be undertaken for posterior fossa meningiomas, but residual or recurrent tumor is frequent. Stereotactic radiosurgery (SRS) has been used to treat meningiomas, and this study evaluates the outcome of this approach for those located in the posterior fossa., Methods: At 7 medical centers participating in the North American Gamma Knife Consortium, 675 patients undergoing SRS for a posterior fossa meningioma were identified, and clinical and radiological data were obtained for these cases. Females outnumbered males at a ratio of 3.8 to 1, and the median patient age was 57.6 years (range 12-89 years). Prior resection was performed in 43.3% of the patient sample. The mean tumor volume was 6.5 cm(3), and a median margin dose of 13.6 Gy (range 8-40 Gy) was delivered to the tumor., Results: At a mean follow-up of 60.1 months, tumor control was achieved in 91.2% of cases. Actuarial tumor control was 95%, 92%, and 81% at 3, 5, and 10 years after radiosurgery. Factors predictive of tumor progression included age greater than 65 years (hazard ratio [HR] 2.36, 95% CI 1.30-4.29, p = 0.005), prior history of radiotherapy (HR 5.19, 95% CI 1.69-15.94, p = 0.004), and increasing tumor volume (HR 1.05, 95% CI 1.01-1.08, p = 0.005). Clinical stability or improvement was achieved in 92.3% of patients. Increasing tumor volume (odds ratio [OR] 1.06, 95% CI 1.01-1.10, p = 0.009) and clival, petrous, or cerebellopontine angle location as compared with petroclival, tentorial, and foramen magnum location (OR 1.95, 95% CI 1.05-3.65, p = 0.036) were predictive of neurological decline after radiosurgery. After radiosurgery, ventriculoperitoneal shunt placement, resection, and radiation therapy were performed in 1.6%, 3.6%, and 1.5%, respectively., Conclusions: Stereotactic radiosurgery affords a high rate of tumor control and neurological preservation for patients with posterior fossa meningiomas. Those with a smaller tumor volume and no prior radiation therapy were more likely to have a favorable response after radiosurgery. Rarely, additional procedures may be required for hydrocephalus or tumor progression.

Background: Resection of cerebellopontine angle (CPA) meningiomas may result in significant neurological morbidity. Radiosurgery offers a minimally invasive alternative to surgery., Objective: To evaluate, in a multicenter cohort study, the outcomes of patients harboring CPA meningiomas who underwent Gamma Knife radiosurgery (GKRS)., Methods: From 7 institutions participating in the North American Gamma Knife Consortium, 177 patients with benign CPA meningiomas treated with GKRS and at least 6 months radiologic follow-up were included for analysis. The mean age was 59 years and 84% were female. Dizziness or imbalance (48%) and cranial nerve (CN) VIII dysfunction (45%) were the most common presenting symptoms. The median tumor volume and prescription dose were 3.6 cc and 13 Gy, respectively. The mean radiologic and clinical follow-up durations were 47 and 46 months, respectively. Multivariate regression analyses were performed to identify the predictors of tumor progression and neurological deterioration., Results: The actuarial rates of progression-free survival at 5 and 10 years were 93% and 77%, respectively. Male sex (P = .014), prior fractionated radiation therapy (P = .010), and ataxia at presentation (P = .002) were independent predictors of tumor progression. Symptomatic adverse radiation effects and permanent neurological deterioration were observed in 1.1% and 9% of patients, respectively. Facial spasms at presentation (P = .007) and lower maximal dose (P = .011) were independently associated with neurological deterioration., Conclusion: GKRS is an effective therapy for CPA meningiomas. Depending on the patient and tumor characteristics, radiosurgery can be an adjuvant treatment to initial surgical resection or a standalone procedure that obviates the need for resection in most patients.

Petroclival meningiomas are difficult to treat due to their intimate location with critical structures, and complete microsurgical resection is often associated with significant morbidity. In this study, we evaluate the outcomes of petroclival meningiomas treated with Gamma Knife radiosurgery (GKRS) as an adjunct to microsurgery or a primary treatment modality. A multicenter study of 254 patients with a benign petroclival meningioma was conducted through the North American Gamma Knife Consortium. One hundred and forty patients were treated with upfront radiosurgery, and 114 following surgery. Multivariate analysis was used to determine predictors of favorable defined as no tumor progression following radiosurgery and the absence of any new or worsening neurological function. At mean follow up of 71 months (range 6-252), tumor volumes increased in 9 % of tumors, remained stable in 52 %, and decreased in 39 %. Kaplan-Meier actuarial progression free survival rates at 3, 5, 8, 10, and 12 years were 97, 93, 87, 84, and 80 % respectively. At last clinical follow-up, 93.6 % of patients demonstrated no change or improvement in their neurological condition whereas 6.4 % of patients experienced progression of symptoms. Favorable outcome was achieved in 87 % of patients and multivariate predictors of favorable outcome included smaller tumor volume (OR = 0.92; 95 % CI 0.87-0.97, p = 0.003), female gender (OR 0.37; 95 % CI 0.15-0.89, p = 0.027), no prior radiotherapy (OR 0.03; 95 % CI 0.01-0.36, p = 0.006), and decreasing maximal dose (OR 0.92; 95 % CI 0.96-0.98, p = 0.010). GKRS of petroclival meningiomas achieves neurological preservation in most patients and with a high rate of tumor control.

Object: Parasellar and sellar meningiomas are challenging tumors owing in part to their proximity to important neurovascular and endocrine structures. Complete resection can be associated with significant morbidity, and incomplete resections are common. In this study, the authors evaluated the outcomes of parasellar and sellar meningiomas managed with Gamma Knife radiosurgery (GKRS) both as an adjunct to microsurgical removal or conventional radiation therapy and as a primary treatment modality., Methods: A multicenter study of patients with benign sellar and parasellar meningiomas was conducted through the North American Gamma Knife Consortium. For the period spanning 1988 to 2011 at 10 centers, the authors identified all patients with sellar and/or parasellar meningiomas treated with GKRS. Patients were also required to have a minimum of 6 months of imaging and clinical follow-up after GKRS. Factors predictive of new neurological deficits following GKRS were assessed via univariate and multivariate analyses. Kaplan-Meier analysis and Cox multivariate regression analysis were used to assess factors predictive of tumor progression., Results: The authors identified 763 patients with sellar and/or parasellar meningiomas treated with GKRS. Patients were assessed clinically and with neuroimaging at routine intervals following GKRS. There were 567 females (74.3%) and 196 males (25.7%) with a median age of 56 years (range 8-90 years). Three hundred fifty-five patients (50.7%) had undergone at least one resection before GKRS, and 3.8% had undergone prior radiation therapy. The median follow-up after GKRS was 66.7 months (range 6-216 months). At the last follow-up, tumor volumes remained stable or decreased in 90.2% of patients. Actuarial progression-free survival rates at 3, 5, 8, and 10 years were 98%, 95%, 88%, and 82%, respectively. More than one prior surgery, prior radiation therapy, or a tumor margin dose < 13 Gy significantly increased the likelihood of tumor progression after GKRS. At the last clinical follow-up, 86.2% of patients demonstrated no change or improvement in their neurological condition, whereas 13.8% of patients experienced symptom progression. New or worsening cranial nerve deficits were seen in 9.6% of patients, with cranial nerve (CN) V being the most adversely affected nerve. Functional improvements in CNs, especially in CNs V and VI, were observed in 34% of patients with preexisting deficits. New or worsened endocrinopathies were demonstrated in 1.6% of patients; hypothyroidism was the most frequent deficiency. Unfavorable outcome with tumor growth and accompanying neurological decline was statistically more likely in patients with larger tumor volumes (p = 0.022) and more than 1 prior surgery (p = 0.021)., Conclusions: Gamma Knife radiosurgery provides a high rate of tumor control for patients with parasellar or sellar meningiomas, and tumor control is accompanied by neurological preservation or improvement in most patients.

Objectives: To provide a clinical overview of treatment-related symptom clusters., Data Sources: Journal articles, research reports, state of the science papers, and clinical practice experience., Conclusion: Although understanding the etiology and interaction of symptoms may lead to targeted interventions, the nurse must often manage symptoms in which the cause or causes cannot be changed or in which there are multiple overlapping etiologies that lead to complex and challenging clinical presentations. Systematic and ongoing evaluation of symptoms, their treatment-related trajectory, and their response to interventions is essential., Implications for Nursing Practice: Systematic assessment of symptoms and symptom cluster presence, severity, and distress can guide the practitioner to intervene using evidence-based practice. Individualized care and evaluation of response is needed.