Health-related quality of life analyses in nonfunctioning pituitary macroadenoma patients identifies at-risk populations.

PURPOSE: The quality of life (QoL) impact of multidisciplinary treatment for patients with nonfunctioning pituitary macroadenomas (NFPMA) is unclear. We sought to investigate associations between patient factors, clinical data, and patient-reported QoL in patients with NFPMA. METHODS: Patients with treated NFPMA and > 1 year of follow up after transsphenoidal surgery (TSS) and with no evidence of progressive disease were evaluated utilizing the following patient-reported outcome measures: RAND-36-Item Health Survey, Multidimensional Fatigue Inventory, Cognitive Failures Questionnaire. RESULTS: 229 eligible patients completed QoL questionnaires a median of 7.7 years after initial transsphenoidal surgery (TSS). 25% of participants received radiation therapy (RT) a median of 2.0 years (0.1-22.5) after initial TSS. Patients who received RT were younger (median age 46 v 58, p < 0.0001), had larger tumors (28 mm v 22 mm, p < 0.0001), were more likely to have visual symptoms (65% v 34%, p = 0.0002), and were more likely to have hypopituitarism (93% v 62%, p < 0.0001). Patients with hypopituitarism reported worse energy and fatigue and cognitive function (p < 0.03). Patients who received RT reported significantly worse general health, physical health, physical fatigue and cognitive functioning (p < 0.05). The largest QoL differences were in patients who experienced a financial stressor, independent of treatment type. CONCLUSION: Hypopituitarism, radiation therapy after TSS, and financial stressors are associated with more impaired QoL in patients with NFPMA. Awareness of these factors can better guide use and timing of radiation therapy in addition to identifying patients who can benefit from multidisciplinary surveillance.

Therapeutic avenues for cancer neuroscience: translational frontiers and clinical opportunities.

With increasing attention on the essential roles of the tumour microenvironment in recent years, the nervous system has emerged as a novel and crucial facilitator of cancer growth. In this Review, we describe the foundational, translational, and clinical advances illustrating how nerves contribute to tumour proliferation, stress adaptation, immunomodulation, metastasis, electrical hyperactivity and seizures, and neuropathic pain. Collectively, this expanding knowledge base reveals multiple therapeutic avenues for cancer neuroscience that warrant further exploration in clinical studies. We discuss the available clinical data, including ongoing trials investigating novel agents targeting the tumour-nerve axis, and the therapeutic potential for repurposing existing neuroactive drugs as an anti-cancer approach, particularly in combination with established treatment regimens. Lastly, we discuss the clinical challenges of these treatment strategies and highlight unanswered questions and future directions in the burgeoning field of cancer neuroscience.

Gender, Productivity, and Philanthropic Fundraising in Academic Oncology.

BACKGROUND: Philanthropic donations are important funding sources in academic oncology but may be vulnerable to implicit or explicit biases toward women. However, the influence of gender on donations has not been assessed quantitatively. METHODS: We queried a large academic cancer center's development database for donations over 10 years to the sundry funds of medical and radiation oncologists. Types of donations and total amounts for medical oncologists and radiation oncologists hired prior to April 1, 2018 (allowing ≥2 years on faculty prior to query), were obtained. We also obtained publicly available data on physician/academic rank, gender, specialty, disease site, and Hirsch-index (h-index), a metric of productivity. RESULTS: We identified 127 physicians: 64% men and 36% women. Median h-index was higher for men (31; range, 1-100) than women (17; range, 3-77; P=.003). Men were also more likely to have spent more time at the institution (median, 15 years; range, 2-43 years) than women (median, 12.5 years; range, 3-22 years; P=.025). Those receiving donations were significantly more likely to be men (70% vs 30%; P=.034). Men received significantly higher median amounts ($259,474; range, $0-$29,507,784) versus women ($37,485; range, $0-$7,483,726; P=.019). On multivariable analysis, only h-index and senior academic rank were associated with donation receipt, and only h-index with donation amount. CONCLUSIONS: We found significant gender disparities in receipt of philanthropic donations on unadjusted analyses. However, on multivariable analyses, only productivity and rank were significantly associated with donations, suggesting gender disparities in productivity and promotions may contribute to these differences.

Central Nervous System Cancers, Version 3.2020, NCCN Clinical Practice Guidelines in Oncology.

The NCCN Guidelines for Central Nervous System (CNS) Cancers focus on management of adult CNS cancers ranging from noninvasive and surgically curable pilocytic astrocytomas to metastatic brain disease. The involvement of an interdisciplinary team, including neurosurgeons, radiation therapists, oncologists, neurologists, and neuroradiologists, is a key factor in the appropriate management of CNS cancers. Integrated histopathologic and molecular characterization of brain tumors such as gliomas should be standard practice. This article describes NCCN Guidelines recommendations for WHO grade I, II, III, and IV gliomas. Treatment of brain metastases, the most common intracranial tumors in adults, is also described.

Increase of pseudoprogression and other treatment related effects in low-grade glioma patients treated with proton radiation and temozolomide.

INTRODUCTION: Concurrent radiotherapy and temozolomide (TMZ) is associated with radiographic pseudoprogression (PsP) in glioblastoma. The occurrence of PsP and other treatment effects is less well understood in low-grade gliomas (LGG). The purpose of this study is to evaluate whether the addition of TMZ to radiotherapy increases the incidence of PsP in adults with LGG treated with proton radiotherapy (PRT). METHODS: Chart review and volumetric MRI-analysis was performed on radiotherapy-naive adults with WHO grade II or IDH mutant WHO grade III gliomas treated with PRT between 2005 and 2015. Progression was defined by histology, new chemotherapy initiation, or progressive increase in lesion volume beyond 40% from baseline. Post treatment related effects (PTRE) were defined as new/increased T2/FLAIR or abnormal enhancement which eventually resolved or stabilized without evidence of progression for a period of 6-12 months. PsP was defined as the subset of PRTE suspicious for progression or volumetrically increased at least 40% from baseline. Pearson's chi-squared test and Cox-proportional hazards models were used for statistical analysis. RESULTS: There were 119 patients meeting inclusion criteria. There was an increased risk of PsP following PRT + TMZ versus PRT-alone (HR = 2.2, p = 0.006, on Cox univariate analysis). Presence of PsP was associated with improved OS (p = 0.02 with PsP as time-varying covariate). CONCLUSIONS: TMZ use, when added to PRT, was associated with increased PsP in patients with LGG; however, patients with PsP tended to achieve longer survival.

Dynamic Changes in Arteriovenous Malformations (AVMs): Spontaneous Growth and Resolution of AVM-Associated Aneurysms in Two Pediatric Patients.

Arteriovenous malformations (AVMs) of the central nervous system are dynamic lesions that can change with time. One of the most clinically important concerns is the development and potential rupture of AVM-associated aneurysms. In this report, we review pediatric cases of de novo development of AVM-associated aneurysms in 2 children and present the relevant clinical and radiographic records. These 2 cases, coupled with a review of the current literature, offer insight into the risks of AVMs in children and underline the importance of timely treatment of appropriate cases.

MicroRNA-378 enhances radiation response in ectopic and orthotopic implantation models of glioblastoma.

Glioblastoma multiforme (GBM) is the most common and highly malignant primary brain tumor, which is virtually incurable due to its therapeutic resistance to radiation and chemotherapy. To develop novel therapeutic approaches for treatment of GBM, we examined the role of miR-378 on tumor growth, angiogenesis, and radiation response in ectopic and orthotopic U87 glioblastoma models. Cell and tumor growth rates, in vitro and in vivo radiation sensitivities, and tumor vascular density were evaluated in U87-GFP and U87-miR-378 tumor lines. Ectopic tumor response to radiation was evaluated under normal blood flow and clamp hypoxic conditions. Results show that in vitro, miR-378 expression moderately increased cell growth rate and plating efficiency, but did not alter radiation sensitivity. U87-miR-378 tumors exhibited a higher transplantation take rate than U87-GFP tumors. In vivo, under oxygenated condition, subcutaneous U87-miR-378 tumors receiving 25 Gy showed a tendency for longer tumor growth delay (TGD) than control U87-GFP tumors. In contrast, under hypoxic condition, U87-miR-378 xenografts exhibited substantially shorter TGD than U87-GFP tumors, indicating that under normal blood flow conditions, U87-miR-378 tumors were substantially more oxygenated than U87-GFP tumors. Intracranial multi-photon laser-scanning microscopy demonstrated increased vascular density of U87-miR-378 versus control U87-GFP tumors. Finally, miR-378 increased TGD following 12 Gy irradiation in U87 intracranial xenografts, and significantly prolonged survival of U87-miR-378 tumor-bearing mice (P = 0.04). In conclusion, higher miR-378 expression in U87-miR-378 cells promotes tumor growth, angiogenesis, radiation-induced TGD, and prolongs survival of orthotopic tumor-bearing hosts. Regulation of VEGFR2 by miR-378 significantly increased vascular density and oxygenation in U87 xenografts.

Correction to: Criteria for the definition of Pituitary Tumor Centers of Excellence (PTCOE): A Pituitary Society Statement.

The original version of this article unfortunately contained an affiliation error in 'Collaborators for The Pituitary Society, Expert Group on Pituitary Tumors' section. Dr. Misa Pfeifer is affiliated with Medical Faculty, University of Ljubljana, Slovenia and the correct email address to contact is misa.pfeifer@gmail.com.

NCCN Guidelines Insights: Central Nervous System Cancers, Version 1.2017.

For many years, the diagnosis and classification of gliomas have been based on histology. Although studies including large populations of patients demonstrated the prognostic value of histologic phenotype, variability in outcomes within histologic groups limited the utility of this system. Nonetheless, histology was the only proven and widely accessible tool available at the time, thus it was used for clinical trial entry criteria, and therefore determined the recommended treatment options. Research to identify molecular changes that underlie glioma progression has led to the discovery of molecular features that have greater diagnostic and prognostic value than histology. Analyses of these molecular markers across populations from randomized clinical trials have shown that some of these markers are also predictive of response to specific types of treatment, which has prompted significant changes to the recommended treatment options for grade III (anaplastic) gliomas.

Criteria for the definition of Pituitary Tumor Centers of Excellence (PTCOE): A Pituitary Society Statement.

INTRODUCTION: With the goal of generate uniform criteria among centers dealing with pituitary tumors and to enhance patient care, the Pituitary Society decided to generate criteria for developing Pituitary Tumors Centers of Excellence (PTCOE). METHODS: To develop that task, a group of ten experts served as a Task Force and through two years of iterative work an initial draft was elaborated. This draft was discussed, modified and finally approved by the Board of Directors of the Pituitary Society. Such document was presented and debated at a specific session of the Congress of the Pituitary Society, Orlando 2017, and suggestions were incorporated. Finally the document was distributed to a large group of global experts that introduced further modifications with final endorsement. RESULTS: After five years of iterative work a document with the ideal criteria for a PTCOE is presented. CONCLUSIONS: Acknowledging that very few centers in the world, if any, likely fulfill the requirements here presented, the document may be a tool to guide improvements of care delivery to patients with pituitary disorders. All these criteria must be accommodated to the regulations and organization of Health of a given country.

Neurocognitive effects of proton radiation therapy in adults with low-grade glioma.

To understand neurocognitive effects of proton radiation therapy (PRT) in patients with low-grade glioma, we evaluated 20 patients who received this therapy prospectively and over 5 years with a comprehensive neuropsychological battery. 20 patients were evaluated at baseline and at yearly intervals for up to 5 years with a battery of neuropsychological measures that assessed intellectual, attention, executive, visuospatial and memory functions as well as mood and functional status. We evaluated change in cognitive functioning over time. We analyzed the relationship between cognitive performance and tumor location and also examined whether patients' performance differed from that reported in a study of normative practice effects. Overall, patients exhibited stability in cognitive functioning. Tumor location played a role in performance; those with tumors in the left hemisphere versus in the right hemisphere were more impaired at baseline on verbal measures (p < .05). However, we found greater improvement in verbal memory over time in patients with left than with right hemisphere tumors (p < .05). Results of our study, the first to investigate, in depth, neurocognitive effects of PRT in adults with low-grade gliomas, are promising. We hypothesize that the conformal advantage of PRT may contribute to preservation of cognitive functioning, although larger sample sizes and a longer period of study are required. Our study also highlights the need to consider normative practice effects when studying neurocognitive functioning in response to treatment over time, and the need to utilize comprehensive neuropsychological batteries given our findings that differentiate patients with left and right hemisphere tumors.

Improved tumor oxygenation and survival in glioblastoma patients who show increased blood perfusion after cediranib and chemoradiation.

Antiangiogenic therapy has shown clear activity and improved survival benefit for certain tumor types. However, an incomplete understanding of the mechanisms of action of antiangiogenic agents has hindered optimization and broader application of this new therapeutic modality. In particular, the impact of antiangiogenic therapy on tumor blood flow and oxygenation status (i.e., the role of vessel pruning versus normalization) remains controversial. This controversy has become critical as multiple phase III trials of anti-VEGF agents combined with cytotoxics failed to show overall survival benefit in newly diagnosed glioblastoma (nGBM) patients and several other cancers. Here, we shed light on mechanisms of nGBM response to cediranib, a pan-VEGF receptor tyrosine kinase inhibitor, using MRI techniques and blood biomarkers in prospective phase II clinical trials of cediranib with chemoradiation vs. chemoradiation alone in nGBM patients. We demonstrate that improved perfusion occurs only in a subset of patients in cediranib-containing regimens, and is associated with improved overall survival in these nGBM patients. Moreover, an increase in perfusion is associated with improved tumor oxygenation status as well as with pharmacodynamic biomarkers, such as changes in plasma placenta growth factor and sVEGFR2. Finally, treatment resistance was associated with elevated plasma IL-8 and sVEGFR1 posttherapy. In conclusion, tumor perfusion changes after antiangiogenic therapy may distinguish responders vs. nonresponders early in the course of this expensive and potentially toxic form of therapy, and these results may provide new insight into the selection of glioblastoma patients most likely to benefit from anti-VEGF treatments.

Proton therapy for low-grade gliomas: Results from a prospective trial.

BACKGROUND: In this prospective study, the authors evaluated potential treatment toxicity and progression-free survival in patients with low-grade glioma who received treatment with proton radiation therapy. METHODS: Twenty patients with World Health Organization grade 2 glioma who were eligible for radiation therapy were enrolled in a prospective, single-arm trial of proton therapy. The patients received proton therapy at a dose of 54 Gy (relative biological effectiveness) in 30 fractions. Comprehensive baseline and regular post-treatment evaluations of neurocognitive function, neuroendocrine function, and quality of life (QOL) were performed. RESULTS: All 20 patients (median age, 37.5 years) tolerated treatment without difficulty. The median follow-up after proton therapy was 5.1 years. At baseline, intellectual functioning was within the normal range for the group and remained stable over time. Visuospatial ability, attention/working memory, and executive functioning also were within normal limits; however, baseline neurocognitive impairments were observed in language, memory, and processing speed in 8 patients. There was no overall decline in cognitive functioning over time. New endocrine dysfunction was detected in 6 patients, and all but 1 had received direct irradiation of the hypothalamic-pituitary axis. QOL assessment revealed no changes over time. The progression-free survival rate at 3 years was 85%, but it dropped to 40% at 5 years. CONCLUSIONS: Patients with low-grade glioma tolerate proton therapy well, and a subset develops neuroendocrine deficiencies. There is no evidence for overall decline in cognitive function or QOL.

Central Nervous System Cancers, Version 1.2015.

The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Central Nervous System (CNS) Cancers provide interdisciplinary recommendations for managing adult CNS cancers. Primary and metastatic brain tumors are a heterogeneous group of neoplasms with varied outcomes and management strategies. These NCCN Guidelines Insights summarize the NCCN CNS Cancers Panel's discussion and highlight notable changes in the 2015 update. This article outlines the data and provides insight into panel decisions regarding adjuvant radiation and chemotherapy treatment options for high-risk newly diagnosed low-grade gliomas and glioblastomas. Additionally, it describes the panel's assessment of new data and the ongoing debate regarding the use of alternating electric field therapy for high-grade gliomas.

Brachytherapy in the treatment of recurrent aggressive falcine meningiomas.

Recurrent aggressive falcine meningiomas are uncommon tumors that recur despite receiving extensive surgery and radiation therapy (RT). We have utilized brachytherapy as a salvage treatment in two such patients with a unique implantation technique. Both patients had recurrence of WHO Grade II falcine meningiomas despite multiple prior surgical and RT treatments. Radioactive I-125 seeds were made into strands and sutured into a mesh implant, with 1 cm spacing, in a size appropriate to cover the cavity and region of susceptible falcine dura. Following resection the vicryl mesh was implanted and fixed to the margins of the falx. Implantation in this interhemispheric space provides good dose conformality with targeting of at-risk tissue and minimal radiation exposure to normal neural tissues. The patients are recurrence free 31 and 10 months after brachytherapy treatment. Brachytherapy was an effective salvage treatment for the recurrent aggressive falcine meningiomas in our two patients.

AZD2171, a pan-VEGF receptor tyrosine kinase inhibitor, normalizes tumor vasculature and alleviates edema in glioblastoma patients.

Using MRI techniques, we show here that normalization of tumor vessels in recurrent glioblastoma patients by daily administration of AZD2171-an oral tyrosine kinase inhibitor of VEGF receptors-has rapid onset, is prolonged but reversible, and has the significant clinical benefit of alleviating edema. Reversal of normalization began by 28 days, though some features persisted for as long as four months. Basic FGF, SDF1alpha, and viable circulating endothelial cells (CECs) increased when tumors escaped treatment, and circulating progenitor cells (CPCs) increased when tumors progressed after drug interruption. Our study provides insight into different mechanisms of action of this class of drugs in recurrent glioblastoma patients and suggests that the timing of combination therapy may be critical for optimizing activity against this tumor.

Underutilization of radiation therapy in patients with glioblastoma: predictive factors and outcomes.

BACKGROUND: Randomized trials have demonstrated that radiation improves survival in patients with glioblastoma. The purpose of this study was to characterize the risk factors and impact of omission of radiation therapy in such patients. METHODS: The Surveillance, Epidemiology, and End Results (SEER) program was used to identify 22,777 patients diagnosed with glioblastoma between 1988 and 2007. Multivariable logistic regression was employed to identify predictors associated with omission of radiation. Cox regression was used to characterize the impact of omitting radiation on all-cause mortality. RESULTS: Among the entire cohort, 16,863 of 22,777 patients (74%) received radiation, whereas 5914 of 22,777 patients (26%) did not. Factors associated with omission of radiation included older age (OR=1.048 per year increase, 95% CI=1.046-1.051, P<.001), lower annual income (OR=0.93 per $10,000 increase, 95% CI=0.90-0.96, P<.001), African American race (reference=white, OR=1.19, 95% CI=1.03-1.37, P=.02), Hispanic race (OR=1.34, 95% CI=1.19-1.50, P< .001), Asian American race (OR=1.24, 95% CI=1.04-1.48, P<.001), unmarried status (OR=1.71, 95% CI=1.60-1.83, P< .001), and subtotal resection/biopsy (OR=1.82, 95% CI=1.69-1.96, P<.001). The use of radiation was significantly associated with improved overall survival (2-year survival: 14.6% versus 4.2%, P<.001; adjusted HR=2.09, 95% CI=2.02-2.16, P<.001). When the population was restricted to patients <50 years old, these findings remained largely unchanged. CONCLUSIONS: Radiation therapy is associated with survival benefit in patients with glioblastoma, and sociodemographic factors play a significant role in the underutilization of radiation. The underlying causes for these disparities in care require further research.

Low-grade gliomas.

Low-grade gliomas (LGGs) are a diverse group of primary brain tumors that often arise in young, otherwise healthy patients and generally have an indolent course with longer-term survival in comparison with high-grade gliomas. Treatment options include observation, surgery, radiation, chemotherapy, or a combined approach, and management is individualized based on tumor location, histology, molecular profile, and patient characteristics. Moreover, in this type of brain tumor with a relatively good prognosis and prolonged survival, the potential benefits of treatment must be carefully weighed against potential treatment-related risks. We review in this article current management strategies for LGG, including surgery, radiotherapy, and chemotherapy. In addition, the importance of profiling the genetic and molecular properties of LGGs in the development of targeted anticancer therapies is also reviewed. Finally, given the prevalence of these tumors in otherwise healthy young patients, the impact of treatment on neurocognitive function and quality of life is also evaluated.

Central nervous system cancers, version 2.2014. Featured updates to the NCCN Guidelines.

The NCCN Guidelines for Central Nervous System Cancers provide multidisciplinary recommendations for the clinical management of patients with cancers of the central nervous system. These NCCN Guidelines Insights highlight recent updates regarding the management of metastatic brain tumors using radiation therapy. Use of stereotactic radiosurgery (SRS) is no longer limited to patients with 3 or fewer lesions, because data suggest that total disease burden, rather than number of lesions, is predictive of survival benefits associated with the technique. SRS is increasingly becoming an integral part of management of patients with controlled, low-volume brain metastases.