Stereotactic Radiosurgery for Vestibular Schwannoma With Radiographic Brainstem Compression.

OBJECTIVE: The safety of single-treatment stereotactic radiosurgery (SRS) for vestibular schwannoma (VS) with radiographic evidence of brainstem compression but without motor deficit is controversial. Data on linear accelerator (linac)-based SRS in this setting are scarce. We address this with an outcomes report from an unselected series of patients with VS with radiographic brainstem compression treated with linac SRS. METHODS: We included 139 patients with unilateral VS (any size) with radiographic brainstem compression (all without serious brainstem neurological deficits). The SRS prescription dose was 12.5 Gy (single fraction) using 6MV linac-produced photon beams, delivered with a multiple arc technique. Inclusion criteria required at least 1 year of radiographic follow-up with magnetic resonance imaging. The primary endpoint was freedom from serious brainstem toxicity (≥grade 3 Common Terminology Criteria for Adverse Events v5); the secondary was freedom from enlargement (tumor progression or any requiring intervention). We assessed serious cranial nerve complications, excluding hearing loss, defined as Common Terminology Criteria for Adverse Events v5 grade 3 toxicity. RESULTS: Median magnetic resonance imaging follow-up time was 5 years, and median tumor size was 2.5 cm in greatest axial dimension and 5 ml in volume. The median brainstem D0.03 ml=12.6 Gy and median brainstem V10 Gy=0.4 ml. At 5 years, the actuarial freedom from serious brainstem toxicity was 100%, and freedom from tumor enlargement (requiring surgery and/or due to progression) was 90%. Severe facial nerve damage in patients without tumor enlargement was 0.9%. CONCLUSION: Linac-based SRS, as delivered in our series for VS with radiographic brainstem compression, is safe and effective.

Repeat single-fraction stereotactic radiosurgery for recurrent vestibular schwannoma.

Background: Data are scarce on the efficacy of a second radiosurgery (SRS) treatment of vestibular schwannoma that has progressed following initial treatment with SRS. We sought to report the outcome of our repeat SRS series with long-term imaging follow-up. Materials and methods: We retrospectively analyzed 6 patients who met the following criteria: Repeat SRS at our institution between 1995 and 2018; solitary unilateral tumor; no evidence of neurofibromatosis; and magnetic resonance (MR) planning for both SRS treatments. All treatments were delivered with a linear accelerator-based system using head frame immobilization. The prescribed dose to the periphery of the tumor was 12.5 Gy in all initial and repeat SRS treatments, except for one repeat treatment to 10 Gy. Results: Follow-up with MR scan following the second SRS treatment was a median 8.4 years. The tumor control rate (lack of progression) following the second SRS treatment was 83% (5/6). Actuarial 10-year outcomes following repeat SRS were: tumor control, 80%; absolute survival, 80%; and cause-specific survival, 100%. Of the patients with at least minimal hearing retention before initial SRS, none had ipsilateral hearing preservation after initial radiation treatment. Improvement in any pretreatment cranial nerve deficits was not seen. The only permanent grade ≥ 3 toxicity from repeat SRS was a case of infraorbital nerve deficit. No patient developed a stroke, malignant transformation, induced second tumor, or facial nerve deficit. Conclusion: There was excellent overall survival, tumor control, and low morbidity in our series for recurrent vestibular schwannoma submitted to repeat single-fraction SRS, supporting additional studies of this treatment strategy.

Clival Paraganglioma, Case Report and Literature Review.

Paragangliomas are rare tumors that may present with cranial neuropathies when located along the skull base. Supratentorial paragangliomas are less likely to secrete catecholamines but should be worked up, nonetheless. We highlight a case of a female in her fourth decade found to have a petroclival lesion following initial presentation that included one month of tooth pain, dysphagia, diplopia, hoarseness and right hemifacial hypoesthesia. Magnetic resonance imaging of the brain demonstrated a T2 hyperintense lesion favored to be a petroclival meningioma. Pre-operative angiography demonstrated a hypervascular tumor. She underwent a combined presigmoid craniotomy with posterior petrosectomy performed by both neurosurgery and neuro-otology. Pathology demonstrated paraganglioma. She had small volume residual tumor and is planned for continued outpatient radiotherapy. Paragangliomas should be on the differential for skull base lesions. Management paradigm involves multidisciplinary care and a combination of surgical resection and post-operative radiation. In this paper, we discuss underlying pathophysiology as well as appropriate workup and management.

Rapid diversification of vascular architecture underlies the Carboniferous fern radiation.

Vascular plants account for 93% of Earth's terrestrial flora. Xylem and phloem, vital for transporting water and nutrients through the plant, unite this diverse clade. Three-dimensional arrangements of these tissues (vascular architecture) are manifold across living and extinct species. However, the evolutionary processes underlying this variation remain elusive. Using ferns, a diverse clade with multiple radiations over their ca 400-million-year history, we synthesized data across 3339 species to explore the tempo and mode of vascular evolution and to contextualize dynamics of phenotypic innovation during major fern diversification events. Our results reveal three paradigm shifts in our understanding of fern vascular evolution. (i) The canonical theory on the stepwise and unidirectional evolution of vascular architecture does not capture the complexities of character evolution among ferns. Rather, a new model permitting additional transitions, rate heterogeneity and multiple reversions is more likely. (ii) Major shifts in vascular architecture correspond to developmental changes in body size, not regional water availability. (iii) The early Carboniferous radiation of crown-group ferns was characterized by an explosion of phenotypic innovation. By contrast, during the Cretaceous and Cenozoic rise of eupolypods, rates of vascular evolution were dramatically low and seemingly decoupled from lineage diversification.

A Distinct DNA Methylation Shift in a Subset of Glioma CpG Island Methylator Phenotypes during Tumor Recurrence.

Glioma diagnosis is based on histomorphology and grading; however, such classification does not have predictive clinical outcome after glioblastomas have developed. To date, no bona fide biomarkers that significantly translate into a survival benefit to glioblastoma patients have been identified. We previously reported that the IDH mutant G-CIMP-high subtype would be a predecessor to the G-CIMP-low subtype. Here, we performed a comprehensive DNA methylation longitudinal analysis of diffuse gliomas from 77 patients (200 tumors) to enlighten the epigenome-based malignant transformation of initially lower-grade gliomas. Intra-subtype heterogeneity among G-CIMP-high primary tumors allowed us to identify predictive biomarkers for assessing the risk of malignant recurrence at early stages of disease. G-CIMP-low recurrence appeared in 9.5% of all gliomas, and these resembled IDH-wild-type primary glioblastoma. G-CIMP-low recurrence can be characterized by distinct epigenetic changes at candidate functional tissue enhancers with AP-1/SOX binding elements, mesenchymal stem cell-like epigenomic phenotype, and genomic instability. Molecular abnormalities of longitudinal G-CIMP offer possibilities to defy glioblastoma progression.

Evidence for parent-of-origin effects and interparental conflict in seeds of an ancient flowering plant lineage.

Theoretical and empirical studies have long connected the evolutionary innovation of endosperm, a genetically biparental product of a double fertilization process unique to flowering plants (angiosperms), to conflicting parental interests over offspring provisioning. Yet, none of these studies examined interparental conflict in representatives of any of the most ancient angiosperm lineages. We performed reciprocal interploidy crosses in the water lily Nymphaea thermarum, a member of one of the most ancient angiosperm lineages, Nymphaeales. We find that an excess of paternal genomes is associated with an increase in endosperm growth. By contrast, maternal ploidy negatively influences development or growth of all seed components, regardless of paternal genome dosage. Most relevant to the conflict over distribution of maternal resources, however, is that growth of the perisperm (seed storage tissue derived from the maternal sporophyte, found in all Nymphaeales) is unaffected by paternal genome dosage-ensuring maternal control of maternal resources. We conclude that the evolutionary transfer of embryo-nourishing function from a genetically biparental endosperm to a genetically maternal perisperm can be viewed as an effective maternal strategy to recapture control of resource distribution among progeny, and thus that interparental conflict has influenced the evolution of seed development in this ancient angiosperm lineage.

Long-term Outcomes After Radiosurgery for Temporal Bone Paragangliomas.

OBJECTIVES: To determine the long-term outcome after stereotactic radiosurgery (SRS) for temporal bone paragangliomas. MATERIALS AND METHODS: We retrospectively reviewed the medical records of 11 patients with temporal bone paragangliomas (10 patients with a glomus jugulare tumor and 1 patient with a glomus tympanicum tumor) treated between January 1997 and July 2012 at the University of Florida with SRS to a median dose of 15 Gy in 1 fraction. Ten previously unirradiated patients received SRS as did 1 patient who received prior fractionated radiotherapy (FRT) and then received salvage SRS for a local recurrence. The major outcome endpoint was local control, meaning no further growth or shrinkage on follow-up computed tomography or magnetic resonance imaging scans. RESULTS: The median follow-up time was 5.3 years. Two patients developed a local recurrence after SRS, including the patient who received salvage SRS after prior FRT. The overall local control rates at 5 and 10 years were both 81%. The cause-specific survival rates at 5 and 10 years were both 88%. The distant metastasis-free survival rates at 5 and 10 years were both 100%. The overall survival rates at 5 and 10 years were both 78%. There were no severe complications. CONCLUSIONS: SRS for benign head and neck paragangliomas is a safe and efficacious treatment associated with minimal morbidity. SRS is suitable for patients with skull base tumors <3 cm when FRT is logistically unsuitable. Surgery is reserved for patients in good health whose risk of associated morbidity is low. Observation is a reasonable option for asymptomatic patients with a limited life expectancy.

Long-term Outcome After Fractionated Radiotherapy for Pituitary Adenoma: The Curse of the Secretory Tumor.

OBJECTIVES: To determine the influence of secretory status on long-term outcome after fractionated radiotherapy (RT) for gross residual pituitary adenoma. MATERIALS AND METHODS: This is a retrospective study of 116 consecutively treated patients who met the following inclusion criteria: tissue diagnosis of pituitary adenoma, visible tumor at the time of RT, treatment with fractionated RT, and imaging follow-up of ≥2 years. Hypersecretion of growth hormone, adrenocorticotrophic hormone, prolactin, or thyroid-stimulating hormone was documented in 30 patients (26%). The RT dose in most (78%) patients was 45 Gy at 1.8 Gy per fraction. The major outcome endpoint is clinical and biochemical control, meaning no growth on follow-up scans and normalization of hypersecretion, if present before RT. RESULTS: Long-term tumor control was outstanding for nonsecretory tumors: 96% at 10 years. There was a major drop in the control rate of secretory tumors: 10-year clinical and biochemical control was 62% (P<0.0001 vs. 96%). Multivariate analysis confirmed secretory status as the only independent prognostic factor (variables analyzed were sex, age, tumor size, RT dose, and secretory status). CONCLUSIONS: Secretory pituitary adenomas have a worse prognosis than nonsecretory tumors after 45 to 50 Gy of conventionally fractionated RT. As a result of this finding, our plan is to increase the intensity of RT in secretory tumors, but our data did not evaluate this approach. The treatment guidelines that we currently use in pituitary adenoma are as follows. Radiosurgery (20 to 30 Gy) is our first-choice treatment of a secretory tumor that cannot be completely resected. When treating gross residual pituitary adenoma with fractionated RT, we use the following dose schedules: Nonsecretory: 45 Gy at 1.8 Gy/fraction, once-daily fractionation. Secretory: 54 Gy at 1.8 Gy/fraction once daily or 55.2 Gy at 1.2 Gy/fraction with twice-daily treatment.

The risk of malignancy anywhere in the body after linear accelerator (LINAC) stereotactic radiosurgery.

BACKGROUND: Despite the conformity of stereotactic radiosurgery (SRS) treatment, there are concerns about the risk of malignancy. OBJECTIVE: We compared the number of cancer cases observed after treatment in a group of SRS patients to the number of cancer cases that would be expected in an age- and gender-matched group. METHODS: We collected data from the University of Florida SRS database for patients treated for meningiomas, intracranial schwannomas, arteriovenous malformations (AVMs), trigeminal neuralgia, pituitary adenomas, cavernous angiomas, and metastases. We used the Florida Cancer Data System (FCDS) to determine the actual cancer rates for SRS-treated patients, and we compared these to the cancer rates in similar groups of non-SRS-treated patients based on rates available from the SEER (surveillance epidemiology and end results) database. RESULTS: A total of 2,369 patients were analyzed. Of these, 862 were patients with metastases who were analyzed only to ensure the sensitivity of using the FCDS to determine malignancy rates. The results for patients with more than 5 years of follow-up are reported. Without the metastases patients, a total of 627 patients had more than 5 years of follow-up data. Follow-up in patient-years was 1,711 for the meningioma patients, 1,851 for the schwannoma patients, 1,407 for the AVM patients and 338 for patients with a diagnosis of 'other'. The observed cancer rate in the meningioma patients was 3.96% compared to the expected rate of 10% (binomial 95% confidence interval, CI = 1.85-7.94). The observed cancer rate in the schwannoma patients was 4.93% compared to the expected rate of 12.5% (95% CI = 2.61-8.89). The observed cancer rate in the AVM patients was 3.64% compared to the expected rate of 4.43% (95% CI = 1.49-8.10). The observed cancer rate in patients treated for other diagnoses (e.g. pituitary adenoma or trigeminal neuralgia) was 0% compared to the expected rate of 6.36% (95% CI = 0-11.7). CONCLUSIONS: In a large population of SRS-treated patients, there was no increased risk of malignancy compared to the general population.

The science of medical decision making: neurosurgery, errors, and personal cognitive strategies for improving quality of care.

During the last 2 decades, there has been a shift in the U.S. health care system towards improving the quality of health care provided by enhancing patient safety and reducing medical errors. Unfortunately, surgical complications, patient harm events, and malpractice claims remain common in the field of neurosurgery. Many of these events are potentially avoidable. There are an increasing number of publications in the medical literature in which authors address cognitive errors in diagnosis and treatment and strategies for reducing such errors, but these are for the most part absent in the neurosurgical literature. The purpose of this article is to highlight the complexities of medical decision making to a neurosurgical audience, with the hope of providing insight into the biases that lead us towards error and strategies to overcome our innate cognitive deficiencies. To accomplish this goal, we review the current literature on medical errors and just culture, explain the dual process theory of cognition, identify common cognitive errors affecting neurosurgeons in practice, review cognitive debiasing strategies, and finally provide simple methods that can be easily assimilated into neurosurgical practice to improve clinical decision making.

Intracranial arteriovenous malformation in a college football player and return-to-play considerations.

: The reported prevalence rates of arteriovenous malformations (AVMs) in the general population range from 0.001% to 0.50%. The following case describes the initial presentation of hemorrhage from an intracranial AVM in an 18-year-old college football player. It also discusses treatment of the AVM with stereotactic radiosurgery and successful return to football 17 months after radiosurgery (18.5 months after initial presentation). It is the first published description of return to contact sports after stereotactic radiosurgery for intracranial AVM.

The accuracy of predicting survival in individual patients with cancer.

OBJECT: Estimating survival time in cancer patients is crucial for clinicians, patients, families, and payers. To provide appropriate and cost-effective care, various data sources are used to provide rational, reliable, and reproducible estimates. The accuracy of such estimates is unknown. METHODS: The authors prospectively estimated survival in 150 consecutive cancer patients (median age 62 years) with brain metastases undergoing radiosurgery. They recorded cancer type, number of brain metastases, neurological presentation, extracranial disease status, Karnofsky Performance Scale score, Recursive Partitioning Analysis class, prior whole-brain radiotherapy, and synchronous or metachronous presentation. Finally, the authors asked 18 medical, radiation, or surgical oncologists to predict survival from the time of treatment. RESULTS: The actual median patient survival was 10.3 months (95% CI 6.4-14). The median physician-predicted survival was 9.7 months (neurosurgeons = 11.8 months, radiation oncologists = 11.0 months, and medical oncologist = 7.2 months). For patients who died before 10 months, both neurosurgeons and radiation oncologists generally predicted survivals that were more optimistic and medical oncologists that were less so, although no group could accurately predict survivors alive at 14 months. All physicians had individual patient survival predictions that were incorrect by as much as 12-18 months, and 14 of 18 physicians had individual predictions that were in error by more than 18 months. Of the 2700 predictions, 1226 (45%) were off by more than 6 months and 488 (18%) were off by more than 12 months. CONCLUSIONS: Although crucial, predicting the survival of cancer patients is difficult. In this study all physicians were unable to accurately predict longer-term survivors. Despite valuable clinical data and predictive scoring techniques, brain and systemic management often led to patient survivals well beyond estimated survivals.

Stereotactic radiosurgery of intracranial arteriovenous malformations.

Stereotactic radiosurgery for intracranial arteriovenous malformations (AVMs) has been performed since the 1970s. When an AVM is treated with radiosurgery, radiation injury to the vascular endothelium induces the proliferation of smooth muscle cells and the elaboration of extracellular collagen, which leads to progressive stenosis and obliteration of the AVM nidus. Obliteration after AVM radiosurgery ranges from 60% to 80%, and relates to the size of the AVM and the prescribed radiation dose. The major drawback of radiosurgical AVM treatment is the risk of bleeding during the latent period (typically 2 years) between treatment and AVM thrombosis.

The somatic genomic landscape of glioblastoma.

We describe the landscape of somatic genomic alterations based on multidimensional and comprehensive characterization of more than 500 glioblastoma tumors (GBMs). We identify several novel mutated genes as well as complex rearrangements of signature receptors, including EGFR and PDGFRA. TERT promoter mutations are shown to correlate with elevated mRNA expression, supporting a role in telomerase reactivation. Correlative analyses confirm that the survival advantage of the proneural subtype is conferred by the G-CIMP phenotype, and MGMT DNA methylation may be a predictive biomarker for treatment response only in classical subtype GBM. Integrative analysis of genomic and proteomic profiles challenges the notion of therapeutic inhibition of a pathway as an alternative to inhibition of the target itself. These data will facilitate the discovery of therapeutic and diagnostic target candidates, the validation of research and clinical observations and the generation of unanticipated hypotheses that can advance our molecular understanding of this lethal cancer.

Mixed-reality simulation for neurosurgical procedures.

BACKGROUND: Surgical education is moving rapidly to the use of simulation for technical training of residents and maintenance or upgrading of surgical skills in clinical practice. To optimize the learning exercise, it is essential that both visual and haptic cues are presented to best present a real-world experience. Many systems attempt to achieve this goal through a total virtual interface. OBJECTIVE: To demonstrate that the most critical aspect in optimizing a simulation experience is to provide the visual and haptic cues, allowing the training to fully mimic the real-world environment. METHODS: Our approach has been to create a mixed-reality system consisting of a physical and a virtual component. A physical model of the head or spine is created with a 3-dimensional printer using deidentified patient data. The model is linked to a virtual radiographic system or an image guidance platform. A variety of surgical challenges can be presented in which the trainee must use the same anatomic and radiographic references required during actual surgical procedures. RESULTS: Using the aforementioned techniques, we have created simulators for ventriculostomy, percutaneous stereotactic lesion procedure for trigeminal neuralgia, and spinal instrumentation. The design and implementation of these platforms are presented. CONCLUSION: The system has provided the residents an opportunity to understand and appreciate the complex 3-dimensional anatomy of the 3 neurosurgical procedures simulated. The systems have also provided an opportunity to break procedures down into critical segments, allowing the user to concentrate on specific areas of deficiency.

Magnetic resonance imaging assessment of cerebral arteriovenous malformation obliteration after stereotactic radiosurgery.

BACKGROUND: Stereotactic radiosurgery is ideal for treating small cerebral arteriovenous malformations (AVMs) that are surgically inaccessible. However, given the inherent delay of AVM obliteration and the potential for radiosurgical failure, detailed evaluation of the neurovascular architecture is necessary to monitor persistence of residual flow. Modern imaging systems such as magnetic resonance imaging (MRI) and angiography allow clinicians to assess transnidus flow after radiosurgical intervention. OBJECTIVE: To determine the accuracy of an MRI diagnosis of complete thrombosis and to identify variables that affect the precision of MRI assessment. METHODS: One hundred twenty patients were reviewed after receiving radiosurgery at the University of Florida from 1990 to 2010. Each patient had an MRI demonstrating AVM obliteration and an angiogram either confirming or denying AVM thrombosis. RESULTS: MRI correctly predicted complete AVM obliteration in 82% of patients. There was a significant correlation between AVM volume and MRI accuracy in 2 separate models. In the first model, logistic regression analysis revealed a significant linear relationship between the natural log of AVM volume and MRI accuracy. The second model showed significant evidence of a cutoff point in MRI accuracy near an AVM volume of 2.80 cm(3), above which MRI agreement with angiography is 90% and below which MRI agreement falls off sharply to remain constant at 70%. CONCLUSION: MRI is a useful diagnostic system for assessing AVM obliteration, but its accuracy is inherently linked to the nidus volume it is measuring. These results suggest that MRI may be able to take on an increasingly independent role in the evaluation of AVM regression.

Radiation therapy for optic nerve sheath meningioma.

PURPOSE: To explain the concepts that radiation oncologists should understand to manage patients with optic nerve sheath meningioma (ONSM). To accomplish this goal we first describe our institution's experience with the treatment of ONSM with radiation therapy and then use this data set as a framework for explaining the role of radiation therapy in the treatment of this uncommon tumor. METHODS AND MATERIALS: We studied the outcomes of all 15 patients treated at our medical center with radiation therapy for ONSM between 1990 and 2006. The minimum follow-up was 5 years (median, 12 years). The median dose was 50.4 Gy at 1.8 Gy per treatment (range, 50-54 Gy). RESULTS: No patient experienced tumor progression. The rates of local control, regional control, and relapse free-survival were all 100%. Radiographic tumor response after radiation therapy was as follows: No change in 93%; and a reduction in size in 7%. Vision status after radiation therapy was as follows: Stable in 60%; improved in 27%; and decreased in 13%. Vision was classified as "useful" at last follow-up in 86% of patients with useful vision at the time of radiation therapy. The only treatment complication was moderate retinopathy in 2 patients. At last follow-up, no patient had developed a second tumor. CONCLUSIONS: Radiation therapy with 50.4 Gy at 1.8 Gy per treatment prevents tumor growth and vision deterioration in most patients with ONSM.

Radiographic response of brain metastasis after linear accelerator radiosurgery.

BACKGROUND: Radiographic response of brain metastasis to stereotactic radiosurgery (SRS) over time has not been well characterized. Being able to predict SRS-induced changes in tumor size over time may allow improved counseling of patients and potentially earlier recognition of poor response to SRS. OBJECTIVE: To quantify the rate of change in size of metastatic brain tumors after treatment with a linear accelerator (LINAC) SRS. METHODS: We performed a retrospective analysis of patients with single metastatic brain tumors treated with LINAC SRS at the University of Florida between 1992 and 2009 who had at least one MRI after treatment. A total of 218 patients with 406 follow-up MRI scans were included in the study. Tumor area was calculated by measuring the largest tumor area on axial imaging and using the equation for area of an ellipse. Primary outcome was percent change in tumor size. The contribution of several factors including gender, primary tumor histology, synchronous or asynchronous presentation, prior treatment, primary tumor control, and SRS dose were examined using multivariate analysis. RESULTS: Mean patient age was 58.3 years (range 4-86), and 48.6% of patients were female. Sixty-three percent of patients had primary tumor control and 70.6% had asynchronous presentation of their brain metastases. SRS peripheral dose range was 1,000-2,250 cGy with a median of 1,750 cGy. The mean percent size change was -22.6% with a mean rate of change of -7.0% per month. The median percent change was -49.7% with a median rate of change of -8.8% per month. The median follow-up was 4.8 months (range 0.3-52.5). Female gender and melanoma histology were found to be significant predictors of an increase in tumor size. Lack of previous surgical resection was a significant predictor of a decrease in tumor size after SRS. Other factors tested with multivariate analysis, including age, synchronicity of presentation, dose, dose volume, Karnofsky performance score, and primary tumor control, were not significant in predicting tumor size change after SRS. CONCLUSION: In this study, brain metastases decreased in size by a median of 50% for a median follow-up of 4.8 months after SRS. The overall rate of decrease was 9% per month after treatment with SRS. Melanoma histology was a predictor of poor tumor control.