Timothy Ryken

INTRODUCTION The Vigilant ObservatIon of GlIadeL WAfer ImplaNT (VIGILANT) registry (NCT02684838) was initiated to evaluate the use of BCNU wafers for treatment of CNS malignancies in contemporary practice and in the new era of molecular analysis. METHODS The VIGILANT registry is an observational study. Each patient receives usual care from treating physicians in routine quarterly visits, with no registry-specific visits required. The VIGILANT registry will enroll up to 500 patients at 35 US sites. Patients must be ≥18 years of age with no medical conditions increasing risk through participation. Patient follow-up will last 3 years. RESULTS The interim analysis is ongoing, with the following preliminary data. Of the 143 patients enrolled to date (mean age 59.8 ± 13.41 years, 60.1% male, 82.5% white), BCNU wafers have been implanted for newly diagnosed glioblastoma (GBM) in 49 (34.3%); for recurrent GBM in 48 (33.6%); for brain metastases in 28 (19.6%); for anaplastic oligodendrogliom...

SUMMARY: One hundred and thirty cases of craniotomy for tumor utilizing BCNU implantable chemotherapy were performed by the authors between including 23 cases for metastatic intracranial disease. The series included 12 woman and 11 men with an average age of 56.9 years. The diagnoses were as follows: non-small lung carcinoma (13), breast cancer (6), small-cell lung cancer (1), colon cancer (1), unknown primary (2). Patients undergoing resection plus implantable chemotherapy following whole brain radiotherapy (5 patients) or following stereotactic radiosurgery (5 patients) were the most common. Only patient developed possible local recurrence (3%). Complications included two cerebrospinal fluid leaks with associated complications requiring reoperations (11%) both following whole brain radiotherapy and 3 patients (17%) with thromboembolic episodes (3 deep venous thromboses, one with a pulmonary embolus and sudural hematoma). In this challenging population, local implantable chemothera...

The extensive heterogeneity both between and within the medulloblastoma (MB) subgroups underscores a critical need for variant-specific biomarkers and therapeutic strategies. We previously identified a role for the CD271/p75 neurotrophin receptor (p75NTR) in regulating stem/progenitor cells in the SHH MB subgroup. Here we demonstrate the utility of CD271 as a novel diagnostic and prognostic marker for SHH MB using immunohistochemical analysis and transcriptome data across 763 primary tumors. RNA sequencing of CD271+ and CD271- cells revealed molecularly distinct, co-existing cellular subsets both in vitro and in vivo. MAPK/ERK signaling was upregulated in the CD271+ population, and inhibiting this pathway reduced endogenous CD271 levels, stem/progenitor cell proliferation, and cell survival as well as cell migration in vitro. Treatment with the MEK inhibitor selumetinib extended survival and reduced CD271 levels in vivo; whereas, treatment with vismodegib, a well-known smoothened (S...

Implantation of biodegradable wafers impregnated with carmustine (BCNU) is one of the few chemotherapeutic modalities that have been evaluated in Phase III trials and approved by the US FDA for treatment of newly diagnosed high-grade glioma and recurrent glioblastoma. Enrolling up to 500 patients for 3-year follow-up at over 30 sites, the prospective Vigilant ObservatIon of GlIadeL WAfer ImplaNT (VIGILANT) registry (NCT02684838) will evaluate BCNU wafers for treatment of CNS malignancies in contemporary practice and in the new era of molecular tumor analysis. Subgroup analyses will include tumor type, molecular marker status, and treatment combinations. Interim analyses from the VIGILANT registry will be reported until complete results are available in 2024.

Object The objective of this systematic review was to use evidence-based medicine to identify the best methodology for diagnosis and treatment of anterior pseudarthrosis. Methods The National Library of Medicine and Cochrane Database were queried using MeSH headings and key words relevant to pseudarthrosis and cervical spine surgery. s were reviewed, after which studies meeting inclusion criteria were selected. The guidelines group assembled an evidentiary table summarizing the quality of evidence (Classes I–III). Disagreements regarding the level of evidence were resolved through an expert consensus conference. The group formulated recommendations that contained the degree of strength based on the Scottish Intercollegiate Guidelines network. Validation was done through peer review by the Joint Guidelines Committee of the American Association of Neurological Surgeons/Congress of Neurological Surgeons. Results Evaluation for pseudarthrosis is warranted, as there may be an association...

Object The objective of this systematic review was to use evidence-based medicine to examine the efficacy of cervical laminectomy and fusion for the treatment of cervical spondylotic myelopathy (CSM). Methods The National Library of Medicine and Cochrane Database were queried using MeSH headings and keywords relevant to cervical laminectomy, fusion, and CSM. s were reviewed, after which studies that met the inclusion criteria were selected. The guidelines group assembled an evidentiary table summarizing the quality of evidence (Class I–III). Disagreements regarding the level of evidence were resolved through an expert consensus conference. The group formulated recommendations which contained the degree of strength based on the Scottish Intercollegiate Guidelines network. Validation was done through peer-review by the Joint Guidelines Committee of the American Association of Neurological Surgeons/Congress of Neurological Surgeons. Results Cervical laminectomy with fusion (arthrodesis...

Object The objective of this systematic review was to use evidence-based medicine to examine the efficacy of anterior cervical surgery for the treatment of cervical spondylotic myelopathy (CSM). Methods The National Library of Medicine and Cochrane Database were queried using MeSH headings and key words relevant to anterior cervical surgery and CSM. s were reviewed, and studies meeting inclusion criteria were selected. The guidelines group assembled an evidentiary table summarizing the quality of evidence (Classes I–III). Disagreements regarding the level of evidence were resolved through an expert consensus conference. The group formulated recommendations that contained the degree of strength based on the Scottish Intercollegiate Guidelines network. Validation was done through peer review by the Joint Guidelines Committee of the American Association of Neurological Surgeons/Congress of Neurological Surgeons. Results Mild CSM (modified Japanese Orthopaedic Association [mJOA] scale s...

Object The objective of this systematic review was to use evidence-based medicine to examine the diagnostic and therapeutic utility of intraoperative electrophysiological (EP) monitoring in the surgical treatment of cervical degenerative disease. Methods The National Library of Medicine and Cochrane Database were queried using MeSH headings and key words relevant to cervical spine surgery and EP monitoring. The guidelines group assembled an evidentiary table summarizing the quality of evidence (Classes I–III). The group formulated recommendations that contained the degree of strength based on the Scottish Intercollegiate Guidelines network. Validation was done through peer review by the Joint Guidelines Committee of the American Association of Neurological Surgeons/Congress of Neurological Surgeons. Results The reliance on changes in EP monitoring as an indication to alter a surgical plan or administer steroids has not been observed to reduce the incidence of neurological injury during routine surgery for cervical spondylotic myelopathy or cervical radiculopathy (Class III). However, there is an absence of study data examining the benefit of altering a surgical plan due to EP changes. Conclusions Although the use of EP monitoring may serve as a sensitive means to diagnose potential neurological injury during anterior spinal surgery for cervical spondylotic myelopathy, the practitioner must understand that intraoperative EP worsening is not specific—it may not represent clinical worsening and its recognition does not necessarily prevent neurological injury, nor does it result in improved outcome (Class II). Intraoperative improvement in EP parameters/indices does not appear to forecast outcome with reliability (conflicting Class I data).

Protein kinase CK2 is an ubiquitous and constitutively active kinase, which phosphorylates many cellular proteins and is implicated in the regulation of cell survival, proliferation and transformation. We investigated its possible involvement in the multidrug ...

From 1970 to 1997, 63 patients with medulloblastoma were treated with craniospinal irradiation followed by a posterior fossa boost. There were 38 males and 25 females with a median age of 9 years (range, 8 months to 53 years). Stage was T1-T3a in 50 (79%) and M0 in 38 patients (60%) according to the Chang staging system. Gross total resection of the primary tumor was achieved in 33 (52%) and median posterior fossa dose was 54 Gy, with 55 (87%) receiving > or =50 Gy. Median radiotherapy treatment duration was 49 days (range, 30-104 days) with 35 patients (56%) completing radiotherapy in <50 days. The most common reasons for a protracted radiotherapy treatment duration > or =50 days were hematologic toxicity (46%) and use of <1.6 Gy fraction size per day (29%). Chemotherapy was used in 22 (35%). Median follow-up time was 10.8 years (range, 2-28.5 years). The 5- and 10-year freedom from progression rates were 58% +/- 13% and 50% +/- 13%, respectively, whereas the 5- and 10-year posterior fossa control rates were 61% +/- 12% and 54% +/- 13%, respectively. On multivariate analysis, age > or =3 years, M0 status, > or =50 Gy PFB dose, radiotherapy treatment duration <50 days, and use of chemotherapy correlated with better freedom from progression and posterior fossa control rates. The 5- and 10-year freedom from progression rates were 67% +/- 15% and 64% +/- 16%, respectively, for patients with radiotherapy treatment duration <50 days and were 42% +/- 20% and 29% +/- 18%, respectively, for duration > or =50 days ( p= 0.0026, log-rank test). The 5- and 10-year posterior fossa control rates were 70% +/- 15% and 70% +/- 15%, respectively, for radiotherapy treatment duration <50 days and 46% +/- 20% and 33% +/- 19%, respectively, for duration > or =50 days ( p= 0.0037, log-rank test). In addition to age > or =3 years, M0 stage, use of adjuvant chemotherapy, and posterior fossa dose > or =50 Gy, our findings also reveal that radiotherapy treatment duration…

In March 2006, the Joint Section on Disorders of the Spine and Peripheral Nerves of the American Association of Neurological Surgeons and Congress of Neurological Surgeons compiled an expert group to perform an evidence-based review of the clinical literature on management of cervical degenerative spine disease. This process culminated in the formation of the Guidelines for the Surgical Management of Cervical Degenerative Disease. The purpose of the Guidelines was to address questions regarding the therapy, diagnosis, and prognosis of cervical degenerative disease using an evidence-based approach. Development of an evidence-based review and recommendations is a multitiered process. Typical guideline development consists of 5 processes: 1) collection and selection of the evidence; 2) assessment of the quality and strength of the evidence; 3) analysis of the evidentiary data; 4) formulation of recommendations; and 5) guideline validation. This manuscript details the methodology in com...

Three-dimensional texture-based volume rendering is a technique that treats a 3D volume as a 3D texture, renders multiple 2D view-oriented slices and blends them into the frame buffers. This technique is thoroughly developed in computer graphics and medical visualization, and widely accepted due to the advancement of computer hardware. This research aims at developing fast parallel slice cutting and partial exposing algorithms used in real-time 3D-texture-based volume rendering for image-guided surgery and therapy planning. In texture-based volume rendering, a large amount of slices are needed to render the volume to achieve high quality image, but for real-time interactive volume rendering, the computation time is critical. Instead of repeating the cutting algorithms for each slice against the volume data as conventional cutting algorithms do, the slice cutting algorithm developed in this paper applies the cutting only to the initial slice, and gets the slice vertexes and 3D texture coordinates for all the others based on the distance between the current slice and the initial slice. The new algorithm dramatically reduces the computation time for slice cutting, and eases the generation of sectional view for a volume. Partial exposing is another useful technique used in volume visualization to reveal important but hidden information. Two depth-based partial exposing algorithms are developed and implemented in this paper. Both partial exposing techniques can work with arbitrary complex, but convex, shapes of cutaway object, and their implementations maintain the interactive frame rate for 3D texture-based volume rendering without apparent performance decline compared to non-cutaway rendering.

The objective of this systematic review was to use evidence-based medicine to identify the indications and utility of anterior cervical nerve root decompression. The National Library of Medicine and Cochrane Database were queried using MeSH headings and key words relevant to surgical management of cervical radiculopathy. Abstracts were reviewed after which studies meeting inclusion criteria were selected. The guidelines group assembled an evidentiary table summarizing the quality of evidence (Classes I-III). Disagreements regarding the level of evidence were resolved through an expert consensus conference. The group formulated recommendations that contained the degree of strength based on the Scottish Intercollegiate Guidelines network. Validation was done through peer review by the Joint Guidelines Committee of the American Association of Neurological Surgeons/Congress of Neurological Surgeons. Anterior nerve root decompression via anterior cervical discectomy (ACD) with or without fusion for radiculopathy is associated with rapid relief (3-4 months) of arm/neck pain, weakness, and/or sensory loss compared with physical therapy (PT) or cervical collar immobilization. Anterior cervical discectomy and ACD with fusion (ACDF) are associated with longer term (12 months) improvement in certain motor functions compared to PT. Other rapid gains observed after anterior decompression (diminished pain, improved sensation, and improved strength in certain muscle groups) are also maintained over the course of 12 months. However, comparable clinical improvements with PT or cervical immobilization therapy are also present in these clinical modalities (Class I). Conflicting evidence exists as to the efficacy of anterior cervical foraminotomy with reported success rates of 52-99% but recurrent symptoms as high as 30% (Class III). Anterior cervical discectomy, ACDF, and anterior cervical foraminotomy may improve cervical radicular symptoms. With regard to ACD and ACDF compared to PT or cervical immobilization, more rapid relief (within 3-4 months) may be seen with ACD or ACDF with maintenance of gains over the course of 12 months (Class I). Anterior cervical foraminotomy is associated with improvement in clinical function but the quality of data are weaker (Class III), and there is a wide range of efficacy (52-99%).

Operative intervention for craniovertebral junction (CVJ) instability in patients with Down syndrome has become controversial, with reports of a low incidence of associated neurological dysfunction and high surgical morbidity rates. The authors analyzed their experience in light of these poor results and attempted to evaluate differences in management. Medical and radiographic records of 36 consecutive patients with Down syndrome and CVJ abnormalities were reviewed. The most common clinical complaints included neck pain (15 patients) and torticollis (12 patients). Cervicomedullary compression was associated with ataxia and progressive weakness. Hyperreflexia was documented in a majority of patients (24 cases), and 13 patients suffered from varying degrees of quadriparesis. Upper respiratory tract infection precipitated the presentation in five patients. Four patients suffered acute neurological insults after a minor fall and two after receiving a general anesthetic agent. Atlantoaxial instability was the most common radiographically observed abnormality (23 patients), with a rotary component present in 14 patients. Occipitoatlantal instability was also frequently observed (16 patients) and was coexistent with atlantoaxial dislocation in 15 patients. Twenty individuals had bone anomalies, the most frequent of which was os odontoideum (12 patients) followed by atlantal arch hypoplasia and bifid anterior or posterior arches (eight patients). Twenty-seven patients underwent surgical procedures without subsequent neurological deterioration, and a 96% fusion rate was observed. In five of 11 patients basilar invagination was irreducible and required transoral decompression. Overall, 24 patients enjoyed good or excellent outcomes. The results of this series highlight the clinicopathological characteristics of CVJ instability in patients with Down syndrome and suggest that satisfactory outcomes can be achieved with low surgical morbidity rates.

The objective of this systematic review was to use evidence-based medicine to examine the efficacy of cervical laminoplasty in the treatment of cervical spondylotic myelopathy (CSM). The National Library of Medicine and Cochrane Database were queried using MeSH headings and keywords relevant to cervical laminoplasty and CSM. Abstracts were reviewed and studies meeting the inclusion criteria were selected. The guidelines group assembled an evidentiary table summarizing the quality of evidence (Classes I-III). Disagreements regarding the level of evidence were resolved through an expert consensus conference. The group formulated recommendations that contained the degree of strength based on the Scottish Intercollegiate Guidelines network. Validation was done through peer review by the Joint Guidelines Committee of the American Association of Neurological Surgeons and Congress of Neurological Surgeons. Cervical laminoplasty has improved functional outcome in the setting of CSM or ossification of the posterior longitudinal ligament. Using the Japanese Orthopaedic Association scale score, approximately 55-60% average recovery rate has been observed (Class III). The functional improvement observed after laminoplasty may be limited by duration of symptoms, severity of stenosis, severity of myelopathy, and poorly controlled diabetes as negative risk factors (Class II). There is conflicting evidence regarding age, with 1 study citing it as a negative risk factor, and another not demonstrating this result. Cervical laminoplasty is recommended for the treatment of CSM or ossification of the posterior longitudinal ligament (Class III).

Primary malignant spinal glioma represents a significant clinical challenge due to the devastating effect on clinical outcomes in the majority of cases. As they are infrequently encountered in any one center, there has been limited population-based data analysis on the incidence patterns of these aggressive tumors. The objective of this study was to use publically available Surveillance, Epidemiology and End Results (SEER) program data to examine the overall incidence and incidence patterns over time with regard to age at diagnosis, sex, race, primary site of tumor, and histological subtype in patients in whom primary malignant spinal cord gliomas were diagnosed between 1973 and 2006. The study population of interest was limited to primary, malignant, pathologically confirmed spinal cord gliomas based on data drawn from the SEER 9 standard registries for patients diagnosed between 1973 and 2006. Variables of interest included age at diagnosis, sex, race, primary site of tumor, and histological subtype of tumor. The SEER*Stat 6.5.2 program was used to calculate frequencies, age-adjusted incidence rates with 95% CIs, and annual percentage change (APC) statistics with a 2-sided p value. In addition, linear correlation coefficients (R(2)) were calculated for the time association stratified by variables of interest. The overall age-adjusted incidence rate for primary malignant spinal gliomas was 0.12 per 100,000, which increased significantly over the study period (APC = 1.74; p = 0.0004; R(2) = 0.36). The incidence was highest in patients diagnosed at ages 35-49 (0.17 per 100,000), males (0.14 per 100,000), whites (0.13 per 100,000), and those with ependymomas (0.07 per 100,000). Over the study period, the incidence of ependymomas increased significantly (APC = 3.17; p < 0.0001; R(2) = 0.58) as did the incidence of these tumors in whites (APC = 2.13; p = 0.0001) and for both males (APC = 1.90, p value < 0.0001) and females (APC = 1.60, p < 0.0001). The authors found no significant changes in the incidence over time by age of diagnosis. This study demonstrates an increasing overall incidence of primary, malignant spinal cord glioma over the past 3 decades. Notably, for ependymoma the incidence has increased, whereas the incidence of most other glioma subtypes remained stable. This may be due to improved diagnostic and surgical techniques, changes in histological classification criteria, and changes in neuropathology diagnostic criteria. Although primary, malignant spinal cord gliomas are rare, an improved understanding of the incidence will assist investigators and clinicians in planning potential studies and preparing for allocation of resources to care for these challenging patients.

What is the optimal imaging technique to be used in the diagnosis of a suspected low grade glioma, specifically: which anatomic imaging sequences are critical for most accurately identifying or diagnosing a low grade glioma (LGG) and do non-anatomic imaging methods and/or sequences add to the diagnostic specificity of suspected low grade gliomas? These recommendations apply to adults with a newly diagnosed lesion with a suspected or histopathologically proven LGG. LEVEL II : In patients with a suspected brain tumor, the minimum magnetic resonance imaging (MRI) exam should be an anatomic exam with both T2 weighted and pre- and post-gadolinium contrast enhanced T1 weighted imaging. CRITICAL IMAGING FOR THE IDENTIFICATION AND DIAGNOSIS OF LOW GRADE GLIOMA : LEVEL II : In patients with a suspected brain tumor, anatomic imaging sequences should include T1 and T2 weighted and Fluid Attenuation Inversion Recovery (FLAIR) MR sequences and will include T1 weighted imaging after the administr...

Bilateral testicular torsion in the neonate, although uncommon, is being reported with increasing frequency. Most previously reported cases have been full term, average to above average weight infants born with nonviable testes. We report a case of bilateral neonatal testicular torsion in a 32-week newborn in whom testicular viability may have been preserved by pre-term birth.

We have modified the cranial fixation technique of the reference array used for the Stealth (Medtronics Inc., Minneapolis, MN) image guided neurosurgical workstation to avoid rigid immobilization and to accommodate patients undergoing awake procedures. The modification allows attachment of a reference array directly to the skull prior to registration, avoiding the requirement for rigid cranial fixation. The accuracy of fiducial registration for the modified reference array was compared to the conventional reference array using a phantom system yielding similar registration results and target accuracy. The successful application of the modified system to two operative cases is described.

A review of the stereotactic cases performed at the University of Iowa between February, 1985, and December, 1990, yielded 12 infratentorial stereotactic biopsies in 11 patients. A definitive diagnosis was obtained in 9 of 11 patients. One patient required a second biopsy to obtain a diagnosis and 1 yielded cystic fluid only. The pathological diagnosis obtained included 4 high-grade gliomas, 2 undifferentiated adenocarcinomas, 2 low-grade astrocytomas, 1 malignant ependymoma, 1 pontine hematoma and 1 cyst. None of the patients experienced increased neurological deficit following biopsy and there was no mortality. One patient developed postoperative meningitis. We conclude that stereotactic biopsy of infratentorial lesions can be performed safely with a high probability of obtaining a diagnosis. Adequate tissue diagnosis is necessary to direct further therapy.

What is the optimal role of biopsy in the initial management of presumptive low-grade glioma in adults? Adult patients with imaging suggestive of a low-grade glioma. LEVEL III: Stereotactic biopsy is recommended when definitive surgical resection is limited by lesions that are deep-seated, not resectable, and/or located within eloquent cortex, or in patients unable to undergo craniotomy due to medical co-morbidities to obtain the critical tissue diagnosis needed for targeted treatment planning for patients with low-grade gliomas. What is the best technique for brain biopsy? Adult patients with imaging suggestive of a low-grade glioma. LEVEL III: Frameless and frame-based stereotactic brain biopsy for low-grade gliomas are recommended based on clinical circumstances as they provide similar diagnostic yield, diagnostic accuracy, morbidity, and mortality. It is recommended the surgeon consider advanced imaging techniques (e.g., perfusion, spectroscopy, metabolic studies) to target spec...

Adult patients (older than 18 years of age) with newly diagnosed World Health Organization (WHO) Grade II gliomas (Oligodendroglioma, astrocytoma, mixed oligoastrocytoma). Is there a role for chemotherapy as adjuvant therapy of choice in treatment of patients with newly diagnosed low-grade gliomas? LEVEL III : Chemotherapy is recommended as a treatment option to postpone the use of radiotherapy, to slow tumor growth and to improve progression free survival (PFS), overall survival (OS) and clinical symptoms in adult patients with newly diagnosed LGG. Who are the patients with newly diagnosed LGG that would benefit the most from chemotherapy? LEVEL III : Chemotherapy is recommended as an optional component alone or in combination with radiation as the initial adjuvant therapy for all patients who cannot undergo gross total resection (GTR) of a newly diagnosed LGG. Patient with residual tumor >1 cm on post-operative MRI, presenting diameter of >4 cm or older than 40 years of age ...

Adult patients (age ≥18 years) who have suspected low-grade diffuse glioma. What are the optimal neuropathological techniques to diagnose low-grade diffuse glioma in the adult? LEVEL I : Histopathological analysis of a representative surgical sample of the lesion should be used to provide the diagnosis of low-grade diffuse glioma. Both frozen section and cytopathologic/smear evaluation should be used to aid the intra-operative assessment of low-grade diffuse glioma diagnosis. A resection specimen is preferred over a biopsy specimen, to minimize the potential for sampling error issues. Patients with histologically-proven WHO grade II diffuse glioma. In adult patients (age ≥18 years) with histologically-proven WHO grade II diffuse glioma, is testing for IDH1 mutation (R132H and/or others) warranted? If so, is there a preferred method? LEVEL II : IDH gene mutation assessment, via IDH1 R132H antibody and/or IDH1/2 mutation hotspot sequencing, is highly-specific for low-grade diffuse gli...

Should patients with imaging suggestive of low grade glioma (LGG) undergo observation versus treatment involving a surgical procedure? These recommendations apply to adults with imaging suggestive of a WHO grade 2 glioma (oligodendroglioma, astrocytoma, or oligo-astrocytoma). Surgical resection is recommended over observation to improve overall survival for patients with diffuse low-grade glioma (Level III) although observation has no negative impact on cognitive performance and quality of life (Level II). What is the impact of extent of resection on progression free survival (PFS) or overall survival (OS) in LGG patients? These recommendations apply to adults with imaging suggestive of a WHO grade 2 glioma (oligodendroglioma, astrocytoma, or oligo-astrocytoma). IMPACT OF EXTENT OF RESECTION ON PFS : LEVEL II : It is recommended that GTR or STR be accomplished instead of biopsy alone when safe and feasible so as to decrease the frequency of tumor progression recognizing that the rat...

These recommendations apply to adult patients with recurrent low-grade glioma (LGG) with initial pathologic diagnosis of a WHO grade II infiltrative glioma (oligodendroglioma, astrocytoma, or oligo-astrocytoma). QUESTION : Do pathologic and molecular characteristics predict outcome/malignant transformation at recurrence? IDH STATUS AND RECURRENCE : (Level III) IDH mutation status should be determined as LGGs with IDH mutations have a shortened time to recurrence. It is unclear whether knowledge of IDH mutation status provides benefit in predicting time to progression or overall survival. TP53 STATUS AND RECURRENCE : (Level III) TP53 mutations occur early in LGG pathogenesis, remain stable, and are not recommended as a marker of predisposition to malignant transformation at recurrence or other measures of prognosis. MGMT STATUS AND RECURRENCE : (Level III) Assessment of MGMT status is recommended as an adjunct to assessing prognosis as LGGs with MGMT promoter methylation are associated with shorter PFS (in the absence of TMZ) and longer post-recurrence survival (in the presence of TMZ), ultimately producing similar overall survival to LGGs without MGMT methylationThe available retrospective reports are conflicting and comparisons between reports are limited CDK2NA STATUS AND RECURRENCE : (Level III) Assessment of CDK2NA status is recommended when possible as the loss of expression of the CDK2NA via either methylation or loss of chromosome 9p is associated with malignant progression of LGGs. PROLIFERATIVE INDEX AND RECURRENCE : (Level III) It is recommended that proliferative indices (MIB-1 or BUdR) be measured in LGGs as higher proliferation indices are associated with increased likelihood of recurrence and shorter progression free and overall survival. 1P/19Q STATUS AND RECURRENCE : There is insufficient evidence to make any recommendations. QUESTION : What role does chemotherapy have in LGG recurrence? TEMOZOLOMIDE AND RECURRENCE : (Level III) Temozolomide is recommended in the therapy of recurrent LGG as it may improve clinical symptoms. Oligodendrogliomas and tumors with 1p/19q co-deletion may derive the most benefit. PCV AND RECURRENCE : (Level III) PCV is recommended in the therapy of LGG at recurrence as it may improve clinical symptoms with the strongest evidence being for oligodendrogliomas. CARBOPLATIN AND RECURRENCE : (Level III) Carboplatin is not recommended as there is no significant benefit from carboplatin as single agent therapy for recurrent LGGs. OTHER TREATMENTS (NITROSUREAS, HYDROXYUREA/IMANITIB, IRINOTECAN, PACLITAXEL) AND RECURRENCE : There is insufficient evidence to make any recommendations. It is recommended that individuals with recurrent LGGs be enrolled in a properly designed clinical trial to assess these chemotherapeutic agents. QUESTION : What role does radiation have in LGG recurrence? RADIATION AT RECURRENCE WITH NO PREVIOUS IRRADIATION : (Level III) Radiation is recommended at recurrence if there was no previous radiation treatment. RE-IRRADIATION AT RECURRENCE : (Level III) It is recommended that re-irradiation be considered in the setting of LGG recurrence as it may provide benefit in disease control. There is insufficient evidence to make any specific recommendations. It is recommended that individuals with recurrent LGGs be enrolled in a properly designed clinical trial to assess the role of surgery at recurrence.

What is the role of immunotherapy/tumor vaccines in the treatment of low grade gliomas? Adult patients with newly diagnosed WHO grade 2 astrocytoma, oligo-astroctyoma, or oligodendroglioma. There is no evidence to support a recommendation in regards to the efficacy of immunotherapy or tumor vaccines for the treatment of low grade gliomas. It is recommended that patients be enrolled in properly designed clinical trials to assess immunotherapies and tumor vaccines for low grade gliomas. What is the role of nutrition in the treatment of low grade gliomas? Adult patients with newly diagnosed WHO grade 2 astrocytoma, oligo-astroctyoma, or oligodendroglioma. There was no evidence to support a recommendation in regard to the efficacy of nutritional therapy for the treatment of low grade gliomas. It is recommended that patients be enrolled in properly designed clinical trials to assess the efficacy of nutrition for this target population. Is there a role for alternative or targeted therapies in the treatment of low grade gliomas? Adult patients with newly diagnosed WHO grade 2 astrocytoma, oligo-astroctyoma, or oligodendroglioma. There was no evidence to support a recommendation in regard to the efficacy of targeted or alternative agents for the treatment of low grade gliomas. It is recommended that patients be enrolled in properly designed clinical trials to assess alternative and targeted therapies for this target population.

Recommendations Level I: The diagnosis of malignant glioma should be based on the histopathologic review of tissue. Level II: Both frozen section and cytopathologic evaluation are recommended for the intra-operative diagnosis of malignant glioma. Consultation from a neuropathologist specialized in brain tumor diagnosis is recommended for problematic cases. Level III: Incorporation of clinical and radiographic information with the final pathologic