Timothy C. Ryken

The role of surgery in the management of patients with diffuse low grade glioma

QuestionShould patients with imaging suggestive of low grade glioma (LGG) undergo observation versus treatment involving a surgical procedure?Target populationThese recommendations apply to adults with imaging suggestive of a WHO grade 2 glioma (oligodendroglioma, astrocytoma, or oligo-astrocytoma).RecommendationsSurgical 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).QuestionWhat is the impact of extent of resection on progression free survival (PFS) or overall survival (OS) in LGG patients?Target populationThese recommendations apply to adults with imaging suggestive of a WHO grade 2 glioma (oligodendroglioma, astrocytoma, or oligo-astrocytoma).RecommendationsImpact of extent of resection on PFSLevel IIIt 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 rate of progression after GTR is fairly high.Impact of extent of resection on OSLevel IIIGreater extent of resection can improve OS in LGG patients.QuestionWhat tools are available to increase extent of resection in LGG patients?Target populationThese recommendations apply to adults with imaging suggestive of a WHO grade 2 glioma (oligodendroglioma, astrocytoma, or oligo-astrocytoma).RecommendationsIntraoperative MRI during surgeryLevel IIIThe use of intraoperative MRI should be considered as a method of increasing the extent of resection of LGGs.QuestionWhat is the impact of surgical resection on seizure control and accuracy of pathology in low grade glioma patients?Target populationThese recommendations apply to adults with imaging suggestive of a WHO grade 2 glioma (oligodendroglioma, astrocytoma, or oligo-astrocytoma).RecommendationsSurgical resection and seizure controlLevel IIIAfter taking into account the patient’s clinical status and tumor location, gross total resection is recommended for patients with diffuse LGG as a way to achieve more favorable seizure control.Accuracy of diagnosisLevel IIITaking into account the patient’s clinical status and tumor location, surgical resection should be carried out to maximize the chance of accurate diagnosis.QuestionWhat tools can improve the safety of surgery for LGGs in eloquent locations?Target populationThese recommendations apply to adults with imaging suggestive of a WHO grade 2 glioma (oligodendroglioma, astrocytoma, or oligo-astrocytoma).RecommendationsPreoperative imagingLevel IIIIt is recommended that preoperative functional MRI and diffusion tensor imaging be utilized in the appropriate clinical setting to improve functional outcome after surgery for LGG.Intraoperative Mapping of Tumors in Eloquent AreasLevel IIIIntraoperative mapping is recommended for patients with diffuse LGGs in eloquent locations compared to patients with non-eloquently located diffuse LGGs as a way of preserving function.

The role of imaging in the management of adults with diffuse low grade glioma

QuestionWhat 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?Target populationThese recommendations apply to adults with a newly diagnosed lesion with a suspected or histopathologically proven LGG.RecommendationLevel IIIn 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 gliomaLevel IIIn 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 administration of gadolinium based contrast. Computed tomography (CT) can provide additional information regarding calcification or hemorrhage, which may narrow the differential diagnosis. At a minimum, these anatomic sequences can help identify a lesion as well as its location, and potential for surgical intervention.Improvement of diagnostic specificity with the addition of non-anatomic (physiologic and advanced imaging) to anatomic imagingLevel IIClass II evidence from multiple studies and a significant number of Class III series support the addition of diffusion and perfusion weighted MR imaging in the assessment of suspected LGGs, for the purposes of discriminating the potential for tumor subtypes and identification of suspicion of higher grade diagnoses.Level IIIMultiple series offer Class III evidence to support the potential for magnetic resonance spectroscopy (MRS) and nuclear medicine methods including positron emission tomography and single-photon emission computed tomography imaging to offer additional diagnostic specificity although these are less well defined and their roles in clinical practice are still being defined.QuestionWhich imaging sequences or parameters best predict the biological behavior or prognosis for patients with LGG?Target populationThese recommendations apply to adults with a newly diagnosed lesion with a suspected or histopathologically proven LGG.RecommendationAnatomic and advanced imaging methods and prognostic stratificationLevel IIIMultiple series suggest a role for anatomic and advanced sequences to suggest prognostic stratification among low grade gliomas. Perfusion weighted imaging, particularly when obtained as a part of diagnostic evaluation (as recommended above) can play a role in consideration of prognosis. Other imaging sequences remain investigational in terms of their role in consideration of tumor prognosis as there is insufficient evidence to support more formal recommendations as to their use at this time.QuestionWhat is the optimal imaging technique to be used in the follow-up of a suspected (or biopsy proven) LGG?Target populationThis recommendation applies to adults with a newly diagnosed low grade glioma.RecommendationsLevel IIIn patients with a diagnosis of LGG, anatomic imaging sequences should include T2/FLAIR MR sequences and T1 weighted imaging before and after the administration of gadolinium based contrast. Serial imaging should be performed to identify new areas of contrast enhancement or significant change in tumor size, which may signify transformation to a higher grade.Level IIIAdvanced imaging utility may depend on tumor subtype. Multicenter clinical trials with larger cohorts are needed. For astrocytic tumors, baseline and longitudinal elevations in tumor perfusion as assessed by dynamic susceptibility contrast perfusion MRI are associated with shorter time to tumor progression, but can be difficult to standardize in clinical practice. For oligodendrogliomas and mixed gliomas, MRS may be helpful for identification of progression.

Management of patients with recurrence of diffuse low grade glioma: A systematic review and evidence-based clinical practice guideline

Target populationThese 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).Pathology at recurrenceQuestionDo pathologic and molecular characteristics predict outcome/malignant transformation at recurrence?RecommendationsIDH 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 limitedCDK2NA 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 recurrenceThere is insufficient evidence to make any recommendations.Chemotherapy at recurrenceQuestionWhat role does chemotherapy have in LGG recurrence?RecommendationsTemozolomide 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 recurrenceThere 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.Radiation at recurrenceQuestionWhat role does radiation have in LGG recurrence?RecommendationsRadiation 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.Surgery at recurrenceThere 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.

Characterization of novel biomarkers in selecting for subtype specific medulloblastoma phenotypes.

Major research efforts have focused on defining cell surface marker profiles for characterization and selection of brain tumor stem/progenitor cells. Medulloblastoma is the most common primary malignant pediatric brain cancer and consists of 4 molecular subgroups: WNT, SHH, Group 3 and Group 4. Given the heterogeneity within and between medulloblastoma variants, surface marker profiles may be subtype-specific. Here, we employed a high throughput flow cytometry screen to identify differentially expressed cell surface markers in self-renewing vs. non-self-renewing SHH medulloblastoma cells. The top 25 markers were reduced to 4, CD271/p75NTR/NGFR, CD106/VCAM1, EGFR and CD171/NCAM-L1, by evaluating transcript levels in SHH tumors relative to samples representing the other variants. However, only CD271/p75NTR/NGFR and CD171/NCAM-L1 maintain differential expression between variants at the protein level. Functional characterization of CD271, a low affinity neurotrophin receptor, in cell lines and primary cultures suggested that CD271 selects for lower self-renewing progenitors or stem cells. Moreover, CD271 levels were negatively correlated with expression of SHH pathway genes. Our study reveals a novel role for CD271 in SHH medulloblastoma and suggests that targeting CD271 pathways could lead to the design of more selective therapies that lessen the broad impact of current treatments on developing nervous systems.

The role of biopsy in the management of patients with presumed diffuse low grade glioma

QuestionWhat is the optimal role of biopsy in the initial management of presumptive low-grade glioma in adults?Target populationAdult patients with imaging suggestive of a low-grade glioma.RecommendationsLevel 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.QuestionWhat is the best technique for brain biopsy?Target populationAdult patients with imaging suggestive of a low-grade glioma.RecommendationsLevel IIIFrameless 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 specific regions of interest to potentially improve diagnostic accuracy.

The role of emerging therapy in the management of patients with diffuse low grade glioma

QuestionWhat is the role of immunotherapy/tumor vaccines in the treatment of low grade gliomas?Target populationAdult patients with newly diagnosed WHO grade 2 astrocytoma, oligo-astroctyoma, or oligodendroglioma.RecommendationsThere 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.QuestionWhat is the role of nutrition in the treatment of low grade gliomas?Target populationAdult patients with newly diagnosed WHO grade 2 astrocytoma, oligo-astroctyoma, or oligodendroglioma.RecommendationsThere 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.QuestionIs there a role for alternative or targeted therapies in the treatment of low grade gliomas?Target populationAdult patients with newly diagnosed WHO grade 2 astrocytoma, oligo-astroctyoma, or oligodendroglioma.RecommendationThere 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.

Blocking epithelial-to-mesenchymal transition in glioblastoma with a sextet of repurposed drugs: the EIS regimen

This paper outlines a treatment protocol to run alongside of standard current treatment of glioblastoma- resection, temozolomide and radiation. The epithelial to mesenchymal transition (EMT) inhibiting sextet, EIS Regimen, uses the ancillary attributes of six older medicines to impede EMT during glioblastoma. EMT is an actively motile, therapy-resisting, low proliferation, transient state that is an integral feature of cancers’ lethality generally and of glioblastoma specifically. It is believed to be during the EMT state that glioblastoma’s centrifugal migration occurs. EMT is also a feature of untreated glioblastoma but is enhanced by chemotherapy, by radiation and by surgical trauma. EIS Regimen uses the antifungal drug itraconazole to block Hedgehog signaling, the antidiabetes drug metformin to block AMP kinase (AMPK), the analgesic drug naproxen to block Rac1, the anti-fibrosis drug pirfenidone to block transforming growth factor-beta (TGF-beta), the psychiatric drug quetiapine to block receptor activator NFkB ligand (RANKL) and the antibiotic rifampin to block Wnt- all by their previously established ancillary attributes. All these systems have been identified as triggers of EMT and worthy targets to inhibit. The EIS Regimen drugs have a good safety profile when used individually. They are not expected to have any new side effects when combined. Further studies of the EIS Regimen are needed.

Onset of symptomatic hydrocephalus requiring emergency cerebrospinal fluid diversion following high-voltage electrical burn injury

High-voltage electrical injuries have been reported to cause a plethora of neurological complications including cognitive, motor, and sensory deficits in an immediate or delayed fashion. In this setting, new-onset symptomatic hydrocephalus requiring CSF shunt placement has not been described. The authors present the case of an 18-year-old man who sustained a high-voltage electrical injury with a calvarial contact point that required emergency CSF diversion within hours of injury and subsequently required placement of a lumboperitoneal shunt. Management of the open calvarial wound, which required rotational flap reconstruction, and the need for ongoing CSF diversion required care and a team approach.

Pharmacological inhibition of the protein kinase MRK/ZAK radiosensitizes medulloblastoma

Medulloblastoma is a cerebellar tumor and the most common pediatric brain malignancy. Radiotherapy is part of the standard care for this tumor, but its effectiveness is accompanied by significant neurocognitive sequelae due to the deleterious effects of radiation on the developing brain. We have previously shown that the protein kinase MRK/ZAK protects tumor cells from radiation-induced cell death by regulating cell-cycle arrest after ionizing radiation. Here, we show that siRNA-mediated MRK depletion sensitizes medulloblastoma primary cells to radiation. We have, therefore, designed and tested a specific small molecule inhibitor of MRK, M443, which binds to MRK in an irreversible fashion and inhibits its activity. We found that M443 strongly radiosensitizes UW228 medulloblastoma cells as well as UI226 patient–derived primary cells, whereas it does not affect the response to radiation of normal brain cells. M443 also inhibits radiation-induced activation of both p38 and Chk2, two proteins that act downstream of MRK and are involved in DNA damage–induced cell-cycle arrest. Importantly, in an animal model of medulloblastoma that employs orthotopic implantation of primary patient–derived UI226 cells in nude mice, M443 in combination with radiation achieved a synergistic increase in survival. We hypothesize that combining radiotherapy with M443 will allow us to lower the radiation dose while maintaining therapeutic efficacy, thereby minimizing radiation-induced side effects. Mol Cancer Ther; 15(8); 1799–808. ©2016 AACR.

Evidence-based clinical practice parameter guidelines for the treatment of adults with diffuse low grade glioma: introduction and methods.

The general classification of ‘‘low grade glioma’’ typically describes a group of tumors originating from the central nervous system whose behavior is neither reliably benign (such as pilocytic astrocytoma) nor overtly aggressive (such as anaplastic astrocytoma or glioblastoma). For these clinical practice guidelines, diffuse low grade glioma will be defined as the WHO Classification grade II tumors specified as astrocytoma, oligodendroglioma or mixed oligoastrocytoma [1]. These relatively rare lesions in the adult population have estimated age adjusted rates per 100,000 of 0.58, 0.27, and 0.21, respectively [2]. Though uncommon, individuals affected by these lesions can develop substantial symptoms including seizures, mental status changes and severe focal neurologic deficits depending on the portion of the nervous system involved [3]. In the past there has been a substantial tendency in the literature provided by respected clinicians and scientists to represent low grade gliomas as benign [4]. However, this obscures the progressive natural history of many of these lesions, particularly when speaking with patients and their families. Though they carry the moniker ‘‘low grade,’’ these lesions pose a serious problem for those who develop them because of the real potential of malignant transformation over time [5]. In fact, low grade gliomas might be more accurately recognized as malignant, life-impairing and life-shortening lesions in view of their eventual transformation to an anaplastic tumor or glioblastoma in many cases [6]. Surgical resection may be limited by indistinct borders so that cure by removal is not possible. The low proliferative activity in these lesions impairs responsiveness to standard cytotoxic agents [3, 6]. Radiation therapy efficacy for these lesions, though relatively positive compared to other modalities, may eventually be overcome by tumor cells that can repair radiation-induced injury or become radioresistant [7]. The problem of longterm tumor control in low grade glioma, even after being subjected to radical surgery, chemotherapy and radiation, lends credence to the impression of many that, except in select instances, low grade gliomas are incurable. Thus, the problem of providing a reliably beneficial therapy for patients with low grade glioma is a substantial one. The medical literature is replete with reports and summaries on management with a number of modalities. To quantify the value of this information, this evidencebased guideline is designed to assess that literature in a systematic fashion so as to provide clarity to its value, provide management recommendations, and set benchmarks for future research on many fronts, including the impact of predictive molecular and genetic biomarkers.