Congress of neurological surgeons systematic review and evidence-based clinical practice parameter guidelines for the treatment of adults with newly diagnosed glioblastoma: Introduction and Methods.

PURPOSE: This is an update of the evidence-based guideline for management of newly diagnosed glioblastomas sponsored by the American Association of Neurological Surgeons (AANS) and Congress of Neurological Surgeons (CNS) initially published in 2008. The objective is to update evidence-based management of newly diagnosed glioblastomas over all commonly used diagnostic and treatment modalities in regularly encountered clinical situations. METHODS: A multidisciplinary writing group was assembled to create documents related to imaging, cytoreductive surgery, neuropathology, radiation therapy, chemotherapy and emerging developments. Questions from the prior set of guidelines, and new and modified questions were used to guide a search of the scientific literature since the last guideline search was completed in June 2005. Citations were screened, classified and used as evidence to create recommendations addressing the questions in a manner that was directly linked to this evidence. RESULTS: The sixteen writers produced 34 questions resulting in eight Level I recommendations, eleven Level II recommendations, and 27 Level II recommendations across all the topics. In some instances, insufficient data was available to answer all or part of a question and this is stated and explained. CONCLUSIONS: This series of guidelines is based upon relevant evidence in the literature related to the management of newly diagnosed glioblastomas. They set a benchmark for the management of this disease while highlighting key areas of weakness in our knowledge and suggest directions for future basic and clinical research to improve evidence quality and recommendation strength.

The role of neuropathology in the management of newly diagnosed glioblastoma: a systematic review and evidence-based clinical practice guideline.

TARGET POPULATION: These recommendations apply to adult patients with newly diagnosed or suspected glioblastoma (GBM) QUESTION : For adult patients with newly diagnosed GBM does testing for Isocitrate Dehydrogenase 1 or 2 (IDH 1/2) mutations afford benefit beyond standard histopathology in providing accurate classification and outcome prognostication? Level III IDH 1/2 mutational status by immunohistochemistry (IHC) and/or sequencing is suggested for classification and prognostic information. Level III Non-canonical IDH 1/2 mutations are very rare in patients aged 55 or older and universal testing of variant mutations by sequence analysis is not suggested for this age range. QUESTION: For adult patients with lower grade infiltrating astrocytomas (WHO grades II and III) can the IDH-wildtype status designation supersede histopathology to predict prognosis and biologic relevance to eventual behavior as a GBM? Level III The designation of infiltrating astrocytomas (WHO grades II and III) as IDH-wildtype is not suggested as sufficient for a higher grade designation alone. Level III It is suggested that IDH-wildtype WHO grades II and III astrocytomas be tested for molecular-genetic alterations typical of IDH-wildtype GBM such as EGFR amplification, gain of chromosome 7/loss of chromosome 10 and TERT-p mutation to substantiate prediction of behavior similar to IDH-wildtype glioblastoma. Level III It is suggested that a diagnosis of diffuse astrocytic glioma, IDH-wildtype, with molecular features of GBM, WHO grade IV be rendered for infiltrating astrocytomas that lack histologic criteria of GBM but harbors molecular-genetic alterations of IDH-wildtype glioblastoma. QUESTION: For adult patients with newly diagnosed infiltrating glioma arising in the midline does testing for H3-K27M mutations provide information beyond that gained by histopathology for accurate classification and outcome prognostication? Level III It is suggested that infiltrating gliomas arising in midline anatomic locations be tested for the H3-K27M mutation as they tend to exhibit WHO grade IV behavior even if they lack histologic criteria for glioblastoma.

Cytoreductive surgery in the management of newly diagnosed glioblastoma in adults: a systematic review and evidence-based clinical practice guideline update.

TARGET POPULATION: These recommendations apply to adults with newly diagnosed or suspected glioblastoma. QUESTION: What is the effect of extent of surgical resection on patient outcome in the initial management of adult patients with suspected newly diagnosed glioblastoma? RECOMMENDATION: Level II: Maximal cytoreductive surgery is recommended in adult patients with suspected newly diagnosed supratentorial glioblastoma with gross total resection defined as removal of contrast enhancing tumor. Level III: Biopsy, subtotal resection, or gross total resection is suggested depending on medical comorbidities, functional status, and location of tumor if maximal resection may cause significant neurologic deficit. QUESTION: What is the role of cytoreductive surgery in adults with newly diagnosed bi-frontal "butterfly" glioblastoma? RECOMMENDATION: Level III: Resection of newly diagnosed bi-frontal "butterfly" glioblastoma is suggested to improve overall survival over biopsy alone. QUESTION: What is the goal of cytoreductive surgery in elderly adult patients with newly diagnosed glioblastoma? RECOMMENDATION: Level III: Elderly patients (> 65 years) show survival benefit with gross total resection and it is suggested they undergo cytoreductive surgery. QUESTION: What is the role of advanced intraoperative guidance techniques in cytoreductive surgery in adults with newly diagnosed glioblastoma? RECOMMENDATION: Level III: The use of intraoperative guidance adjuncts such as intraoperative MRI (iMRI) or 5-aminolevulinic acid (5-ALA) are suggested to maximize extent of resection in newly diagnosed glioblastoma. There is insufficient evidence to make a suggestion on the use of fluorescein, indocyanine green, or intraoperative ultrasound.

The role of initial chemotherapy for the treatment of adults with diffuse low grade glioma : A systematic review and evidence-based clinical practice guideline.

TARGET POPULATION: Adult patients (older than 18 years of age) with newly diagnosed World Health Organization (WHO) Grade II gliomas (Oligodendroglioma, astrocytoma, mixed oligoastrocytoma). QUESTION: 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. QUESTION: 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 should be considered for adjuvant therapy as well. QUESTION: Are there tumor markers that can predict which patients can benefit the most from initial treatment with chemotherapy? LEVEL III: The addition of chemotherapy to standard RT is recommended in LGG patients that carry IDH mutation. In addition, temozolomide (TMZ) is recommended as a treatment option to slow tumor growth in patients who harbor the 1p/19q co-deletion. QUESTION: How soon should the chemotherapy be started once the diagnosis of LGG is confirmed? RECOMMENDATION: There is insufficient evidence to make a definitive recommendation on the timing of starting chemotherapy after surgical/pathological diagnosis of LGG has been made. However, using the 12 weeks mark as the latest timeframe to start adjuvant chemotherapy is suggested. It is recommended that patients be enrolled in properly designed clinical trials to assess the timing of chemotherapy initiation once diagnosis is confirmed for this target population. QUESTION: What chemotherapeutic agents should be used for treatment of newly diagnosed LGG? RECOMMENDATION: There is insufficient evidence to make a recommendation of one particular regimen. Enrollment of subjects in properly designed trials comparing the efficacy of these or other agents is recommended so as to determine which of these regimens is superior. QUESTION: What is the optimal duration and dosing of chemotherapy as initial treatment for LGG? RECOMMENDATION: Insufficient evidence exists regarding the duration of any specific cytotoxic drug regimen for treatment of newly diagnosed LGG. Enrollment of subjects in properly designed clinical investigations assessing the optimal duration of this therapy is recommended. QUESTION: Should chemotherapy be given alone or in conjunction with RT as initial therapy for LGG? RECOMMENDATION: Insufficient evidence exists to make recommendations in this regard. Hence, enrollment of patients in properly designed clinical trials assessing the difference between chemotherapy alone, RT alone or a combination of them is recommended. QUESTION: Should chemotherapy be given in addition to other type of adjuvant therapy to patients with newly diagnosed LGG? RECOMMENDATION: Level II: It is recommended that chemotherapy be added to the RT in patients with unfavorable LGG to improve their progression free survival.

The role of radiotherapy in the management of patients with diffuse low grade glioma: A systematic review and evidence-based clinical practice guideline.

QUESTIONS: (1) What is the optimal role of external beam radiotherapy in the management of adult patients with newly diagnosed low-grade glioma (LGG) in terms of improving outcome (i.e., survival, complications, seizure control or other reported outcomes of interest)? (2) Which radiation strategies (dose, timing, fractionation, stereotactic radiation, brachytherapy, chemotherapy) improve outcomes compared to standard external beam radiation therapy in the initial management of low grade gliomas in adults? (3) Do specific factors (e.g., age, volume, extent of resection, genetic subtype) identify subgroups with better outcomes following radiation therapy than the general population of adults with newly diagnosed low-grade gliomas? TARGET POPULATION: These recommendations apply to adults with newly diagnosed diffuse LGG. RECOMMENDATIONS: OUTCOMES IN ADULT PATIENTS WITH NEWLY DIAGNOSED LOW GRADE GLIOMA TREATED WITH RADIOTHERAPY: Level I Radiotherapy is recommended in the management of newly diagnosed low-grade glioma in adults to prolong progression free survival, irrespective of extent of resection. Level II Radiotherapy is recommended in the management of newly diagnosed low grade glioma in adults as an equivalent alternative to observation in preserving cognitive function, irrespective of extent of resection. Level III Radiotherapy is recommended in the management of newly diagnosed low grade glioma in adults to improve seizure control in patients with epilepsy and subtotal resection. Level III Radiotherapy is recommended in the management of newly diagnosed low-grade glioma in adults to prolong overall survival in patients with subtotal resection. Level III Consideration of the risk of radiation induced morbidity, including cognitive decline, imaging abnormalities, metabolic dysfunction and malignant transformation, is recommended when the delivery of radiotherapy is selected in the management of newly diagnosed low-grade glioma in adults. STRATEGIES OF RADIOTHERAPY IN ADULT PATIENTS WITH NEWLY DIAGNOSED LOW GRADE GLIOMA: Level I Lower dose radiotherapy is recommended as an equivalent alternative to higher dose immediate postoperative radiotherapy (45-50.4 vs. 59.4-64.8 Gy) in the management of newly diagnosed low-grade glioma in adults with reduced toxicity. Level III Delaying radiotherapy until recurrence or progression is recommended as an equivalent alternative to immediate postoperative radiotherapy in the management of newly diagnosed low-grade glioma in adults but may result in shorter time to progression. Level III The addition of chemotherapy to radiotherapy is not recommended over whole brain radiotherapy alone in the management of low-grade glioma, as it provides no additional survival benefit. Level III Limited-field radiotherapy is recommended over whole brain radiotherapy in the management of low-grade glioma. Level III Either stereotactic radiosurgery or brachytherapy are recommended as acceptable alternatives to external radiotherapy in selected patients. PROGNOSTIC FACTORS IN ADULT PATIENTS WITH NEWLY DIAGNOSED LOW GRADE GLIOMA TREATED WITH RADIOTHERAPY: Level II It is recommended that age greater than 40 years, astrocytic pathology, diameter greater than 6 cm, tumor crossing the midline and preoperative neurological deficit be considered as negative prognostic indicators when predicting overall survival in adult low grade glioma patients treated with radiotherapy. Level II It is recommended that smaller tumor size, extent of surgical resection and higher mini-mental status exam be considered as positive prognostic indicators when predicting overall survival and progression free survival in patients in adult low grade glioma patients treated with radiotherapy. Level III It is recommended that seizures at presentation, presence of oligodendroglial histological component and 1p19q deletion (along with additional relevant factors-see Table 1) be considered as positive prognostic indicators when predicting response to radiotherapy in adults with low grade gliomas. Level III It is recommended that increasing age, decreasing performance status, decreasing cognition, presence of astrocytic histological component (along with additional relevant factors (see Tables 1, 2) be considered as negative prognostic indicators when predicting response to radiotherapy.

The role of biopsy in the management of patients with presumed diffuse low grade glioma: A systematic review and evidence-based clinical practice guideline.

QUESTION: What is the optimal role of biopsy in the initial management of presumptive low-grade glioma in adults? TARGET POPULATION: 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. QUESTION: What is the best technique for brain biopsy? TARGET POPULATION: 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 specific regions of interest to potentially improve diagnostic accuracy.

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

QUESTION: What is the role of immunotherapy/tumor vaccines in the treatment of low grade gliomas? TARGET POPULATION: Adult patients with newly diagnosed WHO grade 2 astrocytoma, oligo-astroctyoma, or oligodendroglioma. RECOMMENDATIONS: 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. QUESTION: What is the role of nutrition in the treatment of low grade gliomas? TARGET POPULATION: Adult patients with newly diagnosed WHO grade 2 astrocytoma, oligo-astroctyoma, or oligodendroglioma. RECOMMENDATIONS: 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. QUESTION: Is there a role for alternative or targeted therapies in the treatment of low grade gliomas? TARGET POPULATION: Adult patients with newly diagnosed WHO grade 2 astrocytoma, oligo-astroctyoma, or oligodendroglioma. RECOMMENDATION: 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.

The role of imaging in the management of adults with diffuse low grade glioma: A systematic review and evidence-based clinical practice guideline.

QUESTION: 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? TARGET POPULATION: 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 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 IMAGING: LEVEL II: Class 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 III: Multiple 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. QUESTION: Which imaging sequences or parameters best predict the biological behavior or prognosis for patients with LGG? TARGET POPULATION: These recommendations apply to adults with a newly diagnosed lesion with a suspected or histopathologically proven LGG. RECOMMENDATION: Anatomic and advanced imaging methods and prognostic stratification LEVEL III: Multiple 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. QUESTION: What is the optimal imaging technique to be used in the follow-up of a suspected (or biopsy proven) LGG? TARGET POPULATION: This recommendation applies to adults with a newly diagnosed low grade glioma. LEVEL II: In 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 III: Advanced 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.

The role of surgery in the management of patients with diffuse low grade glioma: A systematic review and evidence-based clinical practice guideline.

QUESTION: Should patients with imaging suggestive of low grade glioma (LGG) undergo observation versus treatment involving a surgical procedure? TARGET POPULATION: These recommendations apply to adults with imaging suggestive of a WHO grade 2 glioma (oligodendroglioma, astrocytoma, or oligo-astrocytoma). RECOMMENDATIONS: 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). QUESTION: What is the impact of extent of resection on progression free survival (PFS) or overall survival (OS) in LGG patients? TARGET POPULATION: These recommendations apply to adults with imaging suggestive of a WHO grade 2 glioma (oligodendroglioma, astrocytoma, or oligo-astrocytoma). RECOMMENDATIONS: 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 rate of progression after GTR is fairly high. LEVEL III: Greater extent of resection can improve OS in LGG patients. QUESTION: What tools are available to increase extent of resection in LGG patients? TARGET POPULATION: These recommendations apply to adults with imaging suggestive of a WHO grade 2 glioma (oligodendroglioma, astrocytoma, or oligo-astrocytoma). RECOMMENDATIONS: INTRAOPERATIVE MRI DURING SURGERY: LEVEL III: The use of intraoperative MRI should be considered as a method of increasing the extent of resection of LGGs. QUESTION: What is the impact of surgical resection on seizure control and accuracy of pathology in low grade glioma patients? TARGET POPULATION: These recommendations apply to adults with imaging suggestive of a WHO grade 2 glioma (oligodendroglioma, astrocytoma, or oligo-astrocytoma). RECOMMENDATIONS: SURGICAL RESECTION AND SEIZURE CONTROL: LEVEL III: After 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. LEVEL III: Taking into account the patient's clinical status and tumor location, surgical resection should be carried out to maximize the chance of accurate diagnosis. QUESTION: What tools can improve the safety of surgery for LGGs in eloquent locations? TARGET POPULATION: These recommendations apply to adults with imaging suggestive of a WHO grade 2 glioma (oligodendroglioma, astrocytoma, or oligo-astrocytoma). RECOMMENDATIONS: PREOPERATIVE IMAGING: LEVEL III: It 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. LEVEL III: Intraoperative 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 neuropathology in the management of patients with diffuse low grade glioma: A systematic review and evidence-based clinical practice guideline.

TARGET POPULATION: Adult patients (age ≥18 years) who have suspected low-grade diffuse glioma. QUESTION: What are the optimal neuropathological techniques to diagnose low-grade diffuse glioma in the adult? RECOMMENDATION: LEVEL I: Histopathological analysis of a representative surgical sample of the lesion should be used to provide the diagnosis of low-grade diffuse glioma. LEVEL III: 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. TARGET POPULATION: Patients with histologically-proven WHO grade II diffuse glioma. QUESTION: 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 glioma, and is recommended as an additional test for classification and prognosis. TARGET POPULATION: Patients with histologically-proven WHO grade II diffuse glioma. QUESTION: In adult patients (age ≥18 years) with histologically-proven WHO grade II diffuse glioma, is testing for 1p/19q loss warranted? If so, is there a preferred method? LEVEL III: 1p/19q loss-of-heterozygosity testing, by FISH, array-CGH or PCR, is recommended as an additional test in oligodendroglial cases for prognosis and potential treatment planning. TARGET POPULATION: Patients with histologically-proven WHO grade II diffuse glioma. QUESTION: In adult patients (age ≥18 years) with histologically-proven WHO grade II diffuse glioma, is MGMT promoter methylation testing warranted? If so, is there a preferred method? RECOMMENDATION: There is insufficient evidence to recommend methyl-guanine methyl-transferase (MGMT) promoter methylation testing as a routine for low-grade diffuse gliomas. It is recommended that patients be enrolled in properly designed clinical trials to assess the value of this and related markers for this target population. TARGET POPULATION: Patients with histologically-proven WHO grade II diffuse glioma. QUESTION: In adult patients (age ≥18 years) with histologically-proven WHO grade II diffuse glioma, is Ki-67/MIB1 immunohistochemistry warranted? If so, is there a preferred method to quantitate results? LEVEL III: Ki67/MIB1 immunohistochemistry is recommended as an option for prognostic assessment.

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

TARGET POPULATION: 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? RECOMMENDATIONS: 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 methylation. The 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? RECOMMENDATIONS: 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? RECOMMENDATIONS: 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. SURGERY AT RECURRENCE: 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.

Examining barriers to implementing a surgical-site infection bundle.

BACKGROUND: Surgical-site infections (SSIs) can be catastrophic. Bundles of evidence-based practices can reduce SSIs but can be difficult to implement and sustain. OBJECTIVE: We sought to understand the implementation of SSI prevention bundles in 6 US hospitals. DESIGN: Qualitative study. METHODS: We conducted in-depth semistructured interviews with personnel involved in bundle implementation and conducted a thematic analysis of the transcripts. SETTING: The study was conducted in 6 US hospitals: 2 academic tertiary-care hospitals, 3 academic-affiliated community hospitals, 1 unaffiliated community hospital. PARTICIPANTS: In total, 30 hospital personnel participated. Participants included surgeons, laboratory directors, clinical personnel, and infection preventionists. RESULTS: Bundle complexity impeded implementation. Other barriers varied across services, even within the same hospital. Multiple strategies were needed, and successful strategies in one service did not always apply in other areas. However, early and sustained interprofessional collaboration facilitated implementation. CONCLUSIONS: The evidence-based SSI bundle is complicated and can be difficult to implement. One implementation process probably will not work for all settings. Multiple strategies were needed to overcome contextual and implementation barriers that varied by setting and implementation climate. Appropriate adaptations for specific settings and populations may improve bundle adoption, fidelity, acceptability, and sustainability.

Patients' experiences and compliance with preoperative screening and decolonization.

BACKGROUND: To improve adherence with pre-surgical screening for Staphylococcus aureus nasal carriage and decolonization, we need more information about patients' experiences with these protocols. METHODS: We surveyed patients undergoing orthopedic, neurosurgical, or cardiac operations at Johns Hopkins Hospitals (JHH), the University of Iowa Hospitals and Clinics (UIHC) at MercyOne Northeast Iowa Neurosurgery (MONIN) to assess patients' experiences with decolonization protocols. RESULTS: Five hundred thirty-four patients responded. Respondents at JHH were significantly more likely than those at the UIHC to report using mupirocin and were significantly more likely than those at the UIHC and MONIN to feel they received adequate information about surgical site infection (SSI) prevention and decolonization. Respondents at JHH were the least likely to not worry about SSI and they were more willing to do anything they could to prevent SSI. Few patients reported barriers to adherence and side effects of mupirocin or chlorhexidine. CONCLUSION: Respondents did not report either major side effects or barriers to adherence. Patients varied in their level of concern about SSI, their willingness to invest effort in preventing SSI, and their assessments of preoperative information. To improve patients' adherence, clinicians and hospitals should assess their patients' needs and desires and tailor their preoperative processes, education, and prophylaxis accordingly.

Intra-operative emergence of occult dural arteriovenous fistula after middle meningeal artery embolization for chronic subdural hematoma: Case report and literature review.

Dural arteriovenous fistulae of the middle meningeal artery (MMA-dAVF) are high risk lesions that can lead to intracranial hemorrhage. We describe the case of an adult male that presented with chronic subdural hematomas and was treated with burr hole craniotomy plus middle meningeal artery (MMA) embolization. Although the pre-embolization angiogram showed no signs of a fistula, a fistula arising from the MMA and draining into the superior sagittal sinus emerged intra-operatively. To our knowledge, this is the first case of intra-operative emergence of occult MMA-dAVF with intracranial drainage during MMA embolization for chronic subdural hematoma treatment. This observation supports monitoring for and embolizing spontaneous MMA-dAVF following MMA embolization.

Association between interhospital transfer and increased in-hospital mortality in patients with spinal epidural abscesses.

BACKGROUND CONTEXT: Spinal epidural abscess (SEA) is an uncommon yet serious infection, associated with significant morbidity and mortality. Patients diagnosed with SEA often require surgical interventions or critical care services that are not available at community hospitals and are therefore transferred to tertiary care centers. Little is known about the effects of interhospital transfer on acute outcomes for patients with SEA. PURPOSE: To study the effects of interhospital transfer on acute outcomes for patients with SEA. STUDY DESIGN: Cross sectional analysis using the 2009 to 2017 National Inpatient Sample (NIS). PATIENT SAMPLE: Using the 2009 to 2017 NIS, we identified cases of SEA using ICD, Ninth, or Tenth Revision diagnosis codes 324.1 & G06.1. OUTCOME MEASURES: Our primary endpoint was in hospital mortality. METHODS: The association between interhospital transfer and inpatient mortality was assessed using multivariable logistic regression to adjust for potential covariates. Patient and hospital factors associated with interhospital transfer were assessed in a secondary analysis. RESULTS: A total of 21.5% of patient with SEA were treated after transfer from another hospital. After adjusting for covariates, those who presented after transfer had higher odds of death during hospitalization (OR: 1.51, 95% CI 1.27-1.78, p<.001). Transferred patients were significantly more likely to live in rural communities (11.4 % vs. 5.3 % for nontransferred patients). CONCLUSIONS: Interhospital transfer, which occurred more frequently in patients from rural hospitals, was associated with death even after controlling for disease severity. Addressing healthcare delivery disparities across the US, including across the rural-urban spectrum, will require better understanding of the observed increased mortality of interhospital transfer as a preventable source of in-hospital mortality for SEA.

Racial Disparities in Outcomes After Spine Surgery: A Systematic Review and Meta-Analysis.

OBJECTIVE: Racial disparities are a major issue in health care but the overall extent of the issue in spinal surgery outcomes is unclear. We conducted a systematic review/meta-analysis of disparities in outcomes among patients belonging to different racial groups who had undergone surgery for degenerative spine disease. METHODS: We searched Ovid MEDLINE, Scopus, Cochrane Review Database, and ClinicalTrials.gov from inception to January 20, 2021 for relevant articles assessing outcomes after spine surgery stratified by race. We included studies that compared outcomes after spine surgery for degenerative disease among different racial groups. RESULTS: We found 30 studies that met our inclusion criteria (28 articles and 2 published abstracts). We included data from 20 cohort studies in our meta-analysis (3,501,830 patients), which were assessed to have a high risk of observation/selection bias. Black patients had a 55% higher risk of dying after spine surgery compared with white patients (relative risk [RR], 1.55, 95% confidence interval [CI], 1.28-1.87; I2 = 70%). Similarly, black patients had a longer length of stay (mean difference, 0.93 days; 95% CI, 0.75-1.10; I2 = 73%), and higher risk of nonhome discharge (RR, 1.63; 95% CI, 1.47-1.81; I2 = 89%), and 30-day readmission (RR, 1.45; 95% CI, 1.03-2.04; I2 = 96%). No significant difference was noted in the pooled analyses for complication or reoperation rates. CONCLUSIONS: Black patients have a significantly higher risk of unfavorable outcomes after spine surgery compared with white patients. Further work in understanding the reasons for these disparities will help develop strategies to narrow the gap among the racial groups.

Improving the Usability of 5-Aminolevulinic Acid Fluorescence-Guided Surgery by Adding an Optimized Secondary Light Source.

BACKGROUND: Tumors that take up and metabolize 5-aminolevulinic acid emit bright pink fluorescence when illuminated with blue light, aiding surgeons in identifying the margin of resection. The adoption of this method is hindered by the blue light illumination, which is too dim to safely operate under and therefore necessitates switching back and forth from white-light mode. The aim of this study was to examine the addition of an optimized secondary illuminant adapter to improve usability of blue-light mode without degrading tumor contrast. METHODS: Color science methods were used to evaluate the color of the secondary illuminant and its impact on color rendering index as well as the tumor-to-background color contrast in data collected from 7 patients with high-grade gliomas (World Health Organization grade III and IV). A secondary illuminant adapter was built to provide 475-600 nm light the intensity of which can be controlled by the surgeon and was evaluated in 2 additional patients. RESULTS: Secondary illuminant color had opposing effects on color rendering index and tumor-to-background color contrast; providing surgeon control of intensity allows this trade-off to be balanced in real time. Demonstration in 2 high-grade glioma cases confirms this, showing that additional visibility adds value when intensity can be controlled by the surgeon. CONCLUSIONS: Addition of a secondary illuminant may mitigate surgeon complaints that the operative field is too dark under the blue light illumination required for 5-aminolevulinic acid fluorescence guidance by providing improved color rendering index without completely sacrificing tumor-to-background color contrast.

The role of stereotactic radiosurgery in the management of patients with newly diagnosed brain metastases: a systematic review and evidence-based clinical practice guideline.

QUESTION: Should patients with newly-diagnosed metastatic brain tumors undergo stereotactic radiosurgery (SRS) compared with other treatment modalities? Target population These recommendations apply to adults with newly diagnosed solid brain metastases amenable to SRS; lesions amenable to SRS are typically defined as measuring less than 3 cm in maximum diameter and producing minimal (less than 1 cm of midline shift) mass effect. Recommendations SRS plus WBRT vs. WBRT alone Level 1 Single-dose SRS along with WBRT leads to significantly longer patient survival compared with WBRT alone for patients with single metastatic brain tumors who have a KPS > or = 70.Level 1 Single-dose SRS along with WBRT is superior in terms of local tumor control and maintaining functional status when compared to WBRT alone for patients with 1-4 metastatic brain tumors who have a KPS > or =70.Level 2 Single-dose SRS along with WBRT may lead to significantly longer patient survival than WBRT alone for patients with 2-3 metastatic brain tumors.Level 3 There is class III evidence demonstrating that single-dose SRS along with WBRT is superior to WBRT alone for improving patient survival for patients with single or multiple brain metastases and a KPS<70 [corrected].Level 4 There is class III evidence demonstrating that single-dose SRS along with WBRT is superior to WBRT alone for improving patient survival for patients with single or multiple brain metastases and a KPS < 70. SRS plus WBRT vs. SRS alone Level 2 Single-dose SRS alone may provide an equivalent survival advantage for patients with brain metastases compared with WBRT + single-dose SRS. There is conflicting class I and II evidence regarding the risk of both local and distant recurrence when SRS is used in isolation, and class I evidence demonstrates a lower risk of distant recurrence with WBRT; thus, regular careful surveillance is warranted for patients treated with SRS alone in order to provide early identification of local and distant recurrences so that salvage therapy can be initiated at the soonest possible time. Surgical Resection plus WBRT vs. SRS +/- WBRT Level 2 Surgical resection plus WBRT, vs. SRS plus WBRT, both represent effective treatment strategies, resulting in relatively equal survival rates. SRS has not been assessed from an evidence-based standpoint for larger lesions (>3 cm) or for those causing significant mass effect (>1 cm midline shift). Level 3: Underpowered class I evidence along with the preponderance of conflicting class II evidence suggests that SRS alone may provide equivalent functional and survival outcomes compared with resection + WBRT for patients with single brain metastases, so long as ready detection of distant site failure and salvage SRS are possible. SRS alone vs. WBRT alone Level 3 While both single-dose SRS and WBRT are effective for treating patients with brain metastases, single-dose SRS alone appears to be superior to WBRT alone for patients with up to three metastatic brain tumors in terms of patient survival advantage.

The role of chemotherapy in the management of newly diagnosed brain metastases: a systematic review and evidence-based clinical practice guideline.

TARGET POPULATION: This recommendation applies to adults with newly diagnosed brain metastases; however, the recommendation below does not apply to the exquisitely chemosensitive tumors, such as germinomas metastatic to the brain. RECOMMENDATION: Should patients with brain metastases receive chemotherapy in addition to whole brain radiotherapy (WBRT)? Level 1 Routine use of chemotherapy following WBRT for brain metastases has not been shown to increase survival and is not recommended. Four class I studies examined the role of carboplatin, chloroethylnitrosoureas, tegafur and temozolomide, and all resulted in no survival benefit. Two caveats are provided in order to allow the treating physician to individualize decision-making: First, the majority of the data are limited to non small cell lung (NSCLC) and breast cancer; therefore, in other tumor histologies, the possibility of clinical benefit cannot be absolutely ruled out. Second, the addition of chemotherapy to WBRT improved response rates in some, but not all trials; response rate was not the primary endpoint in most of these trials and end-point assessment was non-centralized, non-blinded, and post-hoc. Enrollment in chemotherapy-related clinical trials is encouraged.