Frailty in patients with IDH-mutant gliomas: experience from a high-volume tumor center.

PURPOSE: Gliomas are increasingly diagnosed in an aging population, with treatment outcomes influenced by factors like tumor genetics and patient frailty. This study focused on IDH-mutant gliomas and assessed how frailty affects 30-day readmission and overall survival (OS). We aimed to address a gap in understanding the impact of frailty on this specific glioma subtype. METHODS: 136 patients with an IDH-mutant glioma between 2007 and 2021 were identified at our institution. High frailty was classified by scores ≥ 1 on the 5-factor modified frailty index (mFI-5) and ≥ 3 on the Charlson Comorbidity Index (CCI). Patient and tumor characteristics including age, sex, race, Karnofsky Performance Status (KPS), Body Mass Index (BMI), tumor type and location, type of operation, and therapy course were recorded. Outcomes measured included 30-day readmission and overall survival (OS). Analysis was conducted utilizing logistic regression and Kaplan-Meier curves. RESULTS: Of the 136 patients, 52 (38%) had high frailty: 18 with CCI ≥ 3, 34 with mFI-5 ≥ 1. High frailty correlated with increased BMI (CCI: 30.2, mFI-5: 30.1 kg/m2), more neurological deficits (CCI: 61%, mFI-5: 56%), and older age at surgery (CCI: 63, mFI-5: 48 years). Hospital readmission within 30 days occurred in 8 (5.9%) patients. Logistic regression indicated no significant difference in 30-day readmission rates (CCI: p = 0.30, mFI-5: p = 0.62) or median OS between high and low frailty groups. However, patients treated at our institution with newly diagnosed tumors with high mFI-5 had a 6.79 times higher adjusted death hazard than those with low mFI-5 (p = .049). CONCLUSION: Our analysis revealed that CCI and mFI-5 were not significantly associated with 30-day nor OS. However, in patients with non-recurrent tumors, there was a significant association of mFI-5 with OS. Further study of frailty with larger cohorts is warranted to enhance prognostication of outcome after neurosurgical treatment.

Revision of failed reverse total shoulder arthroplasty with reverse: short-term clinical outcomes.

BACKGROUND: The prevalence of failed reverse total shoulder arthroplasty (rTSA) is increasing. This can often present a challenging clinical situation with substantial bone loss and limited reconstruction options. This study reports a single tertiary referral center's experience with revision of failed rTSA managed with revision rTSA of bone-interfacing components. METHODS: After institutional review board approval, all revision shoulder arthroplasty cases performed at a single institution between 2012 and 2020 were reviewed. Cases in which rTSA was revised to a new rTSA construct with revision of at least 1 bone-interfacing implant (humeral stem and/or baseplate) with a minimum 2-year follow-up were identified. Characteristics of revision cases-including indications, bony stock, revised components, and use of bone graft-were collected. All patients were contacted for patient-reported outcome measures at a minimum of 2 years after surgery. In addition, the incidence and indication for any reoperation after revision were determined. RESULTS: Thirty-three patients with an average age of 66 years (range: 46-82 years), with 19 (58%) being female, met the inclusion criteria and had a mean follow-up of 4.2 years (range: 2-8 years). The most common indication for revision rTSA included humeral component loosening (33%; 11/33), baseplate loosening (27%; 9/33), and instability (21%; 7/33). Prerevision infectious workup demonstrated no cases of periprosthetic shoulder infection. Thirteen cases had massive bone loss-5 treated with humeral allograft prosthetic composite, 5 with glenoid bone grafting, and 3 with custom glenoid implant. In total, 10 of 33 cases (30%) required reoperation at a mean of 13 months (range: 1-44 months) for instability (4), humeral loosening (2), infection (1), baseplate loosening (1), or periprosthetic fracture (1). The reoperation rate for patients with revised baseplates only, humerus only, or combined was 23% (3/13), 28% (5/18), and 27% (3/11), respectively. Overall, the visual analog scale pain score improved from 6.5 preoperatively to 2.0 (P < .001), and the American Shoulder and Elbow Surgeons score improved from 30.7 to 67.5 (P < .001). However, the postoperative Single Assessment Numeric Evaluation score averaged only 51.2% (range: 2-100%). CONCLUSION: This study demonstrates that failed rTSA can be salvaged with a revision rTSA. However, patient expectations for functional improvements should be tempered, and a high reoperation rate should be expected.

Three-dimensional analysis of biplanar glenoid deformities: what are they and can they be virtually reconstructed with anatomic total shoulder arthroplasty implants?

BACKGROUND: Descriptions of glenoid deformities in glenohumeral osteoarthritis (GHOA) have focused on the axial plane. Less is known regarding arthritic glenoids with higher amounts of superior inclination and little evidence exists to guide management of inclination or combined version-inclination deformity when performing anatomic total shoulder arthroplasty (aTSA). We hypothesized that biplanar deformities (BD) would be present in a higher proportion of GHOA patients than previously appreciated, and these deformities would be difficult to adequately reconstruct with contemporary aTSA implants. METHODS: A retrospective query was performed of GHOA patients indicated for TSA 2012-2017 with a computed tomography (CT) scan within three months of surgery. Images were uploaded to three-dimensional (3D) software for automated measurements. Glenoids with superior inclination ≥10°, and retroversion ≥20° were considered to have BD. Walch classification was determined, and C-type glenoids were excluded. Rotator-cuff muscle cross-sectional area (CSA) was measured and fatty infiltration was graded. Glenoids with BD were virtually planned for aTSA with correction to neutral inclination and version, then with 5° superior inclination and 10° retroversion. RESULTS: Two-hundred and sixty-eight shoulders in 250 patients were included; average age was 65 years, 67% male. There were no differences in inclination between Walch types (P = .25). Twenty-nine shoulders with BD were identified (11%). These deformities were not associated with age (P = .47) or gender (P = .50) but were skewed towards Walch B-type, specifically B2 (P = .03). Acromial index and posterior humeral head subluxation were higher in BD patients (P = .04, P < .001, respectively). Biplanar deformities had similar cuff CSA compared to those without but were less frequently associated with fatty infiltration of the subscapularis (P = .05). When correcting to neutral version and inclination, 41% BD could not be reconstructed. Of those that could, 94% required augmented implants. When correcting to 5° superior inclination and 10° retroversion, 10% could not be reconstructed. Of those that could, 58% required augmented implants. With partial correction, augment use was predicted by retroversion >26° (P = .009). Inclination did not predict augment use (P = .90). Final implant position commonly involved unseating in the posterosuperior quadrant and cancellous exposure in the anteroinferior quadrant. CONCLUSIONS: This retrospective computed tomography (CT)-based study of 268 shoulders with GHOA found an 11% prevalence of BD. These deformities were commonly associated with Walch B2 wear patterns. Virtual aTSA planning showed a high failure rate (41%) when correcting to neutral version and inclination. Posteriorly augmented implants were frequently required, and often still involved unseating in the posterosuperior quadrant, increased cancellous exposure in the anteroinferior quadrant, and vault perforation.

Predictors of pain development for contralateral asymptomatic degenerative rotator cuff tears based on features of an ipsilateral painful cuff tear: a prospective longitudinal cohort study.

BACKGROUND: Prior rotator cuff disease natural history studies have focused on tear-related factors that predict disease progression within a given shoulder. The purpose of this study was to examine both patient- and tear-related characteristics of a painful rotator cuff tear that predict future pain development and functional impairment in a shoulder with a contralateral asymptomatic cuff tear. METHODS: This was a prospective longitudinal cohort study of patients aged ≤65 years who underwent surgery for a painful degenerative rotator cuff tear and possessed an asymptomatic contralateral tear. Patients were followed up prospectively by shoulder ultrasound, physical examination, and functional score assessment. The primary outcome was change in the American Shoulder and Elbow Surgeons (ASES) score at 2 years. Secondary outcomes included the Western Ontario Rotator Cuff Index (WORC) score, Patient-Reported Outcomes Measurement Information System (PROMIS) score, Hospital Anxiety Depression Scale (HADS) depression and anxiety scores, and Veterans RAND-12 (VR-12) mental component score (MCS). RESULTS: Sixty-five patients were included, with a mean follow-up period of 37 months (range, 24-42 months). In 17 patients (26%), contralateral shoulder pain developed at a median of 15.2 months (interquartile range [IQR], 10.5 months). No difference in age, sex, Charlson Comorbidity Index, or occupational demand was noted between patients in whom pain developed and those in whom pain did not develop. In the presenting painful shoulder, there was no difference in baseline tear size, muscle degeneration, or biceps pathology between groups. The mean baseline tear length (8.6 mm vs. 3.8 mm, P = .0008) and width (8.4 mm vs. 3.2 mm, P = .0004) were larger in asymptomatic shoulders in which pain subsequently developed compared with those in which pain did not develop. However, there was no difference in mean tear enlargement (P = .51 for length and P = .90 for width). There were no differences in baseline ASES, WORC, Patient-Reported Outcomes Measurement Information System (PROMIS), or HADS depression and anxiety scores between shoulders in which pain developed and those in which pain did not develop; however, patients in whom pain developed reported a lower baseline VR-12 MCS (53.3 vs. 57.6, P = .04). Shoulders in which pain developed had higher visual analog scale pain scores (2.9 [standard deviation (SD), 2.5] vs. 0.6 [SD, 1.0]; P = .016), lower ASES scores 75 [SD, 33] vs. 100 [SD, 11.6]; P = .001), and significant changes in all WORC scales with pain onset compared with those that remained asymptomatic. The study showed no significant difference in changes in the HADS anxiety and depression scores but found a significant increase in the VR-12 MCS in patients in whom pain developed (7.1 [interquartile range, 12.6] vs. -1.9 [interquartile range, 8.7]; P = .036). CONCLUSION: In one-quarter of patients with painful cuff tears, pain developed in a contralateral asymptomatic cuff tear that resulted in a measurable decline in function within 3 years. Our analysis showed that only the baseline tear size of the asymptomatic shoulder was predictive of pain development. There were no tear-related features of the presenting painful rotator cuff tear or indices of mental health and physical function or occupational demand that were predictive of future pain development at short-term follow-up.

Does Surgical Intervention Alter the Natural History of Degenerative Rotator Cuff Tears? Comparative Analysis from a Prospective Longitudinal Study.

INTRODUCTION: The natural history of rotator cuff tears often involves progressive pain development, tear enlargement, and advancing muscle fatty degeneration. Both surgery and conservative management have proven to be effective treatments. Our study purpose was to compare the short to mid-term effects of rotator cuff repair on shoulder function, progression of tear size, and muscle degeneration compared to controls with asymptomatic tears that developed pain and were managed nonoperatively. METHODS: This comparative study consists of two separate longitudinal study arms. The control group consisted of asymptomatic degenerative cuff tears followed until pain development and then managed nonoperatively with continued surveillance. The surgical group consisted of subjects with degenerative tears that failed nonoperative treatment and underwent surgical intervention with a minimum of 2 years follow-up. Outcomes included VAS pain, ASES, AROM, strength, and ultrasonography. RESULTS: There were 83 controls and 65 surgical shoulders. The surgical group was younger at enrollment (58.9±5.3 yr vs. 61.2±7.8 yr, p=0.04). The median follow-up for control subjects after pain development was 5.1 years (IQR 3.6) and the median postoperative follow-up for the surgical group was 3.0 years (IQR 0.2). Baseline tear widths (median 14 mm, IQR 9 vs. 13 mm, IQR 8; p=0.45) and tear lengths (median 14 mm, IQR 13 vs. median 11 mm, IQR 8; p=0.06) were similar between the surgical group and controls. There were no differences in the baseline prevalence of fatty degeneration of the supraspinatus or infraspinatus muscles between groups (p=0.43 and p=0.58, respectively). At final follow-up, the surgical group demonstrated significantly lower VAS pain (0 [IQR 2] vs. 3.5 [IQR 4], p=0.0002), higher composite ASES (95 [IQR 13] vs. 65.8 [IQR 32], p=0.0002) and ADL scores (29 [IQR 4] vs. 22 [IQR 8], p=0.0002), greater abduction strength (69.6 N [SD 29] vs. 35.9 N [SD 29], p=0.0002), greater active forward elevation (155˚ [SD 8] vs. 142˚ [SD 28], p=0.002), greater active external rotation in abduction (mean 98.5˚, SD 12 vs. mean 78.2˚, SD 20; p=0.0002) compared to controls. Additionally, the prevalence of fatty muscle degeneration was lower in the surgical group for the supraspinatus and infraspinatus (25% vs. 41%, p=0.05; 17% vs. 34%, p=0.03; respectively). CONCLUSION: This prospective longitudinal study comparing a surgical cohort undergoing rotator cuff repair with a control group treated nonoperatively supports the notion that surgical intervention has the potential to alter the early natural history of degenerative rotator cuff disease. Patients in the surgical group demonstrated clinically relevant differences in pain and functional outcomes. Surgical intervention was protective against progressive muscle degeneration compared to nonoperative treatment.

Clinical and descriptive characteristics associated with high-grade meningioma in a large clinical series.

PURPOSE: We studied 571 patients with intracranial meningioma for clinical characteristics and tumor location associated with high grade meningioma (WHO II/III). MATERIALS AND METHODS: Patients were participants in a multicentre epidemiologic study of risk factors for primary brain tumors including meningioma recruited from September 2005 to November 2019. We included patients 18 or older with a recent diagnosis of a primary intracranial meningioma of any subtype (ICD9/10: 9530-0, 9531-0, 9532-0, 9537-0, 9533-0, 9534-0, 9530-0, 9538-1, 9538-3) who were enrolled at neuro-oncology and neuro-surgery clinics in the southeastern U.S. RESULTS: The median patient age was 58 years (IQR: 48-68) and the majority of patients were female (n = 415; 72.7%) and Caucasian (n = 516; 90.4%). Most patients were symptomatic (n = 460; 80.6%) and their tumours more commonly occurred in a non-skull base location (n = 298; 52.2%). A total of 86 patients (15.0%) had a WHO grade II/III meningioma. Compared to patients with WHO grade I tumours, patients with WHO II/III meningiomas were over 3-times more likely to be male (odds ratio (OR): 3.25; 95% confidence interval (CI): 1.98, 5.35) adjusting for age, race, symptomatic presentation, and skull-based location. Moreover, a WHO grade II/III meningioma was substantially less likely to be observed in asymptomatic patients (OR: 0.15, 95% CI: 0.04, 0.42), and in patients with a skull-based tumour (OR: 0.40, 95% CI: 0.24, 0.66), adjusting for other factors. Male gender, symptomatic tumour, and a non-skull base location were independently associated with WHO grade II/III meningioma. CONCLUSION: These findings may shed additional light on the underlying pathogenesis of meningioma.

Congress of Neurological Surgeons systematic review and evidence-based guidelines for the treatment of adults with progressive glioblastoma update: introduction and methods.

INTRODUCTION: The management of glioblastoma at the time of progression is an important facet of all physicians involved in neuro-oncology. This is an update of the evidence-based guidelines for management of progressive glioblastoma published by the Congress of Neurological Surgeons and American Association of Neurological Surgeons in 2014. METHODS: The medical literature from July 1, 2012 through March 31, 2019 was searched in MEDLINE® and Embase® and the Cochrane Database of Systematic Reviews, Cochrane Controlled Trials Registry, and Cochrane Database of Abstracts of Reviews of Effects to determine if information was available to update, modify or create new recommendations related to imaging, cytoreductive surgery, neuropathology, radiotherapy, cytotoxic chemotherapy, targeted therapy, and immunotherapy. RESULTS: The writing group utilized the information from the updated literature search to formulate recommendations that were exclusively evidence based and not founded on potentially biased consensus or expert opinion. CONCLUSION: The series of guideline documents provides an update of the information and recommendations that could be derived in the 2014 version. It sets a benchmark as to what we really know about the management of this difficult disease. It also provides clues to key investigations that are necessary to move us toward truly effective disease control.

Congress of Neurological Surgeons systematic review and evidence-based guidelines update on the role of radiation therapy in the management of progressive and recurrent glioblastoma in adults.

TARGET POPULATION: These recommendations apply to adult patients (18 years of age and above) with progressive/recurrent glioblastoma multiforme (pGBM) after first line combined multimodality treatment. QUESTION: Can re-irradiation (by using conventional radiotherapy, fractionated radiosurgery, or single fraction radiosurgery) be used in patients with pGBM after the first adjuvant combined multimodality treatment with radiation and chemotherapy? RECOMMENDATION: Level III: When the target tumor is amenable for additional radiation, re-irradiation is recommended as it provides improved local tumor control, as measured by best imaging response. Such re-irradiation can take the form of conventional fractionation radiotherapy, fractionated radiosurgery, or single fraction radiosurgery. LEVEL III: Re-Irradiation is recommended in order to maintain or improve a patient's neurological status and quality of life prior to any further tumor progression.

Congress of neurological surgeons systematic review and evidence-based guidelines update on the role of neuropathology in the management of progressive glioblastoma in adults.

TARGET POPULATION: These recommendations apply to adult patients with progressive or recurrent glioblastoma (GBM). QUESTION: For adult patients with progressive glioblastoma does testing for Isocitrate Dehydrogenase (IDH) 1 or 2 mutations provide new additional management or prognostic information beyond that derived from the tumor at initial presentation? RECOMMENDATION: Level III: Repeat IDH mutation testing is not necessary if the tumor is histologically similar to the primary tumor and the patient's clinical course is as expected. QUESTION: For adult patients with progressive glioblastoma does repeat testing for MGMT promoter methylation provide new or additional management or prognostic information beyond that derived from the tumor at initial presentation and what methods of detection are optimal? RECOMMENDATION: Level III: Repeat MGMT promoter methylation is not recommended. QUESTION: For adult patients with progressive glioblastoma does EGFR amplification or mutation testing provide management or prognostic information beyond that provided by histologic analysis and if performed on previous tissue samples, does it need to be repeated? RECOMMENDATION: Level III: In cases that are difficult to classify as glioblastoma on histologic features EGFR amplification testing may help in classification. If a previous EGFR amplification was detected, repeat testing is not necessary. Repeat EGFR amplification or mutational testing may be recommended in patients in which target therapy is being considered. QUESTION: For adult patients with progressive glioblastoma does large panel or whole genome sequencing provide management or prognostic information beyond that derived from histologic analysis? RECOMMENDATION: Level III: Primary or repeat large panel or whole genome sequencing may be considered in patients who are eligible or interested in molecularly guided therapy or clinical trials. QUESTION: For adult patients with progressive glioblastoma should immune checkpoint biomarker testing be performed to provide management and prognostic information beyond that obtained from histologic analysis? RECOMMENDATION: Level III: The current evidence does not support making PD-L1 or mismatch repair (MMR) enzyme activity a component of standard testing. QUESTION: For adult patients with progressive glioblastoma are there meaningful biomarkers for bevacizumab responsiveness and does their assessment provide additional information for tumor management and prognosis beyond that learned by standard histologic analysis? RECOMMENDATION: Level III: No established Bevacizumab biomarkers are currently available based upon the inclusion criteria of this guideline.

Congress of Neurological Surgeons systematic review and evidence-based guidelines update on the role of targeted therapies and immunotherapies in the management of progressive glioblastoma.

The following questions and recommendations are pertinent to the following: TARGET POPULATION: These recommendations apply to adults with progressive GBM who have undergone standard primary treatment with surgery and/or chemoradiation. QUESTION 1: In adults with progressive glioblastoma is the use of bevacizumab as monotherapy superior to standard salvage cytotoxic chemotherapy as measured by progression free survival and overall survival? RECOMMENDATION: Level III: Treatment with bevacizumab is suggested in the treatment of progressive GBM, as it provides improved disease control compared to historical controls as measured by best imaging response and progression free survival at 6 months, while not providing evidence for improvement in overall survival. QUESTION 2: In adults with progressive glioblastoma is the use of bevacizumab as combination therapy with cytotoxic agents superior to standard salvage cytotoxic chemotherapy as measured by progression free survival and overall survival? RECOMMENDATION: Level III: There is insufficient evidence to show benefit or harm of bevacizumab in combination with cytotoxic therapies in progressive glioblastoma due to a lack of evidence supporting a clearly defined benefit without significant toxicity. QUESTION 3: In adults with progressive glioblastoma is the use of bevacizumab as a combination therapy with targeted agents superior to standard salvage cytotoxic chemotherapy as measured by progression free survival and overall survival? RECOMMENDATION: There is insufficient evidence to support a recommendation regarding this question. QUESTION 4: In adults with progressive glioblastoma is the use of targeted agents as monotherapy superior to standard salvage cytotoxic chemotherapy as measured by progression free survival and overall survival? RECOMMENDATION: There is insufficient evidence to support a recommendation regarding this question. QUESTION 5: In adults with progressive glioblastoma is the use of targeted agents in combination with cytotoxic therapies superior to standard salvage cytotoxic chemotherapy as measured by progression free survival and overall survival? RECOMMENDATION: There is insufficient evidence to support a recommendation regarding this question. QUESTION 6: In adults with progressive glioblastoma is the use of immunotherapy monotherapy superior to standard salvage cytotoxic chemotherapy as measured by progression free survival and overall survival? RECOMMENDATION: There is insufficient evidence to support a recommendation regarding this question. QUESTION 7: In adults with progressive glioblastoma is the use of immunotherapy in combination with targeted agents superior to standard salvage cytotoxic chemotherapy as measured by progression free survival and overall survival? RECOMMENDATION: There is insufficient evidence to support a recommendation regarding this question. QUESTION 8: In adults with progressive glioblastoma is the use of immunotherapy in combination with bevacizumab superior to standard salvage cytotoxic chemotherapy as measured by progression free survival and overall survival? RECOMMENDATION: There is insufficient evidence to support a recommendation regarding this question.

Congress of Neurological Surgeons systematic review and evidence-based guidelines update on the role of cytotoxic chemotherapy and other cytotoxic therapies in the management of progressive glioblastoma in adults.

TARGET POPULATION: These recommendations apply to adult patients diagnosed with progressive glioblastoma (pGBM). QUESTION (Q1): In adult patients with pGBM does the use of temozolomide (TMZ) with alternative dosing or the use of TMZ in combination with other cytotoxic treatments result in increased overall survival compared to other chemotherapy? RECOMMENDATION: Level III: Adult patients with pGBM might derive benefit in treatment with TMZ, especially those who progress after more than 5 months of TMZ-treatment free interval. LEVEL III: Combination of TMZ with other cytotoxic agents such as nitrosourea, cisplatin, electrohyperthermia, or tamoxifen is not suggested in adult patients with pGBM as a stand-alone therapy. There is insufficient data to make a recommendation about which alternative TMZ dosing provides the best benefits. QUESTION (Q2): In adult patients with pGBM does the use of systemic or in situ nitrosourea result in increased overall survival compared to other chemotherapy? RECOMMENDATION: Level III: In the setting of pGBM, fotemustine is suggested in elderly patients with methylated MGMT promoter status. There is insufficient evidence to compare fotemustine to other nitrosoureas. There is insufficient evidence to make a recommendation about the use of in situ nitrosourea in patients with pGBM who underwent the Stupp regimen. QUESTION (Q3): In adult patients with pGBM does the use of platinum compounds and topoisomerase result in increased survival compared to other chemotherapy? RECOMMENDATION: Level III: Other chemotherapy including platinum compounds and topoisomerase inhibitors are not suggested to be used in adult patients with pGBM. LEVEL III: Other cytotoxic therapies like perillyl acohol or ketogenic diet are not suggested for use in adult patients with pGBM as a stand-alone therapy. QUESTION (Q4): In adult patients with pGBM does the use of tumor treating field (TTF) result in increased overall survival compared to chemotherapy? RECOMMENDATION: Level III: The use of TTF with other chemotherapy may be considered when treating adult patients with pGBM. There is insufficient evidence to recommend TTF to increase overall survival in adult patients with pGBM. QUESTION (Q5): In adult patients with pGBM does the use of oncolytic virotherapy result in increased survival compared to chemotherapy? RECOMMENDATION: Level III: Oncolytic virotherapy is not suggested in patients with pGBM.

Congress of neurological surgeons systematic review and evidence-based guidelines update on the role of cytoreductive surgery in the management of progressive glioblastoma in adults.

QUESTION: In patients with previously diagnosed glioblastoma who are suspected of experiencing progression, does repeat cytoreductive surgery improve progression free survival or overall survival compared to alternative interventions? TARGET POPULATION: These recommendations apply to adults with previously diagnosed glioblastoma who are suspected of experiencing progression of the neoplastic process and are amenable to surgical resection. RECOMMENDATION: Level II: Repeat cytoreductive surgery is recommended in progressive glioblastoma patients to improve overall survival.

Clinical and radiographic characteristics of diffuse astrocytic glioma, IDH-wildtype, with molecular features of glioblastoma: a single institution review.

PURPOSE: Genetic analyses of gliomas have identified key molecular features that impact treatment paradigms beyond conventional histomorphology. Despite at-times lower grade histopathologic appearances, IDH-wildtype infiltrating gliomas expressing certain molecular markers behave like higher-grade tumors. For IDH-wildtype infiltrating gliomas lacking traditional features of glioblastoma, these markers form the basis for the novel diagnosis of diffuse astrocytic glioma, IDH-wildtype (wt), with molecular features of glioblastoma (GBM), WHO grade-IV (DAG-G). However, given the novelty of this approach to diagnosis, literature detailing the exact clinical, radiographic, and histopathologic findings associated with these tumors remain in development. METHODS: Data for 25 patients matching the DAG-G diagnosis were obtained from our institution's retrospective database. Information regarding patient demographics, treatment regimens, radiographic imaging, and genetic pathology were analyzed to determine association with clinical outcomes. RESULTS: The initial radiographic findings, histopathology, and symptomatology of patients with DAG-G were similar to lower-grade astrocytomas (WHO grade 2/3). Overall survival (OS) and progression free survival (PFS) associated with our cohort, however, were similar to that of IDH-wt GBM, indicating a more severe clinical course than expected from other associated features (15.1 and 5.39 months respectively). CONCLUSION: Despite multiple features similar to lower-grade gliomas, patients with DAG-G experience clinical courses similar to GBM. Such findings reinforce the need for biopsy and subsequent analysis of molecular features associated with any astrocytoma regardless of presenting characteristics.

82Rubidium chloride positron emission tomography discrimination of recurrent intracranial malignancy from radiation necrosis.

BACKGROUND: Accurate identification and discrimination of post treatment changes from recurrent disease remains a challenge for patients with intracranial malignancies despite advances in molecular and magnetic resonance imaging. We have explored the ability of readily available Rubidium-82 chloride (82RbCl) positron emission tomography (PET) to identify and distinguish progressive intracranial disease from radiation necrosis in patients previously treated with radiation therapy. METHODS: Six patients with a total of 9 lesions of either primary (N.=3) or metastatic (N.=6) intracranial malignancies previously treated with stereotactic radiation surgery (SRS) and persistent contrast enhancement on MRI underwent brain 82RbCl PET imaging. Two patients with arteriovenous malformations previously treated with SRS, also had brain 82RbCl PET imaging for a total of 11 lesions studied. Histological confirmation via stereotactic biopsy/excisional resection was obtained for 9 lesions with the remaining 2 classified as either recurrent tumor or radiation necrosis based on subsequent MRI examinations. 82RbCl PET time activity curve analysis was performed which comprised lesion SUVmax, contralateral normal brain SUVmax, and tumor to background ratios (TBmax). RESULTS: 82RbCl demonstrates uptake greater than normal brain parenchyma in all lesions studied. Time activity curves demonstrated progressive uptake of 82RbCl in all lesions without evidence of washout. While recurrent disease demonstrated a greater mean SUVmax compared to radiation necrosis, no statistically significant difference between lesion SUVmax nor TBmax was found (P>0.05). CONCLUSIONS: 82RbCl PET produces high-contrast uptake of both recurrent disease and radiation necrosis compared to normal brain. However, no statistically significant difference was found between recurrent tumor and radiation necrosis.

Guidelines in the management of CNS tumors.

INTRODUCTION: Evidence-based, clinical practice guidelines in the management of central nervous system tumors (CNS) continue to be developed and updated through the work of the Joint Section on Tumors of the Congress of Neurological Surgeons (CNS) and the American Association of Neurological Surgeons (AANS). METHODS: The guidelines are created using the most current and clinically relevant evidence using systematic methodologies, which classify available data and provide recommendations for clinical practice. CONCLUSION: This update summarizes the Tumor Section Guidelines developed over the last five years for non-functioning pituitary adenomas, low grade gliomas, vestibular schwannomas, and metastatic brain tumors.

Predictors of traumatic nerve injury and nerve recovery following humeral shaft fracture.

INTRODUCTION: Nerve palsy is common after humeral shaft fracture, with the radial nerve being the most commonly injured nerve. Isolated nerve injuries usually recover spontaneously, and operative intervention is rarely indicated. Our goal was to study the predictors of traumatic nerve injury and recovery in a large cohort of patients with humeral shaft fractures. METHODS: A total of 376 patients with humeral shaft fracture, including 96 patients with documented traumatic nerve palsy and 280 with intact neurovascular examination on presentation, were retrospectively included in the study. The primary outcome was incidence of a traumatic nerve palsy, and the secondary outcome was nerve recovery. RESULTS: Nerve palsy was present in 96 patients (25.5%) at the time of injury. Radial nerve was the most commonly injured nerve (93.6%), followed by the ulnar (5.1%) and axillary (1.2%) nerves. Seventeen patients (17.7%) had multiple nerves palsies. A multivariable regression analysis revealed that the concomitant vascular injury (odds ratio [OR] 52, 95% confidence interval [CI] 5.6-480.6), distal one-third fractures (OR 6.3, 95% CI 2.7-14.7), and middle one-third (OR 2.8, 95% CI 1.2-6.5) vs. proximal fractures, open fracture (OR 2.1, 95% CI 1.1-4.4), and high-energy trauma (OR 1.7, 95% CI 1.1-2.9) were independent predictors of nerve palsy. Iatrogenic nerve injury was detected in 7 patients (4.6%), all affecting the radial nerve. Spontaneous recovery of traumatic nerve injuries was detected in 87 patients (91%), with 19% partial and 72% complete recovery. The initial sign of recovery was observed at median times of 7 and 9 weeks for those managed conservatively or fracture fixation. Operative treatment of the fracture had no effect on the outcome of nerve recovery (88.5% vs. 100%, P = .14). Ten patients (14.1%) had transected nerves at the time of exploration and open fractures (22.7% vs. 6.8%, P = .04), and concomitant vascular injury (33.3% vs. 7.3%, P = .02) were associated with nerve transection, portending a worse prognosis for nerve recovery compared with nerves in continuity (40% vs. 95.3%, P = .004). DISCUSSION: The incidence of nerve injury after humeral shaft fracture was 25%, reflecting an abundance of high-energy and open injuries in this cohort. Ninety-one percent of patients experienced improvement in their nerve function with a median time to recovery of 7-9 weeks. Operative treatment of the fracture did not change the rate of nerve recovery. Patients with multiple nerve palsies and concurrent vascular insult had worse nerve recovery. We recommend nerve studies if no sign of recovery is observed by 9 weeks.

Glioma risk associated with extent of estimated European genetic ancestry in African Americans and Hispanics.

Glioma incidence is highest in non-Hispanic Whites, and to date, glioma genome-wide association studies (GWAS) to date have only included European ancestry (EA) populations. African Americans and Hispanics in the US have varying proportions of EA, African (AA) and Native American ancestries (NAA). It is unknown if identified GWAS loci or increased EA is associated with increased glioma risk. We assessed whether EA was associated with glioma in African Americans and Hispanics. Data were obtained for 832 cases and 675 controls from the Glioma International Case-Control Study and GliomaSE Case-Control Study previously estimated to have <80% EA, or self-identify as non-White. We estimated global and local ancestry using fastStructure and RFMix, respectively, using 1,000 genomes project reference populations. Within groups with ≥40% AA (AFR≥0.4 ), and ≥15% NAA (AMR≥0.15 ), genome-wide association between local EA and glioma was evaluated using logistic regression conditioned on global EA for all gliomas. We identified two regions (7q21.11, p = 6.36 × 10-4 ; 11p11.12, p = 7.0 × 10-4 ) associated with increased EA, and one associated with decreased EA (20p12.13, p = 0.0026) in AFR≥0.4 . In addition, we identified a peak at rs1620291 (p = 4.36 × 10-6 ) in 7q21.3. Among AMR≥0.15 , we found an association between increased EA in one region (12q24.21, p = 8.38 × 10-4 ), and decreased EA in two regions (8q24.21, p = 0. 0010; 20q13.33, p = 6.36 × 10-4 ). No other significant associations were identified. This analysis identified an association between glioma and two regions previously identified in EA populations (8q24.21, 20q13.33) and four novel regions (7q21.11, 11p11.12, 12q24.21 and 20p12.13). The identifications of novel association with EA suggest regions to target for future genetic association studies.

Optimal timing of chemoradiotherapy after surgical resection of glioblastoma: Stratification by validated prognostic classification.

BACKGROUND: Previous studies examining the time to initiate chemoradiation (CRT) after surgical resection of glioblastoma have been conflicting. To better define the effect that the timing of adjuvant treatment may have on outcomes, the authors examined patients within the National Cancer Database (NCDB) stratified by a validated prognostic classification system. METHODS: Patients with glioblastoma in the NCDB who underwent surgery and CRT from 2004 through 2013 were analyzed. Radiation Therapy Oncology Group recursive partitioning analysis (RPA) class (III, IV, V) was extrapolated for the cohort. Time intervals were grouped weekly, with weeks 4 to 5 serving as the reference category for analyses. Kaplan-Meier analysis, log-rank testing, and multivariate (MVA) Cox proportional hazards regression were performed. RESULTS: In total, 30,414 patients were included. RPA classes III, IV, and V contained 5250, 20,855, and 4309 patients, respectively. On MVA, no time point after week 5 was associated with a change in overall survival for the entire cohort or for any RPA class subgroup. The periods of weeks 0 to 1 (hazard ratio [HR], 1.18; 95% CI, 1.02-1.36), >1 to 2 (HR, 1.23; 95% CI, 1.16-1.31), and >2 to 3 (HR, 1.11; 95% CI, 1.07-1.15) demonstrated slightly worse overall survival (all P < .03). The detriment to early initiation was consistent across each RPA class subgroup. CONCLUSIONS: The current data provide insight into the optimal timing of CRT in patients with glioblastoma and describe RPA class-specific outcomes. In general, short delays beyond 5 weeks did not negatively affect outcomes, whereas early initiation before 3 weeks may be detrimental.

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.

Congress of neurological surgeons systematic review and evidence-based guidelines update on the role of emerging developments in the management of newly diagnosed glioblastoma.

TARGET POPULATION: These recommendations apply to adult patients with newly diagnosed or suspected glioblastoma. IMAGING: Question What imaging modalities are in development that may be able to provide improvements in diagnosis, and therapeutic guidance for individuals with newly diagnosed glioblastoma? RECOMMENDATION: Level III: It is suggested that techniques utilizing magnetic resonance imaging for diffusion weighted imaging, and to measure cerebral blood and magnetic spectroscopic resonance imaging of N-acetyl aspartate, choline and the choline to N-acetyl aspartate index to assist in diagnosis and treatment planning in patients with newly diagnosed or suspected glioblastoma. SURGERY: Question What new surgical techniques can be used to provide improved tumor definition and resectability to yield better tumor control and prognosis for individuals with newly diagnosed glioblastoma? RECOMMENDATIONS: Level II: The use of 5-aminolevulinic acid is recommended to improve extent of tumor resection in patients with newly diagnosed glioblastoma. Level II: The use of 5-aminolevulinic acid is recommended to improve median survival and 2 year survival in newly diagnosed glioblastoma patients with clinical characteristics suggesting poor prognosis. Level III: It is suggested that, when available, patients be enrolled in properly designed clinical trials assessing the value of diffusion tensor imaging in improving the safety of patients with newly diagnosed glioblastoma undergoing surgery. NEUROPATHOLOGY: Question What new pathology techniques and measurement of biomarkers in tumor tissue can be used to provide improved diagnostic ability, and determination of therapeutic responsiveness and prognosis for patients with newly diagnosed glioblastomas? RECOMMENDATIONS: Level II: Assessment of tumor MGMT promoter methylation status is recommended as a significant predictor of a longer progression free survival and overall survival in patients with newly diagnosed with glioblastoma. Level II: Measurement of tumor expression of neuron-glia-2, neurofilament protein, glutamine synthetase and phosphorylated STAT3 is recommended as a predictor of overall survival in patients with newly diagnosed with glioblastoma. Level III: Assessment of tumor IDH1 mutation status is suggested as a predictor of longer progression free survival and overall survival in patients with newly diagnosed with glioblastoma. Level III: Evaluation of tumor expression of Phosphorylated Mitogen-Activated Protein Kinase protein, EGFR protein, and Insulin-like Growth Factor-Binding Protein-3 is suggested as a predictor of overall survival in patients with newly diagnosed with glioblastoma. RADIATION: Question What radiation therapy techniques are in development that may be used to provide improved tumor control and prognosis for individuals with newly diagnosed glioblastomas? RECOMMENDATIONS: Level III: It is suggested that patients with newly diagnosed glioblastoma undergo pretreatment radio-labeled amino acid tracer positron emission tomography to assess areas at risk for tumor recurrence to assist in radiation treatment planning. Level III: It is suggested that, when available, patients be with newly diagnosed glioblastomas be enrolled in properly designed clinical trials of radiation dose escalation, altered fractionation, or new radiation delivery techniques. CHEMOTHERAPY: Question What emerging chemotherapeutic agents or techniques are available to provide better tumor control and prognosis for patients with newly diagnosed glioblastomas? RECOMMENDATION: Level III: As no emerging chemotherapeutic agents or techniques were identified in this review that improved tumor control and prognosis it is suggested that, when available, patients with newly diagnosed glioblastomas be enrolled in properly designed clinical trials of chemotherapy. MOLECULAR AND TARGETED THERAPY: Question What new targeted therapy agents are available to provide better tumor control and prognosis for individuals with newly diagnosed glioblastomas? RECOMMENDATION: Level III: As no new molecular and targeted therapies have clearly provided better tumor control and prognosis it is suggested that, when available, patients with newly diagnosed glioblastomas be enrolled in properly designed clinical trials of molecular and targeted therapies IMMUNOTHERAPY: Question What emerging immunotherapeutic agents or techniques are available to provide better tumor control and prognosis for patients with newly diagnosed glioblastomas? RECOMMENDATION: Level III: As no immunotherapeutic agents have clearly provided better tumor control and prognosis it is suggested that, when available, patients with newly diagnosed glioblastomas be enrolled in properly designed clinical trials of immunologically-based therapies. NOVEL THERAPIES: Question What novel therapies or techniques are in development to provide better tumor control and prognosis for individuals with newly diagnosed glioblastomas? RECOMMENDATIONS: Level II: The use of tumor-treating fields is recommended for patients with newly diagnosed glioblastoma who have undergone surgical debulking and completed concurrent chemoradiation without progression of disease at the time of tumor-treating field therapy initiation. Level II: It is suggested that, when available, enrollment in properly designed studies of vector containing herpes simplex thymidine kinase gene and prodrug therapies be considered in patients with newly diagnosed glioblastoma.