RANO 2.0: Update to the Response Assessment in Neuro-Oncology Criteria for High- and Low-Grade Gliomas in Adults.

PURPOSE: The Response Assessment in Neuro-Oncology (RANO) criteria for high-grade gliomas (RANO-HGG) and low-grade gliomas (RANO-LGG) were developed to improve reliability of response assessment in glioma trials. Over time, some limitations of these criteria were identified, and challenges emerged regarding integrating features of the modified RANO (mRANO) or the immunotherapy RANO (iRANO) criteria. METHODS: Informed by data from studies evaluating the different criteria, updates to the RANO criteria are proposed (RANO 2.0). RESULTS: We recommend a standard set of criteria for both high- and low-grade gliomas, to be used for all trials regardless of the treatment modalities being evaluated. In the newly diagnosed setting, the postradiotherapy magnetic resonance imaging (MRI), rather than the postsurgical MRI, will be used as the baseline for comparison with subsequent scans. Since the incidence of pseudoprogression is high in the 12 weeks after radiotherapy, continuation of treatment and confirmation of progression during this period with a repeat MRI, or histopathologic evidence of unequivocal recurrent tumor, are required to define tumor progression. However, confirmation scans are not mandatory after this period nor for the evaluation of treatment for recurrent tumors. For treatments with a high likelihood of pseudoprogression, mandatory confirmation of progression with a repeat MRI is highly recommended. The primary measurement remains the maximum cross-sectional area of tumor (two-dimensional) but volumetric measurements are an option. For IDH wild-type glioblastoma, the nonenhancing disease will no longer be evaluated except when assessing response to antiangiogenic agents. In IDH-mutated tumors with a significant nonenhancing component, clinical trials may require evaluating both the enhancing and nonenhancing tumor components for response assessment. CONCLUSION: The revised RANO 2.0 criteria refine response assessment in gliomas.

Haploinsufficiency of NFKBIA reshapes the epigenome antipodal to the IDH mutation and imparts disease fate in diffuse gliomas.

Genetic alterations help predict the clinical behavior of diffuse gliomas, but some variability remains uncorrelated. Here, we demonstrate that haploinsufficient deletions of chromatin-bound tumor suppressor NFKB inhibitor alpha (NFKBIA) display distinct patterns of occurrence in relation to other genetic markers and are disproportionately present at recurrence. NFKBIA haploinsufficiency is associated with unfavorable patient outcomes, independent of genetic and clinicopathologic predictors. NFKBIA deletions reshape the DNA and histone methylome antipodal to the IDH mutation and induce a transcriptome landscape partly reminiscent of H3K27M mutant pediatric gliomas. In IDH mutant gliomas, NFKBIA deletions are common in tumors with a clinical course similar to that of IDH wild-type tumors. An externally validated nomogram model for estimating individual patient survival in IDH mutant gliomas confirms that NFKBIA deletions predict comparatively brief survival. Thus, NFKBIA haploinsufficiency aligns with distinct epigenome changes, portends a poor prognosis, and should be incorporated into models predicting the disease fate of diffuse gliomas.

Joint Final Report of EORTC 26951 and RTOG 9402: Phase III Trials With Procarbazine, Lomustine, and Vincristine Chemotherapy for Anaplastic Oligodendroglial Tumors.

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the basis of the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.Anaplastic oligodendroglial tumors (AOTs) are chemotherapy-sensitive brain tumors. We report the final very long-term survival results from European Organization for the Research and Treatment of Cancer 26951 and Radiation Therapy Oncology Group 9402 phase III trials initiated in 1990s, which both studied radiotherapy with/without neo/adjuvant procarbazine, lomustine, and vincristine (PCV) for newly diagnosed anaplastic oligodendroglial tumors. The median follow-up duration in both was 18-19 years. For European Organization for the Research and Treatment of Cancer 26951, median, 14-year, and probable 20-year overall survival rates without versus with PCV were 2.6 years, 13.4%, and 10.1% versus 3.5 years, 25.1%, and 16.8% (N = 368 overall; hazard ratio [HR] 0.78; 95% CI, 0.63 to 0.98; P = .033), with 1p19q codeletion 9.3 years, 26.2%, and 13.6% versus 14.2 years, 51.0%, and 37.1% (n = 80; HR 0.60; 95% CI, 0.35 to 1.03; P = .063), respectively. For Radiation Therapy Oncology Group 9402, analogous results were 4.8 years, 16.5%, and 11.2% versus 4.8 years, 29.1%, and 24.6% (N = 289 overall; HR 0.79; 95% CI, 0.61 to 1.03; P = .08), with codeletion 7.3 years, 25.0%, and 14.9% versus 13.2 years, 46.1%, and 37% (n = 125; HR 0.61; 95% CI, 0.40 to 0.94; P = .02), respectively. With that, the studies show similar long-term survival even without tumor recurrence in a significant proportion of patients after first-line treatment with radiotherapy/PCV.

Opioid Prescription Following Wrist and Ankle Fracture Fixation in Scotland-Tradition Prevails.

The American 'opioid crisis' is rapidly spreading internationally. Perioperative opioid use increases the risk of long-term opioid use. We review opioid use following wrist and ankle fracture fixation across Scotland, establishing prescribing patterns and associations with patient, injury, or perioperative factors. Six Scottish orthopedic units contributed. A total of 598 patients were included. Patient demographics were similar across all sites. There was variation in anesthetic practice, length of stay, and AO fracture type (p < 0.01). For wrist fractures, 85.6% of patients received a discharge opioid prescription; 5.0% contained a strong opioid. There was no significant variation across the six units in prescribing practice. For ankle fractures, 82.7% of patients received a discharge opioid prescription; 17% contained a strong opioid. Dundee and Edinburgh used more strong opioids; Inverness and Paisley gave the least opioids overall (p < 0.01). Younger patient age, location, and length of stay were independent predictors of increased prescription on binary regression. Despite variability in perioperative practices, discharge opioid analgesic prescription remains overwhelmingly consistent. We believe that the biggest influence lies with the prescriber-institutional 'standard practice'. Education of these prescribing clinicians regarding the risk profile of opioids is key to reducing their use following surgery, thus lowering long-term opioid dependence.

Evaluation of sound levels in elective orthopaedic theatres during primary hip and knee arthroplasty.

BACKGROUND: Orthopaedic surgery involves tools which could cause noise-induced hearing loss in theatre staff. Threshold levels for occupational noise exposure have been developed in the U.K., above which action is required to reduce exposure. The aims of our study were to determine whether equivalent continuous sound pressure levels during elective arthroplasty can be measured using readily available materials, and to assess whether noise exposure levels stand within acceptable occupational noise exposure levels. MATERIALS AND METHODS: Sound pressure levels of orthopaedic saws were recorded using the MicW i436 connected to an iPhone 4S and the iOS SoundMeter application, and using a professional sound meter. Equivalent sound pressure levels were recorded for total hip replacement (THR) and total knee replacement (TKR) using the MicW i436 SoundMeter application. Data obtained was then used to calculate a "worst case" daily exposure value to assess if sound levels were compliant with U.K. RESULTS: Sound pressure levels recorded using the MicW i436 and Soundmeter application were accurate compared to professional soundmeter readings. THR showed equivalent sound pressure levels (LAeq) of 77 dBA and TKR showed a LAeq of 80 db. Calculated "worst case" scenarios for daily noise exposure using these values did not meet the lower exposure action values set out by U.K. CONCLUSIONS: It is possible to accurately measure continuous sound pressure levels during elective orthopaedic surgery using readily available materials. Noise exposure values during TKR meet lower exposure action values, and when "worst case" daily exposure levels are calculated this level is still lower than the threshold.

Cycling injuries requiring orthopaedic intervention during the first COVID-19 lockdown period: A multi-centre SCottish Orthopaedic Research collaborativE (SCORE) study.

INTRODUCTION: The COVID-19 lockdown resulted in decreased vehicle use and an increased uptake in cycling. This study investigated the trends in cycling-related injuries requiring orthopaedic intervention during the COVID-19 lockdown period compared with similar time periods in 2018 and 2019. METHODS: Data were collected prospectively for patients in 2020 and collected retrospectively for 2019 and 2018, from hospitals within four NHS Scotland Health Boards encompassing three major trauma centres. All patients who sustained an injury as a result of cycling requiring orthopaedic intervention were included. Patient age, sex, mechanism of injury, diagnosis and treatment outcome from electronic patient records. RESULTS: Number of injuries requiring surgery 2020: 77 (mean age/years - 42.7); 2019: 47 (mean age/years - 42.7); 2018: 32 (mean age/years - 31.3). Overall incidence of cycling injuries 2020: 6.7%; 2019: 3.0%; 2018: 2.1%. Commonest mechanism of injury: fall from bike 2020 n = 54 (70.1%); 2019 n = 41 (65.1%); 2018 n = 25 (67.6%). Commonest injury type: fracture 2020 n = 68 (79.1%); 2019 n = 33 (70.2%); 2018 n = 20 (62.5%). Commonest areas affected: Upper extremity: 2020 n = 45 (58.5%); 2019 n = 25 (53.2%); 2018 n = 25 (78.1%). Lower extremity: 2020 n = 23 (29.9%); 2019 n = 14 (29.7%); 2018 n = 7 (21.8%). CONCLUSION: A significant increase in the number of cycling related injuries requiring orthopaedic intervention, a greater proportion of female cyclists and an older mean age of patients affected was observed during the COVID-19 lockdown period compared with previous years. The most common types of injury were fractures followed by lacerations and fracture-dislocations. The upper extremity was the commonest area affected.

Long-Term Report of a Comprehensive Molecular and Genomic Analysis in NRG Oncology/RTOG 0424: A Phase II Study of Radiation and Temozolomide in High-Risk Grade II Glioma.

PURPOSE: This study sought to determine the prognostic significance of the WHO-defined glioma molecular subgroups along with additional alterations, including MGMT promoter methylation and mutations in ATRX, CIC, FUBP1, TERT, and TP53, in NRG/RTOG 0424 using long-term follow-up data. METHODS: Mutations were determined using an Ion Torrent sequencing panel. 1p/19q co-deletion and MGMT promoter methylation were determined by Affymetrix OncoScan and Illumina 450K arrays. Progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method and tested using the log-rank test. Hazard ratios were calculated using the Cox proportional hazard model. Multivariable analyses (MVAs) included patient pretreatment characteristics. RESULTS: We obtained complete molecular data to categorize 80/129 eligible patients within the WHO subgroups. Of these, 26 (32.5%) were IDHmutant/co-deleted, 28 (35%) were IDHmutant/non-co-deleted, and 26 (32.5%) were IDHwild-type. Upon single-marker MVA, both IDHmutant subgroups were associated with significantly better OS and PFS (P values < .001), compared with the IDHwild-type subgroup. MGMT promoter methylation was obtained on 76 patients, where 58 (76%) were methylated and 18 (24%) were unmethylated. Single-marker MVAs demonstrated that MGMT promoter methylation was statistically significant for OS (P value < .001) and PFS (P value = .003). In a multimarker MVA, one WHO subgroup comparison (IDHmutant/co-deleted v IDHwild-type) was significant for OS (P value = .045), whereas MGMT methylation did not retain significance. CONCLUSION: This study reports the long-term prognostic effect of the WHO molecular subgroups, MGMT promoter methylation, and other mutations in NRG/RTOG 0424. These results demonstrate that the WHO molecular classification and MGMT both serve as strong prognostic indicators, but that MGMT does not appear to add statistically significant prognostic value to the WHO subgrouping, above and beyond IDH and 1p/19q status.

Real time measurement of intramuscular pH during routine knee arthroscopy using a tourniquet : a preliminary study.

AIMS: Tourniquets have potential adverse effects including postoperative thigh pain, likely caused by their ischaemic and possible compressive effects. The aims of this preliminary study were to determine if it is possible to directly measure intramuscular pH in human subjects over time, and to measure the intramuscular pH changes resulting from tourniquet ischaemia in patients undergoing knee arthroscopy. METHODS: For patients undergoing short knee arthroscopic procedures, a sterile calibrated pH probe was inserted into the anterior fascial compartment of the leg after skin preparation, but before tourniquet inflation. The limb was elevated for three minutes prior to tourniquet inflation to 250 mmHg or 300 mmHg. Intramuscular pH was recorded at one-second intervals throughout the procedure and for 20 minutes following tourniquet deflation. Probe-related adverse events were recorded. RESULTS: A total of 27 patients were recruited to the study. Mean tourniquet time was 21 minutes (10 to 56). Tourniquet pressure was 300 mmHg for 21 patients and 250 mmHg for six patients. Mean muscle pH prior to tourniquet inflation was 6.80. Muscle pH decreased upon tourniquet inflation, with a steeper fall in the first ten minutes than for the rest of the procedure. Change in muscle pH was significant after five minutes of tourniquet ischaemia (p < 0.001). Mean muscle pH prior to tourniquet release was 6.58 and recovered to 6.75 within 20 minutes following release. No probe related adverse events were recorded. CONCLUSION: It is possible to directly measure skeletal muscle pH in human subjects over time. Tourniquet ischaemia results in a decrease in human skeletal muscle pH over time during short procedures. Cite this article: Bone Joint Res 2021;10(6):363-369.

Simultaneous ipsilateral tibial tuberosity and patellar fractures in an adult patient.

We present the case of a 56-year-old man who sustained a tibial tuberosity fracture with an associated patellar fracture. In the adult population there are only a few documented cases of tibial tuberosity fractures. This is only the second recorded case of bifocal patella tendon avulsion. The patient was managed successfully by fixation of the tibial tuberosity alone as the patella fracture was undisplaced and the patella retinaculum intact. A key point was screening the patella fracture at time of fixation to aid this decision. We achieved a good outcome at one year with internal fixation and early mobilisation.

Effects of the COVID-19 lockdown on orthopaedic trauma: a multicentre study across Scotland.

AIMS: The UK government declared a national lockdown on 23 March 2020 to reduce transmission of COVID-19. This study aims to identify the effect of lockdown on the rates, types, mechanisms, and mortality of musculoskeletal trauma across Scotland. METHODS: Data for all musculoskeletal trauma requiring operative treatment were collected prospectively from five key orthopaedic units across Scotland during lockdown (23 March 2020 to 28 May 2020). This was compared with data for the same timeframe in 2019 and 2018. Data collected included all cases requiring surgery, injury type, mechanism of injury, and inpatient mortality. RESULTS: A total of 1,315 patients received operative treatment from 23 March 2020 to 28 May 2020 compared with 1,791 in 2019 and 1,719 in 2018. The numbers of all injury types decreased, but the relative frequency of hip fractures increased (36.3% in 2020 vs 30.2% in 2019, p < 0.0001 and 30.7% in 2018, p < 0.0001). Significant increases were seen in the proportion of DIY-related injuries (3.1% in 2020 vs 1.7% in 2019, p = 0.012 and 1.6% in 2018, p < 0.005) and injuries caused by falls (65.6% in 2020 vs 62.6% in 2019, p = 0.082 and 61.9% in 2018, p = 0.047). Significant decreases were seen in the proportion of road traffic collisions (2.6% in 2020 vs 5.4% in 2019, p < 0.0001 and 4.2% in 2018, p = 0.016), occupational injuries (1.8% in 2020 vs 3.0% in 2019, p = 0.025 and 2.3% in 2018, p = 0.012) and infections (6.8% in 2020 vs 7.8% in 2019, p = 0.268 and 10.3% in 2018, p < 0.012). Cycling injuries increased (78 in 2020 vs 64 in 2019 vs 42 in 2018). A significant increase in the proportion of self-harm injuries was seen (1.7% in 2020 vs 1.1% in 2019, p = 0.185 and 0.5% in 2018, p < 0.0001). Mortality of trauma patients was significantly higher in 2020 (5.0%) than in 2019 (2.8%, p = 0.002) and 2018 (1.8%, p < 0.0001). CONCLUSION: The UK COVID-19 lockdown has resulted in a marked reduction in musculoskeletal trauma patients undergoing surgery in Scotland. There have been significant changes in types and mechanisms of injury and, concerningly, mortality of trauma patients has risen significantly.Cite this article: Bone Joint Open 2020;1-9:541-548.

Prolonged response to vismodegib in a patient with systemic medulloblastoma metastases.

Some patients with metastatic medulloblastoma can be successfully treated with targeted therapy. We report the case of a 42-year-old woman who was diagnosed with sonic hedgehog (SHH)-subgroup medulloblastoma. She was treated with surgery, radiation and chemotherapy. She then developed bone pain. A positron emission tomography (PET) scan confirmed widespread bone metastases from her medulloblastoma. She was started on vismodegib, an oral smoothened inhibitor that targets her tumour type. Her bone pain resolved. A repeat PET scan showed resolution of almost all metastases. Fourteen months after starting vismodegib, her disease recurred and she was transitioned to temozolomide chemotherapy. We document an important case of prolonged response to vismodegib in a patient with systemic SHH-subgroup medulloblastoma metastases.

Predictors of Medical Serious Adverse Events in Hip Fracture Patients Treated With Arthroplasty.

AIM: Patients with hip fractures are often frail with multiple comorbidities and at risk of medical serious adverse events (SAEs). We investigated the HEALTH trial patient population to ascertain predictors of SAEs. METHODS: We performed a multivariable Cox regression analysis. Occurrence of SAEs was included as the dependent variable with 31 potential prognostic factors being included as independent variables. RESULTS: One thousand four hundred forty-one patients were included in this analysis. Three hundred seventy (25.6%) patients suffered from an SAE. The most common events were cardiac (38.4%, n = 105), respiratory (20.8%, n = 77), and neurological (14.1%, n = 77). The majority of SAEs (50.8%, n = 188) occurred in the first 90 days after hip fracture with 35.4% occurring in the first 30 days (n = 131). Body mass index (BMI) between 18.5 and 24.9 compared with BMI between 25 and 29.9 [hazard ratio (HR) 1.32, P = 0.03] and receiving a total hip arthroplasty compared with a bipolar hemiarthroplasty (HR 1.36, P = 0.03) were associated with a higher risk of a medical SAE within 24 months of femoral neck fracture. Age (P = 0.09), use of femoral cement (P = 0.59), and use of canal pressurization (P = 0.37) were not associated with a medical SAE. CONCLUSION: Total hip arthroplasty is associated with more SAEs in the immediate postoperative period, and care should be taken in selecting patients for this treatment compared with a hemiarthroplasty. A higher BMI may be protective in hip fracture patients while age alone does not predict SAEs and neither does the use of femoral cement and/or pressurization. LEVEL OF EVIDENCE: Prognostic Level II. See Instructions for Authors for a complete description of levels of evidence.

Venous Thromboembolism in Hip Fracture Patients: A Subanalysis of the FAITH and HEALTH Trials.

BACKGROUND: The primary objective of this study was to determine the incidence of symptomatic venous thromboembolism (VTE), including pulmonary embolism (PE) and deep vein thrombosis (DVT), in the hip fracture population. Secondary objectives included determining timing of VTE diagnosis, VTE thromboprophylaxis given, and identifying any factors associated with VTE. METHODS: Using data from the FAITH and HEALTH trials, the incidence of VTE, including DVT and PE, and the timing of VTE were determined. A multivariable Cox regression analysis was used to determine which factors were associated with increased risk of VTE, including age, treatment for comorbidity, thromboprophylaxis, time to surgery, and method of fracture management. RESULTS: 2520 hip fracture patients were included in the analysis. Sixty-four patients (2.5%) had a VTE [DVT: 36 (1.4%), PE: 28 (1.1%)]. Thirty-five (54.7%) were diagnosed less than 6 weeks postfracture and 29 (45.3%) more than 6 weeks postfracture. One thousand nine hundred ninety-three (79%) patients received thromboprophylaxis preoperatively and 2502 (99%) received thromboprophylaxis postoperatively. The most common method of preoperative (46%) and postoperative (73%) thromboprophylaxis was low molecular weight heparin. Treatment with arthroplasty compared to internal fixation was the only variable associated with increased risk of VTE (hazard ratio 2.67, P = 0.02). CONCLUSIONS: The incidence of symptomatic VTE in hip fracture patients recruited to the 2 trials was 2.5%. Although over half of the cases were diagnosed within 6 weeks of fracture, VTE is still prevalent after this period. The majority of patients received thromboprophylaxis. Treatment with arthroplasty rather than fixation was associated with increased incidence of VTE. LEVEL OF EVIDENCE: Therapeutic Level II. See Instructions for Authors for a complete description of levels of evidence.

Phase 2 Study of a Temozolomide-Based Chemoradiation Therapy Regimen for High-Risk, Low-Grade Gliomas: Long-Term Results of Radiation Therapy Oncology Group 0424.

PURPOSE: To report the long-term outcomes of the RTOG 0424 study of a high-risk, low-grade glioma population treated with concurrent and adjuvant temozolomide (TMZ) and radiation therapy (RT). METHODS AND MATERIALS: For this single-arm, phase 2 study, patients with low-grade gliomas with ≥3 risk factors (age ≥40 years, astrocytoma, bihemispheric tumor, size ≥6 cm, or preoperative neurologic function status >1) received RT (54 Gy in 30 fractions) with TMZ and up to 12 cycles of post-RT TMZ. The initial primary endpoint P was overall survival (OS) at 3 years after registration. Secondary endpoints included progression-free survival (PFS) and the association of survival outcomes with methylation status. The initial 3-year report of this study was published in 2015. RESULTS: The study accrued 136 patients, of whom 129 were analyzable. The median follow-up for surviving patients was 9.0 years. The 3-year OS was 73.5% (95% confidence interval, 65.8%-81.1%), numerically superior to the 3-year OS historical control of 54% (P < .001). The median survival time was 8.2 years (95% confidence interval, 5.6-9.1). Five- and 10-year OS rates were 60.9% and 34.6%, respectively, and 5- and 10-year PFS rates were 46.8% and 25.5%, respectively. CONCLUSIONS: The long-term results confirmed the findings from the initial report for efficacy, suggesting OS and PFS outcomes with the RT-TMZ regimen exceeded historical control groups treated with radiation alone. Toxicity was acceptable.

Can Total Hip Arthroplasty for Hip Fracture Be Safely Performed by Trainees? A Retrospective Cohort Study.

BACKGROUND: No research is available comparing trainee and consultant outcomes for total hip arthroplasty (THA) for hip fracture. The aim of our study is to determine whether trainee-performed and consultant-performed THA produced equivalent radiological outcomes and complication rates for this patient cohort. METHODS: We performed a retrospective cohort study at our institution, with inclusion of patients who underwent a primary THA for hip fracture between March 30, 2017 and February 07, 2019. Relevant perioperative and outcome data were collected through electronic records. Radiological outcomes were assessed by 2 independent reviewers. Follow-up was performed until August 07, 2019. RESULTS: Eighty-seven patients were included in the study. The mean length of follow-up was 13 months (range, 6-29). Forty-three patients underwent consultant-led operations and 44 underwent trainee-performed (ST3-ST8) operations under consultant supervision. There were no significant differences between the 2 groups regarding complication risk (no recorded dislocation, infection requiring reoperation, revision or 30-day mortality in either group). There were also no significant differences between trainees and consultants regarding the radiological outcomes of mean acetabular component inclination (37.2° vs 36.7°, respectively, P = .74); offset difference (+7.1 mm vs +7.2 mm, respectively, P = .91); leg length difference (+6.4 mm vs +5.7 mm, respectively, P = .56); and barrack grade for femoral cement mantle. CONCLUSION: This study suggests that radiological and safety outcomes for trainees performing THA for hip fracture with appropriate supervision are equivalent to consultant surgeons. However, given the low event rate of complications, a larger study is required to determine whether there is any statistically significant difference.

Simultaneous bilateral hip fractures following a simple fall in an elderly patient: A case report.

Bilateral fractured necks of femur are rare, particularly in the absence of high energy trauma or metabolic bone disease. We describe a case of an 89 year old man with no history of metabolic bone disease who presented with bilateral neck of femur fractures following a simple fall. Clinicians must be vigilant to ensure that bilateral neck of femur fractures are identified and treated appropriately.

Operative Complications with and without Image Guidance: A Systematic Review and Meta-Analysis of the Ommaya Reservoir Literature.

BACKGROUND: The use of image guidance (IG) in neurosurgery is ubiquitous, even though evidence from patient outcome data has remained limited to smaller, mostly observational, studies. Ommaya reservoir insertion (ORI) has been available as a treatment option for targeted intraventricular pharmacotherapy since the 1960s, far preceding the modern neuronavigation era. We conducted a systematic review and meta-analysis investigating the impact of IG on surgical outcome from ORI. METHODS: A systematic database search of MEDLINE and EMBASE was performed to identify studies on operative outcomes from ORI. Only studies reporting patient demographics and perioperative outcomes (hemorrhage, infection, malposition, malfunction, and mortality) were included. Study quality was assessed via MINORS criteria. RESULTS: Of the 3560 records screened, 43 studies met study inclusion criteria, for a total of 1995 ORI procedures. Pooled rates of outcome for IG compared with non-IG were 6.4% versus 14.1% for overall complications; 2.0% compared with 2.8% for catheter malfunction; 2.3% compared with 3.3% for catheter malposition; 0.7% compared with 4.5% for early infection; and 0.6% compared with 1.4% for mortality. Postoperative hemorrhage was increased at 3.4% compared with 2.4%. Subgroup analysis revealed a difference in early infection rate between frameless and frame-based IG at 0.0% versus 1.9%. Meta-regression revealed a relationship between publication date and all operative outcomes except for catheter malposition and hemorrhage. CONCLUSIONS: This study offers a historical context on the evolution of the practice of ORI and comprises the largest observational analysis of operative outcomes providing objective support for the use of IG in neurosurgery.

Acute Achilles tendon rupture: Do cast boots produce adequate equinus when used for functional rehabilitation?

Acute Achilles tendon rupture is frequently treated conservatively using functional rehabilitation protocols in which the ankle is held in equinus. Equinus is achieved using a variety of means including equinus casts and rigid boots with heel wedges. Concerns have been raised that rigid boots with heel wedges do not achieve adequate equinus. Patients presenting to our institutions with an acute Achilles tendon rupture were randomised to treatment with an equinus cast or rigid boot with heel wedges. After application of these lateral radiographs of the hindfoot and ankle were taken, and these used to measure tibiotalar angle (TTA), tibio-1st metatarsal angle (TMA) and posterior malleolar to calcaneal tip height (PCH). 15 patients were randomised to a rigid boot and 14 to an equinus cast. The mean TTA was 124° in the rigid boot group and 136° in the equinus cast group (p<0.001). The mean TMA was 134° in the rigid boot group and 147° in the equinus cast group (p<0.001). The mean PCH was 25mm in the rigid boot group and 15mm in the equinus cast group (p<0.05). Our results demonstrate that the rigid boots with heel wedges used in our institutions produce significantly less equinus than an equinus cast. Whilst the clinical relevance of this remains uncertain, clinicians should be aware that rigid boots with wedges and equinus casts may not achieve the same degree of Achilles tendon shortening.

Association of MGMT Promoter Methylation Status With Survival Outcomes in Patients With High-Risk Glioma Treated With Radiotherapy and Temozolomide: An Analysis From the NRG Oncology/RTOG 0424 Trial.

Importance: The initial report of NRG Oncology/Radiation Therapy Oncology Group (RTOG) 0424 demonstrated a 3-year overall survival benefit with the addition of temozolomide to radiotherapy compared with a historical control. However, an important end point of the trial-evaluation of the association between O6-methylgaunine-DNA-methyltransferase (MGMT) promoter methylation and survival outcomes-was not previously reported. Objective: To examine the proportion of patients in NRG Oncology/RTOG 0424 with MGMT promoter methylation and its association with survival outcomes. Design, Setting, and Participants: Specimens collected were analyzed after trial completion to determine MGMT promoter methylation and IDH1/2 status and the association between MGMT status and survival outcomes. A model derived from logistic regression (MGMT-STP27) was used to calculate MGMT promoter methylation status. Univariate and multivariable analyses were performed using the Cox proportional hazards regression model to determine the association of MGMT status with survival outcomes. Patient pretreatment characteristics were included as covariates in multivariable analyses. Main Outcomes and Measures: Progression-free survival (PFS) and overall survival (OS). Results: Of all 129 eligible patients in NRG Oncology/RTOG 0424, 75 (58.1%) had MGMT status available (median age, 48 years; age range, 20-76 years; 42 [56.0%] male): 57 (76.0%) methylated and 18 (24.0%) unmethylated. A total of 13 unmethylated patients (72.2%) had astrocytoma as opposed to oligoastrocytoma or oligodendroglioma, whereas 23 methylated patients (40.4%) had astrocytoma. On univariate analyses, an unmethylated MGMT promoter was significantly associated with worse OS (hazard ratio [HR], 3.52; 95% CI, 1.64-7.56; P < .001) and PFS (HR, 3.06; 95% CI, 1.55-6.04; P < .001). The statistical significances were maintained in multimarker multivariable analyses, including IDH1/2 status for both OS (HR, 2.70; 95% CI, 1.02-7.14; P = .045) and PFS (HR, 2.74; 95% CI, 1.19-6.33; P = .02). Conclusions and Relevance: In this study, MGMT promoter methylation was an independent prognostic biomarker of high-risk, low-grade glioma treated with temozolomide and radiotherapy. This is the first study, to our knowledge, to validate the prognostic importance of MGMT promoter methylation in patients with grade II glioma treated with combined radiotherapy and temozolomide and highlights its potential prognostic value beyond IDH1/2 mutation status. Trial Registration: ClinicalTrials.gov Identifier: NCT00114140.

Corticosteroid use endpoints in neuro-oncology: Response Assessment in Neuro-Oncology Working Group.

Background: Corticosteroids are the mainstay of treatment for peritumor edema but are often associated with significant side effects. Therapies that can reduce corticosteroid use would potentially be of significant benefit to patients. However, currently there are no standardized endpoints evaluating corticosteroid use in neuro-oncology clinical trials. Methods: The Response Assessment in Neuro-Oncology (RANO) Working Group has developed consensus recommendations for endpoints evaluating corticosteroid use in clinical trials in both adults and children with brain tumors. Results: Responders are defined as patients with a 50% reduction in total daily corticosteroid dose compared with baseline or reduction of the total daily dose to ≤2 mg of dexamethasone (or equivalent dose of other corticosteroid); baseline dose must be at least 4 mg of dexamethasone daily (or equivalent dose of other corticosteroids) for at least one week. Patients must have stable or improved Neurologic Assessment in Neuro-Oncology (NANO) score or Karnofsky performance status score or Eastern Cooperative Oncology Group (ECOG) (Lansky score for children age <16 y), and an improved score on a relevant clinical outcome assessment tool. These criteria must be sustained for at least 4 weeks after baseline assessment to be considered a response, and are confirmed 4 weeks after that (ie, 8 wk after baseline assessment) to be considered a sustained response. Conclusions: This RANO proposal for corticosteroid use endpoints in neuro-oncology clinical trials may need to be refined and will require prospective validation in clinical studies.