ALL-tRNAseq enables robust tRNA profiling in tissue samples.

Transfer RNAs (tRNAs) are small adaptor RNAs essential for mRNA translation. Alterations in the cellular tRNA population can directly affect mRNA decoding rates and translational efficiency during cancer development and progression. To evaluate changes in the composition of the tRNA pool, multiple sequencing approaches have been developed to overcome reverse transcription blocks caused by the stable structures of these molecules and their numerous base modifications. However, it remains unclear whether current sequencing protocols faithfully capture tRNAs existing in cells or tissues. This is specifically challenging for clinical tissue samples that often present variable RNA qualities. For this reason, we developed ALL-tRNAseq, which combines the highly processive MarathonRT and RNA demethylation for the robust assessment of tRNA expression, together with a randomized adapter ligation strategy prior to reverse transcription to assess tRNA fragmentation levels in both cell lines and tissues. Incorporation of tRNA fragments not only informed on sample integrity but also significantly improved tRNA profiling of tissue samples. Our data showed that our profiling strategy effectively improves classification of oncogenic signatures in glioblastoma and diffuse large B-cell lymphoma tissues, particularly for samples presenting higher levels of RNA fragmentation, further highlighting the utility of ALL-tRNAseq for translational research.

Sodium and Its Impact on Outcome After Aneurysmal Subarachnoid Hemorrhage in Patients With and Without Delayed Cerebral Ischemia.

OBJECTIVES: To perform a detailed examination of sodium levels, hyponatremia and sodium fluctuations, and their association with delayed cerebral ischemia (DCI) and poor outcome after aneurysmal subarachnoid hemorrhage (aSAH). DESIGN: An observational cohort study from a prospective SAH Registry. SETTING: Tertiary referral center focused on SAH treatment in the Amsterdam metropolitan area. PATIENTS: A total of 964 adult patients with confirmed aSAH were included between 2011 and 2021. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: A total of 277 (29%) developed DCI. Hyponatremia occurred significantly more often in DCI patients compared with no-DCI patients (77% vs. 48%). Sodium levels, hyponatremia, hypernatremia, and sodium fluctuations did not predict DCI. However, higher sodium levels were significantly associated with poor outcome in DCI patients (DCI onset -7, DCI +0, +1, +2, +4, +5, +8, +9 d), and in no-DCI patients (postbleed day 6-10 and 12-14). Also, hypernatremia and greater sodium fluctuations were significantly associated with poor outcome in both DCI and no-DCI patients. CONCLUSIONS: Sodium levels, hyponatremia, and sodium fluctuations were not associated with the occurrence of DCI. However, higher sodium levels, hypernatremia, and greater sodium fluctuations were associated with poor outcome after aSAH irrespective of the presence of DCI. Therefore, sodium levels, even with mild changes in levels, warrant close attention.

Torticollis with Atlantoaxial Rotatory Subluxation in Children: A Clinical Review.

A small proportion of children with a sudden onset torticollis ("wry neck") presents with an atlantoaxial rotatory subluxation, usually after mild trauma or recent head or neck infection. Torticollis is a clinical diagnosis and imaging is usually not indicated, though often performed in clinical practice. Atlantoaxial rotatory subluxation on imaging is often a physiological phenomenon in torticollis, and concomitant neurological symptoms are therefore rare. Treatment is primarily conservative, with analgesics, a rigid neck collar, and if needed benzodiazepines to counteract muscle spasms and anxiety. In case of treatment failure or chronic subluxation, cervical repositioning and fixation under general anesthesia may be considered. Surgical treatment is only indicated in a small percentage of patients with chronic refractory subluxation, concomitant cervical fractures, or congenital anomalies. Early diagnosis and treatment are important, since this is associated with a more successful conservative outcome than a prolonged approach.

Predictive value of the five-repetition sit-to-stand test for outcomes after surgery for lumbar disc herniation: prospective study.

OBJECTIVE: It is unknown whether presence of pre-operative objective functional impairment (OFI) can predict post-operative outcomes in patients with lumbar disc herniation (LDH). We aimed to determine whether pre-operative OFI measured by the five-repetition sit-to-stand test (5R-STS) could predict outcomes at 12-months post-discectomy. METHODS: Adult patients with LDH scheduled for surgery were prospectively recruited from a Dutch short-stay spinal clinic. The 5R-STS time and patient reported outcome measures (PROMs) including Oswestry Disability Index, Roland-Morris Disability Questionnaire, Visual Analogue Scale (VAS) for back and leg pain, EQ-5D-3L health-related quality of life, EQ5D-VAS and ability to work were recorded pre-operatively and at 12-months. A 5R-STS time cut-off of ≥ 10.5 s was used to determine OFI. Mann-Whitney and Chi-square tests were employed to determine significant differences in post-operative outcomes between groups stratified by presence of pre-operative OFI. RESULTS: We recruited 134 patients in a prospective study. Twelve-month follow-up was completed by 103 (76.8%) patients. Mean age was 53.2 ± 14.35 years and 50 (48.5%) patients were female. Pre-operatively, 53 (51.5%) patients had OFI and 50 (48.5%) did not. Post-operatively, patients with OFI experienced a significantly greater mean change (p < 0.001) across all PROMs compared to patients without OFI, except leg pain (p = 0.176). There were no significant differences in absolute PROMs between groups at 12-months (all p > 0.05). CONCLUSIONS: The presence of OFI based on 5R-STS time does not appear to decrease a patient's likelihood of experiencing satisfactory post-operative outcomes. The 5R-STS cannot predict how a patient with LDH will respond to surgery at 12-month follow-up.

Calculation of the minimum clinically important difference (MCID) using different methodologies: case study and practical guide.

INTRODUCTION: Establishing thresholds of change that are actually meaningful for the patient in an outcome measurement instrument is paramount. This concept is called the minimum clinically important difference (MCID). We summarize available MCID calculation methods relevant to spine surgery, and outline key considerations, followed by a step-by-step working example of how MCID can be calculated, using publicly available data, to enable the readers to follow the calculations themselves. METHODS: Thirteen MCID calculations methods were summarized, including anchor-based methods, distribution-based methods, Reliable Change Index, 30% Reduction from Baseline, Social Comparison Approach and the Delphi method. All methods, except the latter two, were used to calculate MCID for improvement of Zurich Claudication Questionnaire (ZCQ) Symptom Severity of patients with lumbar spinal stenosis. Numeric Rating Scale for Leg Pain and Japanese Orthopaedic Association Back Pain Evaluation Questionnaire Walking Ability domain were used as anchors. RESULTS: The MCID for improvement of ZCQ Symptom Severity ranged from 0.8 to 5.1. On average, distribution-based methods yielded lower MCID values, than anchor-based methods. The percentage of patients who achieved the calculated MCID threshold ranged from 9.5% to 61.9%. CONCLUSIONS: MCID calculations are encouraged in spinal research to evaluate treatment success. Anchor-based methods, relying on scales assessing patient preferences, continue to be the "gold-standard" with receiver operating characteristic curve approach being optimal. In their absence, the minimum detectable change approach is acceptable. The provided explanation and step-by-step example of MCID calculations with statistical code and publicly available data can act as guidance in planning future MCID calculation studies.

Identifying clusters of objective functional impairment in patients with degenerative lumbar spinal disease using unsupervised learning.

OBJECTIVES: The five-repetition sit-to-stand (5R-STS) test was designed to capture objective functional impairment (OFI), and thus provides an adjunctive dimension in patient assessment. It is conceivable that there are different subsets of patients with OFI and degenerative lumbar disease. We aim to identify clusters of objectively functionally impaired individuals based on 5R-STS and unsupervised machine learning (ML). METHODS: Data from two prospective cohort studies on patients with surgery for degenerative lumbar disease and 5R-STS times of ≥ 10.5 s-indicating presence of OFI. K-means clustering-an unsupervised ML algorithm-was applied to identify clusters of OFI. Cluster hallmarks were then identified using descriptive and inferential statistical analyses. RESULTS: We included 173 patients (mean age [standard deviation]: 46.7 [12.7] years, 45% male) and identified three types of OFI. OFI Type 1 (57 pts., 32.9%), Type 2 (81 pts., 46.8%), and Type 3 (35 pts., 20.2%) exhibited mean 5R-STS test times of 14.0 (3.2), 14.5 (3.3), and 27.1 (4.4) seconds, respectively. The grades of OFI according to the validated baseline severity stratification of the 5R-STS increased significantly with each OFI type, as did extreme anxiety and depression symptoms, issues with mobility and daily activities. Types 1 and 2 are characterized by mild to moderate OFI-with female gender, lower body mass index, and less smokers as Type I hallmarks. CONCLUSIONS: Unsupervised learning techniques identified three distinct clusters of patients with OFI that may represent a more holistic clinical classification of patients with OFI than test-time stratifications alone, by accounting for individual patient characteristics.

Clinical response following hypertension induction for clinical delayed cerebral ischemia following subarachnoid hemorrhage: A retrospective, multicenter, cohort study.

BACKGROUND: Hypertension induction (HTI) is often used for treating delayed cerebral ischemia (DCI) following aneurysmal subarachnoid hemorrhage (aSAH); however, high-quality studies on its efficacy are lacking. We studied immediate and 3-/6-month clinical efficacy of HTI in aSAH patients with clinical DCI. METHODS: A retrospective, multicenter, comparative, observational cohort study in aSAH patients with clinical deterioration due to DCI, admitted to three tertiary referral hospitals in the Netherlands from 2015 to 2019. Two hospitals used a strategy of HTI (HTI group) and one hospital had no such strategy (control group). We calculated adjusted relative risks (aRR) using Poisson regression analyses for the two primary (clinical improvement of DCI symptoms at days 1 and 5 after DCI onset) and secondary outcomes (DCI-related cerebral infarction, in-hospital mortality, and poor clinical outcome [modified Rankin Scale 4-6] assessed at 3 or 6 months), using the intention-to-treat principle. We also performed as-treated and per-protocol analyses. RESULTS: The aRR for clinical improvement on day 1 after DCI in the HTI group was 1.63 (95% CI 1.17-2.27) and at day 5 after DCI 1.04 (95% CI 0.84-1.29). Secondary outcomes were comparable between the groups. The as-treated and per-protocol analyses yielded similar results. CONCLUSIONS: No clinical benefit of HTI is observed 5 days after DCI due to spontaneous reversal of DCI symptoms in patients treated without HTI. The 3-/6-month clinical outcome was similar for both groups. Therefore, these data suggest that one may consider to not apply HTI in aSAH patients with clinical DCI.

Predictors of five-repetition sit-to-stand test performance in patients with lumbar degenerative disease.

BACKGROUND: The five-repetition sit-to-stand test (5R-STS) has recently been validated as an objective measure of functional impairment in patients with lumbar degenerative disease (LDD). Knowledge of factors influencing 5R-STS performance is useful to correct for confounders, create personalized adjusted test times, and potentially identify prognostic subgroups. We evaluate factors predicting the 5R-STS performance in patients with LDD. METHODS: Patients with LDD requiring surgery were included. Each participant performed the 5R-STS and completed a questionnaire that included their age, gender, weight, height, body mass index (BMI), smoking status, education level, employment type, ability to work, analgesic drug usage, history of previous spinal surgery, and EQ5D depression and anxiety domain. Surgical indication and index level of the spinal pathology were also recorded. Predictors of 5R-STS were identified through multivariable linear regression. RESULTS: The cohort consisted of 240 patients, 47.9% being female (mean age, 47.7 ± 13.6 years). In the final multivariable model incorporating confounders, height (regression coefficient (RC), 0.08; 95% confidence interval (CI), 0.003/0.16, p = 0.042) and being an active smoker (RC, 2.44; 95%CI, 0.56/4.32, p = 0.012) were significant predictors of worse 5R-STS performance. Full ability to work (RC, - 2.39; 95%CI, - 4.39/ - 0.39, p = 0.020) was associated with a better 5R-STS performance. Age, height, surgical indication, index level of pathology, history of previous spine surgery, history of pain, analgesic drug use, employment type, and severity of anxiety and depression symptoms demonstrated confounding effect on the 5R-STS time. CONCLUSIONS: Greater height, being an active smoker, and inability to work are significant predictors of worse 5R-STS performance in patients with LDD. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03303300 and NCT03321357.

Safety and technical efficacy of early minimally invasive endoscopy-guided surgery for intracerebral haemorrhage: the Dutch Intracerebral haemorrhage Surgery Trial pilot study.

BACKGROUND: Previous randomised controlled trials could not demonstrate that surgical evacuation of intracerebral haemorrhage (ICH) improves functional outcome. Increasing evidence suggests that minimally invasive surgery may be beneficial, in particular when performed early after symptom onset. The aim of this study was to investigate safety and technical efficacy of early minimally invasive endoscopy-guided surgery in patients with spontaneous supratentorial ICH. METHODS: The Dutch Intracerebral Haemorrhage Surgery Trial pilot study was a prospective intervention study with blinded outcome assessment in three neurosurgical centres in the Netherlands. We included adult patients with spontaneous supratentorial ICH ≥10mL and National Institute of Health Stroke Scale (NIHSS) score ≥2 for minimally invasive endoscopy-guided surgery within 8 h after symptom onset in addition to medical management. Primary safety outcome was death or increase in NIHSS ≥4 points at 24 h. Secondary safety outcomes were procedure-related serious adverse events (SAEs) within 7 days and death within 30 days. Primary technical efficacy outcome was ICH volume reduction (%) at 24 h. RESULTS: We included 40 patients (median age 61 years; IQR 51-67; 28 men). Median baseline NIHSS was 19.5 (IQR 13.3-22.0) and median ICH volume 47.7mL (IQR 29.4-72.0). Six patients had a primary safety outcome, of whom two already deteriorated before surgery and one died within 24 h. Sixteen other SAEs were reported within 7 days in 11 patients (of whom two patients that already had a primary safety outcome), none device related. In total, four (10%) patients died within 30 days. Median ICH volume reduction at 24 h was 78% (IQR 50-89) and median postoperative ICH volume 10.5mL (IQR 5.1-23.8). CONCLUSIONS: Minimally invasive endoscopy-guided surgery within 8 h after symptom onset for supratentorial ICH appears to be safe and can effectively reduce ICH volume. Randomised controlled trials are needed to determine whether this intervention also improves functional outcome. TRIAL REGISTRATION: Clinicaltrials.gov : NCT03608423, August 1st, 2018.

Multidisciplinary integrated care pathway for von Hippel-Lindau disease.

BACKGROUND: Clinical pathways are care plans established to describe essential steps in the care of patients with a specific clinical problem. They translate (inter)national guidelines into local applicable protocols and clinical practice. The purpose of this article is to establish a multidisciplinary integrated care pathway for specialists and allied health care professionals in caring for individuals with von Hippel-Lindau (VHL) disease. METHODS: Using a modified Delphi consensus-making process, a multidisciplinary panel from 5 Dutch University Medical Centers produced an integrated care pathway relating to the provision of care for patients with VHL by medical specialists, specialized nurses, and associated health care professionals. Patient representatives cocreated the pathway and contributed quality criteria from the patients' perspective. RESULTS: The panel agreed on recommendations for the optimal quality of care for individuals with a VHL gene mutation. These items were the starting point for the development of a patient care pathway. With international medical guidelines addressing the different VHL-related disorders, this article presents a patient care pathway as a flowchart that can be incorporated into VHL expertise clinics or nonacademic treatment clinics. CONCLUSIONS: Medical specialists (internists, urologists, neurosurgeons, ophthalmologists, geneticists, medical oncologists, neurologists, gastroenterologists, pediatricians, and ear-nose-throat specialists) together with specialized nurses play a vital role alongside health care professionals in providing care to people affected by VHL and their families. This article presents a set of consensus recommendations, supported by organ-specific guidelines, for the roles of these practitioners in order to provide optimal VHL care. This care pathway can form the basis for the development of comprehensive, integrated pathways for multiple neoplasia syndromes.

Ultra-early tranexamic acid after subarachnoid haemorrhage (ULTRA): a randomised controlled trial.

BACKGROUND: In patients with aneurysmal subarachnoid haemorrhage, short-term antifibrinolytic therapy with tranexamic acid has been shown to reduce the risk of rebleeding. However, whether this treatment improves clinical outcome is unclear. We investigated whether ultra-early, short-term treatment with tranexamic acid improves clinical outcome at 6 months. METHODS: In this multicentre prospective, randomised, controlled, open-label trial with masked outcome assessment, adult patients with spontaneous CT-proven subarachnoid haemorrhage in eight treatment centres and 16 referring hospitals in the Netherlands were randomly assigned to treatment with tranexamic acid in addition to care as usual (tranexamic acid group) or care as usual only (control group). Tranexamic acid was started immediately after diagnosis in the presenting hospital (1 g bolus, followed by continuous infusion of 1 g every 8 h, terminated immediately before aneurysm treatment, or 24 h after start of the medication, whichever came first). The primary endpoint was clinical outcome at 6 months, assessed by the modified Rankin Scale, dichotomised into a good (0-3) or poor (4-6) clinical outcome. Both primary and safety analyses were according to intention to treat. This trial is registered at ClinicalTrials.gov, NCT02684812. FINDINGS: Between July 24, 2013, and July 29, 2019, we enrolled 955 patients; 480 patients were randomly assigned to tranexamic acid and 475 patients to the control group. In the intention-to-treat analysis, good clinical outcome was observed in 287 (60%) of 475 patients in the tranexamic acid group, and 300 (64%) of 470 patients in the control group (treatment centre adjusted odds ratio 0·86, 95% CI 0·66-1·12). Rebleeding after randomisation and before aneurysm treatment occurred in 49 (10%) patients in the tranexamic acid and in 66 (14%) patients in the control group (odds ratio 0·71, 95% CI 0·48-1·04). Other serious adverse events were comparable between groups. INTERPRETATION: In patients with CT-proven subarachnoid haemorrhage, presumably caused by a ruptured aneurysm, ultra-early, short-term tranexamic acid treatment did not improve clinical outcome at 6 months, as measured by the modified Rankin Scale. FUNDING: Fonds NutsOhra.

FUSE-ML: development and external validation of a clinical prediction model for mid-term outcomes after lumbar spinal fusion for degenerative disease.

BACKGROUND: Indications and outcomes in lumbar spinal fusion for degenerative disease are notoriously heterogenous. Selected subsets of patients show remarkable benefit. However, their objective identification is often difficult. Decision-making may be improved with reliable prediction of long-term outcomes for each individual patient, improving patient selection and avoiding ineffective procedures. METHODS: Clinical prediction models for long-term functional impairment [Oswestry Disability Index (ODI) or Core Outcome Measures Index (COMI)], back pain, and leg pain after lumbar fusion for degenerative disease were developed. Achievement of the minimum clinically important difference at 12 months postoperatively was defined as a reduction from baseline of at least 15 points for ODI, 2.2 points for COMI, or 2 points for pain severity. RESULTS: Models were developed and integrated into a web-app ( https://neurosurgery.shinyapps.io/fuseml/ ) based on a multinational cohort [N = 817; 42.7% male; mean (SD) age: 61.19 (12.36) years]. At external validation [N = 298; 35.6% male; mean (SD) age: 59.73 (12.64) years], areas under the curves for functional impairment [0.67, 95% confidence interval (CI): 0.59-0.74], back pain (0.72, 95%CI: 0.64-0.79), and leg pain (0.64, 95%CI: 0.54-0.73) demonstrated moderate ability to identify patients who are likely to benefit from surgery. Models demonstrated fair calibration of the predicted probabilities. CONCLUSIONS: Outcomes after lumbar spinal fusion for degenerative disease remain difficult to predict. Although assistive clinical prediction models can help in quantifying potential benefits of surgery and the externally validated FUSE-ML tool may aid in individualized risk-benefit estimation, truly impacting clinical practice in the era of "personalized medicine" necessitates more robust tools in this patient population.

Uncommon presentations of a neurosurgical site infection: impaired wound healing with hypergranulation and crust formation.

Hypergranulation and crust formation after cranial neurosurgery is rare. We report three patients with an uncommon form of hypergranulation with extensive crust formation after cranial neurosurgery, associated with a St. Aureus infection of the scalp, and propose that this is a form of pyogenic dermatitis, as is commonly seen among domestic animals with a coat of fur. It can be treated conservatively. We propose a treatment algorithm.

Deferred Consent in an Acute Stroke Trial from a Patient, Proxy, and Physician Perspective: A Cross-Sectional Survey.

BACKGROUND: In some acute care trials, immediate informed consent is not possible, but deferred consent is often considered problematic. We investigated the opinions of patients, proxies, and physicians about deferred consent in an acute stroke trial to gain insight into its acceptability and effects. METHODS: Paper-based surveys were sent to patients who were randomly assigned in the Ultra-early Tranexamic Acid After Subarachnoid Hemorrhage (ULTRA) trial between 2015 and 2018 in two tertiary referral centers and to physicians of centers who agreed or declined to participate. The primary outcome measure was the proportion of respondents who agreed with deferral of consent in the ULTRA trial. Secondary outcomes included respondents' preferred consent procedure for the ULTRA trial, the effect of deferred consent on trust in physicians and scientific research, and the willingness to participate in future research. RESULTS: Eighty-nine of 135 (66%) patients or proxies and 20 of 30 (67%) physicians completed the survey. Of these, 82 of 89 (92%) patients or proxies and 14 of 20 (70%) physicians agreed with deferral of consent in the ULTRA trial. When asked for their preferred consent procedure for the ULTRA trial, 31 of 89 (35%) patients or proxies indicated deferred consent, 15 of 89 (17%) preferred immediate informed consent, and 32 of 89 (36%) had no preference. None of the patients' or proxies' trust in physicians or scientific research had decreased because of the deferred consent procedure. Willingness to participate in future studies remained the same or increased in 84 of 89 (94%) patients or proxies. CONCLUSIONS: A large majority of the surveyed patients and proxies and a somewhat smaller majority of the surveyed physicians agreed with deferred consent in the ULTRA trial. Deferred consent may enable acute care trials in an acceptable manner without decreasing trust in medicine. Future research should investigate factors facilitating the responsible use of deferred consent, such as in-depth interviews, to study the minority of participants who agreed with deferred consent but still preferred immediate informed consent.

Neurosurgical Intervention for Supratentorial Intracerebral Hemorrhage.

OBJECTIVE: The effect of surgical treatment for supratentorial spontaneous intracerebral hemorrhage (ICH) and whether it is modified by key baseline characteristics and timing remains uncertain. METHODS: We performed a systematic review and meta-analysis of randomized controlled trials of surgical treatment of supratentorial spontaneous ICH aimed at clot removal. We searched MEDLINE, Embase, and Cochrane databases up to February 21, 2019. Primary outcome was good functional outcome at follow-up; secondary outcomes were death and serious adverse events. We analyzed all types of surgery combined and minimally invasive approaches separately. We pooled risk ratios with 95% confidence intervals and assessed the modifying effect of age, Glasgow Coma Scale, hematoma volume, and timing of surgery with meta-regression analysis. RESULTS: We included 21 studies with 4,145 patients; 4 (19%) were of the highest quality. Risk ratio of good functional outcome after any type of surgery was 1.40 (95% confidence interval [CI] = 1.22-1.60, I2 = 46%, 20 studies), and after minimally invasive surgery it was 1.47 (95% CI = 1.26-1.72, I2 = 47%, 12 studies). For death, the risk ratio for any type of surgery was 0.77 (95% CI = 0.68-0.85, I2 = 23%, 21 studies), and for minimally invasive surgery it was 0.68 (95% CI = 0.56-0.83, I2 = 14%, 13 studies). Serious adverse events were reported infrequently. Surgery seemed more effective when performed sooner after symptom onset (p = 0.04, 12 studies). Age, Glasgow Coma Scale, and hematoma volume did not modify the effect of surgery. INTERPRETATION: Surgical treatment of supratentorial spontaneous ICH may be beneficial, in particular with minimally invasive procedures and when performed soon after symptom onset. Further well-designed randomized trials are needed to demonstrate whether (minimally invasive) surgery improves functional outcome after ICH and to determine the optimal time window of the treatment after symptom onset. ANN NEUROL 2020;88:239-250.

A phase I/II study of bevacizumab, irinotecan and erlotinib in children with progressive diffuse intrinsic pontine glioma.

INTRODUCTION: This study investigates the safety, tolerability, and preliminary efficacy of combined treatment with VEGF inhibitor bevacizumab, topoisomerase I inhibitor irinotecan, and EGFR inhibitor erlotinib in children with progressive diffuse intrinsic pontine glioma (DIPG). METHODS: Biweekly bevacizumab (10 mg/kg) and irinotecan (125 mg/m2) were combined with daily erlotinib. Two cohorts received increasing doses of erlotinib (65 and 85 mg/m2) following a 3 + 3 dose-escalation schedule, until disease progression with a maximum of one year. Dose-limiting toxicities (DLT) were monitored biweekly. Secondary progression free survival (sPFS) and overall survival (OS) were determined based on clinical and radiological response measurements. Quality of life (QoL) during treatment was also assessed. RESULTS: Between November 2011 and March 2018, nine patients with disease progression after initial radiotherapy were enrolled. Median PFS at start of the study was 7.3 months (range 3.5-10.0). In the first dose cohort, one patient experienced a DLT (grade III acute diarrhea), resulting in enrollment of three additional patients in this cohort. No additional DLTs were observed in consecutive patients receiving up to a maximum dose of 85 mg/m2. Median sPFS was 3.2 months (range 1.0-10.9), and median OS was 13.8 months (range 9.3-33.0). Overall QoL was stable during treatment. CONCLUSIONS: Daily erlotinib is safe and well tolerated in doses up to 85 mg/m2 when combined with biweekly bevacizumab and irinotecan in children with progressive DIPG. Median OS of the study patients was longer than known form literature.

Cerebral circulation time on DSA during endovascular treatment in WFNS grade I aneurysmal SAH patients-a predictor of DCI?

PURPOSE: Delayed cerebral ischemia (DCI) remains a contributor to poor outcome following aneurysmal subarachnoid hemorrhage (aSAH). We evaluated cerebral circulation time (CCT) on digital subtraction angiography (DSA) during endovascular treatment (EVT) in WFNS grade I aSAH patients as a predictor of DCI. METHODS: Of 135 consecutive WNFS grade I aSAH patients, 90 were included. Age, gender, time of DSA from ictus (< 72 h or > 72 h), Fisher scale, severe vasospasm, development of DCI, EVD-dependent hydrocephalus, re-bleeding, and procedural complications were recorded. CCT was calculated retrospectively from multiphase DSA. Association with DCI was established through univariate and, subsequently, multivariable logistic regression. An optimal threshold value was identified using ROC curve analysis. Patient groups defined by threshold CCT value, DCI, and, subsequently, time of DSA from ictus were analyzed using χ2 and Fisher's exact test. RESULTS: CCT was the only significant factor in the multivariable logistic regression for the outcome development of DCI (OR/second increase in CCT = 1.46 [95% CI 1.14-1.86, p = .003]). When CCT was dichotomized at 8.5 s, the odds ratio for developing DCI was 7.12 (95% CI 1.93-26.34, p = .003) for CCT > 8.5 s compared with < 8.5 s. There was a significant difference for DCI in all patient groups dichotomized by CCT < 8.5 s and > 8.5 s (all patients, p = .001; patients imaged before and after 72 h of ictus, p = .024 and p = .034, respectively). CONCLUSION: A CCT > 8.5 s on DSA during EVT in WFNS grade I aSAH patients is associated with an increased risk of developing DCI and may aid in the management of high-risk patients.

Magnetic resonance imaging-based synthetic computed tomography of the lumbar spine for surgical planning: a clinical proof-of-concept.

OBJECTIVE: Computed tomography scanning of the lumbar spine incurs a radiation dose ranging from 3.5 mSv to 19.5 mSv as well as relevant costs and is commonly necessary for spinal neuronavigation. Mitigation of the need for treatment-planning CT scans in the presence of MRI facilitated by MRI-based synthetic CT (sCT) would revolutionize navigated lumbar spine surgery. The authors aim to demonstrate, as a proof of concept, the capability of deep learning-based generation of sCT scans from MRI of the lumbar spine in 3 cases and to evaluate the potential of sCT for surgical planning. METHODS: Synthetic CT reconstructions were made using a prototype version of the "BoneMRI" software. This deep learning-based image synthesis method relies on a convolutional neural network trained on paired MRI-CT data. A specific but generally available 4-minute 3D radiofrequency-spoiled T1-weighted multiple gradient echo MRI sequence was supplemented to a 1.5T lumbar spine MRI acquisition protocol. RESULTS: In the 3 presented cases, the prototype sCT method allowed voxel-wise radiodensity estimation from MRI, resulting in qualitatively adequate CT images of the lumbar spine based on visual inspection. Normal as well as pathological structures were reliably visualized. In the first case, in which a spiral CT scan was available as a control, a volume CT dose index (CTDIvol) of 12.9 mGy could thus have been avoided. Pedicle screw trajectories and screw thickness were estimable based on sCT findings. CONCLUSIONS: The evaluated prototype BoneMRI method enables generation of sCT scans from MRI images with only minor changes in the acquisition protocol, with a potential to reduce workflow complexity, radiation exposure, and costs. The quality of the generated CT scans was adequate based on visual inspection and could potentially be used for surgical planning, intraoperative neuronavigation, or for diagnostic purposes in an adjunctive manner.

Machine learning-augmented objective functional testing in the degenerative spine: quantifying impairment using patient-specific five-repetition sit-to-stand assessment.

OBJECTIVE: What is considered "abnormal" in clinical testing is typically defined by simple thresholds derived from normative data. For instance, when testing using the five-repetition sit-to-stand (5R-STS) test, the upper limit of normal (ULN) from a population of spine-healthy volunteers (10.5 seconds) is used to identify objective functional impairment (OFI), but this fails to consider different properties of individuals (e.g., taller and shorter, older and younger). Therefore, the authors developed a personalized testing strategy to quantify patient-specific OFI using machine learning. METHODS: Patients with disc herniation, spinal stenosis, spondylolisthesis, or discogenic chronic low-back pain and a population of spine-healthy volunteers, from two prospective studies, were included. A machine learning model was trained on normative data to predict personalized "expected" test times and their confidence intervals and ULNs (99th percentiles) based on simple demographics. OFI was defined as a test time greater than the personalized ULN. OFI was categorized into types 1 to 3 based on a clustering algorithm. A web app was developed to deploy the model clinically. RESULTS: Overall, 288 patients and 129 spine-healthy individuals were included. The model predicted "expected" test times with a mean absolute error of 1.18 (95% CI 1.13-1.21) seconds and R2 of 0.37 (95% CI 0.34-0.41). Based on the implemented personalized testing strategy, 191 patients (66.3%) exhibited OFI. Type 1, 2, and 3 impairments were seen in 64 (33.5%), 91 (47.6%), and 36 (18.8%) patients, respectively. Increasing detected levels of OFI were associated with statistically significant increases in subjective functional impairment, extreme anxiety and depression symptoms, being bedridden, extreme pain or discomfort, inability to carry out activities of daily living, and a limited ability to work. CONCLUSIONS: In the era of "precision medicine," simple population-based thresholds may eventually not be adequate to monitor quality and safety in neurosurgery. Individualized assessment integrating machine learning techniques provides more detailed and objective clinical assessment. The personalized testing strategy demonstrated concurrent validity with quality-of-life measures, and the freely accessible web app (https://neurosurgery.shinyapps.io/5RSTS/) enabled clinical application.