Early prediction of ventricular peritoneal shunt dependency in aneurysmal subarachnoid haemorrhage patients by recurrent neural network-based machine learning using routine intensive care unit data.

Aneurysmal subarachnoid haemorrhage (aSAH) can lead to complications such as acute hydrocephalic congestion. Treatment of this acute condition often includes establishing an external ventricular drainage (EVD). However, chronic hydrocephalus develops in some patients, who then require placement of a permanent ventriculoperitoneal (VP) shunt. The aim of this study was to employ recurrent neural network (RNN)-based machine learning techniques to identify patients who require VP shunt placement at an early stage. This retrospective single-centre study included all patients who were diagnosed with aSAH and treated in the intensive care unit (ICU) between November 2010 and May 2020 (n = 602). More than 120 parameters were analysed, including routine neurocritical care data, vital signs and blood gas analyses. Various machine learning techniques, including RNNs and gradient boosting machines, were evaluated for their ability to predict VP shunt dependency. VP-shunt dependency could be predicted using an RNN after just one day of ICU stay, with an AUC-ROC of 0.77 (CI: 0.75-0.79). The accuracy of the prediction improved after four days of observation (Day 4: AUC-ROC 0.81, CI: 0.79-0.84). At that point, the accuracy of the prediction was 76% (CI: 75.98-83.09%), with a sensitivity of 85% (CI: 83-88%) and a specificity of 74% (CI: 71-78%). RNN-based machine learning has the potential to predict VP shunt dependency on Day 4 after ictus in aSAH patients using routine data collected in the ICU. The use of machine learning may allow early identification of patients with specific therapeutic needs and accelerate the execution of required procedures.

A recurrent machine learning model predicts intracranial hypertension in neurointensive care patients.

The evolution of intracranial pressure (ICP) of critically ill patients admitted to a neurointensive care unit (ICU) is difficult to predict. Besides the underlying disease and compromised intracranial space, ICP is affected by a multitude of factors, many of which are monitored on the ICU, but the complexity of the resulting patterns limits their clinical use. This paves the way for new machine learning techniques to assist clinical management of patients undergoing invasive ICP monitoring independent of the underlying disease. An institutional cohort (ICP-ICU) of patients with invasive ICP monitoring (n = 1346) was used to train recurrent machine learning models to predict the occurrence of ICP increases of ≥22 mmHg over a long (>2 h) time period in the upcoming hours. External validation was performed on patients undergoing invasive ICP measurement in two publicly available datasets [Medical Information Mart for Intensive Care (MIMIC, n = 998) and eICU Collaborative Research Database (n = 1634)]. Different distances (1-24 h) between prediction time point and upcoming critical phase were evaluated, demonstrating a decrease in performance but still robust AUC-ROC with larger distances (24 h AUC-ROC: ICP-ICU 0.826 ± 0.0071, MIMIC 0.836 ± 0.0063, eICU 0.779 ± 0.0046, 1 h AUC-ROC: ICP-ICU 0.982 ± 0.0008, MIMIC 0.965 ± 0.0010, eICU 0.941 ± 0.0025). The model operates on sparse hourly data and is stable in handling variable input lengths and missingness through its nature of recurrence and internal memory. Calculation of gradient-based feature importance revealed individual underlying decisions for our long short time memory-based model and thereby provided improved clinical interpretability. Recurrent machine learning models have the potential to be an effective tool for the prediction of ICP increases with high translational potential.

Acute low-pressure hydrocephalus in aneurysmal subarachnoid hemorrhage.

OBJECTIVE: Acute and chronic hydrocephalus are common pathologies after aneurysmal subarachnoid hemorrhage (SAH). Generally, the presence of acute hydrocephalus is associated with elevated intracranial pressure (ICP) treated with a ventricular drain. Subsequently, however, pronounced hydrocephalus without elevated ICP may develop in some patients with SAH in the postacute phase. This is described as acute low-pressure hydrocephalus (aLPH), and there are very limited data in the literature of this pathology. The aim of this study was to evaluate the rate of and factors associated with aLPH and describe its clinical course. METHODS: In this retrospective single-center cohort study, the frequency and clinical characteristics of SAH-associated aLPH were investigated. Acute LPH was defined as an increase in ventricular size as measured by the Evans index, ICP within the normal range (< 5 mm Hg) at the time of ventricular enlargement, and timely neurological improvement after indwelling ventricular CSF drainage with negative pressure up to 5 cm H2O below normal level. Demographic and SAH-specific factors in patients with SAH treated using an external ventricular drain were extracted from the electronic medical chart and further analyzed. RESULTS: From November 2010 to May 2020, 15 (3.7.%) of 406 patients with SAH fulfilled the criteria for aLPH. Acute LPH was diagnosed after an average of 13.1 ± 7.7 days. The presence of IVH and its extension were associated with the occurrence of aLPH. After undergoing the transient phase of aLPH, these patients subsequently developed a chronic, typical malresorptive hydrocephalus requiring a ventriculoperitoneal shunt more often (66.7% vs 17.4%, p < 0.001) and stayed longer in the intensive care unit (27 vs 20.5 days, p = 0.043) and in the hospital (36.4 vs 26.3 days, p = 0.004). CONCLUSIONS: Acute LPH is a rare pathology in patients with SAH and negatively impacts the clinical course. It should be especially considered in patients with a lack of neurological improvement, an increase in ventricular width, and normal ICP values, so that forced CSF drainage is implemented.

Diffusion tensor imaging changes in patients with glioma-associated seizures.

INTRODUCTION: Structural white matter changes associated with certain epilepsy subtypes have been demonstrated using diffusion tensor imaging (DTI). This observational study aims to identify potential water diffusion abnormalities in glioma patients with associated seizures. METHODS: Two cohorts from two centers were analyzed independently: (A) Prospectively recruited patients diagnosed with glioma who received preoperative DTI to measure mean diffusivity (MD) and fractional anisotropy (FA) in regions-of-interest (ROIs) including the marginal tumor zone (TU), adjacent peritumoral white matter as well as distant ipsilateral and contralateral white matter and cortex. Data were compared between patients with and without seizures and tested for statistical significance. (B) A retrospective cohort using an alternative technical approach sampling ROIs in contrast enhancement, necrosis, non-enhancing tumor, marginal non-enhancing tumor zone, peritumoral tissue, edema and non-tumorous tissue. RESULTS: (A) The prospective study cohort consisted of 23 patients with 12 (52.2%) presenting with a history of seizures. There were no significant seizure-associated differences in MD or FA for non-tumor white matter or cortical areas. MD-TU was significantly lower in patients with seizures (p = 0.005). (B) In the retrospective cohort consisting of 46 patients with a seizure incidence of 50.0%, significantly decreased normalized values of MD were observed for non-enhancing tumor regions of non-glioblastoma multiforme (GBM) cases in patients with seizures (p = 0.022). CONCLUSION: DTI analyses in glioma patients demonstrated seizure-associated diffusion restrictions in certain tumor-related areas. No other structural abnormalities in adjacent or distant white matter or cortical regions were detected.

False-positive results in transcranial motor evoked potentials for outcome prognostication during surgery for supratentorial lesions.

During monitoring of motor evoked potentials (MEP) elicited by transcranial electrical stimulation (TES) for prognostication of postoperative motor deficit, significant MEP changes without postoperative deterioration of motor function represent false-positive results. We aimed to investigate this phenomenon in a large series of patients who underwent resection of supratentorial lesions. TES was applied in 264 patients during resection of motor-eloquent supratentorial lesions. MEP were recorded bilaterally from arm, leg, and/ or facial muscles. The threshold criterion was applied assessing percentage increase in threshold level, which was considered significant if being > 20% higher on affected side than on the unaffected side. Subcortical stimulation was additionally applied to estimate the distance to corticospinal tract. Motor function was evaluated at 24 h after surgery and at 3-month follow-up. Patients with false-positive results were analyzed regarding tumor location, tumor volume, and characteristics of the monitoring. MEP were recorded from 399 muscles (264 arm muscles, 75 leg muscles, and 60 facial muscles). Motor function was unchanged postoperatively in 359 muscles in 228 patients. Among these cases, the threshold level did not change significantly in 354 muscles in 224 patients, while it increased significantly in the remaining 5 muscles in 4 patients (abductor pollicis brevis in all four patients and orbicularis oris in one patient), leading to a false-positive rate of 1.1%. Tumor volume, opening the ventricle, and negative subcortical stimulation did not significantly correlate with false-positive results, while the tumor location in the parietal lobe dorsal to the postcentral gyrus correlated significantly (p = 0.012, odds ratio 11.2, 95% CI 1.8 to 69.8). False-negative results took place in 1.1% of cases in a large series of TES-MEP monitoring using the threshold criterion. Tumor location in the parietal lobe dorsal to the postcentral gyrus was the only predictor of false-positive results.

Hyperoxia is Dose-Dependently Associated with an Increase of Unfavorable Outcomes in Ventilated Patients with Aneurysmal Subarachnoid Hemorrhage: A Retrospective Cohort Study.

BACKGROUND: Adequate oxygenation in patients with aneurysmal subarachnoid hemorrhage (SAH) is imperative. However, hyperoxia increases formation of reactive oxygen species and may be associated with a dose-dependent toxicity. We postulated a threshold for arterial partial pressure of oxygen (paO2) above which toxicity effects precipitate and sought to study the effects on 30-day mortality, favorable outcome at discharge and at 3 months, and delayed cerebral ischemia. METHODS: In this retrospective single-center cohort study, patients with SAH and mechanical ventilation > 72 h were included. Oxygen integrals were calculated above the following thresholds: 80, 100, 120, and 150 mm Hg and time-weighted mean paO2. All calculations were done from admission to end of day 1, day 3, and day 14. We conducted multivariable logistic regression analyses adjusted for age, sex, duration of ventilation, and Hunt and Hess grade. Time-weighted mean paO2 was categorized by quartiles. Favorable outcome was defined as Glasgow Outcome Scale scores of 4 and 5. RESULTS: From November 2010 to February 2021, 282 of 549 patients fulfilled the inclusion criteria. Odds ratios for 30-day mortality increased dose dependently and were as follows: 1.07 (95% confidence interval [CI] 1.03-1.11; p = 0.001) for each 1 mm Hg per day above 80 mm Hg; 1.16 (95% CI 1.07-1.27), above 100 mm Hg; 1.36 (95% CI 1.15-1.61), above 120 mm Hg; and 1.59 (95% CI 1.22-2.08), above 150 mm Hg (all p < 0.001) at day 14. For favorable outcome at 3 months, odds ratios were 0.96 (95% CI 0.92-0.99) for each 1 mm Hg per day above 80 mm Hg; 0.90 (95% CI 0.84-0.98), above 100 mm Hg; 0.83 (95% CI 0.72-0.97), above 120 mm Hg; and 0.77 (95% CI 0.61-0.97), above 150 mm Hg (all p < 0.05). For time-weighted mean paO2, lowest 30-day mortality and highest favorable outcome at 3 months were found in the second quartile (78-85 mm Hg). Thirty-day mortality increased above 93 mm Hg (fourth quartile), with an odds ratio of 3.4 (95% CI 1.4-8.4, p = 0.007). Odds ratios for favorable outcome at 3 months were 0.28 (95% CI 0.12-0.69), 0.27 (95% CI 0.11-0.67), and 0.24 (95% CI 0.10-0.59) for the first, third, and fourth quartiles, respectively (all p < 0.01). No significant association was found at day 1 and day 3, for favorable outcome at discharge, or for delayed cerebral ischemia. CONCLUSIONS: Integrals above the defined paO2 thresholds were dose-dependently associated with an increase in mortality in ventilated patients with SAH. When we considered time-weighted mean paO2, unfavorable outcomes and 30-day mortality were more frequent both below and above a certain range. Unfavorable outcomes increased in paO2 ranges usually defined as normoxia. This emphasizes the necessity to further characterize oxygenation thresholds in ventilated patients with SAH in prospective clinical studies.

The faster the better? Time to first CT scan after admission in moderate-to-severe traumatic brain injury and its association with mortality.

Fast acquisition of a first computed tomography (CT) scan after traumatic brain injury (TBI) is recommended. This study is aimed at investigating whether the length of the period preceding initial CT scan influences mortality in patients with leading TBI. A retrospective cohort analysis of patients registered in the TraumaRegister DGU® was conducted including adult patients with TBI, defined as Abbreviated Injury ScaleHead ≥ 3 and GCS ≤ 13 who had been treated in level 1 or 2 trauma centers from 2007-2016. Patients were grouped according to time intervals either from trauma or from admission to CT. A total of 6904 patients met the inclusion criteria. Mean time period from trauma to hospital admission was 68.8 min. From admission to first CT, a mean of 19.0 min elapsed. Trauma severity was higher in groups with a longer duration from trauma to CT as represented by a mean (± standard deviation) Injury Severity Score (ISS) of 19.8 ± 9.0, 20.7 ± 9.3, and 21.4 ± 7.5 and similar distribution of mortality of 24.9%, 29.9%, and 36.3% in the ≤ 60-min, 61-120-min, and ≥ 121-min groups, respectively. An adjusted multivariable logistic regression model showed a significant influence of the level of the trauma center (p = 0.037) but not for interval from admission to CT (p = 0.528). TBI patients with a longer time span from trauma to first CT were more severely injured and demonstrated a worse prognosis, but received a CT scan faster when duration from admission is observed. The duration until the CT scan was obtained showed no significant impact on the mortality.

Operative versus non-operative treatment of traumatic brain injuries in patients 80 years of age or older.

Traumatic brain injury (TBI) in older adults is an increasing issue in modern medicine. Nevertheless, it remains unclear which patients presenting with TBI and 80 years of age or older benefit from an operative treatment. The aim of this study was to explore the effect of an operative treatment in isolated TBI patients ≥ 80 years of age. Data were derived from the TraumaRegister DGU® from 2002 to 2016. Inclusion criteria were ≥ 80 years of age, an Abbreviated Injury ScaleHead (AIS) ≥ 3, and an AISNon-Head ≤ 1. The cohort was split in operatively and non-operatively treated patients, and outcome was assessed at discharge using the Glasgow Outcome Scale (GOS). A favorable outcome was defined as a GOS of 4 or 5. A total of 1.693 patients (431 operatively and 1.262 non-operatively treated patients) were analyzed. Mortality rate was 54.4% (687 patients) in the non-operative group and 49.4% in the operative group. Simultaneously, there were more patients discharged with a GOS 2 (persistent vegetative state) in the operative group (7.9%, 34 patients) than in the non-operative group (1.0%, 13 patients). An analysis of the operatively treated patients showed an association between a higher mortality risk and brainstem hemorrhage (p = 0.04), fixed pupils (p = 0.001), initial intubation (p = 0.03), and an AISHead of 5/6 (p = 0.03). Patients 80 years of age or older seem to benefit from an operative treatment regarding mortality rate. However, there has been a higher rate of a poor neurological outcome particularly with regard to persistent vegetative state in the operative treatment group at discharge.

Real-life analysis of 280 patients with surgically treated acromegaly: a single-center experience from 2008 to 2015.

OBJECTIVE: The purpose of this study was to analyze the clinical and biochemical outcome of consecutive patients with acromegaly after microscopic transsphenoidal surgery (MTS) at a single center over an 8-year period. METHODS: A retrospective analysis of patients with acromegaly treated via MTS between 2008 and 2015 at the authors' center was performed. The mean follow-up was 29 months (range 1-120 months). Parameters investigated included tumor size, pre- and postoperative insulin-like growth factor-I, growth hormone levels, pretreatment, perioperative complications, and clinical outcome. RESULTS: A total of 280 patients with acromegaly were treated surgically at the authors' center over the abovementioned time frame and were included in analyses. For 231 of these patients, complete follow-up data were available for evaluation. One hundred eighty-eight patients (81%) showed remission initially according to current criteria. So far, 23 of these patients relapsed in the further course, so that on follow-up 165 patients (71%) demonstrated full remission by surgery alone. Most patients in whom remission after surgery failed were treated with somatostatin receptor ligands and/or dopamine agonists as second-line treatment. The main postoperative complications included transient hyponatremia and diabetes insipidus (13/280; 4.6%). CSF leakage only occurred in 2 cases (2/280; 0.7%). No surgery-related death occurred. CONCLUSIONS: The data underline the effectiveness of MTS in acromegaly. Many patients with recurrent disease or incomplete tumor resection can be successfully managed pharmacologically.

The role of frameless stereotactic biopsy in contemporary neuro-oncology: molecular specifications and diagnostic yield in biopsied glioma patients.

INTRODUCTION: With the 2016 World Health Organization Classification of Tumors of the Central Nervous System (2016 CNS WHO), diagnosis of glioma is based on molecular parameters in addition to histology potentially leading to additional demands on quality of tissue samples. This may challenge the role of minimally invasive biopsy procedures. This study aims to evaluate the diagnostic yield of glioma samples from frameless stereotactic biopsies with focus on molecular information and explore the neuromolecular profile of a glioma biopsy cohort. METHODS: In a case series analysis, 180 consecutive frameless stereotactic biopsies with the Brainlab® Varioguide system from January 2011 to October 2017 were reviewed and patients with suspected or verified glioma were identified. Neuropathological samples were reprocessed in accordance with 2016 CNS WHO standards. RESULTS: One hundred nineteen glioma patients were identified. Analysis of IDH status could be performed in 95.8% resulting in a cumulative mutation rate of 9.6%. A complete diagnosis according to 2016 CNS WHO including grading and molecular features was achieved in 110 cases (92.4%). Entities were revised in four cases. Most common diagnosis was IDH-wildtype glioblastoma (66.4%) followed by IDH-wildtype anaplastic astrocytoma (21.8%). CONCLUSIONS: A formally complete diagnosis according to 2016 CNS WHO was achieved in the majority of cases. The biopsy cohort showed a prognostically unfavorable distribution of diagnoses and molecular features. Frameless stereotactic biopsy seems to be confirmed as a useful diagnostic tool in contemporary neuro-oncology-however, certain potential limitations should be considered.

Early clinical course after aneurysmal subarachnoid hemorrhage: comparison of patients treated with Woven EndoBridge, microsurgical clipping, or endovascular coiling.

BACKGROUND: The Woven EndoBridge (WEB) device has been increasingly used for the treatment of intracranial aneurysms after aneurysmal subarachnoid hemorrhage (SAH). Still, recent major clinical trials on patient management after SAH have defined WEB embolization as an exclusion criterion. In an analysis of an unselected patient cohort, we evaluate the early clinical course of SAH patients after WEB treatment compared to those treated with endovascular coiling or surgical clipping. METHODS: Data of all patients with proven SAH who were either treated with a WEB device, coil embolization, or neurosurgical clipping between March 2015 and August 2018 was systematically reviewed. Clinical parameters on intensive care unit (ICU), medical history and mortality rates were evaluated and compared between the different treatment approaches. RESULTS: Of all 201 patients included, 107 patients received endovascular coil embolization, 56 patients were treated with clipping and in 38 cases a WEB device was placed. The overall mortality was 17.9%. Thirteen patients (34.2%) in the WEB group had a Hunt and Hess grade > 3. Essential medical factors showed no clinically relevant differences between the treatment groups, and the analyzed blood parameters were predominantly within physiological limits without any relevant outliers. The Hunt and Hess grade but not the treatment modality was identified as independent risk-factor associated with ICU-mortality in the overall cohort (p < 0.001). CONCLUSION: In this study, there was no difference in the early clinical course between those treated with WEB embolization, coil embolization, or neurosurgical clipping. Since WEB embolization is a valuable treatment alternative to coiling, it seems not justified to exclude this procedure from upcoming clinical SAH trials, yet the clinical long-term outcome, aneurysm occlusion, and retreatment rates have to be analyzed in further studies. CLINICAL TRIAL REGISTRATION NUMBER: not applicable.

Rate and impact of multidrug-resistant organisms in patients with aneurysmal subarachnoid hemorrhage.

BACKGROUND: Multidrug-resistant organisms (MDRO) are an increasing problem in critical care medicine. This study describes for the first time the rate and impact of MDRO in patients suffering from aneurysmal subarachnoid hemorrhage (SAH). METHODS: Anonymized data of SAH patients admitted to our institution from November 2010 to August 2017 were retrospectively reviewed. Patients with microbiological tests positive for MDRO were identified. Screening of MDRO was in consensus with national recommendations. RESULTS: 449 SAH patients were reviewed with 18 patients (prevalence: four MDRO-positive patients per 100 SAH patients) having positive tests for MDRO during their hospital stay. The prevalence upon admission was 1.3 MDRO-positive patients per 100 patients. The acquisition rate was 1.1 MDRO-positive patients per 1000 hospital days. Patients positive for an MDRO had a significantly extended length of stay in intensive care (mean ± SD 26.7 ± 13.0 versus 18.4 ± 11.7 days, p = 0.004) and in hospital (mean ± SD 33.9 ± 12.4 versus 24.4 ± 12.6 days, p = 0.002). MDRO detection was associated with a significant prolonged duration of mechanical ventilation (median (IQR) 254.0 (14.9-632.8) versus 37.5 (3.3-277.0) hours, p = 0.02). There was no statistically significant effect on the Glasgow Outcome Scale (GOS) at discharge and at follow-up after 164.4 ± 113.0 days. CONCLUSIONS: MDRO positivity is present in 4% of aneurysmal SAH patients. It seems to be associated with a prolonged length of stay and prolonged duration of mechanical ventilation. The importance of infection control standards in neurointensive care units is emphasized.

Intrathecal penetration of meropenem and vancomycin administered by continuous infusion in patients suffering from ventriculitis-a retrospective analysis.

BACKGROUND: Vancomycin and meropenem are frequently used as empiric treatment for ventriculitis. Penetration into the cerebrospinal fluid (CSF) depends on various factors with a high inter-individual variability. Because attaining and maintaining adequate concentrations of meropenem and vancomycin in the CSF is crucial for their bactericidal effect, we introduced a routine therapeutic drug monitoring (TDM) from CSF and serum for both antibiotics. We studied the antibiotic penetration into the CSF. METHODS: Patient data including serum and CSF concentrations for meropenem and vancomycin were collected in a retrospective fashion. Antibiotic CSF penetration ratio was calculated for each patient. Antibiotics were administered by continuous infusion aiming for serum target concentrations of 20-30 mg/L for vancomycin and 16-32 mg/L for meropenem. RESULTS: Twenty-two patients with 36 CSF/serum pairs for meropenem and 43 pairs for vancomycin were studied. No patient suffered from renal or liver insufficiency. Mean vancomycin serum concentration was 22 ± 8 mg/L and the mean CSF concentration 4.5 ± 2.6 mg/L. CSF penetration was 20 ± 11% (coefficient of determination (R2) 0.02). For meropenem, the mean serum concentration was 30.7 ± 14.9 mg/L, mean CSF concentration 5.5 ± 5.2 mg/L, and a penetration of 18 ± 12%, R2 = 0.42. CONCLUSION: Penetration of meropenem and vancomycin into the CSF is low while showing a high interindividual variability. Various patients in our study cohort were at risk for insufficient target attainment in CSF. Continuous administration of antibiotics under routine TDM appears to be a feasible and reasonable approach for optimization of intrathecal drug levels in patients suffering from ventriculitis. TDM might guide individual dosing adaptation and efforts to predict the CSF penetration of meropenem and vancomycin in cases of ventriculitis.

Evaluation of a New Multiparameter Brain Probe for Simultaneous Measurement of Brain Tissue Oxygenation, Cerebral Blood Flow, Intracranial Pressure, and Brain Temperature in a Porcine Model.

BACKGROUND: A novel multiparameter brain sensor (MPBS) allows the simultaneous measurement of brain tissue oxygenation (ptiO2), cerebral blood flow (CBF), intracranial pressure (ICP), and brain temperature with a single catheter. This laboratory investigation evaluates the MPBS in an animal model in relation to established reference probes. METHODS: The study group consisted of 17 juvenile male pigs. Four MPBS and four reference probes were implanted per pig and compared simultaneously. The measured parameters were challenged by standardized provocations such as hyperoxia, dobutamine, and norepinephrine application, hypercapnia and hypoxia in combination with and without a controlled cortical impact (CCI) injury. Mean values over 2 min were collected for predefined time points and were analyzed using Bland-Altman plots. RESULTS: The protocol was successfully conducted in 15 pigs of which seven received CCI. ICP and ptiO2 were significantly influenced by the provocations. Subtraction of MPBS from reference values revealed a mean difference (limits of agreement) of 3.7 (- 20.5 to 27.9) mm Hg, - 2.9 (- 7.9 to 2.1) mm Hg, and 5.1 (- 134.7 to 145.0) % for ptiO2, ICP, and relative CBF, respectively. CONCLUSIONS: The MPBS is a promising measurement tool for multiparameter neuromonitoring. The conducted study demonstrates the in vivo functionality of the probe. Comparison with standard probes revealed a deviation which is mostly analogous to other multiparameter devices. However, further evaluation of the device is necessary before it can reliably be used for clinical decision making.

Prior malignancies in patients harboring glioblastoma: an institutional case-study of 2164 patients.

More patients are surviving long-term following a cancer diagnosis and as such are at risk for second malignancies. As the most common primary brain tumor, glioblastoma (GBM) will not infrequently occur in this population. No study has examined the incidence of prior cancer (PC) in patients harboring GBM. Here we evaluate the epidemiological features, as well as the molecular and clinical characteristics of GBM as a second cancer. Utilizing a web-based cancer data management system at our institution, we identified 2164 patients harboring GBM from 2007 to 2014. We collected baseline demographic, molecular, and clinical data. Univariate analysis was performed to compare the cohort of GBM patients with and without PC diagnosis. Survival differences were analyzed with Kaplan-Meier and log-rank testing. A Cox-proportional hazards model was fit for multivariable analysis. 170 patients (7.9%) harboring GBM had a PC diagnosis. The median interval between diagnoses was 79 months. The most common pathologies were breast (18.8%) and prostate (18.8%) cancer. Patients with a PC were older at the time of GBM diagnosis than those without PC (66 vs. 59 years, p < 0.001) and were more likely to be white (88.2 vs. 72.8%, p < 0.001). Patients with PC were more likely to harbor an EGFR (20 vs. 12.3%, p < 0.001) or MGMT mutation (17.6 vs. 11.6%, p < 0.001). Median survival was 13 months in the PC cohort and 15 months in the cohort without PC (p = NS). Age, KPS, and diagnosis year were the only factors which influenced outcome in multivariable analysis. Patients who develop GBM following a prior malignancy constitute ~8% of patients with GBM. Despite significant molecular differences these two cohorts appear to have a similar overall prognosis and clinical course. Thus, whether or not a patient harbors a malignancy prior to diagnosis of GBM should not exclude him or her from aggressive treatment or for consideration of novel investigational therapies.

Patient perception and satisfaction in awake burr hole trepanation under local anesthesia for evacuation of chronic subdural hematoma.

Evacuation of chronic subdural hematoma (CSDH) will be one of the most common neurosurgical procedures in the future in the increasingly aging societies. Performing cranial surgery on awake patients may place a psychological burden on them. Aim of this study was to evaluate the psychological distress of patients during awake CSDH relief. Patients with awake evacuation of CSDH via burr hole trepanation were included in our monocentric prospective study. Patient perception and satisfaction were measured using standardized surveys 3-5 days and 6 months after surgery. Among other questionnaires, the Hospital Anxiety and Depression and the Impact of Event Scale, were used to quantify patients' stress. A total of 50 patients (mean age 72.9 years (range 51 - 92)) were included. During surgery, 28 patients reported pain (mean 4.1 (SD 3.3)). Postoperatively, 26 patients experienced pain (mean 2.7 (SD 2.6)). Patients' satisfaction with intraoperative communication was reported with a mean of 8.3 (SD 2.1). There was a significant negative correlation between intraoperatively perceived pain and satisfaction with intraoperative communication (p = 0.023). Good intraoperative communication during evacuation of CSDH in awake patients is associated with positive patient perception and correlates with pain reduction.

Myeloid cell replacement is neuroprotective in chronic experimental autoimmune encephalomyelitis.

Multiple sclerosis (MS) is an autoimmune disease characterized by demyelination of the central nervous system (CNS). Autologous hematopoietic cell transplantation (HCT) shows promising benefits for relapsing-remitting MS in open-label clinical studies, but the cellular mechanisms underlying its therapeutic effects remain unclear. Using single-nucleus RNA sequencing, we identify a reactive myeloid cell state in chronic experimental autoimmune encephalitis (EAE) associated with neuroprotection and immune suppression. HCT in EAE mice results in an increase of the neuroprotective myeloid state, improvement of neurological deficits, reduced number of demyelinated lesions, decreased number of effector T cells and amelioration of reactive astrogliosis. Enhancing myeloid cell incorporation after a modified HCT further improved these neuroprotective effects. These data suggest that myeloid cell manipulation or replacement may be an effective therapeutic strategy for chronic inflammatory conditions of the CNS.

A scalable and cGMP-compatible autologous organotypic cell therapy for Dystrophic Epidermolysis Bullosa.

We present Dystrophic Epidermolysis Bullosa Cell Therapy (DEBCT), a scalable platform producing autologous organotypic iPS cell-derived induced skin composite (iSC) grafts for definitive treatment. Clinical-grade manufacturing integrates CRISPR-mediated genetic correction with reprogramming into one step, accelerating derivation of COL7A1-edited iPS cells from patients. Differentiation into epidermal, dermal and melanocyte progenitors is followed by CD49f-enrichment, minimizing maturation heterogeneity. Mouse xenografting of iSCs from four patients with different mutations demonstrates disease modifying activity at 1 month. Next-generation sequencing, biodistribution and tumorigenicity assays establish a favorable safety profile at 1-9 months. Single cell transcriptomics reveals that iSCs are composed of the major skin cell lineages and include prominent holoclone stem cell-like signatures of keratinocytes, and the recently described Gibbin-dependent signature of fibroblasts. The latter correlates with enhanced graftability of iSCs. In conclusion, DEBCT overcomes manufacturing and safety roadblocks and establishes a reproducible, safe, and cGMP-compatible therapeutic approach to heal lesions of DEB patients.

A cell therapy approach to restore microglial Trem2 function in a mouse model of Alzheimer's disease.

Alzheimer's disease (AD) remains one of the grand challenges facing human society. Much controversy exists around the complex and multifaceted pathogenesis of this prevalent disease. Given strong human genetic evidence, there is little doubt, however, that microglia play an important role in preventing degeneration of neurons. For example, loss of function of the microglial gene Trem2 renders microglia dysfunctional and causes an early-onset neurodegenerative syndrome, and Trem2 variants are among the strongest genetic risk factors for AD. Thus, restoring microglial function represents a rational therapeutic approach. Here, we show that systemic hematopoietic cell transplantation followed by enhancement of microglia replacement restores microglial function in a Trem2 mutant mouse model of AD.

Extracorporeal membrane oxygenation in traumatic brain injury - A retrospective, multicenter cohort study.

INTRODUCTION: Patients with traumatic brain injury (TBI) regularly require intensive care with prolonged invasive ventilation. Consequently, these patients are at increased risk of pulmonary failure, potentially requiring extracorporeal membrane oxygenation (ECMO). The aim of this work was to provide an overview of ECMO treatment in TBI patients based upon data captured into the TraumaRegister DGU® (TR-DGU). METHODS: A retrospective multi-center cohort analysis of patients registered in the TR-DGU was conducted. Adult patients with relevant TBI (AISHead ≥3) who had been treated in German, Austrian, or Swiss level I or II trauma centers using ECMO therapy between 2015 and 2019 were included. A multivariable logistic regression analysis was used to identify risk factors for the need for ECMO treatment. RESULTS: 12,247 patients fulfilled the inclusion criteria. The overall rate of ECMO treatment was 1.1% (134 patients). Patients on ECMO had an overall hospital mortality rate of 38% (51/134 patients) while 13% (1523/12,113 patients) of TBI patients without ECMO therapy died. Male gender (p = 0.014), AISChest 3+ (p<0.001), higher Injury Severity Score (p<0.001) and packed red blood cell (pRBC) transfusion (p<0.001) were associated with ECMO treatment. CONCLUSION: ECMO therapy is a potentially lifesaving modality for the treatment of moderate-to-severe TBI when combined with severe chest trauma and pulmonary failure. The in-hospital mortality is increased in this high-risk population, but the majority of patients is surviving.