Serial S100B Sampling Detects Intracranial Lesion Development in Patients on Extracorporeal Membrane Oxygenation

Introduction: Intracranial lesion development is a recognized complication in adults treated with extracorporeal membrane oxygenation (ECMO) and is associated with increased mortality. As neurological assessment during ECMO treatment remains challenging, protein biomarkers of cerebral injury could provide an opportunity to detect intracranial lesion development at an early stage. The aim of this study was to determine if serially sampled S100B could be used to detect intracranial lesion development during ECMO treatment.Methods: We conducted an observational cohort study of all patients treated with ECMO at ECMO Center Karolinska (Karolinska University Hospital, Stockholm, Sweden) between January and August 2018, excluding patients who did not undergo a computerized tomography scan (CT) during treatment. S100B was prospectively collected at hospital admission and then once daily. The primary end-point was any type of CT verified intracranial lesion. Receiver operating characteristics (ROC) curves and Cox proportional hazards models were employed.Results: Twenty-nine patients were included, of which 15 (52%) developed an intracranial lesion and exhibited higher levels of S100B overall. S100B had a robust association with intracranial lesion development, especially during the first 200 hours following admission. The best area-under-curve (AUC) to predict intracranial lesion development was 40 and 140 hours following ECMO initiation, were a S100B level of 0.69μg/L had an AUC of 0.81 (0.628-0.997). S100B levels were markedly increased following the development of intracranial hemorrhage.Conclusions: Serial serum S100B samples in ECMO patients were both significantly elevated and had an increasing trajectory in patients developing intracranial lesions. Larger prospective trials are warranted to validate these findings and to ascertain their clinical utility

BRCA1-regulated RRM2 expression protects glioblastoma cells from endogenous replication stress and promotes tumorigenicity

Oncogene-evoked replication stress (RS) fuels genomic instability in diverse cancer types. Here we report that BRCA1, traditionally regarded a tumour suppressor, plays an unexpected tumour-promoting role in glioblastoma (GBM), safeguarding a protective response to supraphysiological RS levels. Higher BRCA1 positivity is associated with shorter survival of glioma patients and the abrogation of BRCA1 function in GBM enhances RS, DNA damage (DD) accumulation and impairs tumour growth. Mechanistically, we identify a novel role of BRCA1 as a transcriptional co-activator of RRM2 (catalytic subunit of ribonucleotide reductase), whereby BRCA1-mediated RRM2 expression protects GBM cells from endogenous RS, DD and apoptosis. Notably, we show that treatment with a RRM2 inhibitor triapine reproduces the BRCA1-depletion GBM-repressive phenotypes and sensitizes GBM cells to PARP inhibition. We propose that GBM cells are addicted to the RS-protective role of the BRCA1-RRM2 axis, targeting of which may represent a novel paradigm for therapeutic intervention in GBM

Chronic p53-independent p21 expression causes genomic instability by deregulating replication licensing

The cyclin-dependent kinase inhibitor p21WAF1/CIP1 (p21) is a cell-cycle checkpoint effector and inducer of senescence, regulated by p53. Yet, evidence suggests that p21 could also be oncogenic, through a mechanism that has so far remained obscure. We report that a subset of atypical cancerous cells strongly expressing p21 showed proliferation features. This occurred predominantly in p53-mutant human cancers, suggesting p53-independent upregulation of p21 selectively in more aggressive tumour cells. Multifaceted phenotypic and genomic analyses of p21-inducible, p53-null, cancerous and near-normal cellular models showed that after an initial senescence-like phase, a subpopulation of p21-expressing proliferating cells emerged, featuring increased genomic instability, aggressiveness and chemoresistance. Mechanistically, sustained p21 accumulation inhibited mainly the CRL4–CDT2 ubiquitin ligase, leading to deregulated origin licensing and replication stress. Collectively, our data reveal the tumour-promoting ability of p21 through deregulation of DNA replication licensing machinery—an unorthodox role to be considered in cancer treatment, since p21 responds to various stimuli including some chemotherapy drugs

The Swedish study of Irrigation-fluid temperature in the evacuation of Chronic subdural hematoma (SIC!) : study protocol for a multicenter randomized controlled trial

Background: Chronic subdural hematoma (cSDH) is one of the most common conditions encountered in neurosurgical practice. Recurrence, observed in 5-30% of patients, is a major clinical problem. The temperature of the irrigation fluid used during evacuation of the hematoma might theoretically influence recurrence rates since irrigation fluid at body temperature (37 degrees C) may beneficially influence coagulation and cSDH solubility when compared to irrigation fluid at room temperature. Should no difference in recurrence rates be observed when comparing irrigation-fluid temperatures, there is no need for warmed fluids during surgery. Our main aim is to investigate the effect of irrigation-fluid temperature on recurrence rates and clinical outcomes after cSDH evacuation using a multicenter randomized controlled trial design. Methods: The study will be conducted in three neurosurgical departments with population-based catchment areas using a similar surgical strategy. In total, 600 patients fulfilling the inclusion criteria will randomly be assigned to either intraoperative irrigation with fluid at body temperature or room temperature. The power calculation is based on a retrospective study performed at our department showing a recurrence rate of 5% versus 12% when comparing irrigation fluid at body temperature versus fluid at room temperature (unpublished data). The primary endpoint is recurrence rate of cSDH analyzed at 6 months post treatment. Secondary endpoints are mortality rate, complications and health-related quality of life. Discussion: Irrigation-fluid temperature might influence recurrence rates in the evacuation of chronic subdural hematomas. We present a study protocol for a multicenter randomized controlled trial investigating our hypothesis that irrigation fluid at body temperature is superior to room temperature in reducing recurrence rates following evacuation of cSDH

Neurosurgical patterns of care for diffuse low-grade gliomas in Sweden between 2005 and 2015

Background: In the last decade, increasing evidence has evolved for early and maximal safe resection of diffuse low-grade gliomas (LGGs) regarding survival. However, changes in clinical practice are known to occur slowly and we do not know if the scientific evidence has yet resulted in changes in neurosurgical patterns of care. Methods: The Swedish Brain Tumor Registry was used to identify all patients with a first-time histopathological diagnosis of LGG between 2005 and 2015. For analysis of surgical treatment patterns, we subdivided assessed time periods into 2005-2008, 2009-2012, and 2013-2015. Population-based data on patient and disease characteristics, surgical management, and outcomes were extracted. Results: A total of 548 patients with diffuse World Health Organization grade II gliomas were identified: 142 diagnosed during 2005-2008, 244 during 2009-2012, and 162 during 2013-2015. Resection as opposed to biopsy was performed in 64.3% during 2005-2008, 74.2% during 2009-2012, and 74.1% during 2013-2015 (P = .08). There was no difference among the 3 periods regarding overall survival (P= .11). However, post hoc analysis of data from the 4 (out of 6) centers that covered all 3 time periods demonstrated a resection rate of 64.3% during 2005-2008, 77.4% during 2009-2012, and 75.4% during 2013-2015 (P = .02) and longer survival of patients diagnosed 2009 and onward (P = .04). Conclusion: In this nationwide, population-based study we observed a shift over time in favor of LGG resection. Further, a positive correlation between the more active surgical strategy and longer survival is shown, although no causality can be claimed because of possible confounding factors

Short-Term Surgical Outcome for Vestibular Schwannoma in Sweden : A Nation-Wide Registry Study

Background: Vestibular Schwannoma (VS) is a benign neoplasm arising from the 8th cranial nerve, with surgery one of the treatment modalities. In a nation-wide registry study, we describe the baseline, treatment characteristics, and short-term outcome in patients surgically treated for VS. Methods: We performed a nationwide study with data from the Swedish Brain Tumor Registry (SBTR) for all adults diagnosed with VS 2009-2015. Patient symptoms, tumor characteristics, and postoperative complications were analyzed. Results: In total 348 patients underwent surgery for VS. Mean age was 50.6 +/- 14.5 years and 165 patients (47.4%) were female. The most common symptom was focal neurological deficit (92.0%), with only 25 (7.2%) being asymptomatic prior to surgery, and 217 (63.6%) had no restriction in activity. Following surgery, 100 (28.7%) patients developed new deficit(s). In terms of postoperative complications; 11 (3.2%) had a hematoma, 35 (10.1%) an infection, 10 (2.9%) a venous thromboembolism, and 23 (6.6%) had a reoperation due to complication. There were no deaths within 30-days after surgery. When grouped according to tumor size (<4 vs. >= 4 cm), those with >= 4 cm tumors were more often males (p = 0.02), had more often ICP related symptoms (p = 0.03) and shorter time from imaging to surgery (p < 0.01). Analysis of the younger (<65 years) vs. elderly (>= 65 years) revealed no difference in outcome except increased 1-year mortality (p = 0.002) in elderly. Conclusion: In this nation-wide registry-study, we benchmark the 30-day complication rate after VS surgery as collected by the SBTR. Further, we present the current neurosurgical outcome data from both VS smaller than 40 mm compared to larger tumors, as well as younger vs. elderly VS patients. Since surgical decision making is a careful consideration of short term risk vs. long term benefit, this information can be useful in clinical decision making

Neuron-Specific Enolase Is Correlated to Compromised Cerebral Metabolism in Patients Suffering from Acute Bacterial Meningitis; An Observational Cohort Study

<div><p>Introduction</p><p>Patients suffering from acute bacterial meningitis (ABM) with a decreased level of consciousness have been shown to have an improved clinical outcome if treated with an intracranial pressure (ICP) guided therapy. By using intracranial microdialysis (MD) to monitor cerebral metabolism in combination with serum samples of biomarkers indicating brain tissue injury, S100B and Neuron Specific Enolase (NSE), additional information might be provided. The aim of this study was to evaluate biomarkers in serum and MD parameters in patients with ABM.</p><p>Methods</p><p>From a prior study on patients (n = 52) with a confirmed ABM and impaired consciousness (GCS ≤ 9, or GCS = 10 combined with lumbar spinal opening pressure > 400 mmH₂O), a subgroup of patients (n = 21) monitored with intracerebral MD and biomarkers was included in the present study. All patients were treated in the NICU with intracranial pressure (ICP) guided therapy. Serum biomarkers were obtained at admission and every 12 hours. The MD parameters glucose, lactate, pyruvate and glycerol were analyzed. Outcome was assessed at 12–55 months after discharge from hospital. Mann-Whitney U-Test and Wilcoxon matched-pairs signed rank test were applied.</p><p>Results</p><p>The included patients had a mean GCS of 8 (range, 3–10) on admission and increased ICP (>20 mmHg) was observed in 62% (n = 13/21) of the patients. Patients with a lactate:pyruvate ratio (LPR) >40 (n = 9/21, 43%) had significantly higher peak levels of serum NSE (p = 0.03), with similar, although non-significant observations made in patients with high levels of glycerol (>500 μmol/L, p = 0.11) and those with a metabolic crisis (Glucose <0.8 mmol/L, LPR >25, p = 0.09). No associations between serum S100B and MD parameters were found. Furthermore, median MD glucose levels decreased significantly between day 1 (0–24h) and day 3 (48–72h) after admission to the NICU (p = 0.0001). No correlation between MD parameters or biomarkers and outcome was found.</p><p>Conclusion</p><p>In this observational cohort study, we were able to show that cerebral metabolism is frequently affected in patients with ABM. Furthermore, patients with high LPR (LPR>40) had significantly higher levels of NSE, suggesting ongoing deterioration in compromised cerebral tissue. However, the potential clinical impact of MD and biomarker monitoring in ABM patients will need to be further elaborated in larger clinical trials.</p></div

Outcome.

<p>Outcome.</p