Surgery for chronic subdural hematoma (CSDH) is one of the most common neurosurgical procedures. The benefit of postoperative passive subdural drainage compared with no drains has been established, ...but other drainage techniques are common, and their effectiveness compared with passive subdural drains remains unknown.
In Scandinavian population-based cohorts the authors conducted a consecutive, parallel cohort study to compare different drainage techniques. The techniques used were continuous irrigation and drainage (CID cohort, n = 166), passive subdural drainage (PD cohort, n = 330), and active subgaleal drainage (AD cohort, n = 764). The primary end point was recurrence in need of reoperation within 6 months of index surgery. Secondary end points were complications, perioperative mortality, and overall survival. The analyses were based on direct regional comparison (i.e., surgical strategy).
Recurrence in need of surgery was observed in 18 patients (10.8%) in the CID cohort, in 66 patients (20.0%) in the PD cohort, and in 85 patients (11.1%) in the AD cohort (p < 0.001). Complications were more common in the CID cohort (14.5%) compared with the PD (7.3%) and AD (8.1%) cohorts (p = 0.019). Perioperative mortality rates were similar between cohorts (p = 0.621). There were some differences in baseline and treatment characteristics possibly interfering with the above-mentioned results. However, after adjusting for differences in baseline and treatment characteristics in a regression model, the drainage techniques were still significantly associated with clinical outcome (p < 0.001 for recurrence, p = 0.017 for complications).
Compared with the AD cohort, more recurrences were observed in the PD cohort and more complications in the CID cohort, also after adjustment for differences at baseline. Although the authors cannot exclude unmeasured confounding factors when comparing centers, AD appears superior to the more common PD.Clinical trial registration no.: NCT01930617 (clinicaltrials.gov).
To investigate predictors of recurrence and moderate to severe complications after burr-hole surgery for chronic subdural hematoma (cSDH).
A retrospective review was conducted in a Scandinavian ...single-center population-based cohort of 759 adult patients with cSDH operated with burr-hole surgery between January 1, 2005 and December 31, 2010. Possible predictors of recurrence and complications, assessed using a standardized reporting system of adverse events, were identified and analyzed in univariable analyses. Variables with a P value < 0.10 were included in a multivariable regression model.
Recurrence was observed in 85 patients (11.2%), whereas moderate to severe complications were observed in 35 patients (4.6%). Bilateral hematoma (odds ratio OR, 2.05; 95% confidence interval CI, 1.25–3.35; P < 0.01) and largest hematoma diameter in millimeters (OR, 1.05; 95% CI, 1.01–1.09; P < 0.01) were independent predictors of recurrence in the multivariable model analysis. Glasgow Coma Scale (GCS) score of <13 (OR, 6.06; 95% CI, 2.72–13.51; P < 0.01) and Charlson Comorbidity Index (CCI) >1 (OR, 2.28; 95% CI, 1.10–4.75; P = 0.03) were independent predictors of moderate to severe complications.
Recurrence after cSDH surgery is more often encountered in patients with radiologically more extensive disease reflected by bilateral hematoma and large hematoma diameter. On the other hand, moderate to severe complications are more often seen in patients in a worse clinical condition, reflected by decreased level of consciousness and more comorbidities.
Chronic Subdural Hematoma (cSDH) is primarily a disease of elderly, and is rare in patients <50 years, and this may in part be related to the increased brain atrophy from 50 years of age. This fact ...may also influence clinical presentation and outcome. The aim of this study was to study the clinical course with emphasis on clinical presentation of cSDH patients in the young (<50 years).
A retrospective review of a population-based cohort of 1,252 patients operated for cSDH from three Scandinavian neurosurgical centers was conducted. The primary end-point was difference in clinical presentation between the patients <50 y/o and the remaining patients (≥50 y/o group). The secondary end-points were differences in perioperative morbidity, recurrence and mortality between the two groups. In addition, a meta-analysis was performed comparing clinical patterns of cSDH in the two age groups.
Fifty-two patients (4.2%) were younger than 50 years. Younger patients were more likely to present with headache (86.5% vs. 37.9%,
< 0.001) and vomiting (25% vs. 5.2%,
< 0.001) than the patients ≥50 y/o, while the ≥50 y/o group more often presented with limb weakness (17.3% vs. 44.8%,
< 0.001), speech impairment (5.8% vs. 26.2%,
= 0.001) and gait disturbance or falls (23.1% vs. 50.7%,
< 0.001). There was no difference between the two groups in recurrence, overall complication rate and mortality within 90 days. Our meta-analysis confirmed that younger patients are more likely to present with headache (
= 0.015) while the hemispheric symptoms are more likely in patients ≥50 y/o (
< 0.001).
Younger patients with cSDH present more often with signs of increased intracranial pressure, while those ≥50 y/o more often present with hemispheric symptoms. No difference exists between the two groups in terms of recurrence, morbidity, and short-term mortality. Knowledge of variations in clinical presentation is important for correct and timely diagnosis in younger cSDH patients.
Introduction: Circulating tumor DNA (ctDNA) has become a relevant biomarker in cancer management, allowing tumor assessment through analysis of minimally invasive liquid biopsies. Applications ...include screening, diagnostics, monitoring of treatment efficacy and detection of minimal residual disease as well as relapse. The potential of ctDNA analysis is significant, but several biological and technical challenges need to be addressed before widespread clinical implementation.
Areas covered: Several clinical applications where ctDNA analysis may be beneficial require detection of individual DNA molecules. Consequently, to acquire accurate and informative data the entire workflow from sampling to final data interpretation needs to be optimized. In this review, we discuss the biological and technical challenges of ctDNA analysis and how preanalytical and analytical approaches affect different cancer applications.
Expert opinion: While numerous studies have demonstrated the potential of using ctDNA in cancer applications, yet few reports about true clinical utility exist. Despite encouraging data, the sensitivity of ctDNA analyses, i.e. the probability to detect presence of cancer in liquid biopsies, is still an issue. Analysis of multiple mutations in combination with simultaneous assessment of other analytes is one solution. Improved standardization and guidelines will also facilitate the introduction of ctDNA analysis into clinical routine.
Elevated intracranial pressure (ICP) is an important cause of secondary brain injury, and a measurement of ICP is often of crucial value in neurosurgical and neurological patients. The gold standard ...for ICP monitoring is through an intraventricular catheter, but this invasive technique is associated with certain risks. Intraparenchymal ICP monitoring methods are considered to be a safer alternative but can, in certain conditions, be imprecise due to zero drift and still require an invasive procedure. An accurate noninvasive method to measure elevated ICP would therefore be desirable. This article is a review of the current literature on noninvasive methods for measuring and evaluating elevated ICP. The main focus is on studies that compare noninvasively measured ICP with invasively measured ICP. The aim is to provide an overview of the current state of the most common noninvasive techniques available. Several methods for noninvasive measuring of elevated ICP have been proposed: radiologic methods including computed tomography and magnetic resonance imaging, transcranial Doppler, electroencephalography power spectrum analysis, and the audiological and ophthalmological techniques. The noninvasive methods have many advantages, but remain less accurate compared with the invasive techniques. None of the noninvasive techniques available today are suitable for continuous monitoring, and they cannot be used as a substitute for invasive monitoring. They can, however, provide a reliable measurement of the ICP and be useful as screening methods in select patients, especially when invasive monitoring is contraindicated or unavailable.
Understanding differences in the repertoire of orthologous gene pairs is vital for interpretation of pharmacological and physiological experiments if conclusions are conveyed between species. Here we ...present a comprehensive dataset for G protein-coupled receptors (GPCRs) in both human and mouse with a phylogenetic road map. We performed systematic searches applying several search tools such as BLAST, BLAT, and Hidden Markov models and searches in literature data. We aimed to gather a full-length version of each human or mouse GPCR in only one copy referring to a single chromosomal position. Moreover, we performed detailed phylogenetic analysis of the transmembrane regions of the receptors to establish accurate orthologous pairs. The results show the identity of 495 mouse and 400 human functional nonolfactory GPCRs. Overall, 329 of the receptors are found in one-to-one orthologous pairs, while 119 mouse and 31 human receptors originate from species-specific expansions or deletions. The average percentage similarity of the orthologue pairs is 85%, while it varies between the main GRAFS families from an average of 59 to 94%. The orthologous pairs for the lipid-binding GPCRs had the lowest levels of conservation, while the biogenic amines had highest levels of conservation. Moreover, we searched for expressed sequence tags (ESTs) and identified more than 17,000 ESTs matching GPCRs in mouse and human, providing information about their expression patterns. On the whole, this is the most comprehensive study of the gene repertoire that codes for human and mouse GPCRs. The datasets are available for downloading.
Abstract
Novel diagnostic tools in oncology, prenatal diagnostics, and transplantation medicine depend on the detection of ultrarare variants. The analysis of cell-free DNA has the potential to ...revolutionize diagnosis, treatment monitoring, and recurrence and resistance of cancer. Yet these analysis remains challenging due to limited amounts of material and low allele frequencies of targeted variants. Simple, Multiplexed, PCR-based barcoding of DNA for Sensitive mutation detection using Sequencing (SiMSen-Seq) enables easy generation of libraries containing unique molecular identifiers (UMI) with minimal DNA input across several kilobases of DNA using two rounds of PCR and allows the detection of rare variants below 0.1% allele frequency. Clinical applications of ctDNA require highly optimized workflows to ensure high sensitivity and reproducibility. Here we present our state-of-the-art liquid biopsy workflow using SiMSen-Seq and simple quality control steps, applicable to almost any liquid biopsy protocol. In a series of case studies with melanoma patients we find that ctDNA mirrors the time-course of established protein markers such as S-100 and in some cases detects minimal residual months in advance of standard clinical diagnostics. SiMSen-Seq efficiently determined even rare mutations across multiple tumor forms in challenging sample types, such as FFPE tissue or cfDNA. We identified mutations in highly degraded FFPE tissue using a 60-plex SiMSen-Seq panel and then analyzed longitudinal cfDNA samples using patient-specific panels in a cohort of metastatic breast cancer patients. Our data indicate that ctDNA might be used as a biomarker for early detection of recurrence in these patients. We were able to detect treatment resistance variants as well as observe tumor recurrence well in advance of the onset of clinical symptoms. Thus, SiMSen-Seq offers an affordable, minimally invasive method for monitoring treatment efficiency and determination of drug resistance development in cancer.
Citation Format: Stefan Filges, Daniel Andersson, Helena Kristiansson, Christoffer Vannas, Gustav Johansson, Junrui Li, Tony E. Godfrey, Max Levin, Barbro Linderholm, Anders Ståhlberg. Ultrasensitive mutation detection in FFPE tissues and circulating tumor DNA using SiMSen-Seq abstract. In: Proceedings of the AACR Special Conference on Advances in Liquid Biopsies; Jan 13-16, 2020; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(11_Suppl):Abstract nr A23.
Objective
To establish the risk of recurrence in patients with chronic subdural hematoma (cSDH) on antithrombotic treatment (AT, i.e., antiplatelets and anticoagulants). Secondary end points were ...perioperative morbidity and mortality between groups (AT vs. no-AT group) and exploration if timing of resumption of AT treatment (i.e., prophylactic early vs. late resumption) influenced the occurrence of thromboembolism and hematoma recurrence.
Materials
In a population-based consecutive cohort, we conducted a retrospective review of 763 patients undergoing primary burr hole procedures for cSDH between January 1, 2005, and December 31, 2010, at the Karolinska University Hospital, Stockholm, Sweden. Early AT resumption was ≤30 days and late >30 days after the procedure.
Results
A total of 308/763 (40.4%) cSDH patients were on AT treatment at the time of diagnosis. There was no difference in cSDH recurrence within 3 months (11.0% vs. 12.0%,
p
= 0.69) nor was there any difference in perioperative mortality (4.0% vs. 2.0%,
p
= 0.16) between those using AT compared to those who were not. However, perioperative morbidity was more common in the AT group compared to no-AT group (10.7% vs. 5.1%,
p
= 0.003). Comparing early vs. late AT resumption, there was no difference with respect to recurrence (7.0% vs. 13.9%,
p
= 0.08), but more thromboembolism in the late AT resumption group (2.0% vs. 7.0%,
p
< 0.01).
Conclusion
In clinical practice, cSDH patients on AT therapy at the time of diagnosis have similar recurrence rates and mortality compared to those without AT therapy, but with higher morbidity. Early resumption was not associated with more recurrence, but with lower thromboembolic frequency. Early AT resumption seems favorable, and a prospective RCT is needed.
Galactokinase catalyses the first committed step of the Leloir pathway, i.e. the ATP-dependent phosphorylation of α-D-galactose at C1-OH. Reduced galactokinase activity results in the inherited ...metabolic disease type II galactosaemia. However, inhibition of galactokinase is considered a viable approach to treating more severe forms of galactosaemia (types I and III). Considerable progress has been made in the identification of high affinity, selective inhibitors. Although the structure of galactokinase from a variety of species is known, its catalytic mechanism remains uncertain. Although the bulk of evidence suggests that the reaction proceeds via an active site base mechanism, some experimental and theoretical studies contradict this. The enzyme has potential as a biocatalyst in the production of sugar 1-phosphates. This potential is limited by its high specificity. A variety of approaches have been taken to identify galactokinase variants which are more promiscuous. These have broadened galactokinase's specificity to include a wide range of D- and L-sugars. Initial studies suggest that some of these alterations result in increased flexibility at the active site. It is suggested that modulation of protein flexibility is at least as important as structural modifications in determining the success or failure of enzyme engineering.
Galactokinase catalyses the site‐ and stereospecific phosphorylation of galactose at the expense of ATP. The specificity of bacterial galactokinase enzymes can be broadened by alteration of a ...tyrosine residue to a histidine. The effects of altering the equivalent residue in human galactokinase (Tyr379) were investigated by testing all 19 possible variants. All of these alterations, except Y379P, resulted in soluble protein on expression in Escherichia coli and all the soluble variants could catalyse the phosphorylation of galactose, except Y379A and Y379E. The variants Y379C, Y379K, Y379R, Y379S and Y379W were all able to catalyse the phosphorylation of a variety of monosaccharides, including ones that are not acted on by the wild‐type enzyme. Novel substrates for these variant galactokinases included D‐mannose and D‐fructose. The latter monosaccharide is presumed to react in the pyranose configuration. Molecular modelling suggested that the alterations do not cause changes to the overall structure of the enzyme. However, alteration of Tyr379 increases the flexibility of the peptide backbone in regions surrounding the active site. Therefore, it is proposed that alteration of Tyr379 affects the substrate specificity by the propagation of changes in flexibility to the active site, permitting a broader range of compounds to be accommodated.
Making moves: The specificity of human galactokinase has been expanded by alteration of a tyrosine residue such that the enzyme is able to catalyse phosphorylation of D‐mannose and D‐fructose. This residue most likely controls the enzyme's specificity by modulating the flexibility of residues in the active site.
PDF
