EpiDiP/NanoDiP: a versatile unsupervised machine learning edge computing platform for epigenomic tumour diagnostics.

DNA methylation analysis based on supervised machine learning algorithms with static reference data, allowing diagnostic tumour typing with unprecedented precision, has quickly become a new standard of care. Whereas genome-wide diagnostic methylation profiling is mostly performed on microarrays, an increasing number of institutions additionally employ nanopore sequencing as a faster alternative. In addition, methylation-specific parallel sequencing can generate methylation and genomic copy number data. Given these diverse approaches to methylation profiling, to date, there is no single tool that allows (1) classification and interpretation of microarray, nanopore and parallel sequencing data, (2) direct control of nanopore sequencers, and (3) the integration of microarray-based methylation reference data. Furthermore, no software capable of entirely running in routine diagnostic laboratory environments lacking high-performance computing and network infrastructure exists. To overcome these shortcomings, we present EpiDiP/NanoDiP as an open-source DNA methylation and copy number profiling suite, which has been benchmarked against an established supervised machine learning approach using in-house routine diagnostics data obtained between 2019 and 2021. Running locally on portable, cost- and energy-saving system-on-chip as well as gpGPU-augmented edge computing devices, NanoDiP works in offline mode, ensuring data privacy. It does not require the rigid training data annotation of supervised approaches. Furthermore, NanoDiP is the core of our public, free-of-charge EpiDiP web service which enables comparative methylation data analysis against an extensive reference data collection. We envision this versatile platform as a useful resource not only for neuropathologists and surgical pathologists but also for the tumour epigenetics research community. In daily diagnostic routine, analysis of native, unfixed biopsies by NanoDiP delivers molecular tumour classification in an intraoperative time frame.

Proteome-based insights for IDH-mutant glioma classification.

In this issue, Bader et al.1 characterize the proteomes of diffuse glioma brain tumors by liquid chromatography mass spectrometry and classify isocitrate dehydrogenase (IDH)-mutant gliomas into two subtypes, which differ in oncogenic pathways and aerobic/anaerobic energy metabolism.

A prospective study of shared decision-making in brain tumor surgery.

PURPOSE: Shared decision-making (SDM) is a key tenet of personalized care and is becoming an essential component of informed consent in an increasing number of countries. The aim of this study is to analyze patient and healthcare staff satisfaction with the SDM process before and after SDM was officially introduced as the standard of care. Decision grids are important tools in the SDM process, and we developed them for three different types of intracranial tumors. METHODS: This prospective study was conducted in a high-volume neuro-oncological center on all consecutive eligible patients undergoing consideration of treatment for intracranial glioma and metastases. Twenty-two patients participated before and 74 after the introduction of SDM. Six and 5 staff members respectively participated in the analysis before and after team training and the introduction of SDM. The main outcome was patient and healthcare staff satisfaction with the SDM process. RESULTS: Patients reported high satisfaction with the SDM process before (mean CollaboRATE score 26 of 27 points) and after (mean CollaboRATE score 26.3 of 27 points, p = 0.23) the introduction of SDM. Interestingly, staff attitude toward SDM improved significantly from 61.68 before to 90.95% after the introduction of SDM (p-value < 0.001). Decision grids that were developed for three different types of intracranial tumors are presented. CONCLUSIONS: Team training in SDM and the introduction of techniques into daily practice can increase staff satisfaction with the SDM process. High levels of patient satisfaction were observed before, with a non-significant increase after the introduction of SDM. Decision grids are an important tool to facilitate the conveyance and understanding of complex information and to achieve SDM in daily clinical practice.

Integrated Molecular-Morphologic Meningioma Classification: A Multicenter Retrospective Analysis, Retrospectively and Prospectively Validated.

PURPOSE: Meningiomas are the most frequent primary intracranial tumors. Patient outcome varies widely from benign to highly aggressive, ultimately fatal courses. Reliable identification of risk of progression for individual patients is of pivotal importance. However, only biomarkers for highly aggressive tumors are established (CDKN2A/B and TERT), whereas no molecularly based stratification exists for the broad spectrum of patients with low- and intermediate-risk meningioma. METHODS: DNA methylation data and copy-number information were generated for 3,031 meningiomas (2,868 patients), and mutation data for 858 samples. DNA methylation subgroups, copy-number variations (CNVs), mutations, and WHO grading were analyzed. Prediction power for outcome was assessed in a retrospective cohort of 514 patients, validated on a retrospective cohort of 184, and on a prospective cohort of 287 multicenter cases. RESULTS: Both CNV- and methylation family-based subgrouping independently resulted in increased prediction accuracy of risk of recurrence compared with the WHO classification (c-indexes WHO 2016, CNV, and methylation family 0.699, 0.706, and 0.721, respectively). Merging all risk stratification approaches into an integrated molecular-morphologic score resulted in further substantial increase in accuracy (c-index 0.744). This integrated score consistently provided superior accuracy in all three cohorts, significantly outperforming WHO grading (c-index difference P = .005). Besides the overall stratification advantage, the integrated score separates more precisely for risk of progression at the diagnostically challenging interface of WHO grade 1 and grade 2 tumors (hazard ratio 4.34 [2.48-7.57] and 3.34 [1.28-8.72] retrospective and prospective validation cohorts, respectively). CONCLUSION: Merging these layers of histologic and molecular data into an integrated, three-tiered score significantly improves the precision in meningioma stratification. Implementation into diagnostic routine informs clinical decision making for patients with meningioma on the basis of robust outcome prediction.

Intraoperative ultrasound-guided compared to stereotactic navigated ventriculoperitoneal shunt placement: study protocol for a randomised controlled study.

BACKGROUND: Ventriculoperitoneal shunt (VPS) placement is one of the most frequent neurosurgical procedures and the operation is performed in a highly standardised manner under maintenance of highest infection precautions. Short operation times are important since longer duration of surgery can increase the risk for VPS complications, especially infections. The position of the proximal ventricular catheter influences shunt functioning and survival. With freehand placement, rates of malpositioned VPS are still high. Several navigation techniques for improvement of shunt placement have been developed. Studies comparing these techniques are sparse. The aim of this study is to prospectively compare ultrasound (US) guided to stereotactic navigated shunt placement using optical tracking with the focus on operation time and efficiency. METHODS: In this prospective randomised, single-centre, partially-blinded study, we will include all patients undergoing VPS placement in our clinic. The patients will be randomised into two groups, one group undergoing US-guided (US-G) and the other group stereotactic navigated VPS placement using optical tracking. The primary outcome will be the surgical intervention time. This time span consists of the surgical preparation time together with the operation time and is given in minutes. Secondary outcomes will be accuracy of catheter positioning, VPS dysfunction and need for revision surgery, total operation and anaesthesia times, and amount of intraoperative ventricular puncture attempts as well as complications, any morbidity and mortality. DISCUSSION: To date, there is no prospective data available comparing these two navigation techniques. A randomised controlled study is urgently needed in order to provide class I evidence for the best possible surgical technique of this frequent surgery. TRIAL REGISTRATION: Business Administration System for Ethical Committees (BASEC) 2019-02157, registered on 21 November 2019, https://www.kofam.ch/de/studienportal/suche/88135/studie/49552 ; clinicalTrials.gov: NCT04450797 , registered on 30 June 2020.

Anaplastic astrocytoma during pregnancy: the importance of an effective multidisciplinary approach.

A 34-year-old pregnant woman at 28 gestational weeks was diagnosed with a brain tumor after experiencing a generalised seizure. After completion of antenatal fetal lung maturation, she underwent an osteoplastic craniotomy parietal on the left side and a microsurgical partial tumor resection under general anaesthesia. With a histology of a diffuse astrocytoma and the postoperative stable amount of residual tumor on follow-up imaging, the pregnancy proceeded until 37 gestational weeks. A healthy baby boy was delivered by elective caesarean section. An awake craniotomy for removal of the residual tumor was planned two weeks later, followed by adjuvant treatment (combined radio-/chemotherapy). A multidisciplinary approach, combined with appropriate timing and a transparent and empathic communication, was able to create the most effective tailored management and optimise maternal and neonatal outcomes.

Ultrasound-Guided Insertion of the Ventricular Catheter in Ventriculoperitoneal Shunt Surgery: Evaluation of Accuracy and Feasibility in a Prospective Cohort.

OBJECTIVE: Ventriculoperitoneal shunt (VPS) placement is one of the most frequent neurosurgical procedures. The position of the proximal catheter is important for shunt survival. Shunt placement is done either without image guidance ("freehand") according to anatomical landmarks or by use of various image-guided techniques. Studies evaluating ultrasound-guided (US-G) VPS placement are sparse. We evaluate the accuracy and feasibility of US-G VPS placement, and compare it to freehand VPS placement. METHODS: We prospectively collected data of consecutive patients undergoing US-G VPS placement. Thereafter, the US cohort was compared with a cohort of patients in whom VPS was inserted using the freehand technique (freehand cohort). Primary outcome was accuracy of catheter positioning, and secondary outcomes were postoperative improvement in Evans' index (EI), rates of shunt dysfunction and revision surgery, perioperative complications, as well as operation, and anesthesia times. RESULTS: We included 15 patients undergoing US-G VPS insertion. Rates of optimally placed shunts were higher in the US cohort (67 vs. 49%, p = 0.28), whereas there were no malpositioned VPS (0%) in the US cohort, compared with 10 (5.8%) in the freehand cohort (p = 0.422). None of the factors in the univariate analysis showed significant association with nonoptimal (NOC) VPS placement in the US cohort. The mean EI improvement was significantly better in the US cohort than in the freehand cohort (0.043 vs. 0.014, p = 0.035). CONCLUSION: Based on our preliminary results, US-G VPS placement seems to be feasible, safe, and increases the rate of optimally placed catheters.

Regulation of glioma cell invasion by 3q26 gene products PIK3CA, SOX2 and OPA1.

Diffuse gliomas progress by invading neighboring brain tissue to promote postoperative relapse. Transcription factor SOX2 is highly expressed in invasive gliomas and maps to chromosome region 3q26 together with the genes for PI3K/AKT signaling activator PIK3CA and effector molecules of mitochondria fusion and cell invasion, MFN1 and OPA1. Gene copy number analysis at 3q26 from 129 glioma patient biopsies revealed mutually exclusive SOX2 amplifications (26%) and OPA1 losses (19%). Both forced SOX2 expression and OPA1 inactivation increased LN319 glioma cell invasion in vitro and promoted cell dispersion in vivo in xenotransplanted D. rerio embryos. While PI3 kinase activity sustained SOX2 expression, pharmacological PI3K/AKT pathway inhibition decreased invasion and resulted in SOX2 nucleus-to-cytoplasm translocation in an mTORC1-independent manner. Chromatin immunoprecipitation and luciferase reporter gene assays together demonstrated that SOX2 trans-activates PIK3CA and OPA1. Thus, SOX2 activates PI3K/AKT signaling in a positive feedback loop, while OPA1 deletion is interpreted to counteract OPA1 trans-activation. Remarkably, neuroimaging of human gliomas with high SOX2 or low OPA1 genomic imbalances revealed significantly larger necrotic tumor zone volumes, corresponding to higher invasive capacities of tumors, while autologous necrotic cells are capable of inducing higher invasion in SOX2 overexpressing or OPA1 knocked-down relative to parental LN319. We thus propose necrosis volume as a surrogate marker for the assessment of glioma invasive potential. Whereas glioma invasion is activated by a PI3K/AKT-SOX2 loop, it is reduced by a cryptic invasion suppressor SOX2-OPA1 pathway. Thus, PI3K/AKT-SOX2 and mitochondria fission represent connected signaling networks regulating glioma invasion.

Effectiveness of a Chlorhexidine Dressing on Silver-coated External Ventricular Drain-associated Colonization and Infection: A Prospective Single-blinded Randomized Controlled Clinical Trial.

Background: Observational studies have shown that dressings containing chlorhexidine gluconate (CHX) lower the incidence external ventricular drain (EVD)-associated infections (EVDAIs). This prospective, randomized controlled trial (RCT) studies the efficacy of CHX-containing dressings in reducing bacterial colonization. Methods: In this RCT, patients aged ≥18 years undergoing emergency EVD placement were randomly given either a CHX-containing or an otherwise identical control dressing at the skin exit wound. The primary end-point was bacterial regrowth in cultured skin swab samples of the EVD exit wound. The secondary end-points were catheters processed by sonication, clinically diagnosed EVDAI and surgical treatment of hydrocephalus. Results: From October 2013 to January 2016, a total of 57 patients were randomized to receive either a CHX or a control dressing (29 and 28 patients, respectively). Cutaneous bacterial regrowth at the EVD exit wound was significantly reduced over time (geometric mean ratio, 0.18; 95% confidence interval, .08-.42; P < .001). The incidence of colonized catheters was lower in the CHX group (5 of 28; 18%) than in the control group (10 of 27; 33%), with less microbial colonization on the subcutaneous portion. The infection rate was 4 of 28 (14%) in the CHX group, compared with 7 of 27 (26%) in the control group, with a substantially lower hydrocephalus treatment rate (7 of 28 [25%] vs 14 of 27 [52%], respectively). Conclusion: Our data support the use of CHX dressings to reduce EVD exit site contamination, potentially reducing EVDAIs and permanent cerebrospinal fluid diversion procedures for hydrocephalus. Clinical Trials Registration: NCT02078830.

Preoperative Two-Dimensional Size of Glioblastoma is Associated with Patient Survival.

BACKGROUND: Although tumor size affects survival of patients with lower-grade glioma, a prognostic effect on patients with glioblastoma remains to be established. METHODS: We performed a retrospective analysis of 61 patients using volumetric data of tumor compartments of 61 patients obtained by preoperative magnetic resonance images using the visual ABC/2 method. Preoperative enhancing, nonenhancing, necrosis, and edema volume, the preoperative tumor area (TA) as a product of the 2 largest tumor diameters perpendicular to each other on axial T1-weighted postcontrast images, as well as postoperative enhancing residual volumes, were measured. Multivariable Cox proportional hazard models were used to associate these parameters with overall survival, adjusting for potential confounders. RESULTS: The median preoperative enhancing tumor volume was 18.2 mL (interquartile range, 8.2-41.7 mL); the median remnant tumor volume was 1.3% (interquartile range, 0.0%-42.9%). During follow-up, 59 patients (92%) died; median survival time and median follow-up time were both 404 days. We found a statistically significant multiplicative effect of TA on survival: the hazard ratio (HR) was increased by 1.096 per unit increase of 200 mm2 (95% confidence interval [CI], 1.027-1.170; P < 0.01). The effect of remnant tumor on HR increased multiplicatively by 1.013 (95% CI, 1.001-1.026; P = 0.04) per unit increase of 1 log (day) and 1% in tumor remnant. HR associated with age at surgery increased by 1.503 per 5 years of age (95% CI, 1.243-1.817; P < 0.01). CONCLUSIONS: Preoperative TA proved to be the only glioblastoma size parameter that affects patient survival.

Experimental Texture Analysis in Glioblastoma: A Methodological Study.

OBJECTIVES: Analysis of a single slice of a tumor to extract biomarkers for texture analysis may result in loss of information. We investigated correlation of fractional volumes to entire tumor volumes and introduced expanded regions of interest (ROIs) outside the visual tumor borders in glioblastoma. MATERIALS AND METHODS: Retrospective slice-by-slice volumetric texture analysis on 46 brain magnetic resonance imaging subjects with histologically confirmed glioblastoma was performed. Fractional volumes were analyzed for correlation to total volume. Expanded ROIs were analyzed for significant differences to conservative ROIs. RESULTS: As fractional tumor volumes increased, correlation with total volume values for mean, SD, mean of positive pixels, skewness, and kurtosis increased. Expanding ROI by 2 mm resulted in significant differences in all textural values. CONCLUSIONS: Fractional volumes may provide an optimal trade-off for texture analysis in the clinical setting. All texture parameters proved significantly different with minimal expansion of the ROI, underlining the susceptibility of texture analysis to generating misrepresentative tumor information.

Preoperative and Postoperative Factors and Laboratory Values Predicting Outcome in Patients Undergoing Lumbar Fusion Surgery.

OBJECTIVE: To determine whether complications in lumbar fusion surgery could be estimated from patient factors and perioperative laboratory values. In addition, risk scores for detection of patients prone to complications were defined. METHODS: We retrospectively collected data of patients undergoing lumbar fusion surgery between 2013 and 2015. The patients were divided into group A (no complications) and group B (systemic and infectious complications within 30 days postoperatively). Patient-related factors and levels of perioperative laboratory values were compared between the groups and analyzed for possible impact on complications and length of stay (LOS) in the hospital. RESULTS: Data of 132 consecutive patients (74 women [56.1%]; median age, 68.5 years) were analyzed. Postoperative complications occurred in 29.5%. Higher postoperative creatine kinase (CK) and C-reactive protein and lower postoperative hemoglobin and thrombocyte values, as well as higher differences between preoperative and postoperative CK, C-reactive protein, and hemoglobin values were associated with postoperative complications. Among others, the combinations of advanced age and elevated body mass index (P = 0.0062, odds ratio: 3.018), or advanced age, elevated body mass index, and postoperative CK >166 U/L (P = 0.0016, odds ratio: 3.637) revealed patients with a threefold risk for complications. The combination of advanced age, American Society of Anesthesiologists score >2, and preoperative hemoglobin <12.9 g/dL was associated with a LOS of 20.3 versus 11 days (P = 0.01). CONCLUSIONS: Patients with postoperative complications and extended LOS seem to show significant differences in various perioperative laboratory values and patient factors. Perioperative risk assessments using cut-off values and risk scores may help identify patients prone to complications and extended resource use.

IDH mutation is associated with higher risk of malignant transformation in low-grade glioma.

Acquisition of IDH1 or IDH2 mutation (IDHmut) is among the earliest genetic events that take place in the development of most low-grade glioma (LGG). IDHmut has been associated with longer overall patient survival. However, its impact on malignant transformation (MT) remains to be defined. A collection of 210 archived adult LGG previously stratified by IDHmut, MGMT methylation (MGMTmet), 1p/19q combined loss of heterozygosity (1p19qloh) and TP53 immunopositivity (TP53pos) status was analyzed. We used multistate models to assess MT-free survival, considering one initial, one transient (MT), and one absorbing state (death). Missing explanatory variables were multiply imputed. Overall, although associated with a lower risk of death (HR(DEATH) = 0.35, P = 0.0023), IDHmut had a non-significantly higher risk of MT (HR(MT) = 1.84; P = 0.1683) compared to IDH wild type (IDHwt). The double combination of IDHmut and MGMTmet and the triple combination of IDHmut, MGMTmet and 1p/19qloh, despite significantly lower hazards for death (HR(DEATH) versus IDHwt: 0.35, P = 0.0194 and 0.15, P = 0.0008, respectively), had non-significantly different hazards for MT. Conversely, the triple combination of IDHmut/MGMTmet/TP53pos, with a non-significantly different hazard for death, had a significantly higher hazard for MT than IDHwt (HR(MT) versus IDHwt: 2.83; P = 0.0452). Although IDHmut status is associated with longer overall patient survival, all IDHmut/MGMTmet subsets consistently showed higher risks of MT than of death, compared to IDHwt LGG. This supports the findings that molecular events relevant to IDH mutations impact early glioma development prior to malignant transformation.

Management of Incidental Dural Tear During Lumbar Spine Surgery. To Suture or Not to Suture?

OBJECTIVE: Incidental durotomy (ID) during lumbar spine surgery is a frequent complication of growing clinical relevance as the number and complexity of spinal procedures increases. Yet, there is still a lack of guidelines for the treatment of ID with a large heterogeneity of established surgical techniques. The aim of this study was to investigate the efficacy of dural suturing in patients having ID during degenerative lumbar spine surgery, compared with other dural closure techniques. METHODS: Of 1173 consecutive patients undergoing degenerative lumbar spine surgery from July 2013 to March 2015, in 64 (5.4%) patients 69 (5.8%) IDs occurred. The patients were divided into 3 groups depending on the dural closure technique used: group A, sole dural suture (n = 12, 19%); group B, patch only (TachoSil and/or muscle and/or fat) (n = 22, 32%); group C, dural suture in combination with a patch (n = 34, 49%). The primary end point was revision surgery caused by complications of cerebrospinal fluid leakage after 6 weeks. The secondary end points were operation time and hospitalization time, as well as surgical morbidity. RESULTS: The 3 groups showed no significant difference in rates of revision surgery (group A: n = 1, 1.4%; group B: n = 4, 5.8%; group C: n = 3; 4.3%; P = 0.5). Furthermore, no significant difference for hospitalization time, operation time, and clinical outcome was found. Extent of ID, American Society of Anesthesiology score, postoperative immobilization, and insertion of a drainage tube were not associated with higher rates of revision surgery. Applying suction once a drainage tube was placed was found to be a significant risk factor for revision surgery (P = 0.003). Furthermore, patients undergoing revision surgery had a significantly higher body mass index (33 kg/m(2) vs. 26.37 kg/m(2); P = 0.006; odds ratio 1.252; P = 0.004). CONCLUSIONS: Based on our results, the dural closure technique after ID does not seem to influence revision surgery rates due to cerebrospinal fluid leakage and its complications. Further prospective randomized studies are needed to confirm our results.

Langer-Giedion syndrome associated with congenital dural arterio-venous fistula.

Langer-Giedion syndrome (LGS) is a rare disease caused by deletion of chromosome 8q23.3-q24.11. Clinical manifestations include among others multiple exostoses, short stature, intellectual disability, and typical facial dysmorphism. Dural arterio-venous shunts (DAVS) in the pediatric age are rare lesions, which have been classified into three types: dural sinus malformations (DSM), infantile type DAVS (IDAVS), and adult type DAVS (ADAVS). We report a case of a patient with a known LGS who was diagnosed with complex intracranial dural AV fistula at the age of 20. An association between LGS and intracranial dural AV fistulas has to our knowledge never been reported before.

IDH/MGMT-driven molecular classification of low-grade glioma is a strong predictor for long-term survival.

BACKGROUND: Low-grade gliomas (LGGs) are rare brain neoplasms, with survival spanning up to a few decades. Thus, accurate evaluations on how biomarkers impact survival among patients with LGG require long-term studies on samples prospectively collected over a long period. METHODS: The 210 adult LGGs collected in our databank were screened for IDH1 and IDH2 mutations (IDHmut), MGMT gene promoter methylation (MGMTmet), 1p/19q loss of heterozygosity (1p19qloh), and nuclear TP53 immunopositivity (TP53pos). Multivariate survival analyses with multiple imputation of missing data were performed using either histopathology or molecular markers. Both models were compared using Akaike's information criterion (AIC). The molecular model was reduced by stepwise model selection to filter out the most critical predictors. A third model was generated to assess for various marker combinations. RESULTS: Molecular parameters were better survival predictors than histology (ΔAIC = 12.5, P< .001). Forty-five percent of studied patients died. MGMTmet was positively associated with IDHmut (P< .001). In the molecular model with marker combinations, IDHmut/MGMTmet combined status had a favorable impact on overall survival, compared with IDHwt (hazard ratio [HR] = 0.33, P< .01), and even more so the triple combination, IDHmut/MGMTmet/1p19qloh (HR = 0.18, P< .001). Furthermore, IDHmut/MGMTmet/TP53pos triple combination was a significant risk factor for malignant transformation (HR = 2.75, P< .05). CONCLUSION: By integrating networks of activated molecular glioma pathways, the model based on genotype better predicts prognosis than histology and, therefore, provides a more reliable tool for standardizing future treatment strategies.