Burr-hole drainage with or without irrigation for chronic subdural haematoma (FINISH): a Finnish, nationwide, parallel-group, multicentre, randomised, controlled, non-inferiority trial.

BACKGROUND: Chronic subdural haematoma is a common surgically treated intracranial emergency. Burr-hole drainage surgery, to evacuate chronic subdural haematoma, involves three elements: creation of a burr hole for access, irrigation of the subdural space, and insertion of a subdural drain. Although the subdural drain has been established as beneficial, the therapeutic effect of subdural irrigation has not been addressed. METHODS: The FINISH trial was an investigator-initiated, pragmatic, multicentre, nationwide, randomised, controlled, parallel-group, non-inferiority trial in five neurosurgical units in Finland that enrolled adults aged 18 years or older with a chronic subdural haematoma requiring burr-hole drainage. Patients were randomly assigned (1:1) by computer-generated block randomisation with block sizes of four, six, or eight, stratified by site, to burr-hole drainage either with or without subdural irrigation. All patients and staff were masked to treatment assignment apart from the neurosurgeon and operating room staff. A burr hole was drilled at the site of maximum haematoma thickness in both groups, and the subdural space was either irrigated or not irrigated before inserting a subdural drain, which remained in place for 48 h. Reoperations, functional outcome, mortality, and adverse events were recorded for 6 months after surgery. The primary outcome was the reoperation rate within 6 months. The non-inferiority margin was set at 7·5%. Key secondary outcomes that were also required to conclude non-inferiority were the proportion of participants with unfavourable functional outcomes (ie, modified Rankin Scale score of 4-6, where 0 indicates no symptoms and 6 indicates death) and mortality rate at 6 months. The primary and key secondary analyses were done in both the intention-to-treat and per-protocol populations. The trial was registered with ClinicalTrials.gov (NCT04203550) and is completed. FINDINGS: From Jan 1, 2020, to Aug 17, 2022, we assessed 1644 patients for eligibility and 589 (36%) patients were randomly assigned to a treatment group and treated (294 assigned to drainage with irrigation and 295 assigned to drainage without irrigation; 165 [28%] women and 424 [72%] men). The 6-month follow-up period extended until Feb 14, 2023. In the intention-to-treat analysis, 54 (18·3%) of 295 participants required reoperation in the group assigned to receive no irrigation versus 37 (12·6%) of 294 in the group assigned to receive irrigation (difference of 6·0 percentage points, 95% CI 0·2-11·7; p=0·30; adjusted for study site). There were no significant between-group differences in the proportion of people with modified Rankin Scale score of 4-6 (37 [13·1%] of 283 in the no-irrigation group vs 36 [12·6%] of 285 in the irrigation group; p=0·89) or mortality rate (18 [6·1%] of 295 in the no-irrigation group vs 21 [7·1%] of 294 in the irrigation group; p=0·58). The findings of the primary intention-to-treat analysis were not materially altered in the per-protocol analysis. There were no significant between-group differences in the number of adverse events, and the most frequent severe adverse events were systemic infections (26 [8·8%] of 295 participants who did not receive irrigation vs 22 [7·5%] of 294 participants who received irrigation), intracranial haemorrhage (13 [4·4%] vs seven [2·4%]), and epileptic seizures (five [1·7%] vs nine [3·1%]). INTERPRETATION: We could not conclude non-inferiority of burr-hole drainage without irrigation. The reoperation rate was 6·0 percentage points higher after burr-hole drainage without subdural irrigation than with subdural irrigation. Considering that there were no differences in functional outcome or mortality between the groups, the trial favours the use of subdural irrigation. FUNDING: State Fund for University Level Health Research (Helsinki University Hospital), Finska Läkaresällskapet, Medicinska Understödsföreningen Liv och Hälsa, and Svenska Kulturfonden.

Aberrant DNA methylation distorts developmental trajectories in atypical teratoid/rhabdoid tumors.

Atypical teratoid/rhabdoid tumors (AT/RTs) are pediatric brain tumors known for their aggressiveness and aberrant but still unresolved epigenetic regulation. To better understand their malignancy, we investigated how AT/RT-specific DNA hypermethylation was associated with gene expression and altered transcription factor binding and how it is linked to upstream regulation. Medulloblastomas, choroid plexus tumors, pluripotent stem cells, and fetal brain were used as references. A part of the genomic regions, which were hypermethylated in AT/RTs similarly as in pluripotent stem cells and demethylated in the fetal brain, were targeted by neural transcriptional regulators. AT/RT-unique DNA hypermethylation was associated with polycomb repressive complex 2 and linked to suppressed genes with a role in neural development and tumorigenesis. Activity of the several NEUROG/NEUROD pioneer factors, which are unable to bind to methylated DNA, was compromised via the suppressed expression or DNA hypermethylation of their target sites, which was also experimentally validated for NEUROD1 in medulloblastomas and AT/RT samples. These results highlight and characterize the role of DNA hypermethylation in AT/RT malignancy and halted neural cell differentiation.

Incidence of surgically treated chronic subdural hematoma after head injury with normal initial computed tomography.

PURPOSE: The objective was to determine the incidence of surgically treated chronic subdural hematoma (cSDH) within six months after head trauma in a consecutive series of head injury patients with a normal initial computed tomography (CT). METHODS: A total of 1941 adult patients with head injuries who underwent head CT within 48 h after injury and were treated at the Tampere University Hospital's emergency department were retrospectively evaluated from medical records (median age = 59 years, IQR = 39-79 years, males = 58%, patients using antithrombotic medication = 26%). Patients with no signs of acute traumatic intracranial pathology or any type of subdural collection on initial head CT were regarded as CT negative (n = 1573, 81%). RESULTS: Two (n = 2) of the 1573 CT negative patients received surgical treatment for cSDH. Consequently, the incidence of surgically treated cSDH after a normal initial head CT during a six-month follow-up was 0.13%. Both patients sustained mild traumatic brain injuries initially. One of the two patients was on antithrombotic medication (warfarin) at the time of trauma, hence incidence of surgically treated cSDH among patients with antithrombotic medication in CT negative patients (n = 376, 23.9%) was 0.27%. Additionally, within CT negative patients, one subdural hygroma was operated shortly after trauma. CONCLUSION: The extremely low incidence of surgically treated cSDH after a normal initial head CT, even in patients on antithrombotic medication, supports the notion that routine follow-up imaging after an initial normal head CT is not indicated to exclude the development of cSDH. Additionally, our findings support the concept of cSDH not being a purely head trauma-related disease.

Genomic characterization of IDH-mutant astrocytoma progression to grade 4 in the treatment setting.

As the progression of low-grade diffuse astrocytomas into grade 4 tumors significantly impacts patient prognosis, a better understanding of this process is of paramount importance for improved patient care. In this project, we analyzed matched IDH-mutant astrocytomas before and after progression to grade 4 from six patients (discovery cohort) with genome-wide sequencing, 21 additional patients with targeted sequencing, and 33 patients from Glioma Longitudinal AnalySiS cohort for validation. The Cancer Genome Atlas data from 595 diffuse gliomas provided supportive information. All patients in our discovery cohort received radiation, all but one underwent chemotherapy, and no patient received temozolomide (TMZ) before progression to grade 4 disease. One case in the discovery cohort exhibited a hypermutation signature associated with the inactivation of the MSH2 and DNMT3A genes. In other patients, the number of chromosomal rearrangements and deletions increased in grade 4 tumors. The cell cycle checkpoint gene CDKN2A, or less frequently RB1, was most commonly inactivated after receiving both chemo- and radiotherapy when compared to other treatment groups. Concomitant activating PDGFRA/MET alterations were detected in tumors that acquired a homozygous CDKN2A deletion. NRG3 gene was significantly downregulated and recurrently altered in progressed tumors. Its decreased expression was associated with poorer overall survival in both univariate and multivariate analysis. We also detected progression-related alterations in RAD51B and other DNA repair pathway genes associated with the promotion of error-prone DNA repair, potentially facilitating tumor progression. In our retrospective analysis of patient treatment and survival timelines (n = 75), the combination of postoperative radiation and chemotherapy (mainly TMZ) outperformed radiation, especially in the grade 3 tumor cohort, in which it was typically given after primary surgery. Our results provide further insight into the contribution of treatment and genetic alterations in cell cycle, growth factor signaling, and DNA repair-related genes to tumor evolution and progression.

Impact of Timing of Surgery and Adjuvant Treatment on Survival of Adult IDH-wild-type Glioblastoma: A Single-center Study of 392 Patients.

BACKGROUND: The purpose of our study was to analyze the impact of time interval from referral to surgery and from surgery to adjuvant treatment on survival of adult isocitrate dehydrogenase-wild-type (IDH-wt) glioblastomas. METHODS: Data on 392 IDH-wt glioblastomas diagnosed at the Tampere University Hospital in 2004-2016 were obtained from the electronic patient record system. Piecewise Cox regression was used to calculate hazard ratios for different time intervals between referral and surgery, as well as between surgery and adjuvant treatments. RESULTS: The median survival time from primary surgery was 9.5 months (interquartile range: 3.8-16.0). Survival among patients with an interval exceeding 4 weeks from referral to surgery was no worse compared to <2 weeks (hazard ratio: 0.78, 95% confidence interval: 0.54-1.14). We found indications of poorer outcome when the interval from surgery to radiotherapy exceeded 30 days (hazard ratio: 1.42, 95% confidence interval: 0.91-2.21 for 31-44 days; and 1.59, 0.94-2.67 for over 45 days). CONCLUSIONS: Interval from referral to surgery in the range of 4-10 weeks was not associated with decreased survivals in IDH-wt glioblastomas. In contrast, delay exceeding 30 days from surgery to adjuvant treatment may decrease long-term survival.

Motor dysfunction as a primary symptom predicts poor outcome: multicenter study of glioma symptoms.

Background and objectives: The objectives of this study were to investigate the prognostic value of primary symptoms and leading symptoms in adult patients with diffuse infiltrating glioma and to provide a clinical perspective for evaluating survival. Methods: This study included a retrospective cohort from two tertiary university hospitals (n = 604, 2006-2013, Tampere University Hospital and Turku University Hospital) and a prospective cohort (n = 156, 2014-2018, Tampere University Hospital). Preoperative symptoms were divided into primary and leading symptoms. Results were validated with the newer WHO 2021 classification criteria. Results: The most common primary symptoms were epileptic seizure (30.8% retrospective, 28.2% prospective), cognitive disorder (13.2% retrospective, 16.0% prospective), headache (8.6% retrospective, 12.8% prospective), and motor paresis (7.0% retrospective, 7.1% prospective). Symptoms that predicted better survival were epileptic seizure and visual or other sense-affecting symptom in the retrospective cohort and epileptic seizure and headache in the prospective cohort. Predictors of poor survival were cognitive disorder, motor dysfunction, sensory symptom, tumor hemorrhage, speech disorder and dizziness in the retrospective cohort and cognitive disorder, motor dysfunction, sensory symptom, and dizziness in the prospective cohort. Motor dysfunction served as an independent predictor of survival in a multivariate model (OR = 1.636). Conclusion: Primary and leading symptoms in diffuse gliomas are associated with prognoses in retrospective and prospective settings. Motor paresis was an independent prognostic factor for poor survival in multivariate analysis for grade 2-4 diffuse gliomas, especially in glioblastomas.

PTPRD and CNTNAP2 as markers of tumor aggressiveness in oligodendrogliomas.

Oligodendrogliomas are typically associated with the most favorable prognosis among diffuse gliomas. However, many of the tumors progress, eventually leading to patient death. To characterize the changes associated with oligodendroglioma recurrence and progression, we analyzed two recurrent oligodendroglioma tumors upon diagnosis and after tumor relapse based on whole-genome and RNA sequencing. Relapsed tumors were diagnosed as glioblastomas with an oligodendroglioma component before the World Health Organization classification update in 2016. Both patients died within 12 months after relapse. One patient carried an inactivating POLE mutation leading to a clearly hypermutated progressed tumor. Strikingly, both relapsed tumors carried focal chromosomal rearrangements in PTPRD and CNTNAP2 genes with associated decreased gene expression. TP53 mutation was also detected in both patients after tumor relapse. In The Cancer Genome Atlas (TCGA) diffuse glioma cohort, PTPRD and CNTNAP2 expression decreased by tumor grade in oligodendrogliomas and PTPRD expression also in IDH-mutant astrocytomas. Low expression of the genes was associated with poor overall survival. Our analysis provides information about aggressive oligodendrogliomas with worse prognosis and suggests that PTPRD and CNTNAP2 expression could represent an informative marker for their stratification.

Incidence of surgically treated post-traumatic hydrocephalus 6 months following head injury in patients undergoing acute head computed tomography.

BACKGROUND: Post-traumatic hydrocephalus (PTH) is a well-known complication of head injury. The percentage of patients experiencing PTH in trauma cohorts (0.7-51.4%) varies greatly in the prior literature depending on the study population and applied diagnostic criteria. The objective was to determine the incidence of surgically treated PTH in a consecutive series of patients undergoing acute head computed tomography (CT) following injury. METHODS: All patients (N = 2908) with head injuries who underwent head CT and were treated at the Tampere University Hospital's Emergency Department (August 2010-July 2012) were retrospectively evaluated from patient medical records. This study focused on adults (18 years or older) who were residents of the Pirkanmaa region at the time of injury and were clinically evaluated and scanned with head CT at the Tampere University Hospital's emergency department within 48 h after injury (n = 1941). A thorough review of records for neurological signs and symptoms of hydrocephalus was conducted for all patients having a radiological suspicion of hydrocephalus. The diagnosis of PTH was based on clinical and radiological signs of the condition within 6 months following injury. The main outcome was surgical treatment for PTH. Clinical evidence of shunt responsiveness was required to confirm the diagnosis of PTH. RESULTS: The incidence of surgically treated PTH was 0.15% (n = 3). Incidence was 0.08% among patients with mild traumatic brain injury (TBI) and 1.1% among those with moderate to severe TBI. All the patients who developed PTH underwent neurosurgery during the initial hospitalization due to the head injury. The incidence of PTH among patients who underwent neurosurgery for acute traumatic intracranial lesions was 2.7%. CONCLUSION: The overall incidence of surgically treated PTH was extremely low (0.15%) in our cohort. Analyses of risk factors and the evaluation of temporal profiles could not be undertaken due to the extremely small number of cases.

Chronic subdural hematoma-incidence, complications, and financial impact.

OBJECTIVE: To examine the population-based incidence, complications, and total, direct hospital costs of chronic subdural hematoma (CSDH) treatment in a neurosurgical clinic during a 26-year period. The aim was also to estimate the necessity of planned postoperative follow-up computed tomography (CT). METHODS: A retrospective cohort (1990-2015) of adult patients living in Pirkanmaa, Finland, with a CSDH was identified using ICD codes and verified by medical records (n = 1148, median age = 76 years, men = 65%). Data collection was performed from medical records. To estimate the total, direct hospital costs, all costs from hospital admission until the last neurosurgical follow-up visit were calculated. All patients were followed until death or the end of 2017. The annual number of inhabitants in the Pirkanmaa Region was obtained from the Statistics Finland (Helsinki, Finland). RESULTS: The incidence of CSDH among the population 80 years or older has increased among both operatively (from 36.6 to 91/100,000/year) and non-operatively (from 4.7 to 36.9/100,000/year) treated cases. Eighty-five percent (n = 978) underwent surgery. Routine 4-6 weeks' postoperative follow-up CT increased the number of re-operations by 18% (n = 49). Most of the re-operations (92%) took place within 2 months from the primary operation. Patients undergoing re-operations suffered more often from seizures (10%, n = 28 vs 3.9%, n = 27; p < 0.001), empyema (4.3%, n = 12 vs 1.1%, n = 8; p = 0.002), and pneumonia (4.7%, n = 13 vs 1.4%, n = 12; p = 0.008) compared with patients with no recurrence. The treatment cost for recurrent CSDHs was 132% higher than the treatment cost of non-recurrent CSDHs, most likely because of longer hospital stay for re-admissions and more frequent outpatient follow-up with CT. The oldest group of patients, 80 years or older, was not more expensive than the others, nor did this group have more frequent complications, besides pneumonia. CONCLUSIONS: Based on our population-based study, the number of CSDH patients has increased markedly during the study period (1990-2015). Reducing recurrences is crucial for reducing both complications and costs. Greater age was not associated with greater hospital costs related to CSDH. A 2-month follow-up period after CSDH seems sufficient for most, and CT controls are advocated only for symptomatic patients.

Long-term excess mortality after chronic subdural hematoma.

OBJECTIVE: To assess possible long-term excess mortality and causes of death of patients with chronic subdural hematoma (CSDH). METHODS: A retrospective study (1990-2015) of adult patients (n = 1133, median age = 76 years old, men = 65%) with CSDH identified by ICD-codes and verified by medical records. All patients were followed until death or the end of 2017. Cumulative relative survival ratios and relative excess risks of death (RER) were estimated by comparing patients' mortality with that in the entire regional matched population. The causes of death were compared with a separate reference group formed by randomly choosing sex, age, and calendar time matched controls (4 controls per each CSDH patient). RESULTS: The median follow-up time was 4.8 years (range = 0-27 years), and 710 (63%) of the patients died (median age at death = 84 years old). The cumulative excess mortality was 1 year = 9%, 5 years = 18%, 10 years = 27%, 15 years = 37%, and 20 years = 48%. A subgroup of CSDH patients (n = 206) with no comorbidity had no excess mortality. Excess mortality was related to poor modified Rankin score at admission (RER = 4.93) and at discharge (RER = 8.31), alcohol abuse (RER = 4.47), warfarin (RER = 2.94), age ≥ 80 years old (RER = 1.83), non-operative treatment (RER = 1.56), and non-traumatic etiology (RER = 1.69). Hematoma characteristics or recurrence were unrelated to excess mortality. Dementia was the most common cause of death among the CSDH patients (21%) and the third most common cause in the reference group (15%, p < 0.001). CONCLUSIONS: Patients with CSDH have continuous excess mortality up to 20 years after diagnosis. Patient-related characteristics have a strong association with excess mortality, whereas specific CSDH-related findings do not. CSDH patients have an increased risk for dementia-related mortality.

The incidence of chronic subdural hematomas from 1990 to 2015 in a defined Finnish population.

OBJECTIVE: The aim of this study was to determine the population-based epidemiology of chronic subdural hematoma (CSDH) over a 26-year period. METHODS: A retrospective study was conducted of all adult patients (≥ 18 years and residents of Pirkanmaa [Finland]) with a diagnosis of CSDH between 1990 and 2015. The cases were identified using ICD codes. Detailed data collection was performed using medical records and death certificates. All patients were monitored until death or the end of year 2017. The annual number of inhabitants in the Pirkanmaa region was obtained from Statistics Finland (Helsinki, Finland). RESULTS: A total of 1168 patients with CSDH were identified from hospital records and death certificates; patients were considered as new-incidence cases if 2 years had elapsed following primary treatment and in cases involving a new contralateral CSDH. From 1990 to 2015, the overall incidence of CSDH doubled from 8.2 to 17.6/100,000/year. Among adults younger than 70 years, the incidence remained quite stable, whereas the incidence clearly increased among the ≥ 80-year-old population, from 46.9 to 129.5/100,000/year. The median age for a CSDH diagnosis increased from 73 to 79 years during the 26-year period. Head trauma was documented in 59% of cases. A ground-level fall was related to the CSDH in 31% of patients younger than 60 years and in 54% of those 80 years or older. The proportion of alcohol-related cases decreased toward the end of the study period (1990-1995: 16% and 2011-2015: 7%), because alcohol abuse was less frequent among the growing group of elderly patients. In contrast, the percentage of patients receiving anticoagulant or antiplatelet medication almost doubled toward 2015 (1990-1995, 27%; and 2011-2015, 49%). The patients' neurological condition on admission, based on both Glasgow Coma Scale score (score < 13: 1990-1995, 18%; and 2011-2015, 7%; p < 0.001) and the modified Rankin Scale score (score 0-2: 1990-1995, 8%; and 2011-2015, 19%; p < 0.001), was better in recent years than in the early 1990s. CONCLUSIONS: From 1990 to 2015, the incidence of CSDH has increased markedly. The incidence of CSDH among the population 80 years or older has nearly tripled since 1990. The use of anticoagulants has increased, but there has been no change regarding the ratio between a traumatic and a spontaneous CSDH etiology. As the world population becomes progressively older, the increasing incidence of CSDH will be a burden to patients and a future challenge for neurosurgical clinics.